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Physiology of Electrolyte Transport in the Gut: Implications for Disease

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ABSTRACT

We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR‐CAS technology, stem cell‐derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na+/K+ ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl channels and the basolateral Na+‐K+‐2Cl cotransporter, NKCC1 and K+ channels. Absorption chiefly involves apical membrane Na+/H+ exchangers and Cl/HCO3 exchangers in the small intestine and proximal colon and Na+ channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947‐1023, 2019.

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Figure 1. Figure 1. Structure of intestinal epithelia. Left: Intestinal epithelial cells are structurally and functionally designed for vectorial transport. (A) The cell membrane is divided into distinct apical and basolateral domains by the tight junctions with an asymmetric distribution of transporters; (B) the sodium pump on the basolateral membrane maintains a low intracellular [Na+] and provides the electrochemical driving force that permits “downhill” entry of Na+ from either surface; (C) water and solutes can cross the epithelium paracellularly or transcellularly; (D) transcellular transport can be passive or active. P.D., potential difference in millivolts. Bottom left: An expansion of the apical membrane, underlying scaffolding network and junctional complexes in the paracellular pathway. JAM, junctional adhesion molecules. Right: Architecture of the healthy intestine: Crypt/villus of small intestine and crypt/surface of the large intestine. The epithelial layer contains enterocytes, goblet cells, enteroendocrine cells, Paneth cells, and stem cells. Arrows depict vectorial movement of solutes and water in a normal gut, where absorption prevails. Both in the crypt:villus and crypt:surface axes, transporters exhibit a spatial distribution. Some are evenly distributed [e.g., the Na+/K+ ATPase pump and Na+/H+ exchanger (NHE)‐1], whereas others show a gradient. Bars represent distribution of ion transporters (blue gray for small intestine and green gray for colon). PAT1, putative anion transporter; SGLT1, sodium‐dependent glucose cotransporter; NHE3, Na+/H+ exchanger‐3; CFTR, cystic fibrosis transmembrane regulator; DRA, downregulated in adenoma; cHKA, colonic H+/K+ ATPase; ois, ouabain‐insensitive; os, ouabain‐sensitive; KCNMA1, K+ channel; ENaC, epithelial Na+ channel.
Figure 2. Figure 2. Regulation of ion transport by MALPINES. This model depicts the many regulatory systems that influence intestinal function. Left: The villus crypt architecture supports a rich supply of blood vessels, innervation, and gut‐associated lymphoid tissue (GALT) to the epithelium. Right: Enlarged section of epithelium to depict MALPINES: Lumen has Microbes (commensal and pathogenic); can release Autocrine factors that can act apically and basolaterally; presence of other Luminal factors such as bile acids, food, bacterial toxins, and viruses; secreted factors could act in a Paracrine fashion; the subepithelium has the unique Immune tissue, GALT; the tissue is richly supplied with the enteric Nervous system that has secretomotor and interneurons; and enterochromaffin cells and blood vessels provide Endocrine substances and all of them together form an integrated regulatory System. The epithelium has a layer of mucus that acts as the first line of defense. For example, intraluminal mechanical/chemical stimuli could trigger interneurons in either the myenteric or submucosal plexuses to stimulate secretory neurons to release acetylcholine (Ach) that acts on epithelial cells to alter ion transport or on muscle cells to alter motility. Immune cells could be triggered to release prostaglandins (PG) that act on the epithelial cell to alter function.
Figure 3. Figure 3. Electrolyte absorption: The transepithelial absorption of Na+, Cl, K+, and SCFA. (A) Sodium and chloride absorption: Sodium entry across the AM, down the electrochemical gradient can occur by (right to left): Na+‐solute carriers like SGLT1, transporting glucose; Na+ channels in the distal colon; and Na+/H+ exchangers (e.g., NHE2, NHE3, and NHE8) in the small intestine and in the proximal colon. Cl can enter the cell via Cl/HCO3 exchangers (PAT‐1 in the small intestine and DRA in the colon). On the BLM (right to left, sodium leaves the cell via the Na+/K+ ATPase and K+ via BLM K+ channels (KCNN4; KCNQ1/KCNE3; see 3B). HCO3 can enter the cell via BLM NBCe transporters. Glucose exits the BLM via facilitated diffusion transporters (Glut‐2), and Cl via channels (CLC2). Cl moves passively through the paracellular pathway or via cellular transporters. BLM NHEs (e.g., NHE1) perform housekeeping functions such as maintenance of intracellular pH and proliferation. Water transport can be transcellular, via aquaporins or cotransporters such as SGLT1, or paraceullar. Increases in intracellular cAMP, cGMP, or Ca2+ can inhibit Na+ and Cl absorption. (B) Potassium absorption: Transepithelial absorption of K+ is passive in the small intestine and occurs paracellularly. In the distal colon (depicted here), apical H+/K+ ATPase pumps absorb K+ especially when luminal concentrations are >25 mEq/L. K+ channels are critical for maintaining the membrane potential and are the major conduit for exit of K+ entering the cell via the pump. K+ exit across the BLM could be via channels including KCNN4 and KCNQ1/KCNE3 or the KCl cotransporter. Not shown are some K+ channels that reside in the AM and help maintain membrane potential. (C) Short‐chain fatty acids (SCFA) absorption: SCFAs are generated by luminal bacteria. At the luminal pH, SCFA are generally ionized and enter the cell via the monocarboxylate transporters (MCTs). Some protonated SCFA (SCFAH) can also diffuse across the AM of colonocytes. SCFA can also traverse by the paracellular pathway. While most SCFA are used by colonocytes as a source of metabolic energy, they can also be transported by different BLM MCT transporters (e.g., MCT4 and MCT5).
Figure 4. Figure 4. Electrolyte secretion. The major ions secreted are Cl and HCO3 throughout the length of the intestine and K+ in the distal colon. (A) Cl secretion: Cl enters the basolateral membrane via a 1Na+:1K+:2Cl cotransporter, and is energized by the BLM Na+/K+ ATPase and K+ channels and accumulates in the cell above its electrochemical equilibrium. An apical Cl channel is responsible for Cl exit, with Na+ and water following passively. In many cells, HCO3 can also be transported via the channel. In the intestine, the cystic fibrosis transmembrane conductance regulator (CFTR) is the most likely candidate Cl channel. Increases in intracellular cAMP, cGMP, or Ca2+ stimulate intestinal Cl secretion by activating one or more of the transporters. (B) K+ secretion: Active transepithelial secretion of K+ occurs through the KCNMA1 channels in the distal colon. K+ is an important contributor to colonic ion secretion and occurs especially when luminal concentrations are <25 mEq/L. The major apical channels responsible for secretion are KCNMA1 and in some cases, the TRAM‐sensitive KCNN4c channel (not shown here). K+ enters the cell via the pump and Na+:K+:2Cl cotransport. In the rest of the intestine, the K+ channels, including BLM, KCNN4, and KCNQ1/KCNE3, are critical for maintaining the membrane potential and for the efflux of K+ that enters the cell.
Figure 5. Figure 5. Cyclic nucleotide signaling. Cyclic nucleotide‐mediated transduction of an external signal into a change in cellular function minimally involve: Receptor; cyclase (xC); cyclic nucleotide (cXMP); protein kinase (PK); target phosphorylatable proteins; the proteins may be in close proximity and compartmentalized, allowing for localized effects. (A) Cyclic adenosine monophosphate (cAMP): Stimulatory (e.g., VIP/PG or bile acids) agents bind to specific membrane G‐protein coupled receptors (GPCRs) to activate Gαs to stimulate membrane adenylate cyclase (AC), while inhibitory (somatostatin) agents bind to their receptors to activate Gαi which inhibits AC. Cyclic AMP can also be generated by soluble AC (sAC) activated by Ca2+ and HCO3. Increased cAMP activates PKA which then phosphorylates transport proteins to increase (CFTR channels) or attenuate (DRA/PAT‐1 or NHE3 antiporter) activity. Cyclic AMP also act via the guanine nucleotide exchange factor, Epac, which acts via RAP2 to activate phospholipase C (PLC). The effects of cAMP can be compartmentalized by binding to scaffolding proteins like A‐Kinase Anchoring Protein (AKAP). ATP, adenosine triphosphate; Gi, inhibitory G protein; Gs, stimulatory G protein; VIP, vasoactive intestinal peptide; PG, prostaglandin; PIP2, phosphatidyl inositol 4,5, bis phosphate; IP3, inositol trisphosphate. (B) Cyclic guanosine monophosphate (cGMP): Some agents (e.g., STa, guanylin) bind to guanylate cyclase (mGC, a.k.a.GUCY2C) where a single molecule has both receptor and enzymatic activity. Activation of GUCY2C results in the production of cGMP from GTP. Cyclic GMP can also be produced from soluble GC (sGC) by activators such as nitric oxide (NO). Cyclic GMP activates PK II (PKG2), which is tethered to the membrane by myristoylation and can be further compartmentalized by anchoring proteins such as the NHE Regulatory Factor, NHERF4. PKG2 phosphorylates target transporters, in a fashion similar to PKA. cGMP can also be transported across the BLM by nucleotide transporters where it acts on nociceptive nerve terminals to attenuate pain. Cyclic GMP can inhibit the hydrolysis of cAMP by phosphodiesterases (PDE3) and elevate [cAMP]i. GTP, guanosine triphosphate; STa, heat‐stable enterotoxin.
Figure 6. Figure 6. Ca2+‐dependent signaling pathways. Neurotransmitters and hormones activate secretion and inhibit absorption (transporters not shown) by elevating [Ca2+]i. For example, acetylcholine (via muscarinic M3) or neurotensin bind to GPCRs to stimulate Gαq; bile acids do so via an unidentified receptor, whereas substance P, stimulates Ca2+ channels. Upon activation, Gαq stimulates phospholipase C‐β (PLC), which hydrolyzes phosphatidyl inositol 4,5, bis phosphate (PIP2) to generate inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3, but not DAG binds to specific IP3 receptors (IP3R) on intracellular compartments, chiefly the endoplasmic reticulum, to release Ca2+. In doing so IP3 displaces the phopsphorylated IP3R binding protein (IRBIT‐P). Increased [Ca2+]i activates many target proteins, including transporters and cytoskeletal elements. Some of this is accomplished by its binding to the ubiquitous Ca2+‐binding protein, calmodulin (CAM), and Ca2+‐CAMPKs. The DAG is rapidly metabolized but also stimulates some isoforms of protein kinase C (PKC). IRBIT‐P, when released from IP3R, can regulate transporters directly at the membrane or stimulate transporter trafficking to the membrane. The IRBIT‐P target transporters include NBCe‐1, CFTR, NHE3, and PAT‐1. Ca2+ signaling is transient.
Figure 7. Figure 7. Cystic fibrosis and CFTR. Inset: This shows the topology of CFTR. The protein has intracellular N and C termini that bracket in sequence a transmembrane spanning domain (MSD1) followed by a nucleotide binding domain (NBD1), a regulatory (R) domain that has ≈10 consensus PKA/PKG phosphorylation sites, followed by MSD2 and NBD2. Main diagram: The CFTR protein is normally trafficked to the apical membrane via the endoplasmic reticulum‐trans Golgi network. In the intestine cAMP and cGMP increase both the activity of the channel and channel insertion into the membrane. The majority of CF patients carry a δF508 deletion in NBD1 which results in a misfolding of the protein, ubiquitinylation and being targeted for degradation via proteasomes to the lysosomes. Other mutations show abnormal conductance and membrane residence time (not shown).
Figure 8. Figure 8. Actions of Vibrio cholerae. In the host V. cholerae maintains a dynamic equilibrium between a sessile state in a biofilm (gray and green ovals) and a motile (free vibrio) state. These are governed by the luminal concentrations of bile and HCO3 the triangles depict their relative lumen to mucosal surface gradients. The motile V. cholerae produce many toxins including a zona occludens toxin (ZOT) that reversibly increases paracellular permeability (see Fig. 12) and the main AB5 enterotoxin (CT). The B subunits of CT bind GM1 gangliosides (GMI) on the apical membrane and the A1 and A2 subunits enter the cell. By retrograde endocytosis, A1 ADP‐ribosylates Gαs, inhibiting its GTPase site and thereby activating adenylate cyclase (AC) irreversibly; (for clarity, the A1‐A2 are not shown separately). Cyclic AMP stimulates Cl secretion in the crypt enterocyte (cell on the right) and inhibits NHE, but not SGLT1 in the apical membrane of the villar cells (cell on the left). CT can also stimulate enterochromaffin cells to release 5‐HT which activate secreto‐motor reflexes proximally and distally (e.g., colon by activating interneurons) and thereby exacerbate secretion. VIP, vasoactive intestinal peptide; PG, prostaglandins.
Figure 9. Figure 9. Actions of rotavirus on intestinal ion transport. Rotaviruses are nonenveloped, double‐stranded RNA, coding for six structural (VP, not shown) and six nonstructural (NSP1‐6) proteins. While absent in the mature virion, upon infection of the host cell, the virus elaborates an enterotoxin, NSP4 which it releases via the AM and BLM. NSP4 binds to α1ß2 and α2ß1 integrin receptors and elicits Cl secretion via a Ca2+‐PLC pathway that stimulates the TMEM16A Cl channel, but not CFTR (not shown), largely in the intestines of young animals. The NSP‐stimulated increases in Ca2+, affect junctional proteins, actin dynamics, microvillar cytoskeleton (left hand cell) and stimulates the release of ROS, and inflammatory mediators (not shown). The luminally released NSP4 acts on enterochromaffin cells, to trigger Ca2+‐mediated BLM release of 5‐HT. The 5‐HT activates ENS secretory‐motor reflexes or on CNS‐mediated reflexes to trigger pain and nausea.
Figure 10. Figure 10. Actions of enteropathogenic Escherichia coli (EPEC). EPEC act by adhering to the host cell, effacing the microvilli, recruiting host cell cytoskeletal machinery to form a characteristic attaching and effacing lesion (A/E Lesion). EPEC utilizes a Type III secretion system (T3SS) to inject effector molecules, including the esp proteins, into the host cell. These factors coopt different intracellular signaling cascades, to affect host cell TJs, mitochondrial metabolism, and ion transport. Minimally EPEC utilizes the following factors: EspF, Map (mitochondrial associated protein), EspG, PKCζ (shown here); and NleA and EspH (not shown), to alter TJ gate and fence functions, including the redistribution of occludin and ZO‐1. Acting via espF, EPEC inhibits AM NHE3 and requires NHERF2. Both espF and Map inhibit Na‐glucose absorption via SGLT1. EPEC activates PKCα, and PKCϵ to increase AM NHE2 activity. In contrast, espG1 and espG2 utilize the host cell microtubule network to inhibit surface expression of DRA, by altering vesicular trafficking.
Figure 11. Figure 11. Model of inflammatory bowel disease (IBD). There are two major forms of IBD ulcerative colitis (UC) and Crohn's disease (CD). UC is generally restricted to the colon; it begins in the rectum and spreads proximally in a continuous fashion, and often involves only the mucosa and submucosa (right middle inset). CD is more prevalent in the distal small intestine and colon, but can affect the entire length of the GI tract; it can involve all layers of the gut wall, is discontinuous in its distribution and microbial translocation is more prevalent (right middle inset). Genetics, the host immune system, environmental factors such as diet, loss of epithelium integrity, and changes in the microbiome, contribute to IBD pathogenesis (right upper inset). A healthy cell is depicted on the left with a small mucus layer and normal Na+ and Cl absorption (thickness of arrows). Initial events cause an increase in mucus thickness and decrease in Na+ and Cl absorption (right hand cell and thin arrows). At later stages diarrhea is mainly due to both an inhibition and loss of AM Cl/HCO3 (DRA) and Na+/H+ (NHE3) exchangers and an increase in paracellular permeability. The latter results in xenobiotics and microbial products entering the lamina propria and immune cells infiltrating the lumen (blue arrow). Activation of various components of the gut associated lymphoid tissue (GALT) results in release of cytokines and immune modulators.
Figure 12. Figure 12. Model of celiac disease. Gluten is made up of gliadins rich in glutamine and proline, which are not readily digested by humans. Gliadins traverse the epithelium by at least two routes: initially, paracellularly and later transcellularly. Enlargement in the right inset: The gliadin peptides bind to the CXC motif receptor 3 on the AM of enterocytes and activate MYD88, which leads to zonulin secretion into the lumen. Zonulin, is the human homolog of the Par2 binding domain of Zot, the V. cholerae toxin. Zonulin binding to AM Par2 and EGF receptors, activates PKCα and other kinases (not shown), leading to ZO‐1 phosphorylation and disassembly of the TJs and an increase in paracellular permeability, including to gliadins. Left‐hand diagram: In the subepithelium, tissue TG released by damaged cells, deamidate gliadins, and release glutamic acid. Negatively charged glutamic acid residues bind to the HLA2DQ2 antigen‐binding groove, and are a ligand for CD4+ T helper cells. Activation of antigen presenting cells (APC) in the lamina propria results in the release of cytokines, which trigger plasma cells to produce IgA and/or IgG against gliadin. The anti‐gliadin IgAs released into the lumen, bind to gliadin, and transports it via IgA‐mediated transcellular cytosis to the lamina propria; this transcellular mechanism is the second for gliadin entry occurring later in the infection cycle and further exacerbates the immune response.
Figure 13. Figure 13. Flow diagram of intestinal malfunction in CF. The genetic defect leading to impaired Cl and HCO3 secretion leads to a series of interrelated events resulting in intestinal dysbiosis and inspissation. (A) Non‐CF intestine: The non‐CF intestine has a balanced Cl and HCO3 secretion and a protective nonviscous mucus layer with expanded mucus glycoproteins (green strings). (B‐H): CF intestine: A defective cf gene (e.g., δF508) leads to defective CFTR protein processing and no expression (B). This leads to decreased Cl, HCO3, and fluid secretion (C) resulting in altered pH and luminal milieu and improper unfolding of mucins (D). The mucus glycoproteins fail to unfold properly leading to a viscous mucus and impaired mucus clearance and turnover (E). The altered luminal milieu leads to microbial dysbiosis and barrier function (F). This results in immune system dysfunction (G) and inspissated mucus and intestinal obstruction (H).
Figure 14. Figure 14. Bile acid action on Cl secretion in the colon. Middle cell: Colonic crypt cell depicting CFTR Cl channel in the AM, Na+/K+ ATPase, Na+/K+/Cl cotransporter, K+ channel in the BLM. Left‐hand cell: Chenodeoxycholic acid (CDCA) stimulates CFTR‐mediated Cl secretion by cross talk between cAMP and Ca2+‐dependent signaling pathways, involving PKA, EPAC, and EGFR signaling. PKA phosphorylates CFTR and activation of EPAC leads to signaling via Rap2 and an increase in Ca2+ mobilization. CDCA initiates this signaling cascade through a yet to be identified receptor that may activate phospholipase C (PLC) directly, or via membrane perturbations. Right‐hand cell: The dehydroxylated derivative of CDCA, lithocholic acid (LCA) drastically attenuates forskolin effects on cAMP production and cAMP‐mediated Cl secretion, but involves neither the GPCRs, bile acid receptor, TGR5, and the m3 muscarinic receptor, nor ERK or Ca2+ signaling. CDCA decreases transepithelial barrier resistance (pore), increases paracellular 10‐kDa dextran permeability (leak) and reverses the cation selectivity of the monolayer (X vs. Y+) (left/middle cell). The effects of CDCA were enhanced by proinflammatory cytokines and CDCA increases ROS production (not shown). LCA has no direct effect on barrier function and does not affect the effects of CDCA on pore function. However, LCA dramatically attenuates CDCA ± cytokines actions on the leak function (middle‐right cell), an ROS‐mediated mechanism.


Figure 1. Structure of intestinal epithelia. Left: Intestinal epithelial cells are structurally and functionally designed for vectorial transport. (A) The cell membrane is divided into distinct apical and basolateral domains by the tight junctions with an asymmetric distribution of transporters; (B) the sodium pump on the basolateral membrane maintains a low intracellular [Na+] and provides the electrochemical driving force that permits “downhill” entry of Na+ from either surface; (C) water and solutes can cross the epithelium paracellularly or transcellularly; (D) transcellular transport can be passive or active. P.D., potential difference in millivolts. Bottom left: An expansion of the apical membrane, underlying scaffolding network and junctional complexes in the paracellular pathway. JAM, junctional adhesion molecules. Right: Architecture of the healthy intestine: Crypt/villus of small intestine and crypt/surface of the large intestine. The epithelial layer contains enterocytes, goblet cells, enteroendocrine cells, Paneth cells, and stem cells. Arrows depict vectorial movement of solutes and water in a normal gut, where absorption prevails. Both in the crypt:villus and crypt:surface axes, transporters exhibit a spatial distribution. Some are evenly distributed [e.g., the Na+/K+ ATPase pump and Na+/H+ exchanger (NHE)‐1], whereas others show a gradient. Bars represent distribution of ion transporters (blue gray for small intestine and green gray for colon). PAT1, putative anion transporter; SGLT1, sodium‐dependent glucose cotransporter; NHE3, Na+/H+ exchanger‐3; CFTR, cystic fibrosis transmembrane regulator; DRA, downregulated in adenoma; cHKA, colonic H+/K+ ATPase; ois, ouabain‐insensitive; os, ouabain‐sensitive; KCNMA1, K+ channel; ENaC, epithelial Na+ channel.


Figure 2. Regulation of ion transport by MALPINES. This model depicts the many regulatory systems that influence intestinal function. Left: The villus crypt architecture supports a rich supply of blood vessels, innervation, and gut‐associated lymphoid tissue (GALT) to the epithelium. Right: Enlarged section of epithelium to depict MALPINES: Lumen has Microbes (commensal and pathogenic); can release Autocrine factors that can act apically and basolaterally; presence of other Luminal factors such as bile acids, food, bacterial toxins, and viruses; secreted factors could act in a Paracrine fashion; the subepithelium has the unique Immune tissue, GALT; the tissue is richly supplied with the enteric Nervous system that has secretomotor and interneurons; and enterochromaffin cells and blood vessels provide Endocrine substances and all of them together form an integrated regulatory System. The epithelium has a layer of mucus that acts as the first line of defense. For example, intraluminal mechanical/chemical stimuli could trigger interneurons in either the myenteric or submucosal plexuses to stimulate secretory neurons to release acetylcholine (Ach) that acts on epithelial cells to alter ion transport or on muscle cells to alter motility. Immune cells could be triggered to release prostaglandins (PG) that act on the epithelial cell to alter function.


Figure 3. Electrolyte absorption: The transepithelial absorption of Na+, Cl, K+, and SCFA. (A) Sodium and chloride absorption: Sodium entry across the AM, down the electrochemical gradient can occur by (right to left): Na+‐solute carriers like SGLT1, transporting glucose; Na+ channels in the distal colon; and Na+/H+ exchangers (e.g., NHE2, NHE3, and NHE8) in the small intestine and in the proximal colon. Cl can enter the cell via Cl/HCO3 exchangers (PAT‐1 in the small intestine and DRA in the colon). On the BLM (right to left, sodium leaves the cell via the Na+/K+ ATPase and K+ via BLM K+ channels (KCNN4; KCNQ1/KCNE3; see 3B). HCO3 can enter the cell via BLM NBCe transporters. Glucose exits the BLM via facilitated diffusion transporters (Glut‐2), and Cl via channels (CLC2). Cl moves passively through the paracellular pathway or via cellular transporters. BLM NHEs (e.g., NHE1) perform housekeeping functions such as maintenance of intracellular pH and proliferation. Water transport can be transcellular, via aquaporins or cotransporters such as SGLT1, or paraceullar. Increases in intracellular cAMP, cGMP, or Ca2+ can inhibit Na+ and Cl absorption. (B) Potassium absorption: Transepithelial absorption of K+ is passive in the small intestine and occurs paracellularly. In the distal colon (depicted here), apical H+/K+ ATPase pumps absorb K+ especially when luminal concentrations are >25 mEq/L. K+ channels are critical for maintaining the membrane potential and are the major conduit for exit of K+ entering the cell via the pump. K+ exit across the BLM could be via channels including KCNN4 and KCNQ1/KCNE3 or the KCl cotransporter. Not shown are some K+ channels that reside in the AM and help maintain membrane potential. (C) Short‐chain fatty acids (SCFA) absorption: SCFAs are generated by luminal bacteria. At the luminal pH, SCFA are generally ionized and enter the cell via the monocarboxylate transporters (MCTs). Some protonated SCFA (SCFAH) can also diffuse across the AM of colonocytes. SCFA can also traverse by the paracellular pathway. While most SCFA are used by colonocytes as a source of metabolic energy, they can also be transported by different BLM MCT transporters (e.g., MCT4 and MCT5).


Figure 4. Electrolyte secretion. The major ions secreted are Cl and HCO3 throughout the length of the intestine and K+ in the distal colon. (A) Cl secretion: Cl enters the basolateral membrane via a 1Na+:1K+:2Cl cotransporter, and is energized by the BLM Na+/K+ ATPase and K+ channels and accumulates in the cell above its electrochemical equilibrium. An apical Cl channel is responsible for Cl exit, with Na+ and water following passively. In many cells, HCO3 can also be transported via the channel. In the intestine, the cystic fibrosis transmembrane conductance regulator (CFTR) is the most likely candidate Cl channel. Increases in intracellular cAMP, cGMP, or Ca2+ stimulate intestinal Cl secretion by activating one or more of the transporters. (B) K+ secretion: Active transepithelial secretion of K+ occurs through the KCNMA1 channels in the distal colon. K+ is an important contributor to colonic ion secretion and occurs especially when luminal concentrations are <25 mEq/L. The major apical channels responsible for secretion are KCNMA1 and in some cases, the TRAM‐sensitive KCNN4c channel (not shown here). K+ enters the cell via the pump and Na+:K+:2Cl cotransport. In the rest of the intestine, the K+ channels, including BLM, KCNN4, and KCNQ1/KCNE3, are critical for maintaining the membrane potential and for the efflux of K+ that enters the cell.


Figure 5. Cyclic nucleotide signaling. Cyclic nucleotide‐mediated transduction of an external signal into a change in cellular function minimally involve: Receptor; cyclase (xC); cyclic nucleotide (cXMP); protein kinase (PK); target phosphorylatable proteins; the proteins may be in close proximity and compartmentalized, allowing for localized effects. (A) Cyclic adenosine monophosphate (cAMP): Stimulatory (e.g., VIP/PG or bile acids) agents bind to specific membrane G‐protein coupled receptors (GPCRs) to activate Gαs to stimulate membrane adenylate cyclase (AC), while inhibitory (somatostatin) agents bind to their receptors to activate Gαi which inhibits AC. Cyclic AMP can also be generated by soluble AC (sAC) activated by Ca2+ and HCO3. Increased cAMP activates PKA which then phosphorylates transport proteins to increase (CFTR channels) or attenuate (DRA/PAT‐1 or NHE3 antiporter) activity. Cyclic AMP also act via the guanine nucleotide exchange factor, Epac, which acts via RAP2 to activate phospholipase C (PLC). The effects of cAMP can be compartmentalized by binding to scaffolding proteins like A‐Kinase Anchoring Protein (AKAP). ATP, adenosine triphosphate; Gi, inhibitory G protein; Gs, stimulatory G protein; VIP, vasoactive intestinal peptide; PG, prostaglandin; PIP2, phosphatidyl inositol 4,5, bis phosphate; IP3, inositol trisphosphate. (B) Cyclic guanosine monophosphate (cGMP): Some agents (e.g., STa, guanylin) bind to guanylate cyclase (mGC, a.k.a.GUCY2C) where a single molecule has both receptor and enzymatic activity. Activation of GUCY2C results in the production of cGMP from GTP. Cyclic GMP can also be produced from soluble GC (sGC) by activators such as nitric oxide (NO). Cyclic GMP activates PK II (PKG2), which is tethered to the membrane by myristoylation and can be further compartmentalized by anchoring proteins such as the NHE Regulatory Factor, NHERF4. PKG2 phosphorylates target transporters, in a fashion similar to PKA. cGMP can also be transported across the BLM by nucleotide transporters where it acts on nociceptive nerve terminals to attenuate pain. Cyclic GMP can inhibit the hydrolysis of cAMP by phosphodiesterases (PDE3) and elevate [cAMP]i. GTP, guanosine triphosphate; STa, heat‐stable enterotoxin.


Figure 6. Ca2+‐dependent signaling pathways. Neurotransmitters and hormones activate secretion and inhibit absorption (transporters not shown) by elevating [Ca2+]i. For example, acetylcholine (via muscarinic M3) or neurotensin bind to GPCRs to stimulate Gαq; bile acids do so via an unidentified receptor, whereas substance P, stimulates Ca2+ channels. Upon activation, Gαq stimulates phospholipase C‐β (PLC), which hydrolyzes phosphatidyl inositol 4,5, bis phosphate (PIP2) to generate inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3, but not DAG binds to specific IP3 receptors (IP3R) on intracellular compartments, chiefly the endoplasmic reticulum, to release Ca2+. In doing so IP3 displaces the phopsphorylated IP3R binding protein (IRBIT‐P). Increased [Ca2+]i activates many target proteins, including transporters and cytoskeletal elements. Some of this is accomplished by its binding to the ubiquitous Ca2+‐binding protein, calmodulin (CAM), and Ca2+‐CAMPKs. The DAG is rapidly metabolized but also stimulates some isoforms of protein kinase C (PKC). IRBIT‐P, when released from IP3R, can regulate transporters directly at the membrane or stimulate transporter trafficking to the membrane. The IRBIT‐P target transporters include NBCe‐1, CFTR, NHE3, and PAT‐1. Ca2+ signaling is transient.


Figure 7. Cystic fibrosis and CFTR. Inset: This shows the topology of CFTR. The protein has intracellular N and C termini that bracket in sequence a transmembrane spanning domain (MSD1) followed by a nucleotide binding domain (NBD1), a regulatory (R) domain that has ≈10 consensus PKA/PKG phosphorylation sites, followed by MSD2 and NBD2. Main diagram: The CFTR protein is normally trafficked to the apical membrane via the endoplasmic reticulum‐trans Golgi network. In the intestine cAMP and cGMP increase both the activity of the channel and channel insertion into the membrane. The majority of CF patients carry a δF508 deletion in NBD1 which results in a misfolding of the protein, ubiquitinylation and being targeted for degradation via proteasomes to the lysosomes. Other mutations show abnormal conductance and membrane residence time (not shown).


Figure 8. Actions of Vibrio cholerae. In the host V. cholerae maintains a dynamic equilibrium between a sessile state in a biofilm (gray and green ovals) and a motile (free vibrio) state. These are governed by the luminal concentrations of bile and HCO3 the triangles depict their relative lumen to mucosal surface gradients. The motile V. cholerae produce many toxins including a zona occludens toxin (ZOT) that reversibly increases paracellular permeability (see Fig. 12) and the main AB5 enterotoxin (CT). The B subunits of CT bind GM1 gangliosides (GMI) on the apical membrane and the A1 and A2 subunits enter the cell. By retrograde endocytosis, A1 ADP‐ribosylates Gαs, inhibiting its GTPase site and thereby activating adenylate cyclase (AC) irreversibly; (for clarity, the A1‐A2 are not shown separately). Cyclic AMP stimulates Cl secretion in the crypt enterocyte (cell on the right) and inhibits NHE, but not SGLT1 in the apical membrane of the villar cells (cell on the left). CT can also stimulate enterochromaffin cells to release 5‐HT which activate secreto‐motor reflexes proximally and distally (e.g., colon by activating interneurons) and thereby exacerbate secretion. VIP, vasoactive intestinal peptide; PG, prostaglandins.


Figure 9. Actions of rotavirus on intestinal ion transport. Rotaviruses are nonenveloped, double‐stranded RNA, coding for six structural (VP, not shown) and six nonstructural (NSP1‐6) proteins. While absent in the mature virion, upon infection of the host cell, the virus elaborates an enterotoxin, NSP4 which it releases via the AM and BLM. NSP4 binds to α1ß2 and α2ß1 integrin receptors and elicits Cl secretion via a Ca2+‐PLC pathway that stimulates the TMEM16A Cl channel, but not CFTR (not shown), largely in the intestines of young animals. The NSP‐stimulated increases in Ca2+, affect junctional proteins, actin dynamics, microvillar cytoskeleton (left hand cell) and stimulates the release of ROS, and inflammatory mediators (not shown). The luminally released NSP4 acts on enterochromaffin cells, to trigger Ca2+‐mediated BLM release of 5‐HT. The 5‐HT activates ENS secretory‐motor reflexes or on CNS‐mediated reflexes to trigger pain and nausea.


Figure 10. Actions of enteropathogenic Escherichia coli (EPEC). EPEC act by adhering to the host cell, effacing the microvilli, recruiting host cell cytoskeletal machinery to form a characteristic attaching and effacing lesion (A/E Lesion). EPEC utilizes a Type III secretion system (T3SS) to inject effector molecules, including the esp proteins, into the host cell. These factors coopt different intracellular signaling cascades, to affect host cell TJs, mitochondrial metabolism, and ion transport. Minimally EPEC utilizes the following factors: EspF, Map (mitochondrial associated protein), EspG, PKCζ (shown here); and NleA and EspH (not shown), to alter TJ gate and fence functions, including the redistribution of occludin and ZO‐1. Acting via espF, EPEC inhibits AM NHE3 and requires NHERF2. Both espF and Map inhibit Na‐glucose absorption via SGLT1. EPEC activates PKCα, and PKCϵ to increase AM NHE2 activity. In contrast, espG1 and espG2 utilize the host cell microtubule network to inhibit surface expression of DRA, by altering vesicular trafficking.


Figure 11. Model of inflammatory bowel disease (IBD). There are two major forms of IBD ulcerative colitis (UC) and Crohn's disease (CD). UC is generally restricted to the colon; it begins in the rectum and spreads proximally in a continuous fashion, and often involves only the mucosa and submucosa (right middle inset). CD is more prevalent in the distal small intestine and colon, but can affect the entire length of the GI tract; it can involve all layers of the gut wall, is discontinuous in its distribution and microbial translocation is more prevalent (right middle inset). Genetics, the host immune system, environmental factors such as diet, loss of epithelium integrity, and changes in the microbiome, contribute to IBD pathogenesis (right upper inset). A healthy cell is depicted on the left with a small mucus layer and normal Na+ and Cl absorption (thickness of arrows). Initial events cause an increase in mucus thickness and decrease in Na+ and Cl absorption (right hand cell and thin arrows). At later stages diarrhea is mainly due to both an inhibition and loss of AM Cl/HCO3 (DRA) and Na+/H+ (NHE3) exchangers and an increase in paracellular permeability. The latter results in xenobiotics and microbial products entering the lamina propria and immune cells infiltrating the lumen (blue arrow). Activation of various components of the gut associated lymphoid tissue (GALT) results in release of cytokines and immune modulators.


Figure 12. Model of celiac disease. Gluten is made up of gliadins rich in glutamine and proline, which are not readily digested by humans. Gliadins traverse the epithelium by at least two routes: initially, paracellularly and later transcellularly. Enlargement in the right inset: The gliadin peptides bind to the CXC motif receptor 3 on the AM of enterocytes and activate MYD88, which leads to zonulin secretion into the lumen. Zonulin, is the human homolog of the Par2 binding domain of Zot, the V. cholerae toxin. Zonulin binding to AM Par2 and EGF receptors, activates PKCα and other kinases (not shown), leading to ZO‐1 phosphorylation and disassembly of the TJs and an increase in paracellular permeability, including to gliadins. Left‐hand diagram: In the subepithelium, tissue TG released by damaged cells, deamidate gliadins, and release glutamic acid. Negatively charged glutamic acid residues bind to the HLA2DQ2 antigen‐binding groove, and are a ligand for CD4+ T helper cells. Activation of antigen presenting cells (APC) in the lamina propria results in the release of cytokines, which trigger plasma cells to produce IgA and/or IgG against gliadin. The anti‐gliadin IgAs released into the lumen, bind to gliadin, and transports it via IgA‐mediated transcellular cytosis to the lamina propria; this transcellular mechanism is the second for gliadin entry occurring later in the infection cycle and further exacerbates the immune response.


Figure 13. Flow diagram of intestinal malfunction in CF. The genetic defect leading to impaired Cl and HCO3 secretion leads to a series of interrelated events resulting in intestinal dysbiosis and inspissation. (A) Non‐CF intestine: The non‐CF intestine has a balanced Cl and HCO3 secretion and a protective nonviscous mucus layer with expanded mucus glycoproteins (green strings). (B‐H): CF intestine: A defective cf gene (e.g., δF508) leads to defective CFTR protein processing and no expression (B). This leads to decreased Cl, HCO3, and fluid secretion (C) resulting in altered pH and luminal milieu and improper unfolding of mucins (D). The mucus glycoproteins fail to unfold properly leading to a viscous mucus and impaired mucus clearance and turnover (E). The altered luminal milieu leads to microbial dysbiosis and barrier function (F). This results in immune system dysfunction (G) and inspissated mucus and intestinal obstruction (H).


Figure 14. Bile acid action on Cl secretion in the colon. Middle cell: Colonic crypt cell depicting CFTR Cl channel in the AM, Na+/K+ ATPase, Na+/K+/Cl cotransporter, K+ channel in the BLM. Left‐hand cell: Chenodeoxycholic acid (CDCA) stimulates CFTR‐mediated Cl secretion by cross talk between cAMP and Ca2+‐dependent signaling pathways, involving PKA, EPAC, and EGFR signaling. PKA phosphorylates CFTR and activation of EPAC leads to signaling via Rap2 and an increase in Ca2+ mobilization. CDCA initiates this signaling cascade through a yet to be identified receptor that may activate phospholipase C (PLC) directly, or via membrane perturbations. Right‐hand cell: The dehydroxylated derivative of CDCA, lithocholic acid (LCA) drastically attenuates forskolin effects on cAMP production and cAMP‐mediated Cl secretion, but involves neither the GPCRs, bile acid receptor, TGR5, and the m3 muscarinic receptor, nor ERK or Ca2+ signaling. CDCA decreases transepithelial barrier resistance (pore), increases paracellular 10‐kDa dextran permeability (leak) and reverses the cation selectivity of the monolayer (X vs. Y+) (left/middle cell). The effects of CDCA were enhanced by proinflammatory cytokines and CDCA increases ROS production (not shown). LCA has no direct effect on barrier function and does not affect the effects of CDCA on pore function. However, LCA dramatically attenuates CDCA ± cytokines actions on the leak function (middle‐right cell), an ROS‐mediated mechanism.
References
 1. Water with sugar and salt. Lancet 2: 300‐301, 1978.
 2. Abumrad NA , Nassir F , Marcus A . Digestion and absorption of dietary fat, carbohydrate, and protein. In: Feldman M , Friedman LS , Brandt LJ , editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia, USA: Elsevier, 2016, pp. 1736‐1764.
 3. Acosta A , Camilleri M . Elobixibat and its potential role in chronic idiopathic constipation. Therap Adv Gastroenterol 7: 167‐175, 2014.
 4. Agarwal S , Mayer L . Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol 11: 1050‐1063, 2013.
 5. Agrawal PB , Wang R , Li HL , Schmitz‐Abe K , Simone‐Roach C , Chen J , Shi J , Louie T , Sheng S , Towne MC , Brainson CF , Matthay MA , Kim CF , Bamshad M , Emond MJ , Gerard NP , Kleyman TR , Gerard C . The epithelial sodium channel is a modifier of the long‐term nonprogressive phenotype associated with F508del CFTR mutations. Am J Respir Cell Mol Biol 57: 711‐720, 2017.
 6. Agre P , King LS , Yasui M , Guggino WB , Ottersen OP , Fujiyoshi Y , Engel A , Nielsen S . Aquaporin water channels–from atomic structure to clinical medicine. J Physiol 542: 3‐16, 2002.
 7. Ahn SH , Shah YM , Inoue J , Morimura K , Kim I , Yim S , Lambert G , Kurotani R , Nagashima K , Gonzalez FJ , Inoue Y . Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm Bowel Dis 14: 908‐920, 2008.
 8. Ahsan MK , Tchernychev B , Kessler MM , Solinga RM , Arthur D , Linde CI , Silos‐Santiago I , Hannig G , Ameen NA . Linaclotide activates guanylate cyclase‐C/cGMP/protein kinase‐II‐dependent trafficking of CFTR in the intestine. Physiol Rep 5: pii: e13299, 2017.
 9. Ahuja M , Jha A , Maleth J , Park S , Muallem S . cAMP and Ca(2)(+) signaling in secretory epithelia: Crosstalk and synergism. Cell Calcium 55: 385‐393, 2014.
 10. Aka AA , Rappaport JA , Pattison AM , Sato T , Snook AE , Waldman SA . Guanylate cyclase C as a target for prevention, detection, and therapy in colorectal cancer. Expert Rev Clin Pharmacol 10: 549‐557, 2017.
 11. Akiba Y , Kaunitz JD . May the truth be with you: Lubiprostone as EP receptor agonist/ClC‐2 internalizing “inhibitor.” Dig Dis Sci 57: 2740‐2742, 2012.
 12. Al‐Hazza A , Linley JE , Aziz Q , Maclennan KA , Hunter M , Sandle GI . Potential role of reduced basolateral potassium (IKCa3.1) channel expression in the pathogenesis of diarrhoea in ulcerative colitis. J Pathol 226: 463‐470, 2012.
 13. Alberts B. Molecular Biology of the Cell. New York: Garland Science, 2014.
 14. Alemi F , Poole DP , Chiu J , Schoonjans K , Cattaruzza F , Grider JR , Bunnett NW , Corvera CU . The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 144: 145‐154, 2013.
 15. Alper SL . Molecular physiology and genetics of Na+‐independent SLC4 anion exchangers. J Exp Biol 212: 1672‐1683, 2009.
 16. Alper SL , Sharma AK . The SLC26 gene family of anion transporters and channels. Mol Aspects Med 34: 494‐515, 2013.
 17. Amasheh S , Barmeyer C , Koch CS , Tavalali S , Mankertz J , Epple HJ , Gehring MM , Florian P , Kroesen AJ , Zeitz M , Fromm M , Schulzke JD . Cytokine‐dependent transcriptional down‐regulation of epithelial sodium channel in ulcerative colitis. Gastroenterology 126: 1711‐1720, 2004.
 18. Ameen N , Alexis J , Salas P . Cellular localization of the cystic fibrosis transmembrane conductance regulator in mouse intestinal tract. Histochem Cell Biol 114: 69‐75, 2000.
 19. Ameen N , Kopic S , Ahsan MK , Kravtsov DV. Secretory diarrhea. In: Hamilton KL , Devor DC , editors. Ion Channels and Transporters of Epithelia in Health and Disease, Physiology in Health and Disease. New York, USA: American Physiology Society, 2016, pp. 957‐990.
 20. Ameen NA , Ardito T , Kashgarian M , Marino CR . A unique subset of rat and human intestinal villus cells express the cystic fibrosis transmembrane conductance regulator. Gastroenterology 108: 1016‐1023, 1995.
 21. Ameen NA , Salas PJ . Microvillus inclusion disease: A genetic defect affecting apical membrane protein traffic in intestinal epithelium. Traffic 1: 76‐83, 2000.
 22. Ammoury RF , Ghishan FK . Pathophysiology of diarrhea and its clinical implications. In: Johnson LR , editor. Physiology of the Gastrointestinal Tract. Academic Press, 2012, pp. 2183‐2197.
 23. Anbazhagan AN , Priyamvada S , Kumar A , Maher DB , Borthakur A , Alrefai WA , Malakooti J , Kwon JH , Dudeja PK . Translational repression of SLC26A3 by miR‐494 in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 306: G123‐G131, 2014.
 24. Anderson JM , Van Itallie CM . Physiology and function of the tight junction. Cold Spring Harb Perspect Biol 1: a002584, 2009.
 25. Ando H , Kawaai K , Mikoshiba K . IRBIT: A regulator of ion channels and ion transporters. Biochim Biophys Acta 1843: 2195‐2204, 2014.
 26. Andrews JM , Brierley SM , Blackshaw LA . Small intestinal motor and sensory function and dysfunction. In: Feldman M , Friedman LS , Brandt LJ , editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia, USA: Elsevier, 2016, pp. 1679‐1695.
 27. Antalis TM , Reeder JA , Gotley DC , Byeon MK , Walsh MD , Henderson KW , Papas TS , Schweinfest CW . Down‐regulation of the down‐regulated in adenoma (DRA) gene correlates with colon tumor progression. Clin Cancer Res 4: 1857‐1863, 1998.
 28. Ao M , Domingue JC , Khan N , Javed F , Osmani K , Sarathy J , Rao MC . Lithocholic acid attenuates cAMP‐dependent Cl‐ secretion in human colonic epithelial T84 cells. Am J Physiol Cell Physiol 310: C1010‐C1023, 2016.
 29. Ao M , Sarathy J , Domingue J , Alrefai WA , Rao MC . Chenodeoxycholic acid stimulates Cl(‐) secretion via cAMP signaling and increases cystic fibrosis transmembrane conductance regulator phosphorylation in T84 cells. Am J Physiol Cell Physiol 305: C447‐C456, 2013.
 30. Ao M , Venkatasubramanian J , Boonkaewwan C , Ganesan N , Syed A , Benya RV , Rao MC . Lubiprostone activates Cl‐ secretion via cAMP signaling and increases membrane CFTR in the human colon carcinoma cell line, T84. Dig Dis Sci 56: 339‐351, 2011.
 31. Aoun J , Hayashi M , Sheikh IA , Sarkar P , Saha T , Ghosh P , Bhowmick R , Ghosh D , Chatterjee T , Chakrabarti P , Chakrabarti MK , Hoque KM . Anoctamin 6 Contributes to Cl‐ Secretion in Accessory Cholera Enterotoxin (Ace)‐stimulated Diarrhea: An essential role for phosphatidylinositol 4,5‐bisphosphate (PIP2) signaling in cholera. J Biol Chem 291: 26816‐26836, 2016.
 32. Arakawa T , Kobayashi‐Yurugi T , Alguel Y , Iwanari H , Hatae H , Iwata M , Abe Y , Hino T , Ikeda‐Suno C , Kuma H , Kang D , Murata T , Hamakubo T , Cameron AD , Kobayashi T , Hamasaki N , Iwata S . Crystal structure of the anion exchanger domain of human erythrocyte band 3. Science 350: 680‐684, 2015.
 33. Arena EA , Longo WE , Roberts KE , Geibel P , Nateqi J , Brandstetter M , Geibel JP . Functional role of NHE4 as a pH regulator in rat and human colonic crypts. Am J Physiol Cell Physiol 302: C412‐C418, 2012.
 34. Arora K , Yarlagadda S , Zhang W , Moon C , Bouquet E , Srinivasan S , Li C , Stokes DC , Naren AP . Personalized medicine in cystic fibrosis: Genistein supplementation as a treatment option for patients with a rare S1045Y‐CFTR mutation. Am J Physiol Lung Cell Mol Physiol 311: L364‐L374, 2016.
 35. Arshad N , Visweswariah SS . The multiple and enigmatic roles of guanylyl cyclase C in intestinal homeostasis. FEBS Lett 586: 2835‐2840, 2012.
 36. Asano K , Matsushita T , Umeno J , Hosono N , Takahashi A , Kawaguchi T , Matsumoto T , Matsui T , Kakuta Y , Kinouchi Y , Shimosegawa T , Hosokawa M , Arimura Y , Shinomura Y , Kiyohara Y , Tsunoda T , Kamatani N , Iida M , Nakamura Y , Kubo M . A genome‐wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41: 1325‐1329, 2009.
 37. Asghar MN , Priyamvada S , Nystrom JH , Anbazhagan AN , Dudeja PK , Toivola DM . Keratin 8 knockdown leads to loss of the chloride transporter DRA in the colon. Am J Physiol Gastrointest Liver Physiol 310: G1147‐G1154, 2016.
 38. Avula LR , Chen T , Kovbasnjuk O , Donowitz M . Both NHERF3 and NHERF2 are necessary for multiple aspects of acute regulation of NHE3 by elevated Ca(2+), cGMP, and lysophosphatidic acid. Am J Physiol Gastrointest Liver Physiol 314: G81‐G90, 2018.
 39. Bachmann O , Seidler U . News from the end of the gut–how the highly segmental pattern of colonic HCO(3)(‐) transport relates to absorptive function and mucosal integrity. Biol Pharm Bull 34: 794‐802, 2011.
 40. Backhed F , Fraser CM , Ringel Y , Sanders ME , Sartor RB , Sherman PM , Versalovic J , Young V , Finlay BB . Defining a healthy human gut microbiome: Current concepts, future directions, and clinical applications. Cell Host Microbe 12: 611‐622, 2012.
 41. Barmeyer C , Erko I , Fromm A , Bojarski C , Loddenkemper C , Dames P , Kerick M , Siegmund B , Fromm M , Schweiger MR , Schulzke JD . ENaC dysregulation through activation of MEK1/2 contributes to impaired Na+ absorption in lymphocytic colitis. Inflamm Bowel Dis 22: 539‐547, 2016.
 42. Barrett KE . Endogenous and exogenous control of gastrointestinal epithelial function: Building on the legacy of Bayliss and Starling. J Physiol 595: 423‐432, 2017.
 43. Barrett KE , Keely SJ . Chloride secretion by the intestinal epithelium: Molecular basis and regulatory aspects. Annu Rev Physiol 62: 535‐572, 2000.
 44. Barrett KE , Keely SJ. Integrative physiology and pathophysiology of intestinal electrolyte transport. In: Johnson LR , editor. Physiology of the Gastrointestinal Tract. New York: Raven Press, 2006, pp. 1931‐1951.
 45. Bastl CP , Barnett CA , Schmidt TJ , Litwack G . Glucocorticoid stimulation of sodium absorption in colon epithelia is mediated by corticosteroid IB receptor. J Biol Chem 259: 1186‐1195, 1984.
 46. Bastl CP , Schulman G , Cragoe EJ, Jr. Low‐dose glucocorticoids stimulate electroneutral NaCl absorption in rat colon. Am J Physiol 257: F1027‐F1038, 1989.
 47. Basu N , Arshad N , Visweswariah SS . Receptor guanylyl cyclase C (GC‐C): Regulation and signal transduction. Mol Cell Biochem 334: 67‐80, 2010.
 48. Basu N , Saha S , Khan I , Ramachandra SG , Visweswariah SS . Intestinal cell proliferation and senescence are regulated by receptor guanylyl cyclase C and p21. J Biol Chem 289: 581‐593, 2014.
 49. Baum M , Martin MG , Booth IW , Holmberg C , Twombley K , Zhang Q , Gattineni J , Moe O . Nucleotide sequence of the Na+/H+ exchanger‐8 in patients with congenital sodium diarrhea. J Pediatr Gastroenterol Nutr 53: 474‐477, 2011.
 50. Benedetto R , Ousingsawat J , Wanitchakool P , Zhang Y , Holtzman MJ , Amaral M , Rock JR , Schreiber R , Kunzelmann K . Epithelial chloride transport by CFTR requires TMEM16A. Sci Rep 7: 12397, 2017.
 51. Benitez JA , Silva AJ . Vibrio cholerae hemagglutinin(HA)/protease: An extracellular metalloprotease with multiple pathogenic activities. Toxicon 115: 55‐62, 2016.
 52. Benya RV , Matkowskyj KA , Danilkovich A , Hecht G . Galanin causes Cl‐ secretion in the human colon. Potential significance of inflammation‐associated NF‐kappa B activation on galanin‐1 receptor expression and function. Ann N Y Acad Sci 863: 64‐77, 1998.
 53. Bhattarai Y , Schmidt BA , Linden DR , Larson ED , Grover M , Beyder A , Farrugia G , Kashyap PC . Human‐derived gut microbiota modulates colonic secretion in mice by regulating 5‐HT3 receptor expression via acetate production. Am J Physiol Gastrointest Liver Physiol 313: G80‐G87, 2017.
 54. Bhunia AK . Foodborne Parasites. In: Foodborne Microbial Pathogens: Mechanisms and Pathogenesis. New York: Springer, 2018, pp. 151‐165.
 55. Bhunia AK . Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus. In: Foodborne Microbial Pathogens: Mechanisms and Pathogenesis. New York: Springer, 2018, pp. 315‐329.
 56. Bhutia YD , Babu E , Ramachandran S , Yang S , Thangaraju M , Ganapathy V . SLC transporters as a novel class of tumour suppressors: Identity, function and molecular mechanisms. Biochem J 473: 1113‐1124, 2016.
 57. Bijvelds MJ , Bot AG , Escher JC , De Jonge HR . Activation of intestinal Cl‐ secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology 137: 976‐985, 2009.
 58. Binder HJ . Role of colonic short‐chain fatty acid transport in diarrhea. Annu Rev Physiol 72: 297‐313, 2010.
 59. Binder HJ , Brown I , Ramakrishna BS , Young GP . Oral rehydration therapy in the second decade of the twenty‐first century. Curr Gastroenterol Rep 16: 376, 2014.
 60. Binder HJ , Filburn C , Volpe BT . Bile salt alteration of colonic electrolyte transport: Role of cyclic adenosine monophosphate. Gastroenterology 68: 503‐508, 1975.
 61. Binder HJ , Rajendran V , Sadasivan V , Geibel JP . Bicarbonate secretion: A neglected aspect of colonic ion transport. J Clin Gastroenterol 39: S53‐S58, 2005.
 62. Binder HJ , Sangan P , Rajendran VM . Physiological and molecular studies of colonic H+,K+‐ATPase. Semin Nephrol 19: 405‐414, 1999.
 63. Binder HJaS GI. Electrolyte absorption and secretion in the mammalian colon. In: Johnson LR , editor. Physiology of the Gastrointestinal Tract. New York: Raven Press, 1987, pp. 1389‐1418.
 64. Bischoff S , Crowe SE . Gastrointestinal food allergy: New insights into pathophysiology and clinical perspectives. Gastroenterology 128: 1089‐1113, 2005.
 65. Blackman SM , Deering‐Brose R , McWilliams R , Naughton K , Coleman B , Lai T , Algire M , Beck S , Hoover‐Fong J , Hamosh A , Fallin MD , West K , Arking DE , Chakravarti A , Cutler DJ , Cutting GR . Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis. Gastroenterology 131: 1030‐1039, 2006.
 66. Bookstein C , DePaoli AM , Xie Y , Niu P , Musch MW , Rao MC , Chang EB . Na+/H+ exchangers, NHE‐1 and NHE‐3, of rat intestine. Expression and localization. J Clin Invest 93: 106‐113, 1994.
 67. Booth IW , Stange G , Murer H , Fenton TR , Milla PJ . Defective jejunal brush‐border Na+/H+ exchange: A cause of congenital secretory diarrhoea. Lancet 1: 1066‐1069, 1985.
 68. Borenshtein D , Schlieper KA , Rickman BH , Chapman JM , Schweinfest CW , Fox JG , Schauer DB . Decreased expression of colonic Slc26a3 and carbonic anhydrase iv as a cause of fatal infectious diarrhea in mice. Infect Immun 77: 3639‐3650, 2009.
 69. Borthakur A , Anbazhagan AN , Kumar A , Raheja G , Singh V , Ramaswamy K , Dudeja PK . The probiotic Lactobacillus plantarum counteracts TNF‐{alpha}‐induced downregulation of SMCT1 expression and function. Am J Physiol Gastrointest Liver Physiol 299: G928‐G934, 2010.
 70. Borthakur A , Priyamvada S , Kumar A , Natarajan AA , Gill RK , Alrefai WA , Dudeja PK . A novel nutrient sensing mechanism underlies substrate‐induced regulation of monocarboxylate transporter‐1. Am J Physiol Gastrointest Liver Physiol 303: G1126‐G1133, 2012.
 71. Borthakur A , Saksena S , Gill RK , Alrefai WA , Ramaswamy K , Dudeja PK . Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: Involvement of NF‐kappaB pathway. J Cell Biochem 103: 1452‐1463, 2008.
 72. Bouziat R , Hinterleitner R , Brown JJ , Stencel‐Baerenwald JE , Ikizler M , Mayassi T , Meisel M , Kim SM , Discepolo V , Pruijssers AJ , Ernest JD , Iskarpatyoti JA , Costes LM , Lawrence I , Palanski BA , Varma M , Zurenski MA , Khomandiak S , McAllister N , Aravamudhan P , Boehme KW , Hu F , Samsom JN , Reinecker HC , Kupfer SS , Guandalini S , Semrad CE , Abadie V , Khosla C , Barreiro LB , Xavier RJ , Ng A , Dermody TS , Jabri B . Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356: 44‐50, 2017.
 73. Bozoky Z , Ahmadi S , Milman T , Kim TH , Du K , Di Paola M , Pasyk S , Pekhletski R , Keller JP , Bear CE , Forman‐Kay JD . Synergy of cAMP and calcium signaling pathways in CFTR regulation. Proc Natl Acad Sci USA 114: E2086‐E2095, 2017.
 74. Bozoky Z , Krzeminski M , Muhandiram R , Birtley JR , Al‐Zahrani A , Thomas PJ , Frizzell RA , Ford RC , Forman‐Kay JD . Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho‐dependent intra‐ and intermolecular interactions. Proc Natl Acad Sci USA 110: E4427‐E4436, 2013.
 75. Bradbury NA . CFTR and Cystic Fibrosis: A need for personalized medicine. In: Hamilton KL , Devor DC , editors. Ion Channels and Transporters of Epithelia in Health and Disease, Physiology in Health and Disease. New York: American Physiological Society, Springer, 2016, pp. 773‐801.
 76. Brant SR , Okou DT , Simpson CL , Cutler DJ , Haritunians T , Bradfield JP , Chopra P , Prince J , Begum F , Kumar A , Huang C , Venkateswaran S , Datta LW , Wei Z , Thomas K , Herrinton LJ , Klapproth JA , Quiros AJ , Seminerio J , Liu Z , Alexander JS , Baldassano RN , Dudley‐Brown S , Cross RK , Dassopoulos T , Denson LA , Dhere TA , Dryden GW , Hanson JS , Hou JK , Hussain SZ , Hyams JS , Isaacs KL , Kader H , Kappelman MD , Katz J , Kellermayer R , Kirschner BS , Kuemmerle JF , Kwon JH , Lazarev M , Li E , Mack D , Mannon P , Moulton DE , Newberry RD , Osuntokun BO , Patel AS , Saeed SA , Targan SR , Valentine JF , Wang MH , Zonca M , Rioux JD , Duerr RH , Silverberg MS , Cho JH , Hakonarson H , Zwick ME , McGovern DP , Kugathasan S . Genome‐wide association study identifies African‐specific susceptibility loci in African Americans with inflammatory bowel disease. Gastroenterology 152: 206‐217 e202, 2017.
 77. Brenna O , Bruland T , Furnes MW , Granlund A , Drozdov I , Emgard J , Bronstad G , Kidd M , Sandvik AK , Gustafsson BI . The guanylate cyclase‐C signaling pathway is down‐regulated in inflammatory bowel disease. Scand J Gastroenterol 50: 1241‐1252, 2015.
 78. Britton RA , Young VB . Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 146: 1547‐1553, 2014.
 79. Bryant AP , Busby RW , Bartolini WP , Cordero EA , Hannig G , Kessler MM , Pierce CM , Solinga RM , Tobin JV , Mahajan‐Miklos S , Cohen MB , Kurtz CB , Currie MG . Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci 86: 760‐765, 2010.
 80. Buckley A , Turner JR . Cell biology of tight junction barrier regulation and mucosal disease. Cold Spring Harb Perspect Biol 10: pii: a029314, 2018.
 81. Busby RW , Bryant AP , Bartolini WP , Cordero EA , Hannig G , Kessler MM , Mahajan‐Miklos S , Pierce CM , Solinga RM , Sun LJ , Tobin JV , Kurtz CB , Currie MG . Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol 649: 328‐335, 2010.
 82. Busby RW , Kessler MM , Bartolini WP , Bryant AP , Hannig G , Higgins CS , Solinga RM , Tobin JV , Wakefield JD , Kurtz CB , Currie MG . Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther 344: 196‐206, 2013.
 83. Cafferata EG , Gonzalez‐Guerrico AM , Giordano L , Pivetta OH , Santa‐Coloma TA . Interleukin‐1beta regulates CFTR expression in human intestinal T84 cells. Biochim Biophys Acta 1500: 241‐248, 2000.
 84. Camilleri M . Advances in understanding of bile acid diarrhea. Expert Rev Gastroenterol Hepatol 8: 49‐61, 2014.
 85. Camilleri M . Guanylate cyclase C agonists: Emerging gastrointestinal therapies and actions. Gastroenterology 148: 483‐487, 2015.
 86. Camilleri M , Park SY , Scarpato E , Staiano A . Exploring hypotheses and rationale for causes of infantile colic. Neurogastroenterol Motil 29: 1‐11, 2017.
 87. Camilleri M , Sellin JH , Barrett KE . Pathophysiology, evaluation, and management of chronic watery diarrhea. Gastroenterology 152: 515‐532 e512, 2017.
 88. Carlos MA , Nwagwu C , Ao M , Venkatasubramanian J , Boonkaewwan C , Prasad R , Chowdhury SA , Vidyasagar D , Rao MC . Epidermal growth factor stimulates chloride transport in primary cultures of weanling and adult rabbit colonocytes. J Pediatr Gastroenterol Nutr 44: 300‐311, 2007.
 89. Carneiro L , Pellerin L . Monocarboxylate transporters: New players in body weight regulation. Obes Rev 16(Suppl 1): 55‐66, 2015.
 90. Catalan MA , Flores CA , Gonzalez‐Begne M , Zhang Y , Sepulveda FV , Melvin JE . Severe defects in absorptive ion transport in distal colons of mice that lack ClC‐2 channels. Gastroenterology 142: 346‐354, 2012.
 91. Cereijido M , Contreras RG , Shoshani L , Flores‐Benitez D , Larre I . Tight junction and polarity interaction in the transporting epithelial phenotype. Biochim Biophys Acta 1778: 770‐793, 2008.
 92. Chandrasekharan B , Srinivasan S . Diabetes and the enteric nervous systems. Neurogastroenterol Motil 19: 951‐960, 2007.
 93. Chang EB , Bergenstal RM , Field M . Diarrhea in streptozocin‐treated rats. Loss of adrenergic regulation of intestinal fluid and electrolyte transport. J Clin Invest 75: 1666‐1670, 1985.
 94. Chang EB , Musch MW , Mayer L . Interleukins 1 and 3 stimulate anion secretion in chicken intestine. Gastroenterology 98: 1518‐1524, 1990.
 95. Chang EB , Rao MC . Intestinal water and electrolyte transport: Mechanisms of physiological and adaptive responses. In: Johnson. LR , editor. Physiology of the Gastrointestinal Tract. New York: Raven Press, 1994, pp. 2027‐2081.
 96. Chang SY , Di A , Naren AP , Palfrey HC , Kirk KL , Nelson DJ . Mechanisms of CFTR regulation by syntaxin 1A and PKA. J Cell Sci 115: 783‐791, 2002.
 97. Charney AN , Feldman GM . Systemic acid‐base disorders and intestinal electrolyte transport. Am J Physiol 247: G1‐G12, 1984.
 98. Charney AN , Goldfarb DS , Egnor RW . Effects of pH and cyclic adenosine monophosphate on ileal electrolyte transport in the rat and rabbit. Gastroenterology 100: 410‐418, 1991.
 99. Chatterjee T , Chatterjee BK , Saha T , Hoque KM , Chakrabarti P . Structure and function of Vibrio cholerae accessory cholera enterotoxin in presence of gold nanoparticles: Dependence on morphology. Biochim Biophys Acta Gen Subj 1861: 977‐986, 2017.
 100. Chatterjee T , Sheikh IA , Chakravarty D , Chakrabarti P , Sarkar P , Saha T , Chakrabarti MK , Hoque KM . Effects of small molecule calcium‐activated chloride channel inhibitors on structure and function of accessory cholera enterotoxin (Ace) of vibrio cholerae. PLoS One 10: e0141283, 2015.
 101. Cheepala S , Hulot JS , Morgan JA , Sassi Y , Zhang W , Naren AP , Schuetz JD . Cyclic nucleotide compartmentalization: Contributions of phosphodiesterases and ATP‐binding cassette transporters. Annu Rev Pharmacol Toxicol 53: 231‐253, 2013.
 102. Chen T , Kocinsky HS , Cha B , Murtazina R , Yang J , Tse CM , Singh V , Cole R , Aronson PS , de Jonge H , Sarker R , Donowitz M . Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: Identification of a multifunctional phosphorylation site. J Biol Chem 290: 1952‐1965, 2015.
 103. Cheng SX . Calcium‐sensing receptor inhibits secretagogue‐induced electrolyte secretion by intestine via the enteric nervous system. Am J Physiol Gastrointest Liver Physiol 303: G60‐G70, 2012.
 104. Cheng SX , Bai HX , Gonzalez‐Peralta R , Mistry PK , Gorelick FS . Calcium ameliorates diarrhea in immunocompromised children. J Pediatr Gastroenterol Nutr 56: 641‐644, 2013.
 105. Cheng SX , Lightfoot YL , Yang T , Zadeh M , Tang L , Sahay B , Wang GP , Owen JL , Mohamadzadeh M . Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses. FEBS Lett 588: 4158‐4166, 2014.
 106. Chiang JY . Bile acid metabolism and signaling. Compr Physiol 3: 1191‐1212, 2013.
 107. Cho JH , Abraham C . Inflammatory bowel disease genetics: Nod2. Annu Rev Med 58: 401‐416, 2007.
 108. Cho JH , Musch MW , DePaoli AM , Bookstein CM , Xie Y , Burant CF , Rao MC , Chang EB . Glucocorticoids regulate Na+/H+ exchange expression and activity in region‐ and tissue‐specific manner. Am J Physiol 267: C796‐C803, 1994.
 109. Chow JY , Carlstrom K , Barrett KE . Growth hormone reduces chloride secretion in human colonic epithelial cells via EGF receptor and extracellular regulated kinase. Gastroenterology 125: 1114‐1124, 2003.
 110. Cid LP , Jentsch TJ , Sepulveda FV . Reply from L. P. Cid, T. J. Jentsch and F. V. Sepulveda: Intestinal electrolyte and fluid secretion ‐ a model in trouble? J Physiol 596: 2465‐2466, 2018.
 111. Cil O , Phuan PW , Lee S , Tan J , Haggie PM , Levin MH , Sun L , Thiagarajah JR , Ma T , Verkman AS . CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol 2: 317‐327, 2016.
 112. Clarke LL , Gawenis LR , Franklin CL , Harline MC. Increased survival of CFTR knockout mice with an oral osmotic laxative. Laboratory Animal Science 46: 612‐618, 1996.
 113. Clarke LL , Grubb BR , Yankaskas JR , Cotton CU , McKenzie A , Boucher RC . Relationship of a non‐cystic fibrosis transmembrane conductance regulator‐mediated chloride conductance to organ‐level disease in Cftr(‐/‐) mice. Proc Natl Acad Sci USA 91: 479‐483, 1994.
 114. Clayburgh DR , Barrett TA , Tang Y , Meddings JB , Van Eldik LJ , Watterson DM , Clarke LL , Mrsny RJ , Turner JR . Epithelial myosin light chain kinase‐dependent barrier dysfunction mediates T cell activation‐induced diarrhea in vivo. J Clin Invest 115: 2702‐2715, 2005.
 115. Coffing H , Priyamvada S , Anbazhagan AN , Salibay C , Engevik M , Versalovic J , Yacyshyn MB , Yacyshyn B , Tyagi S , Saksena S , Gill RK , Alrefai WA , Dudeja PK . Clostridium difficile toxins A and B decrease intestinal SLC26A3 protein expression. Am J Physiol Gastrointest Liver Physiol 315: G43‐G52, 2018.
 116. Cohen MB , Guarino A , Shukla R , Giannella RA . Age‐related differences in receptors for Escherichia coli heat‐stable enterotoxin in the small and large intestine of children. Gastroenterology 94: 367‐373, 1988.
 117. Cohn JA , Nairn AC , Marino CR , Melhus O , Kole J . Characterization of the cystic fibrosis transmembrane conductance regulator in a colonocyte cell line. Proc Natl Acad Sci USA 89: 2340‐2344, 1992.
 118. Collaco A , Jakab R , Hegan P , Mooseker M , Ameen N . Alpha‐AP‐2 directs myosin VI‐dependent endocytosis of cystic fibrosis transmembrane conductance regulator chloride channels in the intestine. J Biol Chem 285: 17177‐17187, 2010.
 119. Collaco AM , Jakab RL , Hoekstra NE , Mitchell KA , Brooks A , Ameen NA . Regulated traffic of anion transporters in mammalian Brunner's glands: A role for water and fluid transport. Am J Physiol Gastrointest Liver Physiol 305: G258‐G275, 2013.
 120. Collins JF , Anderson GJ . Molecular mechanism of intestinal iron transport. In: Johnson LR , editor. Physiology of the Gastrointestinal Tract. London, UK: Academic Press, 2012, pp. 1921‐1950.
 121. Crawford SE , Ramani S , Tate JE , Parashar UD , Svensson L , Hagbom M , Franco MA , Greenberg HB , O'Ryan M , Kang G , Desselberger U , Estes MK . Rotavirus infection. Nat Rev Dis Primers 3: 17083, 2017.
 122. Cuppoletti J , Malinowska DH , Tewari KP , Li QJ , Sherry AM , Patchen ML , Ueno R . SPI‐0211 activates T84 cell chloride transport and recombinant human ClC‐2 chloride currents. Am J Physiol Cell Physiol 287: C1173‐C1183, 2004.
 123. Currie MG , Fok KF , Kato J , Moore RJ , Hamra FK , Duffin KL , Smith CE . Guanylin: An endogenous activator of intestinal guanylate cyclase. Proc Natl Acad Sci USA 89: 947‐951, 1992.
 124. Cuthbert AW , Halstead J , Ratcliff R , Colledge WH , Evans MJ . The genetic advantage hypothesis in cystic fibrosis heterozygotes: A murine study. J Physiol 482(Pt 2): 449‐454, 1995.
 125. Cuthbert AW , MacVinish LJ , Hickman ME , Ratcliff R , Colledge WH , Evans MJ . Ion‐transporting activity in the murine colonic epithelium of normal animals and animals with cystic fibrosis. Pflugers Arch 428: 508‐515, 1994.
 126. Dames P , Bergann T , Fromm A , Bucker R , Barmeyer C , Krug SM , Fromm M , Schulzke JD . Interleukin‐13 affects the epithelial sodium channel in the intestine by coordinated modulation of STAT6 and p38 MAPK activity. J Physiol 593: 5269‐5282, 2015.
 127. Dang S , Feng S , Tien J , Peters CJ , Bulkley D , Lolicato M , Zhao J , Zuberbuhler K , Ye W , Qi L , Chen T , Craik CS , Nung Jan Y , Minor DL, Jr., Cheng Y , Yeh Jan L . Cryo‐EM structures of the TMEM16A calcium‐activated chloride channel. Nature 552: 426‐429, 2017.
 128. Daniel H , Zietek T . Taste and move: Glucose and peptide transporters in the gastrointestinal tract. Exp Physiol 100: 1441‐1450, 2015.
 129. Darsigny M , Babeu JP , Dupuis AA , Furth EE , Seidman EG , Levy E , Verdu EF , Gendron FP , Boudreau F . Loss of hepatocyte‐nuclear‐factor‐4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PLoS One 4: e7609, 2009.
 130. Das S , Jayaratne R , Barrett KE . The role of ion transporters in the pathophysiology of infectious diarrhea. Cell Mol Gastroenterol Hepatol 6: 33‐45, 2018.
 131. Davidson GP , Cutz E , Hamilton JR , Gall DG . Familial enteropathy: A syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy. Gastroenterology 75: 783‐790, 1978.
 132. Dawson PA , Huxley S , Gardiner B , Tran T , McAuley JL , Grimmond S , McGuckin MA , Markovich D . Reduced mucin sulfonation and impaired intestinal barrier function in the hyposulfataemic NaS1 null mouse. Gut 58: 910‐919, 2009.
 133. Dawson PA , Karpen SJ . Intestinal transport and metabolism of bile acids. J Lipid Res 56: 1085‐1099, 2015.
 134. de Jonge HR , Rao MC . Cyclic nucleotide‐dependent protein kinases: Role in ion transport. In: Lebenthal E , Duffey, ME , editors. Secretory Diarrhea. Raven Press, 1990, pp. 191‐207.
 135. De Lisle RC , Borowitz D . The cystic fibrosis intestine. Cold Spring Harb Perspect Med 3: a009753, 2013.
 136. De Lisle RC , Meldi L , Flynn M , Jansson K . Altered eicosanoid metabolism in the cystic fibrosis mouse small intestine. J Pediatr Gastroenterol Nutr 47: 406‐416, 2008.
 137. De Lisle RC , Meldi L , Mueller R . Intestinal smooth muscle dysfunction develops postnatally in cystic fibrosis mice. J Pediatr Gastroenterol Nutr 55: 689‐694, 2012.
 138. De Lisle RC , Meldi L , Roach E , Flynn M , Sewell R . Mast cells and gastrointestinal dysmotility in the cystic fibrosis mouse. PLoS One 4: e4283, 2009.
 139. De Lisle RC , Mueller R , Roach E . Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype. BMC Gastroenterol 10: 107, 2010.
 140. De Lisle RC , Roach E , Jansson K . Effects of laxative and N‐acetylcysteine on mucus accumulation, bacterial load, transit, and inflammation in the cystic fibrosis mouse small intestine. Am J Physiol Gastrointest Liver Physiol 293: G577‐G584, 2007.
 141. de Lisle RC , Sewell R , Meldi L . Enteric circular muscle dysfunction in the cystic fibrosis mouse small intestine. Neurogastroenterol Motil 22: 341‐e387, 2010.
 142. De S , Olson R . Crystal structure of the Vibrio cholerae cytolysin heptamer reveals common features among disparate pore‐forming toxins. Proc Natl Acad Sci USA 108: 7385‐7390, 2011.
 143. Debellis L , Diana A , Arcidiacono D , Fiorotto R , Portincasa P , Altomare DF , Spirli C , de Bernard M . The Vibrio cholerae cytolysin promotes chloride secretion from intact human intestinal mucosa. PLoS One 4: e5074, 2009.
 144. Debyser G , Mesuere B , Clement L , Van de Weygaert J , Van Hecke P , Duytschaever G , Aerts M , Dawyndt P , De Boeck K , Vandamme P , Devreese B . Faecal proteomics: A tool to investigate dysbiosis and inflammation in patients with cystic fibrosis. J Cyst Fibros 15: 242‐250, 2016.
 145. Degirolamo C , Rainaldi S , Bovenga F , Murzilli S , Moschetta A . Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr‐Fgf15 axis in mice. Cell Rep 7: 12‐18, 2014.
 146. Dekkers JF , Wiegerinck CL , de Jonge HR , Bronsveld I , Janssens HM , de Winter‐de Groot KM , Brandsma AM , de Jong NW , Bijvelds MJ , Scholte BJ , Nieuwenhuis EE , van den Brink S , Clevers H , van der Ent CK , Middendorp S , Beekman JM . A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat Med 19: 939‐945, 2013.
 147. Del Castillo IC , Fedor‐Chaiken M , Song JC , Starlinger V , Yoo J , Matlin KS , Matthews JB . Dynamic regulation of Na(+)‐K(+)‐2Cl(‐) cotransporter surface expression by PKC‐{epsilon} in Cl(‐)–secretory epithelia. Am J Physiol Cell Physiol 289: C1332‐C1342, 2005.
 148. Delpire E . The mammalian family of sterile 20p‐like protein kinases. Pflugers Arch 458: 953‐967, 2009.
 149. Delpire E , Gagnon KB . Na(+) ‐K(+) ‐2Cl(‐) cotransporter (NKCC) physiological function in nonpolarized cells and transporting epithelia. Compr Physiol 8: 871‐901, 2018.
 150. Desai GN , Sahi J , Reddy PM , Venkatasubramanian J , Vidyasagar D , Rao MC . Chloride transport in primary cultures of rabbit colonocytes at different stages of development. Gastroenterology 111: 1541‐1550, 1996.
 151. Devkota S , Wang Y , Musch MW , Leone V , Fehlner‐Peach H , Nadimpalli A , Antonopoulos DA , Jabri B , Chang EB . Dietary‐fat‐induced taurocholic acid promotes pathobiont expansion and colitis in Il10‐/‐ mice. Nature 487: 104‐108, 2012.
 152. Dharmsathaphorn K , Huott PA , Vongkovit P , Beuerlein G , Pandol SJ , Ammon HV . Cl‐ secretion induced by bile salts. A study of the mechanism of action based on a cultured colonic epithelial cell line. J Clin Invest 84: 945‐953, 1989.
 153. Di A , Brown ME , Deriy LV , Li C , Szeto FL , Chen Y , Huang P , Tong J , Naren AP , Bindokas V , Palfrey HC , Nelson DJ . CFTR regulates phagosome acidification in macrophages and alters bactericidal activity. Nat Cell Biol 8: 933‐944, 2006.
 154. Di Pierro M , Lu R , Uzzau S , Wang W , Margaretten K , Pazzani C , Maimone F , Fasano A . Zonula occludens toxin structure‐function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain. J Biol Chem 276: 19160‐19165, 2001.
 155. Diamond JM , Bossert WH . Standing‐gradient osmotic flow. A mechanism for coupling of water and solute transport in epithelia. J Gen Physiol 50: 2061‐2083, 1967.
 156. Ding L , Lu Z , Foreman O , Tatum R , Lu Q , Renegar R , Cao J , Chen YH . Inflammation and disruption of the mucosal architecture in claudin‐7‐deficient mice. Gastroenterology 142: 305‐315, 2012.
 157. Dinning PG , Costa M , Brookes SJH . Colonic motor and sensory function and dysfunction. In: Feldman M , Friedman, LS , Brandt LJ , editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia, USA: Elsevier, 2016, pp. 1696‐1712.
 158. Domingue JC , Ao M , Sarathy J , George A , Alrefai WA , Nelson DJ , Rao MC . HEK‐293 cells expressing the cystic fibrosis transmembrane conductance regulator (CFTR): a model for studying regulation of Cl‐ transport. Physiol Rep 2: pii: e12158, 2014.
 159. Domingue JC , Ao M , Sarathy J , Rao MC . Chenodeoxycholic acid requires activation of EGFR, EPAC, and Ca2+ to stimulate CFTR‐dependent Cl‐ secretion in human colonic T84 cells. Am J Physiol Cell Physiol 311: C777‐C792, 2016.
 160. Domingue JC , Rao MC . CFTR and GM1 “gangl‐ing” up to heal thy wound. Focus on “Reduced GM1 ganglioside in CFTR‐deficient human airway cells results in decreased beta1‐integrin signaling and delayed wound repair.” Am J Physiol Cell Physiol 306: C789‐C791, 2014.
 161. Domingue JC , Rao MC . Pyk and ERK your way to the hub by taking a RSK 2. Focus on “Regulation of NHE3 by lysophosphatidic acid is mediated by phosphorylation of NHE3 by RSK2.” Am J Physiol Cell Physiol 309: C11‐C13, 2015.
 162. Donowitz M , Li X . Regulatory binding partners and complexes of NHE3. Physiol Rev 87: 825‐872, 2007.
 163. Donowitz M , Ming Tse C , Fuster D . SLC9/NHE gene family, a plasma membrane and organellar family of Na(+)/H(+) exchangers. Mol Aspects Med 34: 236‐251, 2013.
 164. Donowitz M , Mohan S , Zhu CX , Chen TE , Lin R , Cha B , Zachos NC , Murtazina R , Sarker R , Li X . NHE3 regulatory complexes. J Exp Biol 212: 1638‐1646, 2009.
 165. Dorwart MR , Shcheynikov N , Baker JM , Forman‐Kay JD , Muallem S , Thomas PJ . Congenital chloride‐losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3. J Biol Chem 283: 8711‐8722, 2008.
 166. Duytschaever G , Huys G , Bekaert M , Boulanger L , De Boeck K , Vandamme P . Cross‐sectional and longitudinal comparisons of the predominant fecal microbiota compositions of a group of pediatric patients with cystic fibrosis and their healthy siblings. Appl Environ Microbiol 77: 8015‐8024, 2011.
 167. Duytschaever G , Huys G , Bekaert M , Boulanger L , De Boeck K , Vandamme P . Dysbiosis of bifidobacteria and Clostridium cluster XIVa in the cystic fibrosis fecal microbiota. J Cyst Fibros 12: 206‐215, 2013.
 168. Eherer AJ , Fordtran JS . Fecal osmotic gap and pH in experimental diarrhea of various causes. Gastroenterology 103: 545‐551, 1992.
 169. Engevik MA , Engevik KA , Yacyshyn MB , Wang J , Hassett DJ , Darien B , Yacyshyn BR , Worrell RT . Human Clostridium difficile infection: Inhibition of NHE3 and microbiota profile. Am J Physiol Gastrointest Liver Physiol 308: G497‐G509, 2015.
 170. Engevik MA , Yacyshyn MB , Engevik KA , Wang J , Darien B , Hassett DJ , Yacyshyn BR , Worrell RT . Human Clostridium difficile infection: Altered mucus production and composition. Am J Physiol Gastrointest Liver Physiol 308: G510‐G524, 2015.
 171. Fares MA . The origins of mutational robustness. Trends Genet 31: 373‐381, 2015.
 172. Farinha CM. CFTR and Cystic Fibrosis. Cham, Switzerland: Springer, 2018, p. 56.
 173. Farkas K , Yeruva S , Rakonczay Z, Jr. , Ludolph L , Molnar T , Nagy F , Szepes Z , Schnur A , Wittmann T , Hubricht J , Riederer B , Venglovecz V , Lazar G , Kiraly M , Zsembery A , Varga G , Seidler U , Hegyi P . New therapeutic targets in ulcerative colitis: The importance of ion transporters in the human colon. Inflamm Bowel Dis 17: 884‐898, 2011.
 174. Farthing MJ . Antisecretory drugs for diarrheal disease. Dig Dis 24: 47‐58, 2006.
 175. Fasano A . Zonulin and its regulation of intestinal barrier function: The biological door to inflammation, autoimmunity, and cancer. Physiol Rev 91: 151‐175, 2011.
 176. Field M . Intestinal ion transport and the pathophysiology of diarrhea. J Clin Invest 111: 931‐943, 2003.
 177. Field M , Rao MC , Chang EB . Intestinal electrolyte transport and diarrheal disease (1). N Engl J Med 321: 800‐806, 1989a.
 178. Field M , Rao MC , Chang EB . Intestinal electrolyte transport and diarrheal disease (2). N Engl J Med 321: 879‐883, 1989b.
 179. Fischer Walker CL , Fontaine O , Young MW , Black RE . Zinc and low osmolarity oral rehydration salts for diarrhoea: A renewed call to action. Bull World Health Organ 87: 780‐786, 2009.
 180. Fiskerstrand T , Arshad N , Haukanes BI , Tronstad RR , Pham KD , Johansson S , Havik B , Tonder SL , Levy SE , Brackman D , Boman H , Biswas KH , Apold J , Hovdenak N , Visweswariah SS , Knappskog PM . Familial diarrhea syndrome caused by an activating GUCY2C mutation. N Engl J Med 366: 1586‐1595, 2012.
 181. Flores CA , Cid LP , Sepulveda FV , Niemeyer MI . TMEM16 proteins: The long awaited calcium‐activated chloride channels? Braz J Med Biol Res 42: 993‐1001, 2009.
 182. Foulke‐Abel J , In J , Yin J , Zachos NC , Kovbasnjuk O , Estes MK , de Jonge H , Donowitz M . Human enteroids as a model of upper small intestinal ion transport physiology and pathophysiology. Gastroenterology 150: 638‐649 e638, 2016.
 183. France MM , Turner JR . The mucosal barrier at a glance. J Cell Sci 130: 307‐314, 2017.
 184. Frerichs RR , Keim PS , Barrais R , Piarroux R . Nepalese origin of cholera epidemic in Haiti. Clin Microbiol Infect 18: E158‐E163, 2012.
 185. Frizzell RA , Hanrahan JW . Physiology of epithelial chloride and fluid secretion. Cold Spring Harb Perspect Med 2: a009563, 2012.
 186. Fu Y , Ho BT , Mekalanos JJ . Tracking vibrio cholerae cell‐cell interactions during infection reveals bacterial population dynamics within intestinal microenvironments. Cell Host Microbe 23: 274‐281 e272, 2018.
 187. Fukumatsu M , Ogawa M , Arakawa S , Suzuki M , Nakayama K , Shimizu S , Kim M , Mimuro H , Sasakawa C . Shigella targets epithelial tricellular junctions and uses a noncanonical clathrin‐dependent endocytic pathway to spread between cells. Cell Host Microbe 11: 325‐336, 2012.
 188. Fukumatsu M , Ogawa M , Kim M , Mimuro H , Sasakawa C . Uptake of Shigella‐containing pseudopodia by neighboring epithelial cells at tricellular junctions via non‐canonical clathrin‐dependent trafficking pathway. Virulence 3: 515‐518, 2012.
 189. Furness JB . The enteric nervous system and neurogastroenterology. Nat Rev Gastroenterol Hepatol 9: 286‐294, 2012.
 190. Gabriel SE , Brigman KN , Koller BH , Boucher RC , Stutts MJ . Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 266: 107‐109, 1994.
 191. Gagnon KB , Delpire E . Molecular physiology of SPAK and OSR1: Two Ste20‐related protein kinases regulating ion transport. Physiol Rev 92: 1577‐1617, 2012.
 192. Gagnon KB , England R , Delpire E . Volume sensitivity of cation‐Cl‐ cotransporters is modulated by the interaction of two kinases: Ste20‐related proline‐alanine‐rich kinase and WNK4. Am J Physiol Cell Physiol 290: C134‐C142, 2006.
 193. Garcia MA , Yang N , Quinton PM . Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator‐dependent bicarbonate secretion. J Clin Invest 119: 2613‐2622, 2009.
 194. Garcia‐Castillo MD , Chinnapen DJ , Lencer WI . Membrane transport across polarized epithelia. Cold Spring Harb Perspect Biol 9: pii: a027912, 2017.
 195. Gareau MG , Barrett KE . Fluid and electrolyte secretion in the inflamed gut: Novel targets for treatment of inflammation‐induced diarrhea. Curr Opin Pharmacol 13: 895‐899, 2013.
 196. Garin‐Laflam MP , Steinbrecher KA , Rudolph JA , Mao J , Cohen MB . Activation of guanylate cyclase C signaling pathway protects intestinal epithelial cells from acute radiation‐induced apoptosis. Am J Physiol Gastrointest Liver Physiol 296: G740‐G749, 2009.
 197. Ge Y , Mansell A , Ussher JE , Brooks AE , Manning K , Wang CJ , Taylor JA . Rotavirus NSP4 triggers secretion of proinflammatory cytokines from macrophages via toll‐like receptor 2. J Virol 87: 11160‐11167, 2013.
 198. Gelbmann CM , Schteingart CD , Thompson SM , Hofmann AF , Barrett KE . Mast cells and histamine contribute to bile acid‐stimulated secretion in the mouse colon. J Clin Invest 95: 2831‐2839, 1995.
 199. Gelfond D , Ma C , Semler J , Borowitz D . Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci 58: 2275‐2281, 2013.
 200. Gennari FJ , Weise WJ . Acid‐base disturbances in gastrointestinal disease. Clin J Am Soc Nephrol 3: 1861‐1868, 2008.
 201. Gershon MD . 5‐HT4‐mediated neuroprotection: A new therapeutic modality on the way? Am J Physiol Gastrointest Liver Physiol 310: G766‐G767, 2016.
 202. Gershon MD , Tack J . The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology 132: 397‐414, 2007.
 203. Ghishan FK , Kiela PR . Epithelial transport in inflammatory bowel diseases. Inflamm Bowel Dis 20: 1099‐1109, 2014.
 204. Ghosh S , Dai C , Brown K , Rajendiran E , Makarenko S , Baker J , Ma C , Halder S , Montero M , Ionescu VA , Klegeris A , Vallance BA , Gibson DL . Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression. Am J Physiol Gastrointest Liver Physiol 301: G39‐G49, 2011.
 205. Gill R , Borthakur WA , Dudeja PK. Intestinal anion absorption. In: Johnson LR , editor. Physiology of the Gastrointestinal Tract. London, UK: Academic Press, 2012, pp. 1819‐1848.
 206. Gill R , Hecht GA. Host‐pathogen interactions in pathophysiology of diarrheal disorders. In: Said HM , editor. Physiology of the Gastrointestinal Tract. London, UK: Academic Press (Elsevier), 2018, pp. 1547‐1577.
 207. Gill RK , Anbazhagan AN , Esmaili A , Kumar A , Nazir S , Malakooti J , Alrefai WA , Saksena S . Epidermal growth factor upregulates serotonin transporter in human intestinal epithelial cells via transcriptional mechanisms. Am J Physiol Gastrointest Liver Physiol 300: G627‐G636, 2011.
 208. Gill RK , Borthakur A , Hodges K , Turner JR , Clayburgh DR , Saksena S , Zaheer A , Ramaswamy K , Hecht G , Dudeja PK . Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli. J Clin Invest 117: 428‐437, 2007.
 209. Gill RK , Saksena S , Alrefai WA , Sarwar Z , Goldstein JL , Carroll RE , Ramaswamy K , Dudeja PK . Expression and membrane localization of MCT isoforms along the length of the human intestine. Am J Physiol Cell Physiol 289: C846‐C852, 2005.
 210. Gill RK , Saksena S , Tyagi S , Alrefai WA , Malakooti J , Sarwar Z , Turner JR , Ramaswamy K , Dudeja PK . Serotonin inhibits Na+/H+ exchange activity via 5‐HT4 receptors and activation of PKC alpha in human intestinal epithelial cells. Gastroenterology 128: 962‐974, 2005.
 211. Gillen AE , Gosalia N , Leir SH , Harris A . MicroRNA regulation of expression of the cystic fibrosis transmembrane conductance regulator gene. Biochem J 438: 25‐32, 2011.
 212. Gillen AE , Harris A . Transcriptional regulation of CFTR gene expression. Front Biosci (Elite Ed) 4: 587‐592, 2012.
 213. Goldstein JL , Nash NT , al‐Bazzaz F , Layden TJ , Rao MC . Rectum has abnormal ion transport but normal cAMP‐binding proteins in cystic fibrosis. Am J Physiol 254: C719‐C724, 1988.
 214. Goldstein JL , Sahi J , Bhuva M , Layden TJ , Rao MC . Escherichia coli heat‐stable enterotoxin‐mediated colonic Cl‐ secretion is absent in cystic fibrosis. Gastroenterology 107: 950‐956, 1994.
 215. Goldstein JL , Shapiro AB , Rao MC , Layden TJ . In vivo evidence of altered chloride but not potassium secretion in cystic fibrosis rectal mucosa. Gastroenterology 101: 1012‐1019, 1991.
 216. Gosalia N , Harris A . Chromatin dynamics in the regulation of CFTR expression. Genes (Basel) 6: 543‐558, 2015.
 217. Goulet O , Kedinger M , Brousse N , Cuenod B , Colomb V , Patey N , de Potter S , Mougenot JF , Canioni D , Cerf‐Bensussan N , Ricour C . Intractable diarrhea of infancy with epithelial and basement membrane abnormalities. J Pediatr 127: 212‐219, 1995.
 218. Greig ER , Boot‐Handford RP , Mani V , Sandle GI . Decreased expression of apical Na+ channels and basolateral Na+, K+‐ATPase in ulcerative colitis. J Pathol 204: 84‐92, 2004.
 219. Groneberg D , Voussen B , Friebe A . Integrative control of gastrointestinal motility by nitric oxide. Curr Med Chem 23: 2715‐2735, 2016.
 220. Grubb BR , Gabriel SE . Intestinal physiology and pathology in gene‐targeted mouse models of cystic fibrosis. Am J Physiol 273: G258‐G266, 1997.
 221. Grubb BR , Lee E , Pace AJ , Koller BH , Boucher RC . Intestinal ion transport in NKCC1‐deficient mice. Am J Physiol Gastrointest Liver Physiol 279: G707‐G718, 2000.
 222. Guandalini S , Assiri A . Celiac disease: A review. JAMA Pediatr 168: 272‐278, 2014.
 223. Guandalini S , Jericho H . Celiac disease and gluten‐related disorders. Adolesc Med State Art Rev 25: 409‐424, 2014.
 224. Guarino A , Guandalini S , Lo Vecchio A . Probiotics for prevention and treatment of diarrhea. J Clin Gastroenterol 49(Suppl 1): S37‐S45, 2015.
 225. Guilbault C , Saeed Z , Downey GP , Radzioch D . Cystic fibrosis mouse models. Am J Respir Cell Mol Biol 36: 1‐7, 2007.
 226. Gujral T , Kumar A , Priyamvada S , Saksena S , Gill RK , Hodges K , Alrefai WA , Hecht GA , Dudeja PK . Mechanisms of DRA recycling in intestinal epithelial cells: Effect of enteropathogenic E. coli. Am J Physiol Cell Physiol 309: C835‐C846, 2015.
 227. Gurney MA , Laubitz D , Ghishan FK , Kiela PR . Pathophysiology of Intestinal Na(+)/H(+) exchange. Cell Mol Gastroenterol Hepatol 3: 27‐40, 2017.
 228. Gustafsson JK , Ermund A , Johansson ME , Schutte A , Hansson GC , Sjovall H . An ex vivo method for studying mucus formation, properties, and thickness in human colonic biopsies and mouse small and large intestinal explants. Am J Physiol Gastrointest Liver Physiol 302: G430‐G438, 2012.
 229. Gutierrez A , Scharl M , Sempere L , Holler E , Zapater P , Almenta I , Gonzalez‐Navajas JM , Such J , Wiest R , Rogler G , Frances R . Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease. Gut 63: 272‐280, 2014.
 230. Gutierrez MG , Saka HA , Chinen I , Zoppino FC , Yoshimori T , Bocco JL , Colombo MI . Protective role of autophagy against Vibrio cholerae cytolysin, a pore‐forming toxin from V. cholerae. Proc Natl Acad Sci USA 104: 1829‐1834, 2007.
 231. Gyomorey K , Rozmahel R , Bear CE . Amelioration of intestinal disease severity in cystic fibrosis mice is associated with improved chloride secretory capacity. Pediatr Res 48: 731‐734, 2000.
 232. Haas M , Forbush B, III . The Na‐K‐Cl cotransporter of secretory epithelia. Annu Rev Physiol 62: 515‐534, 2000.
 233. Hadj‐Rabia S , Baala L , Vabres P , Hamel‐Teillac D , Jacquemin E , Fabre M , Lyonnet S , De Prost Y , Munnich A , Hadchouel M , Smahi A . Claudin‐1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: A tight junction disease. Gastroenterology 127: 1386‐1390, 2004.
 234. Hadjiliadis D , Khoruts A , Zauber AG , Hempstead SE , Maisonneuve P , Lowenfels AB , Cystic Fibrosis Colorectal Cancer Screening Task F. Cystic fibrosis colorectal cancer screening consensus recommendations. Gastroenterology 154: 736‐745 e714, 2018.
 235. Haila S , Saarialho‐Kere U , Karjalainen‐Lindsberg ML , Lohi H , Airola K , Holmberg C , Hastbacka J , Kere J , Hoglund P . The congenital chloride diarrhea gene is expressed in seminal vesicle, sweat gland, inflammatory colon epithelium, and in some dysplastic colon cells. Histochem Cell Biol 113: 279‐286, 2000.
 236. Halestrap AP . The monocarboxylate transporter family–Structure and functional characterization. IUBMB Life 64: 1‐9, 2012.
 237. Halestrap AP , Meredith D . The SLC16 gene family‐from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447: 619‐628, 2004.
 238. Halm DR . Physiologic influences of transepithelial K+ secretion. In: Hamilton KL , Devor DC , editors. Ion Channels and Transporters of Epithelia in Health and Disease: Physiology in Health and Disease. New York: American Physiological Society, Springer, 2016, pp. 95‐130.
 239. Halm ST , Zhang J , Halm DR . beta‐Adrenergic activation of electrogenic K+ and Cl‐ secretion in guinea pig distal colonic epithelium proceeds via separate cAMP signaling pathways. Am J Physiol Gastrointest Liver Physiol 299: G81‐G95, 2010.
 240. Halpern MD , Dvorak B . Does abnormal bile acid metabolism contribute to NEC? Semin Perinatol 32: 114‐121, 2008.
 241. Han X , Mann E , Gilbert S , Guan Y , Steinbrecher KA , Montrose MH , Cohen MB . Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PLoS One 6: e16139, 2011.
 242. Hannig G , Tchernychev B , Kurtz CB , Bryant AP , Currie MG , Silos‐Santiago I . Guanylate cyclase‐C/cGMP: An emerging pathway in the regulation of visceral pain. Front Mol Neurosci 7: 31, 2014.
 243. Hansen MB , Witte AB . The role of serotonin in intestinal luminal sensing and secretion. Acta Physiol (Oxf) 193: 311‐323, 2008.
 244. Harig JM , Ng EK , Dudeja PK , Brasitus TA , Ramaswamy K . Transport of n‐butyrate into human colonic luminal membrane vesicles. Am J Physiol 271: G415‐G422, 1996.
 245. Harrell JE , Cheng SX . Inability to reduce morbidity of diarrhea by ORS: Can we design a better therapy? Pediatr Res 83: 559‐563, 2017.
 246. Harris JB , LaRocque RC , Qadri F , Ryan ET , Calderwood SB . Cholera. Lancet 379: 2466‐2476, 2012.
 247. Harris KG , Chang EB . The intestinal microbiota in the pathogenesis of inflammatory bowel diseases: New insights into complex disease. Clin Sci (Lond) 132: 2013‐2028, 2018.
 248. Harris WT , Kirk KL . CFTR and cystic fibrosis. In: Hamilton KL , Devor, DC , editors. Ion Channels and Transporters of Epithelia in Health and Disease, Physiology in Health and Disease. New York: American Physiological Society, Springer, 2016.
 249. Harvey BJ , Alzamora R , Stubbs AK , Irnaten M , McEneaney V , Thomas W . Rapid responses to aldosterone in the kidney and colon. J Steroid Biochem Mol Biol 108: 310‐317, 2008.
 250. Hata T , Asano Y , Yoshihara K , Kimura‐Todani T , Miyata N , Zhang XT , Takakura S , Aiba Y , Koga Y , Sudo N . Regulation of gut luminal serotonin by commensal microbiota in mice. PLoS One 12: e0180745, 2017.
 251. Hatch M , Freel RW . The roles and mechanisms of intestinal oxalate transport in oxalate homeostasis. Semin Nephrol 28: 143‐151, 2008.
 252. Hayashi H , Szaszi K , Coady‐Osberg N , Furuya W , Bretscher AP , Orlowski J , Grinstein S . Inhibition and redistribution of NHE3, the apical Na+/H+ exchanger, by Clostridium difficile toxin B. J Gen Physiol 123: 491‐504, 2004.
 253. Hayashi H , Yamashita Y . Role of N‐glycosylation in cell surface expression and protection against proteolysis of the intestinal anion exchanger SLC26A3. Am J Physiol Cell Physiol 302: C781‐C795, 2012.
 254. He P , Lee SJ , Lin S , Seidler U , Lang F , Fejes‐Toth G , Naray‐Fejes‐Toth A , Yun CC . Serum‐ and glucocorticoid‐induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids. Mol Biol Cell 22: 3812‐3825, 2011.
 255. Heinz‐Erian P , Muller T , Krabichler B , Schranz M , Becker C , Ruschendorf F , Nurnberg P , Rossier B , Vujic M , Booth IW , Holmberg C , Wijmenga C , Grigelioniene G , Kneepkens CM , Rosipal S , Mistrik M , Kappler M , Michaud L , Doczy LC , Siu VM , Krantz M , Zoller H , Utermann G , Janecke AR . Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea. Am J Hum Genet 84: 188‐196, 2009.
 256. Heitzmann D , Warth R . Physiology and pathophysiology of potassium channels in gastrointestinal epithelia. Physiol Rev 88: 1119‐1182, 2008.
 257. Helander HF , Fandriks L . Surface area of the digestive tract ‐ revisited. Scand J Gastroenterol 49: 681‐689, 2014.
 258. Helenius TO , Misiorek JO , Nystrom JH , Fortelius LE , Habtezion A , Liao J , Asghar MN , Zhang H , Azhar S , Omary MB , Toivola DM . Keratin 8 absence down‐regulates colonocyte HMGCS2 and modulates colonic ketogenesis and energy metabolism. Mol Biol Cell 26: 2298‐2310, 2015.
 259. Hempson SJ , Matkowskyj K , Bansal A , Tsao E , Habib I , Benya R , Mackow ER , Shaw RD . Rotavirus infection of murine small intestine causes colonic secretion via age restricted galanin‐1 receptor expression. Gastroenterology 138: 2410‐2417, 2010.
 260. Higashi T , Tokuda S , Kitajiri S , Masuda S , Nakamura H , Oda Y , Furuse M . Analysis of the ‘angulin’ proteins LSR, ILDR1 and ILDR2–tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis. J Cell Sci 126: 966‐977, 2013.
 261. Hiribarren A , Heyman M , L'Helgouac'h A , Desjeux JF . Effect of cytokines on the epithelial function of the human colon carcinoma cell line HT29 cl 19A. Gut 34: 616‐620, 1993.
 262. Hirschhorn N , Kinzie JL , Sachar DB , Northrup RS , Taylor JO , Ahmad SZ , Phillips RA . Decrease in net stool output in cholera during intestinal perfusion with glucose‐containing solutions. N Engl J Med 279: 176‐181, 1968.
 263. Hodges K , Gill R . Infectious diarrhea: Cellular and molecular mechanisms. Gut Microbes 1: 4‐21, 2010.
 264. Hodges K , Gill R , Ramaswamy K , Dudeja PK , Hecht G . Rapid activation of Na+/H+ exchange by EPEC is PKC mediated. Am J Physiol Gastrointest Liver Physiol 291: G959‐G968, 2006.
 265. Hofmann AF . Bile acids: Trying to understand their chemistry and biology with the hope of helping patients. Hepatology 49: 1403‐1418, 2009.
 266. Hogan DL , Rapier RC , Dreilinger A , Koss MA , Basuk PM , Weinstein WM , Nyberg LM , Isenberg JI . Duodenal bicarbonate secretion: Eradication of Helicobacter pylori and duodenal structure and function in humans. Gastroenterology 110: 705‐716, 1996.
 267. Hogenauer C , Santa Ana CA , Porter JL , Millard M , Gelfand A , Rosenblatt RL , Prestidge CB , Fordtran JS . Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: An evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion. Am J Hum Genet 67: 1422‐1427, 2000.
 268. Hoglund P , Haila S , Scherer SW , Tsui LC , Green ED , Weissenbach J , Holmberg C , de la Chapelle A , Kere J . Positional candidate genes for congenital chloride diarrhea suggested by high‐resolution physical mapping in chromosome region 7q31. Genome Res 6: 202‐210, 1996.
 269. Hoglund P , Haila S , Socha J , Tomaszewski L , Saarialho‐Kere U , Karjalainen‐Lindsberg ML , Airola K , Holmberg C , de la Chapelle A , Kere J . Mutations of the Down‐regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet 14: 316‐319, 1996.
 270. Hollister EB , Gao C , Versalovic J . Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology 146: 1449‐1458, 2014.
 271. Holzer P . Opioid receptors in the gastrointestinal tract. Regul Pept 155: 11‐17, 2009.
 272. Hoque KM , Binder HJ . Zinc in the treatment of acute diarrhea: Current status and assessment. Gastroenterology 130: 2201‐2205, 2006.
 273. Hoque KM , Rajendran VM , Binder HJ . Zinc inhibits cAMP‐stimulated Cl secretion via basolateral K‐channel blockade in rat ileum. Am J Physiol Gastrointest Liver Physiol 288: G956‐G963, 2005.
 274. Hoque KM , Sarkar P , Ali I , Chakraborty S . Zinc recovers altered intestinal ion‐transport and barrier function by Shigella infection in T84 cells. FASEB J 28(1) 2014.
 275. Hoque KM , Sarker R , Guggino SE , Tse CM . A new insight into pathophysiological mechanisms of zinc in diarrhea. Ann N Y Acad Sci 1165: 279‐284, 2009.
 276. Horisberger JD , Chraibi A . Epithelial sodium channel: A ligand‐gated channel? Nephron Physiol 96: p37‐p41, 2004.
 277. Hu S , Wang Y , Lichtenstein L , Tao Y , Musch MW , Jabri B , Antonopoulos D , Claud EC , Chang EB . Regional differences in colonic mucosa‐associated microbiota determine the physiological expression of host heat shock proteins. Am J Physiol Gastrointest Liver Physiol 299: G1266‐G1275, 2010.
 278. Hwang SJ , Blair PJ , Britton FC , O'Driscoll KE , Hennig G , Bayguinov YR , Rock JR , Harfe BD , Sanders KM , Ward SM . Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles. J Physiol 587: 4887‐4904, 2009.
 279. Ikarashi N , Kon R , Sugiyama K . Aquaporins in the colon as a new therapeutic target in diarrhea and constipation. Int J Mol Sci 17: 1172, 2016.
 280. Ikenouchi J , Furuse M , Furuse K , Sasaki H , Tsukita S , Tsukita S . Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171: 939‐945, 2005.
 281. Ikpa PT , Bijvelds MJ , de Jonge HR . Cystic fibrosis: Toward personalized therapies. Int J Biochem Cell Biol 52: 192‐200, 2014.
 282. Inagaki T , Moschetta A , Lee YK , Peng L , Zhao G , Downes M , Yu RT , Shelton JM , Richardson JA , Repa JJ , Mangelsdorf DJ , Kliewer SA . Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 103: 3920‐3925, 2006.
 283. Ingber DE . Reverse engineering human pathophysiology with organs‐on‐chips. Cell 164: 1105‐1109, 2016.
 284. Isenring P , Jacoby SC , Chang J , Forbush B . Mutagenic mapping of the Na‐K‐Cl cotransporter for domains involved in ion transport and bumetanide binding. J Gen Physiol 112: 549‐558, 1998.
 285. Islam RS , DiBaise JK . Bile Acids: An Underrecognized and underappreciated cause of chronic diarrhea. Practical Gastroneterology 110: 32‐44, 2012.
 286. Itokazu Y , Pagano RE , Schroeder AS , O'Grady SM , Limper AH , Marks DL . Reduced GM1 ganglioside in CFTR‐deficient human airway cells results in decreased beta1‐integrin signaling and delayed wound repair. Am J Physiol Cell Physiol 306: C819‐C830, 2014.
 287. Iwanaga T , Takebe K , Kato I , Karaki S , Kuwahara A . Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8. Biomed Res 27: 243‐254, 2006.
 288. Jabri B , Sollid LM . T cells in celiac disease. J Immunol 198: 3005‐3014, 2017.
 289. Jacob P , Rossmann H , Lamprecht G , Kretz A , Neff C , Lin‐Wu E , Gregor M , Groneberg DA , Kere J , Seidler U . Down‐regulated in adenoma mediates apical Cl‐/HCO3‐ exchange in rabbit, rat, and human duodenum. Gastroenterology 122: 709‐724, 2002.
 290. Jakab RL , Collaco AM , Ameen NA . Physiological relevance of cell‐specific distribution patterns of CFTR, NKCC1, NBCe1, and NHE3 along the crypt‐villus axis in the intestine. Am J Physiol Gastrointest Liver Physiol 300: G82‐G98, 2011.
 291. Jakab RL , Collaco AM , Ameen NA . Lubiprostone targets prostanoid signaling and promotes ion transporter trafficking, mucus exocytosis, and contractility. Dig Dis Sci 57: 2826‐2845, 2012.
 292. Jakab RL , Collaco AM , Ameen NA . Characterization of CFTR high expresser cells in the intestine. Am J Physiol Gastrointest Liver Physiol 305: G453‐G465, 2013.
 293. Janecke AR , Heinz‐Erian P , Muller T . Congenital sodium diarrhea: A form of intractable diarrhea, with a link to inflammatory bowel disease. J Pediatr Gastroenterol Nutr 63: 170‐176, 2016.
 294. Janecke AR , Heinz‐Erian P , Muller T . Reduced NHE3 activity results in congenital diarrhea and can predispose to inflammatory bowel disease. Am J Physiol Regul Integr Comp Physiol 312: R311, 2017.
 295. Janecke AR , Heinz‐Erian P , Yin J , Petersen BS , Franke A , Lechner S , Fuchs I , Melancon S , Uhlig HH , Travis S , Marinier E , Perisic V , Ristic N , Gerner P , Booth IW , Wedenoja S , Baumgartner N , Vodopiutz J , Frechette‐Duval MC , De Lafollie J , Persad R , Warner N , Tse CM , Sud K , Zachos NC , Sarker R , Zhu X , Muise AM , Zimmer KP , Witt H , Zoller H , Donowitz M , Muller T . Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Hum Mol Genet 24: 6614‐6623, 2015.
 296. Jericho H , Assiri A , Guandalini S . Celiac disease and wheat intolerance syndrome: A critical update and reappraisal. J Pediatr Gastroenterol Nutr 64: 15‐21, 2017.
 297. Jiang Z , Asplin JR , Evan AP , Rajendran VM , Velazquez H , Nottoli TP , Binder HJ , Aronson PS . Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet 38: 474‐478, 2006.
 298. Johansson ME , Gustafsson JK , Holmen‐Larsson J , Jabbar KS , Xia L , Xu H , Ghishan FK , Carvalho FA , Gewirtz AT , Sjovall H , Hansson GC . Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63: 281‐291, 2014.
 299. Johansson ME , Hansson GC . Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol 16: 639‐649, 2016.
 300. Julio‐Kalajzic F , Villanueva S , Burgos J , Ojeda M , Cid LP , Jentsch TJ , Sepulveda FV . K2P TASK‐2 and KCNQ1‐KCNE3 K(+) channels are major players contributing to intestinal anion and fluid secretion. J Physiol 596: 393‐407, 2017.
 301. Kakizaki F , Aoki K , Miyoshi H , Carrasco N , Aoki M , Taketo MM . CDX transcription factors positively regulate expression of solute carrier family 5, member 8 in the colonic epithelium. Gastroenterology 138: 627‐635, 2010.
 302. Kalin N , Claass A , Sommer M , Puchelle E , Tummler B . DeltaF508 CFTR protein expression in tissues from patients with cystic fibrosis. J Clin Invest 103: 1379‐1389, 1999.
 303. Kamada N , Nunez G . Regulation of the immune system by the resident intestinal bacteria. Gastroenterology 146: 1477‐1488, 2014.
 304. Kammermeier J , Drury S , James CT , Dziubak R , Ocaka L , Elawad M , Beales P , Lench N , Uhlig HH , Bacchelli C , Shah N . Targeted gene panel sequencing in children with very early onset inflammatory bowel disease–evaluation and prospective analysis. J Med Genet 51: 748‐755, 2014.
 305. Kanchanapoo J , Ao M , Prasad R , Moore C , Kay C , Piyachaturawat P , Rao MC . Role of protein kinase C‐delta in the age‐dependent secretagogue action of bile acids in mammalian colon. Am J Physiol Cell Physiol 293: C1851‐C1861, 2007.
 306. Kanthesh BM , Sandle GI , Rajendran VM . Enhanced K(+) secretion in dextran sulfate‐induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1). Am J Physiol Cell Physiol 305: C972‐C980, 2013.
 307. Kashlan OB , Kleyman TR . Epithelial Na(+) channel regulation by cytoplasmic and extracellular factors. Exp Cell Res 318: 1011‐1019, 2012.
 308. Kashyap PC , Marcobal A , Ursell LK , Larauche M , Duboc H , Earle KA , Sonnenburg ED , Ferreyra JA , Higginbottom SK , Million M , Tache Y , Pasricha PJ , Knight R , Farrugia G , Sonnenburg JL . Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice. Gastroenterology 144: 967‐977, 2013.
 309. Keating N , Mroz MS , Scharl MM , Marsh C , Ferguson G , Hofmann AF , Keely SJ . Physiological concentrations of bile acids down‐regulate agonist induced secretion in colonic epithelial cells. J Cell Mol Med 13: 2293‐2303, 2009.
 310. Keely SJ , Scharl MM , Bertelsen LS , Hagey LR , Barrett KE , Hofmann AF . Bile acid‐induced secretion in polarized monolayers of T84 colonic epithelial cells: Structure‐activity relationships. Am J Physiol Gastrointest Liver Physiol 292: G290‐G297, 2007.
 311. Kelly CP . Celiac disease. In: Feldman M , Friedman LS , Brandt LJ , editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia, USA: Elsevier, 2016, pp. 1849‐1872.
 312. Kelly OB , Mroz MS , Ward JB , Colliva C , Scharl M , Pellicciari R , Gilmer JF , Fallon PG , Hofmann AF , Roda A , Murray FE , Keely SJ . Ursodeoxycholic acid attenuates colonic epithelial secretory function. J Physiol 591: 2307‐2318, 2013.
 313. Khaleghi S , Ju JM , Lamba A , Murray JA . The potential utility of tight junction regulation in celiac disease: Focus on larazotide acetate. Therap Adv Gastroenterol 9: 37‐49, 2016.
 314. Khor B , Gardet A , Xavier RJ . Genetics and pathogenesis of inflammatory bowel disease. Nature 474: 307‐317, 2011.
 315. Kiela PR , Collins JF , Ghishan FK . Molecular mechanisms of intestinal transport of calcium, phosphate and magnesium. In: Johnson LR , editor. Physiology of the Gastrointestinal Tract. London, UK: Academic Press, 2012, pp. 1877‐1920.
 316. King SK , Sutcliffe JR , Ong SY , Lee M , Koh TL , Wong SQ , Farmer PJ , Peck CJ , Stanton MP , Keck J , Cook DJ , Chow CW , Hutson JM , Southwell BR . Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow‐transit constipation. Neurogastroenterol Motil 22: 883‐892, e234, 2010.
 317. Klinge CM . Steroid Hormone Receptors and Signal Transduction Processes. In: Belfiore A , LeRoith D , editor. Principles of Endocrinology and Hormone Action. Endocrinology. Cham, Switzerland: Springer, 2018.
 318. Knauf F , Thomson RB , Heneghan JF , Jiang Z , Adebamiro A , Thomson CL , Barone C , Asplin JR , Egan ME , Alper SL , Aronson PS . Loss of cystic fibrosis transmembrane regulator impairs intestinal oxalate secretion. J Am Soc Nephrol 28: 242‐249, 2017.
 319. Knowles CH , Farrugia G . Gastrointestinal neuromuscular pathology in chronic constipation. Best Pract Res Clin Gastroenterol 25: 43‐57, 2011.
 320. Ko SB , Zeng W , Dorwart MR , Luo X , Kim KH , Millen L , Goto H , Naruse S , Soyombo A , Thomas PJ , Muallem S . Gating of CFTR by the STAS domain of SLC26 transporters. Nat Cell Biol 6: 343‐350, 2004.
 321. Kocinsky HS , Girardi ACC , Biemesderfer D , Nguyen T , Mentone S , Orlowski J , Aronson PS . Use of phospho‐specific antibodies to determine the phosphorylation of endogenous Na+/H+ exchanger NHE3 at PKA consensus sites. Am J Physiol Renal Physiol 289: F249‐F258, 2005.
 322. Koeppen BM , Stanton BS , editors. Berne and Levy Physiology. Philadelphia, USA: Elsevier, 2018, p. 880.
 323. Koestler BJ , Waters CM . Intestinal GPS: Bile and bicarbonate control cyclic di‐GMP to provide Vibrio cholerae spatial cues within the small intestine. Gut Microbes 5: 775‐780, 2014.
 324. Kostic AD , Xavier RJ , Gevers D . The microbiome in inflammatory bowel disease: Current status and the future ahead. Gastroenterology 146: 1489‐1499, 2014.
 325. Kraidith K , Svasti S , Teerapornpuntakit J , Vadolas J , Chaimana R , Lapmanee S , Suntornsaratoon P , Krishnamra N , Fucharoen S , Charoenphandhu N . Hepcidin and 1,25(OH)2D3 effectively restore Ca2+ transport in beta‐thalassemic mice: Reciprocal phenomenon of Fe2+ and Ca2+ absorption. Am J Physiol Endocrinol Metab 311: E214‐E223, 2016.
 326. Kravtsov D , Mashukova A , Forteza R , Rodriguez MM , Ameen NA , Salas PJ . Myosin 5b loss of function leads to defects in polarized signaling: Implication for microvillus inclusion disease pathogenesis and treatment. Am J Physiol Gastrointest Liver Physiol 307: G992‐G1001, 2014.
 327. Kravtsov DV , Ahsan MK , Kumari V , van Ijzendoorn SC , Reyes‐Mugica M , Kumar A , Gujral T , Dudeja PK , Ameen NA . Identification of intestinal ion transport defects in microvillus inclusion disease. Am J Physiol Gastrointest Liver Physiol 311: G142‐G155, 2016.
 328. Kravtsov DV , Ameen NA . Molecular motors and apical CFTR traffic in epithelia. Int J Mol Sci 14: 9628‐9642, 2013.
 329. Kreda SM , Davis CW , Rose MC . CFTR, mucins, and mucus obstruction in cystic fibrosis. Cold Spring Harb Perspect Med 2: a009589, 2012.
 330. Kretzschmar K , Clevers H . Wnt/beta‐catenin signaling in adult mammalian epithelial stem cells. Dev Biol 428: 273‐282, 2017.
 331. Kumar A , Anbazhagan AN , Coffing H , Chatterjee I , Priyamvada S , Gujral T , Saksena S , Gill RK , Alrefai WA , Borthakur A , Dudeja PK . Lactobacillus acidophilus counteracts inhibition of NHE3 and DRA expression and alleviates diarrheal phenotype in mice infected with Citrobacter rodentium. Am J Physiol Gastrointest Liver Physiol 311: G817‐G826, 2016.
 332. Kumar A , Chatterjee I , Gujral T , Alakkam A , Coffing H , Anbazhagan AN , Borthakur A , Saksena S , Gill RK , Alrefai WA , Dudeja PK . Activation of nuclear factor‐kappaB by tumor necrosis factor in intestinal epithelial cells and mouse intestinal epithelia reduces expression of the chloride transporter SLC26A3. Gastroenterology 153: 1338‐1350 e1333, 2017.
 333. Kumar A , Priyamvada S , Chatterjee I , Anbazhagan AN , Singhal M , Borthakur A , Saksena S , Gill R , Alrefai W , Dudeja PK . Dexamethasone upregulates human SLC26A3 transporter expression in intestinal epithelial cells. FASEB J 30: 1023, 2016.
 334. Kumari V , Desai S , Ameen NA . AP2 alpha modulates cystic fibrosis transmembrane conductance regulator function in the human intestine. J Cyst Fibros 16: 327‐334, 2017.
 335. Laforenza U . Water channel proteins in the gastrointestinal tract. Mol Aspects Med 33: 642‐650, 2012.
 336. Lamprecht G , Gaco V , Turner JR , Natour D , Gregor M . Regulation of the intestinal anion exchanger DRA (downregulated in adenoma). Ann N Y Acad Sci 1165: 261‐266, 2009.
 337. Lamprecht G , Heil A , Baisch S , Lin‐Wu E , Yun CC , Kalbacher H , Gregor M , Seidler U . The down regulated in adenoma (dra) gene product binds to the second PDZ domain of the NHE3 kinase A regulatory protein (E3KARP), potentially linking intestinal Cl‐/HCO3‐ exchange to Na+/H+ exchange. Biochemistry 41: 12336‐12342, 2002.
 338. LaRock DL , Chaudhary A , Miller SI . Salmonellae interactions with host processes. Nat Rev Microbiol 13: 191‐205, 2015.
 339. Laubitz D , Larmonier CB , Bai A , Midura‐Kiela MT , Lipko MA , Thurston RD , Kiela PR , Ghishan FK . Colonic gene expression profile in NHE3‐deficient mice: Evidence for spontaneous distal colitis. Am J Physiol Gastrointest Liver Physiol 295: G63‐G77, 2008.
 340. Lawrence SP , Bright NA , Luzio JP , Bowers K . The sodium/proton exchanger NHE8 regulates late endosomal morphology and function. Mol Biol Cell 21: 3540‐3551, 2010.
 341. Lee JH , Nam JH , Park J , Kang DW , Kim JY , Lee MG , Yoon JS . Regulation of SLC26A3 activity by NHERF4 PDZ‐mediated interaction. Cell Signal 24: 1821‐1830, 2012.
 342. Lee JS , Lee YM , Kim JY , Park HW , Grinstein S , Orlowski J , Kim E , Kim KH , Lee MG . BetaPix up‐regulates Na+/H+ exchanger 3 through a Shank2‐mediated protein‐protein interaction. J Biol Chem 285: 8104‐8113, 2010.
 343. Leone V , Gibbons SM , Martinez K , Hutchison AL , Huang EY , Cham CM , Pierre JF , Heneghan AF , Nadimpalli A , Hubert N , Zale E , Wang Y , Huang Y , Theriault B , Dinner AR , Musch MW , Kudsk KA , Prendergast BJ , Gilbert JA , Chang EB . Effects of diurnal variation of gut microbes and high‐fat feeding on host circadian clock function and metabolism. Cell Host Microbe 17: 681‐689, 2015.
 344. Levens NR . Control of intestinal absorption by the renin‐angiotensin system. Am J Physiol 249: G3‐G15, 1985.
 345. Levy EI , Lemmens R , Vandenplas Y , Devreker T . Functional constipation in children: Challenges and solutions. Pediatric Health Med Ther 8: 19‐27, 2017.
 346. Li C , Naren AP . CFTR chloride channel in the apical compartments: Spatiotemporal coupling to its interacting partners. Integr Biol (Camb) 2: 161‐177, 2010.
 347. Li J , Xia F , Reithmeier RA . N‐glycosylation and topology of the human SLC26 family of anion transport membrane proteins. Am J Physiol Cell Physiol 306: C943‐C960, 2014.
 348. Li P , Lin JE , Chervoneva I , Schulz S , Waldman SA , Pitari GM . Homeostatic control of the crypt‐villus axis by the bacterial enterotoxin receptor guanylyl cyclase C restricts the proliferating compartment in intestine. Am J Pathol 171: 1847‐1858, 2007.
 349. Li P , Schulz S , Bombonati A , Palazzo JP , Hyslop TM , Xu Y , Baran AA , Siracusa LD , Pitari GM , Waldman SA . Guanylyl cyclase C suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic integrity. Gastroenterology 133: 599‐607, 2007.
 350. Li Q , Zhang Q , Wang C , Li N , Li J . Invasion of enteropathogenic Escherichia coli into host cells through epithelial tight junctions. FEBS J 275: 6022‐6032, 2008.
 351. Li WJ , Xu C , Wang K , Li TY , Wang XN , Yang H , Xing T , Li WX , Chen YH , Gao H , Ding L . Severe intestinal inflammation in the small intestine of mice induced by controllable deletion of Claudin‐7. Dig Dis Sci 63: 1200‐1209, 2018.
 352. Lin JE , Li P , Snook AE , Schulz S , Dasgupta A , Hyslop TM , Gibbons AV , Marszlowicz G , Pitari GM , Waldman SA . The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling. Gastroenterology 138: 241‐254, 2010.
 353. Lin R , Murtazina R , Cha B , Chakraborty M , Sarker R , Chen TE , Lin Z , Hogema BM , de Jonge HR , Seidler U , Turner JR , Li X , Kovbasnjuk O , Donowitz M . D‐glucose acts via sodium/glucose cotransporter 1 to increase NHE3 in mouse jejunal brush border by a Na+/H+ exchange regulatory factor 2‐dependent process. Gastroenterology 140: 560‐571, 2011.
 354. Lin S , Yeruva S , He P , Singh AK , Zhang H , Chen M , Lamprecht G , de Jonge HR , Tse M , Donowitz M , Hogema BM , Chun J , Seidler U , Yun CC . Lysophosphatidic acid stimulates the intestinal brush border Na(+)/H(+) exchanger 3 and fluid absorption via LPA(5) and NHERF2. Gastroenterology 138: 649‐658, 2010.
 355. Lissner S , Hsieh CJ , Nold L , Bannert K , Bodammer P , Sultan A , Seidler U , Graeve L , Lamprecht G . The PDZ‐interaction of the intestinal anion exchanger downregulated in adenoma (DRA; SLC26A3) facilitates its movement into Rab11a‐positive recycling endosomes. Am J Physiol Gastrointest Liver Physiol 304: G980‐G990, 2013.
 356. Lissner S , Nold L , Hsieh CJ , Turner JR , Gregor M , Graeve L , Lamprecht G . Activity and PI3‐kinase dependent trafficking of the intestinal anion exchanger downregulated in adenoma depend on its PDZ interaction and on lipid rafts. Am J Physiol Gastrointest Liver Physiol 299: G907‐G920, 2010.
 357. Liu C , Xu H , Zhang B , Johansson ME , Li J , Hansson GC , Ghishan FK . NHE8 plays an important role in mucosal protection via its effect on bacterial adhesion. Am J Physiol Cell Physiol 305: C121‐C128, 2013.
 358. Liu F , Zhang Z , Csanady L , Gadsby DC , Chen J . Molecular structure of the human CFTR ion channel. Cell 169: 85‐95 e88, 2017.
 359. Liu H , Singla A , Ao M , Gill RK , Venkatasubramanian J , Rao MC , Alrefai WA , Dudeja PK . Calcitonin receptor‐mediated CFTR activation in human intestinal epithelial cells. J Cell Mol Med 15: 2697‐2705, 2011.
 360. Liu JZ , van Sommeren S , Huang H , Ng SC , Alberts R , Takahashi A , Ripke S , Lee JC , Jostins L , Shah T , Abedian S , Cheon JH , Cho J , Dayani NE , Franke L , Fuyuno Y , Hart A , Juyal RC , Juyal G , Kim WH , Morris AP , Poustchi H , Newman WG , Midha V , Orchard TR , Vahedi H , Sood A , Sung JY , Malekzadeh R , Westra HJ , Yamazaki K , Yang SK , International Multiple Sclerosis Genetics C, International IBDGC, Barrett JC , Alizadeh BZ , Parkes M , Bk T , Daly MJ , Kubo M , Anderson CA , Weersma RK . Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 47: 979‐986, 2015.
 361. Lloyd‐Price J , Abu‐Ali G , Huttenhower C . The healthy human microbiome. Genome Med 8: 51, 2016.
 362. Loffing J , Moyer BD , McCoy D , Stanton BA . Exocytosis is not involved in activation of Cl secretion via CFTR in Calu‐3 airway epithelial cells. Am J Physiol (Cell Physiology) 275(Pt 1): C913‐C920, 1998.
 363. Loffing J , Schild L . Functional domains of the epithelial sodium channel. J Am Soc Nephrol 16: 3175‐3181, 2005.
 364. Lohi H , Makela S , Pulkkinen K , Hoglund P , Karjalainen‐Lindsberg ML , Puolakkainen P , Kere J . Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis. Am J Physiol Gastrointest Liver Physiol 283: G567‐G575, 2002.
 365. Lomax RB , Sandle GI . Comparison of aldosterone‐ and RU‐28362‐induced apical Na+ and K+ conductances in rat distal colon. Am J Physiol 267: G485‐G493, 1994.
 366. Lorrot M , Vasseur M . How do the rotavirus NSP4 and bacterial enterotoxins lead differently to diarrhea? Virol J 4: 31, 2007.
 367. Lorrot M , Vasseur M . Physiopathology of Rotavirus diarrhea. Arch Pediatr 14 (Suppl 3): S145‐S151, 2007.
 368. Lucas ML . An alternative explanation for the occurrence of short circuit current increases in the small intestine following challenge by bacterial enterotoxins. Med Hypotheses 81: 601‐606, 2013.
 369. Lucas ML . Lack of applicability of the enterocyte chloride ion secretion paradigm to the pathology of cystic fibrosis. Arch Asthma Allergy Immunol 1: 061‐085, 2017.
 370. Lukacs GL , Verkman AS. CFTR: Folding, misfolding and correcting the DeltaF508 conformational defect. Trends Mol Med 18: 81‐91, 2012.
 371. Lytle C . Activation of the avian erythrocyte Na‐K‐Cl cotransport protein by cell shrinkage, cAMP, fluoride, and calyculin‐A involves phosphorylation at common sites. J Biol Chem 272: 15069‐15077, 1997.
 372. Madan JC , Koestler DC , Stanton BA , Davidson L , Moulton LA , Housman ML , Moore JH , Guill MF , Morrison HG , Sogin ML , Hampton TH , Karagas MR , Palumbo PE , Foster JA , Hibberd PL , O'Toole GA . Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: Interaction between intestinal and respiratory tracts and impact of nutritional exposures. MBio 3: e00251‐12, 2012.
 373. Maheshwari A , Corbin LL , Schelonka RL . Neonatal necrotizing enterocolitis. Res Report Neonatol 1: 39‐53, 2011.
 374. Majumdar S , Mishra V , Nandi S , Abdullah M , Barman A , Raghavan A , Nandi D , Visweswariah SS . Absence of receptor guanylyl cyclase C enhances ileal damage and reduces cytokine and antimicrobial peptide production during oral Salmonella Typhimurium infection. Infect Immun 86: pii: e00799‐17, 2018.
 375. Maloy KJ , Powrie F . Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474: 298‐306, 2011.
 376. Manzella C , Singhal M , Alrefai WA , Saksena S , Dudeja PK , Gill RK . Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR. Sci Rep 8: 6103, 2018.
 377. Marchiando AM , Graham WV , Turner JR . Epithelial barriers in homeostasis and disease. Annu Rev Pathol 5: 119‐144, 2010.
 378. Margolis KG , Gershon MD . Enteric neuronal regulation of intestinal inflammation. Trends Neurosci 39: 614‐624, 2016.
 379. Martinez KB , Leone V , Chang EB . Microbial metabolites in health and disease: Navigating the unknown in search of function. J Biol Chem 292: 8553‐8559, 2017.
 380. Martinez KB , Leone V , Chang EB . Western diets, gut dysbiosis, and metabolic diseases: Are they linked? Gut Microbes 8: 130‐142, 2017.
 381. Martinez‐Guryn K , Hubert N , Frazier K , Urlass S , Musch MW , Ojeda P , Pierre JF , Miyoshi J , Sontag TJ , Cham CM , Reardon CA , Leone V , Chang EB . Small intestine microbiota regulate host digestive and absorptive adaptive responses to dietary lipids. Cell Host Microbe 23: 458‐469 e455, 2018.
 382. Mathialahan T , Sandle GI . Dietary potassium and laxatives as regulators of colonic potassium secretion in end‐stage renal disease. Nephrol Dial Transplant 18: 341‐347, 2003.
 383. Matkowskyj KA , Danilkovich A , Marrero J , Savkovic SD , Hecht G , Benya RV . Galanin‐1 receptor up‐regulation mediates the excess colonic fluid production caused by infection with enteric pathogens. Nat Med 6: 1048‐1051, 2000.
 384. Matkowskyj KA , Nathaniel R , Prasad R , Weihrauch D , Rao M , Benya RV . Galanin contributes to the excess colonic fluid secretion observed in dextran sulfate sodium murine colitis. Inflamm Bowel Dis 10: 408‐416, 2004.
 385. Matos JE , Sausbier M , Beranek G , Sausbier U , Ruth P , Leipziger J . Role of cholinergic‐activated KCa1.1 (BK), KCa3.1 (SK4) and KV7.1 (KCNQ1) channels in mouse colonic Cl‐ secretion. Acta Physiol (Oxf) 189: 251‐258, 2007.
 386. Matthews JB . Molecular regulation of Na+‐K+‐2Cl‐ cotransporter (NKCC1) and epithelial chloride secretion. World J Surg 26: 826‐830, 2002.
 387. Mawe GM , Hoffman JM . Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 10: 473‐486, 2013.
 388. McCole DF . Phosphatase regulation of intercellular junctions. Tissue Barriers 1: e26713, 2013.
 389. Megiorni F , Cialfi S , Dominici C , Quattrucci S , Pizzuti A . Synergistic post‐transcriptional regulation of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) by miR‐101 and miR‐494 specific binding. PLoS One 6: e26601, 2011.
 390. Melvin JE , Park K , Richardson L , Schultheis PJ , Shull GE . Mouse down‐regulated in adenoma (DRA) is an intestinal Cl(‐)/HCO(3)(‐) exchanger and is up‐regulated in colon of mice lacking the NHE3 Na(+)/H(+) exchanger. J Biol Chem 274: 22855‐22861, 1999.
 391. Meneton P , Schultheis PJ , Greeb J , Nieman ML , Liu LH , Clarke LL , Duffy JJ , Doetschman T , Lorenz JN , Shull GE . Increased sensitivity to K+ deprivation in colonic H,K‐ATPase‐deficient mice. J Clin Invest 101: 536‐542, 1998.
 392. Messer JS . The cellular autophagy/apoptosis checkpoint during inflammation. Cell Mol Life Sci 74: 1281‐1296, 2017.
 393. Messer JS , Chang EB . Microbial physiology of the digestive tract and its role in inflammatory bowel diseases. In: Said HM , editor. Physiology of the Gastrointestinal Tract. London, UK: Elsevier‐Academic Press, 2018, pp. 795‐810.
 394. Michail S , Collins JF , Xu H , Kaufman S , Vanderhoof J , Ghishan FK . Abnormal expression of brush‐border membrane transporters in the duodenal mucosa of two patients with microvillus inclusion disease. J Pediatr Gastroenterol Nutr 27: 536‐542, 1998.
 395. Mine Y , Shuto T , Nikawa H , Kawai T , Ohara M , Kawahara K , Ohta K , Kukita T , Terada Y , Makihira S . Inhibition of RANKL‐dependent cellular fusion in pre‐osteoclasts by amiloride and a NHE10‐specific monoclonal antibody. Cell Biol Int 39: 696‐709, 2015.
 396. Miyauchi S , Gopal E , Fei YJ , Ganapathy V . Functional identification of SLC5A8, a tumor suppressor down‐regulated in colon cancer, as a Na(+)‐coupled transporter for short‐chain fatty acids. J Biol Chem 279: 13293‐13296, 2004.
 397. Miyoshi J , Chang EB . The gut microbiota and inflammatory bowel diseases. Transl Res 179: 38‐48, 2017.
 398. Moeser AJ , Nighot PK , Engelke KJ , Ueno R , Blikslager AT . Recovery of mucosal barrier function in ischemic porcine ileum and colon is stimulated by a novel agonist of the ClC‐2 chloride channel, lubiprostone. Am J Physiol Gastrointest Liver Physiol 292: G647‐G656, 2007.
 399. Mokry M , Middendorp S , Wiegerinck CL , Witte M , Teunissen H , Meddens CA , Cuppen E , Clevers H , Nieuwenhuis EE . Many inflammatory bowel disease risk loci include regions that regulate gene expression in immune cells and the intestinal epithelium. Gastroenterology 146: 1040‐1047, 2014.
 400. Montoro DT , Haber AL , Biton M , Vinarsky V , Lin B , Birket SE , Yuan F , Chen S , Leung HM , Villoria J , Rogel N , Burgin G , Tsankov AM , Waghray A , Slyper M , Waldman J , Nguyen L , Dionne D , Rozenblatt‐Rosen O , Tata PR , Mou H , Shivaraju M , Bihler H , Mense M , Tearney GJ , Rowe SM , Engelhardt JF , Regev A , Rajagopal J . A revised airway epithelial hierarchy includes CFTR‐expressing ionocytes. Nature 560: 319‐324, 2018.
 401. Morampudi V , Graef FA , Stahl M , Dalwadi U , Conlin VS , Huang T , Vallance BA , Yu HB , Jacobson K . Tricellular tight junction protein tricellulin is targeted by the enteropathogenic Escherichia coli effector EspG1, leading to epithelial barrier disruption. Infect Immun 85: pii: e00700‐16, 2017.
 402. Moriarty KJ , Higgs NB , Lees M , Tonge A , Wardle TD , Warhurst G . Influence of atrial natriuretic peptide on mammalian large intestine. Gastroenterology 98: 647‐653, 1990.
 403. Morris AP , Scott JK , Ball JM , Zeng CQ , O'Neal WK , Estes MK . NSP4 elicits age‐dependent diarrhea and Ca(2+)mediated I(‐) influx into intestinal crypts of CF mice. Am J Physiol 277: G431‐G444, 1999.
 404. Morth JP , Pedersen BP , Buch‐Pedersen MJ , Andersen JP , Vilsen B , Palmgren MG , Nissen P . A structural overview of the plasma membrane Na+,K+‐ATPase and H+‐ATPase ion pumps. Nat Rev Mol Cell Biol 12: 60‐70, 2011.
 405. Mowat A . Why does cystic fibrosis display the prevalence and distribution observed in human populations? Curr Pediatr Res 21: 164‐171, 2017.
 406. Mueller JL , McGeough MD , Pena CA , Sivagnanam M . Functional consequences of EpCam mutation in mice and men. Am J Physiol Gastrointest Liver Physiol 306: G278‐G288, 2014.
 407. Mugie SM , Di Lorenzo C , Benninga MA . Constipation in childhood. Nat Rev Gastroenterol Hepatol 8: 502‐511, 2011.
 408. Muller T , Hess MW , Schiefermeier N , Pfaller K , Ebner HL , Heinz‐Erian P , Ponstingl H , Partsch J , Rollinghoff B , Kohler H , Berger T , Lenhartz H , Schlenck B , Houwen RJ , Taylor CJ , Zoller H , Lechner S , Goulet O , Utermann G , Ruemmele FM , Huber LA , Janecke AR . MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet 40: 1163‐1165, 2008.
 409. Muller T , Rasool I , Heinz‐Erian P , Mildenberger E , Hulstrunk C , Muller A , Michaud L , Koot BG , Ballauff A , Vodopiutz J , Rosipal S , Petersen BS , Franke A , Fuchs I , Witt H , Zoller H , Janecke AR , Visweswariah SS . Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C. Gut 65: 1306‐1313, 2016.
 410. Muller T , Wijmenga C , Phillips AD , Janecke A , Houwen RH , Fischer H , Ellemunter H , Fruhwirth M , Offner F , Hofer S , Muller W , Booth IW , Heinz‐Erian P . Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes. Gastroenterology 119: 1506‐1513, 2000.
 411. Munck A . Cystic fibrosis: Evidence for gut inflammation. Int J Biochem Cell Biol 52: 180‐183, 2014.
 412. Murad F . Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 355: 2003‐2011, 2006.
 413. Murek M , Kopic S , Geibel J . Evidence for intestinal chloride secretion. Exp Physiol 95: 471‐478, 2010.
 414. Musch MW , Arvans DL , Wu GD , Chang EB . Functional coupling of the downregulated in adenoma Cl‐/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3. Am J Physiol Gastrointest Liver Physiol 296: G202‐G210, 2009.
 415. Musch MW , Bookstein C , Xie Y , Sellin JH , Chang EB . SCFA increase intestinal Na absorption by induction of NHE3 in rat colon and human intestinal C2/bbe cells. Am J Physiol Gastrointest Liver Physiol 280: G687‐G693, 2001.
 416. Musch MW , Clarke LL , Mamah D , Gawenis LR , Zhang Z , Ellsworth W , Shalowitz D , Mittal N , Efthimiou P , Alnadjim Z , Hurst SD , Chang EB , Barrett TA . T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+‐ATPase. J Clin Invest 110: 1739‐1747, 2002.
 417. Myung SJ , Rerko RM , Yan M , Platzer P , Guda K , Dotson A , Lawrence E , Dannenberg AJ , Lovgren AK , Luo G , Pretlow TP , Newman RA , Willis J , Dawson D , Markowitz SD . 15‐Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis. Proc Natl Acad Sci USA 103: 12098‐12102, 2006.
 418. Nataraja S , Venkatasubramanian J , Vidyasagar D , Rao MC . Ontogeny of cGMP stimulated chloride transport in rabbit colon. Gastroenterology 114: G1636, 1998.
 419. Nazir S , Kumar A , Chatterjee I , Anbazhagan AN , Gujral T , Priyamvada S , Saksena S , Alrefai WA , Dudeja PK , Gill RK . Mechanisms of intestinal serotonin transporter (SERT) upregulation by TGF‐beta1 induced non‐Smad pathways. PLoS One 10: e0120447, 2015.
 420. Neurath MF . Cytokines in inflammatory bowel disease. Nat Rev Immunol 14: 329‐342, 2014.
 421. Neurath MF . Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol 14: 269‐278, 2017.
 422. Newton K , Dixit VM . Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol 4: pii: a006049, 2012.
 423. Ngo P , Furuta G , Burks W . The pathobiology of eosinophilic gastroenteritis of childhood: Is it really the eosinophil, allergic mediated, or something else? Curr Gastroenterol Rep 6: 436‐440, 2004.
 424. Nichols JM , Maiellaro I , Abi‐Jaoude J , Curci S , Hofer AM . “Store‐operated” cAMP signaling contributes to Ca2+‐activated Cl‐ secretion in T84 colonic cells. Am J Physiol Gastrointest Liver Physiol 309: G670‐G679, 2015.
 425. Nighot PK , Moeser A , Ali RA , Blikslager AT , Koci MD . Astrovirus infection induces sodium malabsorption and redistributes sodium hydrogen exchanger expression. Virology 401: 146‐154, 2010.
 426. Nighot PK , Moeser AJ , Ryan KA , Ghashghaei T , Blikslager AT . ClC‐2 is required for rapid restoration of epithelial tight junctions in ischemic‐injured murine jejunum. Exp Cell Res 315(1): 110‐118, 2009.
 427. Nocerino A , Iafusco M , Guandalini S . Cholera toxin‐induced small intestinal secretion has a secretory effect on the colon of the rat. Gastroenterology 108: 34‐39, 1995.
 428. Norman JM , Handley SA , Virgin HW . Kingdom‐agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology 146: 1459‐1469, 2014.
 429. O'Mahony SM , Clarke G , Borre YE , Dinan TG , Cryan JF . Serotonin, tryptophan metabolism and the brain‐gut‐microbiome axis. Behav Brain Res 277: 32‐48, 2015.
 430. Ohana E , Shcheynikov N , Moe OW , Muallem S . SLC26A6 and NaDC‐1 transporters interact to regulate oxalate and citrate homeostasis. J Am Soc Nephrol 24: 1617‐1626, 2013.
 431. Onyiah JC , Colgan SP . Cytokine responses and epithelial function in the intestinal mucosa. Cell Mol Life Sci 73: 4203‐4212, 2016.
 432. Osmani K , Ao M , Domingue J , Sarathy J. , Rao M. Phorbol dibutyrate (PDB) regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) may involve down‐regulation of microRNAs (miRs). FASEB J 30: 1223.1221, 2016.
 433. Osmani K , Ao M , Domingue J Sarathy, J. , Rao, MC . Phorbol dibutyrate (PDB) regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) does not involve MicroRNAs. FASEB J 29: 855.855, 2015.
 434. Ott CJ , Blackledge NP , Leir SH , Harris A . Novel regulatory mechanisms for the CFTR gene. Biochem Soc Trans 37: 843‐848, 2009a.
 435. Ott CJ , Suszko M , Blackledge NP , Wright JE , Crawford GE , Harris A . A complex intronic enhancer regulates expression of the CFTR gene by direct interaction with the promoter. J Cell Mol Med 13: 680‐692, 2009b.
 436. Ousingsawat J , Mirza M , Tian Y , Roussa E , Schreiber R , Cook DI , Kunzelmann K . Rotavirus toxin NSP4 induces diarrhea by activation of TMEM16A and inhibition of Na+ absorption. Pflugers Arch 461: 579‐589, 2011.
 437. Padan E . Functional and structural dynamics of NhaA, a prototype for Na(+) and H(+) antiporters, which are responsible for Na(+) and H(+) homeostasis in cells. Biochim Biophys Acta 1837: 1047‐1062, 2014.
 438. Palfrey HC , Rao MC . Na/K/Cl co‐transport and its regulation. J Exp Biol 106: 43‐54, 1983.
 439. Park JH , Rhee PL , Lee JH , Kim JJ , Rhee JC , Kim SJ , Lee J . Segmental heterogeneity of electrogenic secretions in human ascending colon and rectum. Int J Colorectal Dis 21: 357‐364, 2006.
 440. Park S , Shcheynikov N , Hong JH , Zheng C , Suh SH , Kawaai K , Ando H , Mizutani A , Abe T , Kiyonari H , Seki G , Yule D , Mikoshiba K , Muallem S . Irbit mediates synergy between ca(2+) and cAMP signaling pathways during epithelial transport in mice. Gastroenterology 145: 232‐241, 2013.
 441. Parker MD , Boron WF . The divergence, actions, roles, and relatives of sodium‐coupled bicarbonate transporters. Physiol Rev 93: 803‐959, 2013.
 442. Patel TS , Crutchley RD , Tucker AM , Cottreau J , Garey KW . Crofelemer for the treatment of chronic diarrhea in patients living with HIV/AIDS. HIV AIDS (Auckl) 5: 153‐162, 2013.
 443. Paulino C , Kalienkova V , Lam AKM , Neldner Y , Dutzler R . Activation mechanism of the calcium‐activated chloride channel TMEM16A revealed by cryo‐EM. Nature 552: 421‐425, 2017.
 444. Payne JL , Wagner A . Mechanisms of mutational robustness in transcriptional regulation. Front Genet 6: 322, 2015.
 445. Pedemonte N , Galietta LJ . Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 94: 419‐459, 2014.
 446. Penn D , Lebenthal E . Intestinal mucosal energy metabolism–a new approach to therapy of gastrointestinal disease. J Pediatr Gastroenterol Nutr 10: 1‐4, 1990.
 447. Perry MD , Sandle GI . Regulation of colonic apical potassium (BK) channels by cAMP and somatostatin. Am J Physiol Gastrointest Liver Physiol 297: G159‐G167, 2009.
 448. Piechotta K , Lu J , Delpire E . Cation chloride cotransporters interact with the stress‐related kinases Ste20‐related proline‐alanine‐rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem 277: 50812‐50819, 2002.
 449. Pier GB , Grout M , Zaidi T , Meluleni G , Mueschenborn SS , Banting G , Ratcliff R , Evans MJ , Colledge WH . Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 393: 79‐82, 1998.
 450. Pierce NF , Banwell JG , Rupak DM , Mitra RC , Caranasos GJ , Keimowitz RI , Mondal A , Manji PM . Effect of intragastric glucose‐electrolyte infusion upon water and electrolyte balance in Asiatic cholera. Gastroenterology 55: 333‐343, 1968.
 451. Pinney SE , Oliver‐Krasinski J , Ernst L , Hughes N , Patel P , Stoffers DA , Russo P , De Leon DD . Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin‐3 gene coding sequence. J Clin Endocrinol Metab 96: 1960‐1965, 2011.
 452. Plasschaert LW , Zilionis R , Choo‐Wing R , Savova V , Knehr J , Roma G , Klein AM , Jaffe AB . A single‐cell atlas of the airway epithelium reveals the CFTR‐rich pulmonary ionocyte. Nature 560: 377‐381, 2018.
 453. Posovszky C . Congenital intestinal diarrhoeal diseases: A diagnostic and therapeutic challenge. Best Pract Res Clin Gastroenterol 30: 187‐211, 2016.
 454. Potter GD , Sellin JH , Burlingame SM . Bile acid stimulation of cyclic AMP and ion transport in developing rabbit colon. J Pediatr Gastroenterol Nutr 13: 335‐341, 1991.
 455. Prasad R , Venkatasubramanian J , Amde M , Rao MC . Phospholipase C and src tyrosine kinases mediate neurotensin‐stimulated Cl‐ secretion in rabbit proximal colon. Dig Dis Sci 49: 1318‐1326, 2004.
 456. Pratha VS , Hogan DL , Martensson BA , Bernard J , Zhou R , Isenberg JI . Identification of transport abnormalities in duodenal mucosa and duodenal enterocytes from patients with cystic fibrosis. Gastroenterology 118: 1051‐1060, 2000.
 457. Priyamvada S , Gomes R , Gill RK , Saksena S , Alrefai WA , Dudeja PK . Mechanisms underlying dysregulation of electrolyte absorption in inflammatory bowel disease‐associated diarrhea. Inflamm Bowel Dis 21: 2926‐2935, 2015.
 458. Priyamvada S , Saksena S , Alrefai WA , Dudeja PK . Intestinal anion absorption. In: Said HM , editor. Physiology of the Gastrointestinal Tract. London, UK: Elsevier‐Academic Press, 2018. pp. 1317‐1350.
 459. Pukatzki S , Ma AT , Sturtevant D , Krastins B , Sarracino D , Nelson WC , Heidelberg JF , Mekalanos JJ . Identification of a conserved bacterial protein secretion system in Vibrio cholerae using the Dictyostelium host model system. Proc Natl Acad Sci USA 103: 1528‐1533, 2006.
 460. Quinton PM . Both ways at once: Keeping small airways clean. Physiology (Bethesda) 32: 380‐390, 2017.
 461. Racke K , Reimann A , Schworer H , Kilbinger H . Regulation of 5‐HT release from enterochromaffin cells. Behav Brain Res 73: 83‐87, 1996.
 462. Raheja G , Singh V , Ma K , Boumendjel R , Borthakur A , Gill RK , Saksena S , Alrefai WA , Ramaswamy K , Dudeja PK . Lactobacillus acidophilus stimulates the expression of SLC26A3 via a transcriptional mechanism. Am J Physiol Gastrointest Liver Physiol 298: G395‐G401, 2010.
 463. Raimondi F , Santoro P , Barone MV , Pappacoda S , Barretta ML , Nanayakkara M , Apicella C , Capasso L , Paludetto R . Bile acids modulate tight junction structure and barrier function of Caco‐2 monolayers via EGFR activation. Am J Physiol Gastrointest Liver Physiol 294: G906‐G913, 2008.
 464. Rajendran VM , Geibel J , Binder HJ . Chloride‐dependent Na‐H exchange. A novel mechanism of sodium transport in colonic crypts. J Biol Chem 270: 11051‐11054, 1995.
 465. Rajendran VM , Sandle GI . Colonic potassium absorption and secretion in health and disease. Compr Physiol 8: 1513‐1536, 2018.
 466. Rajendran VM , Sangan P , Geibel J , Binder HJ . Ouabain‐sensitive H,K‐ATPase functions as Na,K‐ATPase in apical membranes of rat distal colon. J Biol Chem 275: 13035‐13040, 2000.
 467. Rajendran VM , Schulzke J‐D , Seidler UE . Ion channels of the gastrointestinal epithelial cells. In: Said HM , editor. Physiology of the Gastrointestinal Tract. London, UK: Elsevier‐Academic Press, 2018, pp. 1363‐1404.
 468. Ramachandran S , Karp PH , Jiang P , Ostedgaard LS , Walz AE , Fisher JT , Keshavjee S , Lennox KA , Jacobi AM , Rose SD , Behlke MA , Welsh MJ , Xing Y , McCray PB, Jr. A microRNA network regulates expression and biosynthesis of wild‐type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA 109: 13362‐13367, 2012.
 469. Ramakrishna BS , Subramanian V , Mohan V , Sebastian BK , Young GP , Farthing MJ , Binder HJ . A randomized controlled trial of glucose versus amylase resistant starch hypo‐osmolar oral rehydration solution for adult acute dehydrating diarrhea. PLoS One 3: e1587, 2008.
 470. Ramakrishna BS , Venkataraman S , Srinivasan P , Dash P , Young GP , Binder HJ . Amylase‐resistant starch plus oral rehydration solution for cholera. N Engl J Med 342: 308‐313, 2000.
 471. Rao MC . Oral rehydration therapy: New explanations for an old remedy. Annu Rev Physiol 66: 385‐417, 2004.
 472. Rao MC , Bissonnette GB , Mahaffey T , Guggino WB , Goldstein JL . Rectal epithelial expression of protein kinase A phosphorylation of cystic fibrosis transmembrane conductance regulator. Gastroenterology 106: 890‐898, 1994.
 473. Rao MC , Chang EB . Gut microbes and host metabolism got rhythm: Implications for metabolic heath, disease, and intervention. The Biochemist 39: 30‐33, 2017.
 474. Rao MC , de Jonge HR . Ca and phospholipid‐dependent protein kinases: Role in ion transport. In: Lebenthal EaD, ME , editor. Secretory Diarrhea. New York: Raven Press, 1990, pp. 209‐232.
 475. Rao MC , Guandalini S , Smith PL , Field M . Mode of action of heat‐stable Escherichia coli enterotoxin. Tissue and subcellular specificities and role of cyclic GMP. Biochim Biophys Acta 632: 35‐46, 1980.
 476. Rao MC , Orellana SA , Field M , Robertson DC , Giannella RA . Comparison of the biological actions of three purified heat‐stable enterotoxins: Effects on ion transport and guanylate cyclase activity in rabbit ileum in vitro. Infect Immun 33: 165‐170, 1981.
 477. Rao MC , Sarathy (nee Venkatasubramanian) J , Ao M . Intestinal water and electrolyte transport in health and disease In: Granger DN , Granger JP , editors. Colloquium Series on Integrated Systems Physiology: from Molecule to Function to Disease, Lecture #31, Claypool Life Sciences 2012, pp. 1‐105.
 478. Rao MC , Sarathy J , Sellin JH . Intestinal electrolyte absorption and secretion. In: Feldman M , Friedman LS , Brandt LJ , editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia, USA: Elsevier, 2016, pp. 1713‐1735.
 479. Rechkemmer G , Halm DR . Aldosterone stimulates K secretion across mammalian colon independent of Na absorption. Proc Natl Acad Sci USA 86: 397‐401, 1989.
 480. Reifen RM , Cutz E , Griffiths AM , Ngan BY , Sherman PM . Tufting enteropathy: A newly recognized clinicopathological entity associated with refractory diarrhea in infants. J Pediatr Gastroenterol Nutr 18: 379‐385, 1994.
 481. Reigstad CS , Salmonson CE , , Szurszewski JH , Linden DR , Sonnenburg JL , Farrugia G , Kashyap PC . Gut microbes promote colonic serotonin production through an effect of short‐chain fatty acids on enterochromaffin cells. FASEB J 29: 1395‐1403, 2015.
 482. Resta‐Lenert S , Barrett KE . Probiotics and commensals reverse TNF‐alpha‐ and IFN‐gamma‐induced dysfunction in human intestinal epithelial cells. Gastroenterology 130: 731‐746, 2006.
 483. Reynolds A , Parris A , Evans LA , Lindqvist S , Sharp P , Lewis M , Tighe R , Williams MR . Dynamic and differential regulation of NKCC1 by calcium and cAMP in the native human colonic epithelium. J Physiol 582: 507‐524, 2007.
 484. Reynolds DA , Rajendran VM , Binder HJ . Bicarbonate‐stimulated [14C]butyrate uptake in basolateral membrane vesicles of rat distal colon. Gastroenterology 105: 725‐732, 1993.
 485. Rhoads JM , Keku EO , Quinn J , Woosely J , Lecce JG . L‐glutamine stimulates jejunal sodium and chloride absorption in pig rotavirus enteritis. Gastroenterology 100: 683‐691, 1991.
 486. Riordan JR . CFTR function and prospects for therapy. Annu Rev Biochem 77: 701‐726, 2008.
 487. Riordan JR , Rommens JM , Kerem B , Alon N , Rozmahel R , Grzelczak Z , Zielenski J , Lok S , Plavsic N , Chou JL , et al. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245: 1066‐1073, 1989.
 488. Ritzka M , Stanke F , Jansen S , Gruber AD , Pusch L , Woelfl S , Veeze HJ , Halley DJ , Tummler B . The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis. Hum Genet 115: 483‐491, 2004.
 489. Rocha F , Musch MW , Lishanskiy L , Bookstein C , Sugi K , Xie Y , Chang EB . IFN‐gamma downregulates expression of Na(+)/H(+) exchangers NHE2 and NHE3 in rat intestine and human Caco‐2/bbe cells. Am J Physiol Cell Physiol 280: C1224‐C1232, 2001.
 490. Romani L , Oikonomou V , Moretti S , Iannitti RG , D'Adamo MC , Villella VR , Pariano M , Sforna L , Borghi M , Bellet MM , Fallarino F , Pallotta MT , Servillo G , Ferrari E , Puccetti P , Kroemer G , Pessia M , Maiuri L , Goldstein AL , Garaci E . Thymosin alpha1 represents a potential potent single‐molecule‐based therapy for cystic fibrosis. Nat Med 23: 590‐600, 2017.
 491. Romi H , Cohen I , Landau D , Alkrinawi S , Yerushalmi B , Hershkovitz R , Newman‐Heiman N , Cutting GR , Ofir R , Sivan S , Birk OS . Meconium ileus caused by mutations in GUCY2C, encoding the CFTR‐activating guanylate cyclase 2C. Am J Hum Genet 90: 893‐899, 2012.
 492. Rosen BH , Chanson M , Gawenis LR , Liu J , Sofoluwe A , Zoso A , Engelhardt JF . Animal and model systems for studying cystic fibrosis. J Cyst Fibros 17: S28‐S34, 2018.
 493. Rowe SM , Miller S , Sorscher EJ . Cystic fibrosis. N Engl J Med 352: 1992‐2001, 2005.
 494. Roxas JL , Viswanathan VK . Modulation of intestinal paracellular transport by bacterial pathogens. Compr Physiol 8: 823‐842, 2018.
 495. Sahi J , Goldstein JL , Layden TJ , Rao MC . Cyclic AMP‐ and phorbol ester‐regulated Cl‐ permeabilities in primary cultures of human and rabbit colonocytes. Am J Physiol 266: G846‐G855, 1994.
 496. Sahi J , Nataraja SG , Layden TJ , Goldstein JL , Moyer MP , Rao MC . Cl‐ transport in an immortalized human epithelial cell line (NCM460) derived from the normal transverse colon. Am J Physiol 275: C1048‐C1057, 1998.
 497. Saksena S , Dwivedi A , Singla A , Gill RK , Tyagi S , Borthakur A , Alrefai WA , Ramaswamy K , Dudeja PK . Characterization of the 5′‐flanking region and regulation of expression of human anion exchanger SLC26A6. J Cell Biochem 105: 454‐466, 2008.
 498. Saksena S , Gill RK , Tyagi S , Alrefai WA , Sarwar Z , Ramaswamy K , Dudeja PK . Involvement of c‐Src and protein kinase C delta in the inhibition of Cl(‐)/OH‐ exchange activity in Caco‐2 cells by serotonin. J Biol Chem 280: 11859‐11868, 2005.
 499. Saksena S , Singla A , Goyal S , Katyal S , Bansal N , Gill RK , Alrefai WA , Ramaswamy K , Dudeja PK . Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN‐{gamma}. Am J Physiol Gastrointest Liver Physiol 298: G159‐G166, 2010.
 500. Saksena S , Tyagi S , Goyal S , Gill RK , Alrefai WA , Ramaswamy K , Dudeja PK . Stimulation of apical Cl(‐)/HCO(3)(‐)(OH(‐)) exchanger, SLC26A3 by neuropeptide Y is lipid raft dependent. Am J Physiol Gastrointest Liver Physiol 299: G1334‐G1343, 2010.
 501. Sala‐Rabanal M , Yurtsever Z , Nichols CG , Brett TJ . Secreted CLCA1 modulates TMEM16A to activate Ca(2+)‐dependent chloride currents in human cells. Elife 4: 2015.
 502. Sandle GI . Pathogenesis of diarrhea in ulcerative colitis: New views on an old problem. J Clin Gastroenterol 39: S49‐S52, 2005.
 503. Sandle GI , Binder HJ . Corticosteroids and intestinal ion transport. Gastroenterology 93: 188‐196, 1987.
 504. Sandle GI , Higgs N , Crowe P , Marsh MN , Venkatesan S , Peters TJ . Cellular basis for defective electrolyte transport in inflamed human colon. Gastroenterology 99: 97‐105, 1990.
 505. Sandle GI , Hunter M . Apical potassium (BK) channels and enhanced potassium secretion in human colon. QJM 103: 85‐89, 2010.
 506. Sandle GI , Perry MD , Mathialahan T , Linley JE , Robinson P , Hunter M , MacLennan KA . Altered cryptal expression of luminal potassium (BK) channels in ulcerative colitis. J Pathol 212: 66‐73, 2007.
 507. Sandle GI , Rajendran VM . Cyclic AMP‐induced K+ secretion occurs independently of Cl‐ secretion in rat distal colon. Am J Physiol Cell Physiol 303: C328‐C333, 2012.
 508. Sandle GI , Warhurst G , Butterfield I , Higgs NB , Lomax RB . Somatostatin peptides inhibit basolateral potassium channels in human colonic crypts. Am J Physiol 277: G967‐G975, 1999.
 509. Sangan P , Rajendran VM , Mann AS , Kashgarian M , Binder HJ . Regulation of colonic H‐K‐ATPase in large intestine and kidney by dietary Na depletion and dietary K depletion. Am J Physiol 272: C685‐C696, 1997.
 510. Sarathy J , Detloff SJ , Ao M , Khan N , French S , Sirajuddin H , Nair T , Rao MC . The Yin and Yang of bile acid action on tight junctions in a model colonic epithelium. Physiol Rep 5: e13294, 2017.
 511. Saslowsky DE , te Welscher YM , Chinnapen DJ , Wagner JS , Wan J , Kern E , Lencer WI . Ganglioside GM1‐mediated transcytosis of cholera toxin bypasses the retrograde pathway and depends on the structure of the ceramide domain. J Biol Chem 288: 25804‐25809, 2013.
 512. Sassone‐Corsi P . The cyclic AMP pathway. Cold Spring Harb Perspect Biol 4: a011148, 2012.
 513. Sato T , Clevers H . Growing self‐organizing mini‐guts from a single intestinal stem cell: Mechanism and applications. Science 340: 1190‐1194, 2013.
 514. Sausbier M , Matos JE , Sausbier U , Beranek G , Arntz C , Neuhuber W , Ruth P , Leipziger J . Distal colonic K(+) secretion occurs via BK channels. J Am Soc Nephrol 17: 1275‐1282, 2006.
 515. Saxena K , Blutt SE , Ettayebi K , Zeng XL , Broughman JR , Crawford SE , Karandikar UC , Sastri NP , Conner ME , Opekun AR , Graham DY , Qureshi W , Sherman V , Foulke‐Abel J , In J , Kovbasnjuk O , Zachos NC , Donowitz M , Estes MK . Human intestinal enteroids: A new model to study human rotavirus infection, host restriction, and pathophysiology. J Virol 90: 43‐56, 2016.
 516. Schiller LR , Sellin JH . Diarrhea. In: Feldman M , Friedman LS , Brandt LJ , editors. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. Philadelphia, USA: Elsevier, 2016, pp. 221‐241.
 517. Schmitt S , Kury S , Giraud M , Dreno B , Kharfi M , Bezieau S . An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum Mutat 30: 926‐933, 2009.
 518. Schreiber R , Faria D , Skryabin BV , Wanitchakool P , Rock JR , Kunzelmann K . Anoctamins support calcium‐dependent chloride secretion by facilitating calcium signaling in adult mouse intestine. Pflugers Arch 467: 1203‐1213, 2015.
 519. Schroeder SA , Gaughan DM , Swift M . Protection against bronchial asthma by CFTR delta F508 mutation: A heterozygote advantage in cystic fibrosis. Nat Med 1: 703‐705, 1995.
 520. Schultheis PJ , Clarke LL , Meneton P , Harline M , Boivin GP , Stemmermann G , Duffy JJ , Doetschman T , Miller ML , Shull GE . Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J Clin Invest 101: 1243‐1253, 1998a.
 521. Schultheis PJ , Clarke LL , Meneton P , Miller ML , Soleimani M , Gawenis LR , Riddle TM , Duffy JJ , Doetschman T , Wang T , Giebisch G , Aronson PS , Lorenz JN , Shull GE . Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet 19: 282‐285, 1998b.
 522. Schulz S , Green CK , Yuen PS , Garbers DL . Guanylyl cyclase is a heat‐stable enterotoxin receptor. Cell 63: 941‐948, 1990.
 523. Schulz S , Lopez MJ , Kuhn M , Garbers DL . Disruption of the guanylyl cyclase‐C gene leads to a paradoxical phenotype of viable but heat‐stable enterotoxin‐resistant mice. J Clin Invest 100: 1590‐1595, 1997.
 524. Schwank G , Koo BK , Sasselli V , Dekkers JF , Heo I , Demircan T , Sasaki N , Boymans S , Cuppen E , van der Ent CK , Nieuwenhuis EE , Beekman JM , Clevers H . Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13: 653‐658, 2013.
 525. Schweinfest CW , Spyropoulos DD , Henderson KW , Kim JH , Chapman JM , Barone S , Worrell RT , Wang Z , Soleimani M . slc26a3 (dra)‐deficient mice display chloride‐losing diarrhea, enhanced colonic proliferation, and distinct up‐regulation of ion transporters in the colon. J Biol Chem 281: 37962‐37971, 2006.
 526. Schwiebert EM , Cid‐Soto LP , Stafford D , Carter M , Blaisdell CJ , Zeitlin PL , Guggino WB , Cutting GR . Analysis of ClC‐2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells. Proc Natl Acad Sci USA 95: 3879‐3884, 1998.
 527. Seidler U , Rottinghaus I , Hillesheim J , Chen M , Riederer B , Krabbenhoft A , Engelhardt R , Wiemann M , Wang Z , Barone S , Manns MP , Soleimani M . Sodium and chloride absorptive defects in the small intestine in Slc26a6 null mice. Pflugers Arch 455: 757‐766, 2008.
 528. Seidler U , Singh A , Chen M , Cinar A , Bachmann O , Zheng W , Wang J , Yeruva S , Riederer B . Knockout mouse models for intestinal electrolyte transporters and regulatory PDZ adaptors: New insights into cystic fibrosis, secretory diarrhoea and fructose‐induced hypertension. Exp Physiol 94: 175‐179, 2009.
 529. Seidler UE . Gastrointestinal HCO3‐ transport and epithelial protection in the gut: New techniques, transport pathways and regulatory pathways. Curr Opin Pharmacol 13: 900‐908, 2013.
 530. Sellin JH . SCFAs: The enigma of weak electrolyte transport in the colon. News Physiol Sci 14: 58‐64, 1999.
 531. Sellin JH , DeSoignie R , Burlingame S . Segmental differences in short‐chain fatty acid transport in rabbit colon: Effect of pH and Na. J Membr Biol 136: 147‐158, 1993.
 532. Selvaraj NG , Prasad R , Goldstein JL , Rao MC . Evidence for the presence of cGMP‐dependent protein kinase‐II in human distal colon and in T84, the colonic cell line. Biochim Biophys Acta 1498: 32‐43, 2000.
 533. Seo NS , Zeng CQ , Hyser JM , Utama B , Crawford SE , Kim KJ , Hook M , Estes MK . Integrins alpha1beta1 and alpha2beta1 are receptors for the rotavirus enterotoxin. Proc Natl Acad Sci USA 105: 8811‐8818, 2008.
 534. Shah VS , Meyerholz DK , Tang XX , Reznikov L , Abou Alaiwa M , Ernst SE , Karp PH , Wohlford‐Lenane CL , Heilmann KP , Leidinger MR , Allen PD , Zabner J , McCray PB, Jr. , Ostedgaard LS , Stoltz DA , Randak CO , Welsh MJ . Airway acidification initiates host defense abnormalities in cystic fibrosis mice. Science 351: 503‐507, 2016.
 535. Shallat S , Schmidt L , Reaka A , Rao D , Chang EB , Rao MC , Ramaswamy K , Layden TJ . NHE‐1 isoform of the Na+/H+ antiport is expressed in the rat and rabbit esophagus. Gastroenterology 109: 1421‐1428, 1995.
 536. Shanahan F , Quigley EMM . Manipulation of the microbiota for treatment of IBS and IBD‐Challenges and Controversies. Gastroenterology 146: 1554‐1563, 2014.
 537. Shawki A , Engevik MA , Kim RS , Knight PB , Baik RA , Anthony SR , Worrell RT , Shull GE , Mackenzie B . Intestinal brush‐border Na+/H+ exchanger‐3 drives H+‐coupled iron absorption in the mouse. Am J Physiol Gastrointest Liver Physiol 311: G423‐G430, 2016.
 538. Shcheynikov N , Wang Y , Park M , Ko SB , Dorwart M , Naruse S , Thomas PJ , Muallem S . Coupling modes and stoichiometry of Cl‐/HCO3‐ exchange by slc26a3 and slc26a6. J Gen Physiol 127: 511‐524, 2006.
 539. Shen L , Weber CR , Raleigh DR , Yu D , Turner JR . Tight junction pore and leak pathways: A dynamic duo. Annu Rev Physiol 73: 283‐309, 2011.
 540. Shneider BL , Dawson PA , Christie DM , Hardikar W , Wong MH , Suchy FJ . Cloning and molecular characterization of the ontogeny of a rat ileal sodium‐dependent bile acid transporter. J Clin Invest 95: 745‐754, 1995.
 541. Siddique I , Hasan F , Khan I . Suppression of Na+/H+ exchanger isoform‐3 in human inflammatory bowel disease: Lack of reversal by 5′‐aminosalicylate treatment. Scand J Gastroenterol 44: 56‐64, 2009.
 542. Siddique I , Khan I . Regulation of Na/H exchanger‐1 in gastroesophageal reflux disease: Possible interaction of histamine receptor. Dig Dis Sci 48: 1832‐1838, 2003.
 543. Silen W , Harper HA , Mawdsley DL , Weirich WL . Effect of antibacterial agents on ammonia production within the intestine. Proc Soc Exp Biol Med 88: 138‐140, 1955.
 544. Silva AJ , Benitez JA . Vibrio cholerae Biofilms and Cholera Pathogenesis. PLoS Negl Trop Dis 10: e0004330, 2016.
 545. Silvis MR , Bertrand CA , Ameen N , Golin‐Bisello F , Butterworth MB , Frizzell RA , Bradbury NA . Rab11b regulates the apical recycling of the cystic fibrosis transmembrane conductance regulator in polarized intestinal epithelial cells. Mol Biol Cell 20: 2337‐2350, 2009.
 546. Singh AK , Liu Y , Riederer B , Engelhardt R , Thakur BK , Soleimani M , Seidler U . Molecular transport machinery involved in orchestrating luminal acid‐induced duodenal bicarbonate secretion in vivo. J Physiol 591: 5377‐5391, 2013.
 547. Singh AK , Riederer B , Chen M , Xiao F , Krabbenhoft A , Engelhardt R , Nylander O , Soleimani M , Seidler U . The switch of intestinal Slc26 exchangers from anion absorptive to HCOFormula secretory mode is dependent on CFTR anion channel function. Am J Physiol Cell Physiol 298: C1057‐C1065, 2010.
 548. Singh SK , Binder HJ , Boron WF , Geibel JP . Fluid absorption in isolated perfused colonic crypts. J Clin Invest 96: 2373‐2379, 1995.
 549. Singh V , Raheja G , Borthakur A , Kumar A , Gill RK , Alakkam A , Malakooti J , Dudeja PK . Lactobacillus acidophilus upregulates intestinal NHE3 expression and function. Am J Physiol Gastrointest Liver Physiol 303: G1393‐G1401, 2012.
 550. Singhal M , Manzella C , Soni V , Alrefai WA , Saksena S , Hecht GA , Dudeja PK , Gill RK . Role of SHP2 protein tyrosine phosphatase in SERT inhibition by enteropathogenic E. coli (EPEC). Am J Physiol Gastrointest Liver Physiol 312: G443‐G449, 2017.
 551. Singla A , Dwivedi A , Saksena S , Gill RK , Alrefai WA , Ramaswamy K , Dudeja PK . Mechanisms of lysophosphatidic acid (LPA) mediated stimulation of intestinal apical Cl‐/OH‐ exchange. Am J Physiol Gastrointest Liver Physiol 298: G182‐G189, 2010.
 552. Singla A , Kumar A , Priyamvada S , Tahniyath M , Saksena S , Gill RK , Alrefai WA , Dudeja PK . LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3K/AKT, and c‐Fos‐dependent pathway. Am J Physiol Gastrointest Liver Physiol 302: G618‐G627, 2012.
 553. Sivagnanam M , Janecke AR , Muller T , Heinz‐Erian P , Taylor S , Bird LM . Case of syndromic tufting enteropathy harbors SPINT2 mutation seen in congenital sodium diarrhea. Clin Dysmorphol 19: 48, 2010.
 554. Sivagnanam M , Mueller JL , Lee H , Chen Z , Nelson SF , Turner D , Zlotkin SH , Pencharz PB , Ngan BY , Libiger O , Schork NJ , Lavine JE , Taylor S , Newbury RO , Kolodner RD , Hoffman HM . Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology 135: 429‐437, 2008.
 555. Sivagnanam M , Schaible T , Szigeti R , Byrd RH , Finegold MJ , Ranganathan S , Gopalakrishna GS , Tatevian N , Kellermayer R . Further evidence for EpCAM as the gene for congenital tufting enteropathy. Am J Med Genet A 152A: 222‐224, 2010.
 556. Smith A , Bulman DE , Goldsmith C , Bareke E , Consortium FC , Majewski J , Boycott KM , Nikkel SM . Meconium ileus in a Lebanese family secondary to mutations in the GUCY2C gene. Eur J Hum Genet 23: 990‐992, 2015.
 557. Smits WK , Lyras D , Lacy DB , Wilcox MH , Kuijper EJ . Clostridium difficile infection. Nature Reviews Disease Primers 2: 16020, 2016.
 558. Snouwaert JN , Brigman KK , Latour AM , Malouf NN , Boucher RC , Smithies O , Koller BH . An animal model for cystic fibrosis made by gene targeting. Science 257: 1083‐1088, 1992.
 559. Sollid LM , Jabri B . Triggers and drivers of autoimmunity: Lessons from coeliac disease. Nat Rev Immunol 13: 294‐302, 2013.
 560. Sonawane ND , Zhao D , Zegarra‐Moran O , Galietta LJ , Verkman AS . Lectin conjugates as potent, nonabsorbable CFTR inhibitors for reducing intestinal fluid secretion in cholera. Gastroenterology 132: 1234‐1244, 2007.
 561. Sorensen MV , Matos JE , Sausbier M , Sausbier U , Ruth P , Praetorius HA , Leipziger J . Aldosterone increases KCa1.1 (BK) channel‐mediated colonic K+ secretion. J Physiol 586: 4251‐4264, 2008.
 562. Sotak M , Polidarova L , Musilkova J , Hock M , Sumova A , Pacha J . Circadian regulation of electrolyte absorption in the rat colon. Am J Physiol Gastrointest Liver Physiol 301: G1066‐G1074, 2011.
 563. Spicer Z , Clarke LL , Gawenis LR , Shull GE . Colonic H(+)‐K(+)‐ATPase in K(+) conservation and electrogenic Na(+) absorption during Na(+) restriction. Am J Physiol Gastrointest Liver Physiol 281: G1369‐G1377, 2001.
 564. Srinivas SR , Gopal E , Zhuang L , Itagaki S , Martin PM , Fei YJ , Ganapathy V , Prasad PD . Cloning and functional identification of slc5a12 as a sodium‐coupled low‐affinity transporter for monocarboxylates (SMCT2). Biochem J 392: 655‐664, 2005.
 565. Stauber T , Weinert S , Jentsch TJ . Cell biology and physiology of CLC chloride channels and transporters. Compr Physiol 2: 1701‐1744, 2012.
 566. Stepensky P , Bartram J , Barth TF , Lehmberg K , Walther P , Amann K , Philips AD , Beringer O , Zur Stadt U , Schulz A , Amrolia P , Weintraub M , Debatin KM , Hoenig M , Posovszky C . Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18‐2 mutations. Pediatr Blood Cancer 60: 1215‐1222, 2013.
 567. Stoner MC , Kellum JM . Both serotonin and a nitric‐oxide donor cause chloride secretion in rat colonocytes by stimulating cGMP. Surgery 130: 236‐241, 2001.
 568. Strong TV , Boehm K , Collins FS . Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization. J Clin Invest 93: 347‐354, 1994.
 569. Stumpff F . A look at the smelly side of physiology: Transport of short chain fatty acids. Pflugers Arch 470: 571‐598, 2018.
 570. Subramanya SB , Rajendran VM , Srinivasan P , Nanda Kumar NS , Ramakrishna BS , Binder HJ . Differential regulation of cholera toxin‐inhibited Na‐H exchange isoforms by butyrate in rat ileum. Am J Physiol Gastrointest Liver Physiol 293: G857‐G863, 2007.
 571. Sugi K , Musch MW , Field M , Chang EB . Inhibition of Na+,K+‐ATPase by interferon gamma down‐regulates intestinal epithelial transport and barrier function. Gastroenterology 120: 1393‐1403, 2001.
 572. Sullivan S , Alex P , Dassopoulos T , Zachos NC , Iacobuzio‐Donahue C , Donowitz M , Brant SR , Cuffari C , Harris ML , Datta LW , Conklin L , Chen Y , Li X . Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: Potential contributors to IBD‐associated diarrhea. Inflamm Bowel Dis 15: 261‐274, 2009.
 573. Sun H , Harris WT , Kortyka S , Kotha K , Ostmann AJ , Rezayat A , Sridharan A , Sanders Y , Naren AP , Clancy JP . Tgf‐beta downregulation of distinct chloride channels in cystic fibrosis‐affected epithelia. PLoS One 9: e106842, 2014.
 574. Sun J , Chang EB . Exploring gut microbes in human health and disease: Pushing the envelope. Genes Dis 1: 132‐139, 2014.
 575. Sung MW , Waxman S . Combination of cytotoxic‐differentiation therapy with 5‐fluorouracil and phenylbutyrate in patients with advanced colorectal cancer. Anticancer Res 27: 995‐1001, 2007.
 576. Swann JR , Want EJ , Geier FM , Spagou K , Wilson ID , Sidaway JE , Nicholson JK , Holmes E . Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA 108(Suppl 1): 4523‐4530, 2011.
 577. Sweiry JH , Binder HJ . Characterization of aldosterone‐induced potassium secretion in rat distal colon. J Clin Invest 83: 844‐851, 1989.
 578. Talbot C , Lytle C . Segregation of Na/H exchanger‐3 and Cl/HCO3 exchanger SLC26A3 (DRA) in rodent cecum and colon. Am J Physiol Gastrointest Liver Physiol 299: G358‐G367, 2010.
 579. Tamayo R , Pratt JT , Camilli A . Roles of cyclic diguanylate in the regulation of bacterial pathogenesis. Annu Rev Microbiol 61: 131‐148, 2007.
 580. Tang L , Cheng CY , Sun X , Pedicone AJ , Mohamadzadeh M , Cheng SX . Corrigendum: The extracellular calcium‐sensing receptor in the intestine: Evidence for regulation of colonic absorption, secretion, motility, and immunity. Front Physiol 7: 315, 2016.
 581. Tang L , Cheng CY , Sun X , Pedicone AJ , Mohamadzadeh M , Cheng SX . The extracellular calcium‐sensing receptor in the intestine: Evidence for regulation of colonic absorption, secretion, motility, and immunity. Front Physiol 7: 245, 2016.
 582. Tang L , Peng M , Liu L , Chang W , Binder HJ , Cheng SX . Calcium‐sensing receptor stimulates Cl(‐)‐ and SCFA‐dependent but inhibits cAMP‐dependent HCO3(‐) secretion in colon. Am J Physiol Gastrointest Liver Physiol 308: G874‐G883, 2015.
 583. Than BL , Linnekamp JF , Starr TK , Largaespada DA , Rod A , Zhang Y , Bruner V , Abrahante J , Schumann A , Luczak T , Niemczyk A , O'Sullivan MG , Medema JP , Fijneman RJ , Meijer GA , Van den Broek E , Hodges CA , Scott PM , Vermeulen L , Cormier RT . CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene 35: 4179‐4187, 2016.
 584. Thangaraju M , Carswell KN , Prasad PD , Ganapathy V . Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J 417: 379‐389, 2009.
 585. Thiagarajah JR , Donowitz M , Verkman AS . Secretory diarrhoea: Mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol 12: 446‐457, 2015.
 586. Thiagarajah JR , Verkman AS . Water transport in the gastrointestinal tract. In: Said HM , editor. Physiology of the Gastrointestinal Tract. London, UK: Elsevier‐Academic Press, 2018, pp. 1249‐1272.
 587. Thibault R , Blachier F , Darcy‐Vrillon B , de Coppet P , Bourreille A , Segain JP . Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: A transport deficiency. Inflamm Bowel Dis 16: 684‐695, 2010.
 588. Thibault R , De Coppet P , Daly K , Bourreille A , Cuff M , Bonnet C , Mosnier JF , Galmiche JP , Shirazi‐Beechey S , Segain JP . Down‐regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology 133: 1916‐1927, 2007.
 589. Thoeni C , Amir A , Guo C , Zhang S , Avitzur Y , Heng YM , Cutz E , Muise AM . A novel nonsense mutation in the EpCAM gene in a patient with congenital tufting enteropathy. J Pediatr Gastroenterol Nutr 58: 18‐21, 2014.
 590. Thoeni CE , Vogel GF , Tancevski I , Geley S , Lechner S , Pfaller K , Hess MW , Muller T , Janecke AR , Avitzur Y , Muise A , Cutz E , Huber LA . Microvillus inclusion disease: Loss of Myosin vb disrupts intracellular traffic and cell polarity. Traffic 15: 22‐42, 2014.
 591. Thomson RB , Thomson CL , Aronson PS . N‐glycosylation critically regulates function of oxalate transporter SLC26A6. Am J Physiol Cell Physiol 311: C866‐C873, 2016.
 592. Thwaites DT , Anderson CM . H+‐coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol 92: 603‐619, 2007.
 593. Toivola DM , Krishnan S , Binder HJ , Singh SK , Omary MB . Keratins modulate colonocyte electrolyte transport via protein mistargeting. J Cell Biol 164: 911‐921, 2004.
 594. Topping DL , Clifton PM . Short‐chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiol Rev 81: 1031‐1064, 2001.
 595. Tradtrantip L , Namkung W , Verkman AS . Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol 77: 69‐78, 2010.
 596. Tresguerres M , Levin LR , Buck J . Intracellular cAMP signaling by soluble adenylyl cyclase. Kidney Int 79: 1277‐1288, 2011.
 597. Troeger H , Epple HJ , Schneider T , Wahnschaffe U , Ullrich R , Burchard GD , Jelinek T , Zeitz M , Fromm M , Schulzke JD . Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum. Gut 56: 328‐335, 2007.
 598. Tronstad RR , Kummen M , Holm K , von Volkmann HL , Anmarkrud JA , Hoivik ML , Moum B , Gilja OH , Hausken T , Baines J , Karlsen TH , Fiskerstrand T , Hov JR . Guanylate cyclase C activation shapes the intestinal microbiota in patients with familial diarrhea and increased susceptibility for Crohn's disease. Inflamm Bowel Dis 23: 1752‐1761, 2017.
 599. Trucksis M , Conn TL , Wasserman SS , Sears CL . Vibrio cholerae ACE stimulates Ca(2+)‐dependent Cl(‐)/HCO(3)(‐) secretion in T84 cells in vitro. Am J Physiol Cell Physiol 279: C567‐C577, 2000.
 600. Turner JR , Rill BK , Carlson SL , Carnes D , Kerner R , Mrsny RJ , Madara JL . Physiological regulation of epithelial tight junctions is associated with myosin light‐chain phosphorylation. Am J Physiol 273: C1378‐C1385, 1997.
 601. Tyagi S , Venugopalakrishnan J , Ramaswamy K , Dudeja PK . Mechanism of n‐butyrate uptake in the human proximal colonic basolateral membranes. Am J Physiol Gastrointest Liver Physiol 282: G676‐G682, 2002.
 602. Vaandrager AB , Bot AG , De Vente J , De Jonge HR . Atriopeptins and Escherichia coli enterotoxin STa have different sites of action in mammalian intestine. Gastroenterology 102: 1161‐1169, 1992.
 603. Vaandrager AB , Bot AG , Ruth P , Pfeifer A , Hofmann F , De Jonge HR . Differential role of cyclic GMP‐dependent protein kinase II in ion transport in murine small intestine and colon. Gastroenterology 118: 108‐114, 2000.
 604. Vaandrager AB , Hogema BM , de Jonge HR . Molecular properties and biological functions of cGMP‐dependent protein kinase II. Front Biosci 10: 2150‐2164, 2005.
 605. Vajanaphanich M , Schultz C , Rudolf MT , Wasserman M , Enyedi P , Craxton A , Shears SB , Tsien RY , Barrett KE , Traynor‐Kaplan A . Long‐term uncoupling of chloride secretion from intracellular calcium levels by Ins(3,4,5,6)P4. Nature 371: 711‐714, 1994.
 606. van der Doef HPJ , Slieker MG , Staab D , Alizadeh BZ , Seia M , Colombo C , van der Ent CK , Nickel R , Witt H , Houwen RHJ . Association of the CLCA1 p.S357N variant with meconium ileus in European patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 50: 347‐349, 2010.
 607. Vanner S , Macnaughton WK . Submucosal secretomotor and vasodilator reflexes. Neurogastroenterol Motil 16(Suppl 1): 39‐43, 2004.
 608. Vedantam G , Clark A , Chu M , McQuade R , Mallozzi M , Viswanathan VK . Clostridium difficile infection: Toxins and non‐toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes 3: 121‐134, 2012.
 609. Veeze HJ , Sinaasappel M , Bijman J , Bouquet J , de Jonge HR . Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis. Gastroenterology 101: 398‐403, 1991.
 610. Venkatasubramanian J , Selvaraj N , Carlos M , Skaluba S , Rasenick MM , Rao MC . Differences in Ca(2+) signaling underlie age‐specific effects of secretagogues on colonic Cl(‐) transport. Am J Physiol Cell Physiol 280: C646‐C658, 2001.
 611. Verkman AS . Knock‐out models reveal new aquaporin functions. Handb Exp Pharmacol 359‐381, 2009.
 612. Viswanathan VK , Hodges K , Hecht G . Enteric infection meets intestinal function: How bacterial pathogens cause diarrhoea. Nat Rev Microbiol 7: 110‐119, 2009.
 613. Visweswariah SS , Shanthi G , Balganesh TS . Interaction of heat‐stable enterotoxins with human colonic (T84) cells: Modulation of the activation of guanylyl cyclase. Microb Pathog 12: 209‐218, 1992.
 614. Vitek L . Bile acid malabsorption in inflammatory bowel disease. Inflamm Bowel Dis 21: 476‐483, 2015.
 615. Vogel GF , Hess MW , Pfaller K , Huber LA , Janecke AR , Muller T . Towards understanding microvillus inclusion disease. Mol Cell Pediatr 3: 3, 2016.
 616. Walker NM , Flagella M , Gawenis LR , Shull GE , Clarke LL . An alternate pathway of cAMP‐stimulated Cl secretion across the NKCC1‐null murine duodenum. Gastroenterology 123: 531‐541, 2002.
 617. Walker NM , Liu J , Stein SR , Stefanski CD , Strubberg AM , Clarke LL . Cellular chloride and bicarbonate retention alters intracellular pH regulation in Cftr KO crypt epithelium. Am J Physiol Gastrointest Liver Physiol 310: G70‐G80, 2016.
 618. Walker NM , Simpson JE , Yen PF , Gill RK , Rigsby EV , Brazill JM , Dudeja PK , Schweinfest CW , Clarke LL . Down‐regulated in adenoma Cl/HCO3 exchanger couples with Na/H exchanger 3 for NaCl absorption in murine small intestine. Gastroenterology 135: 1645‐1653 e1643, 2008.
 619. Walters JR . Bile acid diarrhoea and FGF19: New views on diagnosis, pathogenesis and therapy. Nat Rev Gastroenterol Hepatol 11: 426‐434, 2014.
 620. Wang D , Zhang H , Lang F , Yun CC . Acute activation of NHE3 by dexamethasone correlates with activation of SGK1 and requires a functional glucocorticoid receptor. Am J Physiol Cell Physiol 292: C396‐C404, 2007.
 621. Wang K , Zhou B , Kuo YM , Zemansky J , Gitschier J . A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71: 66‐73, 2002.
 622. Wang Y , Balvers MGJ , Hendriks HFJ , Wilpshaar T , van Heek T , Witkamp RF , Meijerink J . Docosahexaenoyl serotonin emerges as most potent inhibitor of IL‐17 and CCL‐20 released by blood mononuclear cells from a series of N‐acyl serotonins identified in human intestinal tissue. Biochim Biophys Acta 1862: 823‐831, 2017.
 623. Wang Y , Devkota S , Musch MW , Jabri B , Nagler C , Antonopoulos DA , Chervonsky A , Chang EB . Regional mucosa‐associated microbiota determine physiological expression of TLR2 and TLR4 in murine colon. PLoS One 5: e13607, 2010.
 624. Ward MA , Pierre JF , Leal RF , Huang Y , Shogan B , Dalal SR , Weber CR , Leone VA , Musch MW , An GC , Rao MC , Rubin DT , Raffals LE , Antonopoulos DA , Sogin ML , Hyman NH , Alverdy JC , Chang EB . Insights into the pathogenesis of ulcerative colitis from a murine model of stasis‐induced dysbiosis, colonic metaplasia, and genetic susceptibility. Am J Physiol Gastrointest Liver Physiol 310: G973‐G988, 2016.
 625. Wedenoja S , Pekansaari E , Hoglund P , Makela S , Holmberg C , Kere J . Update on SLC26A3 mutations in congenital chloride diarrhea. Hum Mutat 32: 715‐722, 2011.
 626. Wedlake L , A'hern R , Russell D , Thomas K , Walters JRF , Andreyev HJN . Systematic review: The prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea‐predominant irritable bowel syndrome. Aliment Pharmacol Ther 30: 707‐717, 2009.
 627. Weihrauch D , Kanchanapoo J , Ao M , Prasad R , Piyachaturawat P , Rao MC . Weanling, but not adult, rabbit colon absorbs bile acids: Flux is linked to expression of putative bile acid transporters. Am J Physiol Gastrointest Liver Physiol 290: G439‐G450, 2006.
 628. Weinman EJ , Cunningham R , Shenolikar S . NHERF and regulation of the renal sodium‐hydrogen exchanger NHE3. Pflugers Arch 450: 137‐144, 2005.
 629. Welsh MJ , Smith PL , Fromm M , Frizzell RA . Crypts are the site of intestinal fluid and electrolyte secretion. Science 218: 1219‐1221, 1982.
 630. Wen G , Jin H , Deng S , Xu J , Liu X , Xie R , Tuo B . Effects of Helicobacter pylori infection on the expressions and functional Activities of human duodenal mucosal bicarbonate transport proteins. Helicobacter 21: 536‐547, 2016.
 631. Werlin SL , Benuri‐Silbiger I , Kerem E , Adler SN , Goldin E , Zimmerman J , Malka N , Cohen L , Armoni S , Yatzkan‐Israelit Y , Bergwerk A , Aviram M , Bentur L , Mussaffi H , Bjarnasson I , Wilschanski M . Evidence of intestinal inflammation in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 51: 304‐308, 2010.
 632. Wernick NL , Chinnapen DJ , Cho JA , Lencer WI . Cholera toxin: An intracellular journey into the cytosol by way of the endoplasmic reticulum. Toxins (Basel) 2: 310‐325, 2010.
 633. Wernick NL , De Luca H , Kam WR , Lencer WI . N‐terminal extension of the cholera toxin A1‐chain causes rapid degradation after retrotranslocation from endoplasmic reticulum to cytosol. J Biol Chem 285: 6145‐6152, 2010.
 634. Whittamore JM , Hatch M . The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man. Urolithiasis 45: 89‐108, 2017.
 635. Wiegerinck CL , Janecke AR , Schneeberger K , Vogel GF , van Haaften‐Visser DY , Escher JC , Adam R , Thoni CE , Pfaller K , Jordan AJ , Weis CA , Nijman IJ , Monroe GR , van Hasselt PM , Cutz E , Klumperman J , Clevers H , Nieuwenhuis EE , Houwen RH , van Haaften G , Hess MW , Huber LA , Stapelbroek JM , Muller T , Middendorp S . Loss of syntaxin 3 causes variant microvillus inclusion disease. Gastroenterology 147: 65‐68 e10, 2014.
 636. Wilson C , Lin JE , Li P , Snook AE , Gong J , Sato T , Liu C , Girondo MA , Rui H , Hyslop T , Waldman SA . The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer. Cancer Epidemiol Biomarkers Prev 23: 2328‐2337, 2014.
 637. Wood JD , Galligan JJ . Function of opioids in the enteric nervous system. Neurogastroenterol Motil 16(Suppl 2): 17‐28, 2004.
 638. Worrell RT , Best A , Crawford OR , Xu J , Soleimani M , Matthews JB . Apical ammonium inhibition of cAMP‐stimulated secretion in T84 cells is bicarbonate dependent. Am J Physiol Gastrointest Liver Physiol 289: G768‐G778, 2005.
 639. Worrell RT , Matthews JB . Effects of ammonium on ion channels and transporters in colonic secretory cells. Adv Exp Med Biol 559: 131‐139, 2004.
 640. Worrell RT , Merk L , Matthews JB . Ammonium transport in the colonic crypt cell line, T84: Role for Rhesus glycoproteins and NKCC1. Am J Physiol Gastrointest Liver Physiol 294: G429‐G440, 2008.
 641. Worrell RT , Oghene J , Matthews JB . Ammonium effects on colonic Cl‐ secretion: Anomalous mole fraction behavior. Am J Physiol Gastrointest Liver Physiol 286: G14‐G22, 2004.
 642. Wright EM . Glucose transport families SLC5 and SLC50. Mol Aspects Med 34: 183‐196, 2013.
 643. Wright EM , Loo DD , Hirayama BA . Biology of human sodium glucose transporters. Physiol Rev 91: 733‐794, 2011.
 644. Xia W , Yu Q , Riederer B , Singh AK , Engelhardt R , Yeruva S , Song P , Tian DA , Soleiman M , Seidler U . The distinct roles of anion transporters Slc26a3 (DRA) and Slc26a6 (PAT‐1) in fluid and electrolyte absorption in the murine small intestine. Pflugers Arch 466: 1541‐1556, 2014.
 645. Xiao F , Juric M , Li J , Riederer B , Yeruva S , Singh AK , Zheng L , Glage S , Kollias G , Dudeja P , Tian DA , Xu G , Zhu J , Bachmann O , Seidler U . Loss of downregulated in adenoma (DRA) impairs mucosal HCO3(‐) secretion in murine ileocolonic inflammation. Inflamm Bowel Dis 18: 101‐111, 2012.
 646. Xiao F , Yu Q , Li J , Johansson ME , Singh AK , Xia W , Riederer B , Engelhardt R , Montrose M , Soleimani M , Tian DA , Xu G , Hansson GC , Seidler U . Slc26a3 deficiency is associated with loss of colonic HCO3 (‐) secretion, absence of a firm mucus layer and barrier impairment in mice. Acta Physiol (Oxf) 211: 161‐175, 2014.
 647. Xie W , Kaetzel MA , Bruzik KS , Dedman JR , Shears SB , Nelson DJ . Inositol 3,4,5,6‐tetrakisphosphate inhibits the calmodulin‐dependent protein kinase II‐activated chloride conductance in T84 colonic epithelial cells. J Biol Chem 271: 14092‐14097, 1996.
 648. Xu H , Li J , Chen H , Wang C , Ghishan FK . NHE8 plays important roles in gastric mucosal protection. Am J Physiol Gastrointest Liver Physiol 304: G257‐G261, 2013.
 649. Xu H , Li Q , Zhao Y , Li J , Ghishan FK . Intestinal NHE8 is highly expressed in goblet cells and its expression is subject to TNF‐alpha regulation. Am J Physiol Gastrointest Liver Physiol 310: G64‐G69, 2016.
 650. Xu H , Zhang B , Li J , Chen H , Tooley J , Ghishan FK . Epidermal growth factor inhibits intestinal NHE8 expression via reducing its basal transcription. Am J Physiol Cell Physiol 299: C51‐C57, 2010a.
 651. Xu H , Zhang B , Li J , Chen H , Wang C , Ghishan FK . Transcriptional inhibition of intestinal NHE8 expression by glucocorticoids involves Pax5. Am J Physiol Gastrointest Liver Physiol 299: G921‐G927, 2010b.
 652. Xu H , Zhang B , Li J , Wang C , Chen H , Ghishan FK . Impaired mucin synthesis and bicarbonate secretion in the colon of NHE8 knockout mice. Am J Physiol Gastrointest Liver Physiol 303: G335‐G343, 2012.
 653. Xue J , Askwith C , Javed NH , Cooke HJ . Autonomic nervous system and secretion across the intestinal mucosal surface. Auton Neurosci 133: 55‐63, 2007.
 654. Yang H , Jiang W , Furth EE , Wen X , Katz JP , Sellon RK , Silberg DG , Antalis TM , Schweinfest CW , Wu GD . Intestinal inflammation reduces expression of DRA, a transporter responsible for congenital chloride diarrhea. Am J Physiol 275: G1445‐G1453, 1998.
 655. Yang H , Ma T . Luminally acting agents for constipation treatment: A review based on literatures and patents. Front Pharmacol 8: 418, 2017.
 656. Yang J , Zhao X , Patel A , Potru R , Azizi‐Ghannad S , Dolinger M , Cao J , Bartholomew C , Mazurkiewicz J , Conti D , Jones D , Huang Y , Zhu XC . Rapamycin inhibition of mTOR reduces levels of the Na+/H+ exchanger 3 in intestines of mice and humans, leading to diarrhea. Gastroenterology 149: 151‐162, 2015.
 657. Ye D , Guo S , Al‐Sadi R , Ma TY . MicroRNA regulation of intestinal epithelial tight junction permeability. Gastroenterology 141: 1323‐1333, 2011.
 658. Yeruva S , Farkas K , Hubricht J , Rode K , Riederer B , Bachmann O , Cinar A , Rakonczay Z , Molnar T , Nagy F , Wedemeyer J , Manns M , Raddatz D , Musch MW , Chang EB , Hegyi P , Seidler U . Preserved Na(+)/H(+) exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis. Inflamm Bowel Dis 16: 1149‐1161, 2010.
 659. Yin L , Vijaygopal P , MacGregor GG , Menon R , Ranganathan P , Prabhakaran S , Zhang L , Zhang M , Binder HJ , Okunieff P , Vidyasagar S . Glucose stimulates calcium‐activated chloride secretion in small intestinal cells. Am J Physiol Cell Physiol 306: C687‐C696, 2014.
 660. Young FD , Newbigging S , Choi C , Keet M , Kent G , Rozmahel RF . Amelioration of cystic fibrosis intestinal mucous disease in mice by restoration of mCLCA3. Gastroenterology 133: 1928‐1937, 2007.
 661. Yu K , Lujan R , Marmorstein A , Gabriel S , Hartzell HC . Bestrophin‐2 mediates bicarbonate transport by goblet cells in mouse colon. J Clin Invest 120: 1722‐1735, 2010.
 662. Yun CC , Kumar A . Diverse roles of LPA signaling in the intestinal epithelium. Exp Cell Res 333: 201‐207, 2015.
 663. Zachos NC , Tse M , Donowitz M . Molecular physiology of intestinal Na+/H+ exchange. Annu Rev Physiol 67: 411‐443, 2005.
 664. Zajac M , Dolowy K . Measurement of ion fluxes across epithelia. Prog Biophys Mol Biol 127: 1‐11, 2017a.
 665. Zajac M , Lewenstam A , Dolowy K . Multi‐electrode system for measurement of transmembrane ion‐fluxes through living epithelial cells. Bioelectrochemistry 117: 65‐73, 2017b.
 666. Zdebik AA , Cuffe JE , Bertog M , Korbmacher C , Jentsch TJ . Additional disruption of the ClC‐2 Cl(‐) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models. J Biol Chem 279: 22276‐22283, 2004.
 667. Zeissig S , Bergann T , Fromm A , Bojarski C , Heller F , Guenther U , Zeitz M , Fromm M , Schulzke JD . Altered ENaC expression leads to impaired sodium absorption in the noninflamed intestine in Crohn's disease. Gastroenterology 134: 1436‐1447, 2008.
 668. Zeuthen T . Water‐transporting proteins. J Membr Biol 234: 57‐73, 2010.
 669. Zhang J , Halm ST , Halm DR . Adrenergic activation of electrogenic K+ secretion in guinea pig distal colonic epithelium: Desensitization via the Y2‐neuropeptide receptor. Am J Physiol Gastrointest Liver Physiol 297: G278‐G291, 2009b.
 670. Zhang J , Halm ST , Halm DR . Adrenergic activation of electrogenic K+ secretion in guinea pig distal colonic epithelium: Involvement of beta1‐ and beta2‐adrenergic receptors. Am J Physiol Gastrointest Liver Physiol 297: G269‐G277, 2009a.
 671. Zhang J , Halm ST , Halm DR . Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon. Am J Physiol Gastrointest Liver Physiol 303: G1322‐G1334, 2012.
 672. Zhang W , Zhang X , Zhang YH , Strokes DC , Naren AP . Lumacaftor/ivacaftor combination for cystic fibrosis patients homozygous for Phe508del‐CFTR. Drugs Today (Barc) 52: 229‐237, 2016.
 673. Zhang W , Zhang Z , Zhang Y , Naren AP . CFTR‐NHERF2‐LPA2 complex in the airway and gut epithelia. Int J Mol Sci 18: 1896, 2017.
 674. Zhang Z , Chen J . Atomic structure of the cystic fibrosis transmembrane conductance regulator. Cell 167: 1586‐1597 e1589, 2016.
 675. Zhang Z , Liu F , Chen J . Conformational changes of CFTR upon phosphorylation and ATP binding. Cell 170: 483‐491 e488, 2017.
 676. Zhao W , Caro F , Robins W , Mekalanos JJ . Antagonism toward the intestinal microbiota and its effect on Vibrio cholerae virulence. Science 359: 210‐213, 2018.
 677. Zhu S , Ding S , Wang P , Wei Z , Pan W , Palm NW , Yang Y , Yu H , Li HB , Wang G , Lei X , de Zoete MR , Zhao J , Zheng Y , Chen H , Zhao Y , Jurado KA , Feng N , Shan L , Kluger Y , Lu J , Abraham C , Fikrig E , Greenberg HB , Flavell RA . Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 546: 667‐670, 2017.
 678. Zihni C , Mills C , Matter K , Balda MS . Tight junctions: From simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 17: 564‐580, 2016.
 679. Zizak M , Chen T , Bartonicek D , Sarker R , Zachos NC , Cha B , Kovbasnjuk O , Korac J , Mohan S , Cole R , Chen Y , Tse CM , Donowitz M . Calmodulin kinase II constitutively binds, phosphorylates, and inhibits brush border Na+/H+ exchanger 3 (NHE3) by a NHERF2 protein‐dependent process. J Biol Chem 287: 13442‐13456, 2012.
 680. Zmora N , Zeevi D , Korem T , Segal E , Elinav E . Taking it personally: Personalized utilization of the human microbiome in health and disease. Cell Host Microbe 19: 12‐20, 2016.
 681. Zmora N , Zilberman‐Schapira G , Suez J , Mor U , Dori‐Bachash M , Bashiardes S , Kotler E , Zur M , Regev‐Lehavi D , Brik RB , Federici S , Cohen Y , Linevsky R , Rothschild D , Moor AE , Ben‐Moshe S , Harmelin A , Itzkovitz S , Maharshak N , Shibolet O , Shapiro H , Pevsner‐Fischer M , Sharon I , Halpern Z , Segal E , Elinav E . Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 174: 1388‐1405 e1321, 2018.

 

Teaching Material

M. C. Rao. Physiology of Electrolyte Transport in the Gut: Implications for Disease. Compr Physiol 9: 2019, 947-1022.

Didactic Synopsis

Major Teaching Points:

  1. The intestine's heterogenous structural organization meets its functional demands of daily processing 9 liters of fluid and excreting 100 ml. Muscle layers, vasculature, neural networks, gut-associated lymphoid tissue, the epithelium and the luminal microbiome work in unison to support a healthy intestine.
  2. The epithelium is critical for barrier function and for vectorial transport. Net fluid absorption is via Na+, Cl and solute-dependent mechanisms and secretion via Cl and distal colonic K+ secretory mechanisms. HCO3 secretion maintains pH and mucus production.
  3. MALPINES: Microbial, autocrine, luminal, paracrine, immune, neural, endocrine, signals engage in a complex network to regulate intestinal electrolyte transport.
  4. The molecular identity of ion transporters provide a basis for the nuanced regulation; compartmentalization is key to function.
  5. Disruption in intestinal structure-function components causes disease. Transporter dysfunction arises from infectious or invasive pathogens, genetic abnormalities, inflammation or a combination thereof and results in diarrhea or constipation.
  6. Didactic Legends

    The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.,

    Figure 1 Structure of intestinal epithelia
    Left: Intestinal epithelial cells are structurally and functionally designed for directional transport: (a) The cell membrane is divided into distinct apical and basolateral domains by the tight junctions with an asymmetric distribution of transporters; (b) the sodium pump on the basolateral membrane maintains a low intracellular [Na+] and provides the electrochemical driving force that permits “downhill” entry of Na+ from either surface; (c) water and solutes can cross the epithelium either between (paracellular) or through (transcellular) the cells; P.D.: electrical potential difference in millivolts.
    Bottom left: An expansion of the apical membrane and underlying scaffolding network and the junctional complexes in the paracellular pathway. JAM: Junctional adhesion molecules.
    Right: Architecture of the healthy intestine: Crypt/villus of small intestine and crypt/surface of the large intestine. The epithelial layer contains enterocytes, goblet cells, enteroendocrine cells, Paneth cells and stem cells. Arrows depict directional movement of solutes and water in a normal gut, where absorption prevails. Bars represent relative distribution of ion transporters along the axes (blue grey for small intestine and green grey for colon). Pump: Na+/K+ ATPase; PAT1: putative anion transporter; SGLT1: Sodium-dependent glucose cotransporter; NHE1 and NHE3: Na+/H+ Exchanger-1 and -3; CFTR: cystic fibrosis transmembrane regulator; DRA: down regulated in adenoma; cHKA: colonic H+/K+ ATPase; ois: ouabain-insensitive; os: ouabain-sensitive; KCNMA1: K+ channel; ENaC: Epithelial Na+ channel.

    Figure 2 Regulation of ion transport by MALPINES
    This model depicts the many regulatory systems that influence intestinal function. Left: The villus crypt architecture allows a rich supply of blood vessels, nerves and gut-associated lymphoid tissue (GALT) to the epithelium. Right: Enlarged section of epithelium to depict MALPINES:: Lumen has Microbes (commensal and pathogenic); can release Autocrine factors which can act apically and basolaterally; presence of other Luminal factors such as bile acids, food, bacterial toxins and viruses; secreted factors could act in a Paracrine fashion; the subepithelium has the unique Immune tissue, GALT; the tissue is richly supplied with the enteric Nervous system which has secretomotor and interneurons; and enterochromaffin cells and blood vessels provide Endocrine substances and all of them together form an integrated regulatory System. The epithelium has a layer of mucus that acts as the first line of defense. For example, intraluminal mechanical/chemical stimuli could trigger interneurons in the nerve plexuses to release acetylcholine (Ach) that acts on epithelial cells to alter ion transport or on muscle cells to alter motility. Immune cells could be triggered to release prostaglandins (PG) that act on the epithelial cell to alter function.

    Figure 3 Electrolyte absorption
    The transepithelial absorption of Na+, Cl, K+ and SCFA.
    A. Sodium and chloride absorption: Sodium entry across the AM, down the electrochemical gradient and can occur by (right to left): Na+-solute carriers like SGLT1, transporting glucose; Na+ channels in the distal colon; and Na+/H+ exchangers (e.g. NHE2, NHE3, NHE8) in the small intestine and in the proximal colon. Cl can enter the cell via Cl/HCO3 exchangers (PAT-1 in the small intestine and DRA in the colon). On the BLM (right to left), sodium leaves the cell via the Na+/K+ ATPase and BLM K+ channels (KCNN4; KCNQ1/KCNE3; see 3B). HCO3 can enter the cell via BLM NBCe transporters. Glucose exits the BLM via facilitated diffusion transporters (Glut-2), and Cl via channels (CLC2). Cl moves passively through the paracellular pathway or via cellular transporters. BLM NHEs (e.g. NHE1) perform housekeeping functions such as maintenance of intracellular pH. Water transport can be transcellular, via aquaporins or cotransporters such as SGLT1,or paraceullar. Increases in intracellular cAMP, cGMP or Ca2+ can inhibit Na and Cl absorption.
    B. Potassium absorption: Transepithelial absorption of K+ is passive in the small intestine and occurs paracellularly. In the distal colon (shown here), apical H+/K+ ATPase pumps absorb K+ especially when luminal concentrations are > 25 mEq/L. K+ channels are critical for maintaining the membrane potential and are the major conduit for exit of K+ entering the cell via the pump. Basolateral channels include KCNN4 and KCNQ1/KCNE3).
    C. Short-chain fatty acids (SCFA) absorption: SCFAs are generated by luminal bacteria. At the luminal pH, SCFA are generally ionized and enter the cell via the monocarboxylate transporters (MCTs). Some protonated SCFA (SCFAH) can also diffuse across the AM of colonocytes. SCFA can also traverse by the paracellular pathway. While most SCFA are used by colonocytes as a source of metabolic energy, they can also be transported by different BLM MCT transporters.

    Figure 4 Electrolyte secretion
    The major ions secreted are Cl and HCO3 throughout the length of the intestine and K+ in the distal colon.
    A. Cl secretion: Cl enters the basolateral membrane via a 1Na+:1K+:2Cl cotransporter, and is energized by the BLM Na+/K+ ATPase and K+ channel and accumulates in the cell above its electrochemical equilibrium. An apical Cl channel is responsible for Cl exit, with Na+ and water following passively. In many cells HCO3 can also be transported via the channel. Increases in intracellular cAMP, cGMP or Ca2+ stimulate intestinal Cl secretion by activating one or more of these transporters.
    B. K+ secretion: Active transepithelial secretion of K+ occurs through the KCNMA1 channels in the distal colon. K+ is an important contributor to colonic ion secretion and occurs especially when luminal concentrations are < 25 mEq/L. K+ enters the cell via the pump and Na+:K+:Cl cotransport. In the rest of the intestine, the K+ channels, including BLM, KCNN4 and KCNQ1/KCNE3, are critical for maintaining the membrane potential and for the efflux of K+ entering the cell.

    Figure 5 Cyclic nucleotide signaling
    Cyclic nucleotide-mediated transduction of an external signal into a change in cellular function minimally involve: Receptor; cyclase (xC); cyclic nucleotide (cXMP); protein kinase (PK); target phosphorylatable protein; the proteins may be in close proximity and compartmentalized, allowing for localized effects.
    A. Cyclic adenosine monophosphate (cAMP): Stimulatory (e.g., VIP/PG or bile acids) agents bind to specific membrane G-protein coupled receptors (GPCRs) to activate Gas to stimulate membrane adenylate cyclase (AC), while inhibitory (somatostatin) agents bind to their receptors to activate Gai which inhibits AC. Cyclic AMP can also be generated by soluble AC (sAC) activated by Ca2+ and HCO3. The cAMP stimulates ion secretion and inhibit absorption.
    B. Cyclic guanosine monophosphate (cGMP): Some agents (e.g., STa, guanylin) bind to guanylate cyclase (mGC, a.k.a.GUCY2C) where a single molecule has both receptor and enzymatic activity. Activation of GUCY2C results in the production of cGMP from GTP. Cyclic GMP can also be produced from soluble GC (sGC). The cGMP stimulates ion secretion and inhibit absorption.

    Figure 6 Ca2+-dependent signaling pathways
    Neurotransmitters and hormones activate secretion and inhibit absorption (transporters not shown) by elevating [Ca2+]i. This then triggers either calmodulin or PKC pathways to alter secretion. Ca2+ signaling is transient.

    Figure 7 Cystic Fibrosis and CFTR
    Inset: This shows the topology of CFTR. The protein is normally trafficked to the apical membrane via the endoplasmic reticulum-trans Golgi network. The majority of CF patients carry a dF508 deletion which results in the protein, being targeted for degradation.

    Figure 8 Actions of Vibrio cholerae
    In the host V. cholerae maintains a dynamic equilibrium between a sessile state in a biofilm (grey and green ovals) and a motile (free vibrio) state. These are governed by the luminal concentrations of bile and HCO3. The motile V. cholerae produce many toxins including a zona occludens toxin (ZOT), that reversibly increases paracellular permeability (see Figure ) and the main AB5 enterotoxin (CT) which acts on the cell machinery to stimulate ion secretion.

    Figure 9 Actions of enteropathogenic Escherichia coli (EPEC)
    EPEC act by adhering to the host cell, effacing the microvilli, recruiting host cell cytoskeletal machinery to form a characteristic attaching and effacing lesion (A/E Lesion). EPEC utilizes a Type III secretion system (T3SS) to inject effector molecules, into the host cell. These factors coopt different intracellular signaling cascades, to affect host cell permeability and inhibit Na, glucose and Cl absorption.

    Figure 10 Model of Inflammatory Bowel Disease (IBD)
    There are two major forms of IBD ulcerative colitis (UC) and Crohn's disease (CD). UC is generally restricted to the colon; it begins in the rectum and spreads proximally in a continuous fashion and often involves only the mucosa and submucosa (right middle inset). CD is more prevalent in the distal small intestine and colon, but can affect the entire length of the GI tract; it can involve all layers of the gut wall, is discontinuous in its distribution and microbial translocation is more prevalent (right middle inset). Genetics, the host immune system, environmental factors such as diet, loss of epithelium integrity, and changes in the microbiome, contribute to IBD pathogenesis(right upper insert). Diarrhea is mainly due to an inhibition and loss of absorptive pathways: left hand cell is normal healthy cell, right hand cell shows an initial decrease in Na+ and Cl absorption and central cells, loss of function and barrier integrity in advanced stages. There is an increase in paracellular permeability resulting in luminal contents accessing and activating the gut associated lymphoid tissue (GALT) and conversely immune cells migrating to the lumen.

    Figure 11 Model of celiac disease
    Gluten is made up of gliadins rich in glutamine and proline, which are not readily digested by humans. Gliadins traverse the epithelium by at least two routes: initially, paracellularly and later transcellularly. Enlargement on the right: shows the paracellular path and the mechanisms involving secretion of zonulin. Diagram on the right: The subepithelial space shows the immune reactions activated by the gliadin breakdown product, glutamic acid. The cell in the middle shows the cellular path, involving IgA-mediated transcellular transport.

    Figure 12 Flow chart of intestinal malfunction in CF
    The genetic defect leading to impaired Cl and HCO3 secretion leads to a series of interrelated events resulting in intestinal dysbiosis and inspissation. (A): Non-CF intestine: The non-CF intestine has a balanced fluid secretion and a protective fluid mucus layer with expanded mucins (green strings). (B-H): CF Intestine: A defective cf gene (e.g. dF508) leads to defective CFTR protein processing and no expression (B). This leads to decreased fluid secretion (C) resulting in altered pH and luminal milieu and improper mucin unfolding (D). The improper folding of mucins leads to a thick mucus and impaired mucus clearance (E). The altered luminal milieu leads to change in the microbial composition and makes the barrier leaky (F). This results in immune system dysfunction (G) and intestinal obstruction (H).

    Figure 13 Bile acid action on Cl secretion
    Middle Cell: Normal colonic crypt cell depicting CFTR Cl channel in the AM, Na+/K=ATPase, Na+/K+/Cl cotransporter, K+ channel in the BLM. Left hand cell: Chenodeoxycholic acid (CDCA) stimulates CFTR-mediated Cl secretion by cross talk between cAMP and Ca2+-dependent signaling pathways, (left cell). It also affects the barrier permeability. Right Hand Cell: The dehydroxylated derivative of CDCA, lithocholic acid (LCA) drastically blunts these actions. CDCA decreases the pore and increases the leak function of the paracellular pathway. LCA blocks the leak but not pore function of the pathway.

    Figure 14 Actions of rotavirus on ion transport
    Rotaviruses are non-enveloped, double-stranded RNA, coding for 6 structural and 6 non-structural (NSP1-6)proteins. Upon infection of the host cell, the virus elaborates an enterotoxin, NSP4 which elicits Cl secretion via a Ca2+- pathway that stimulates TMEM16A, largely in the intestines of young animals. The NSP-stimulated increases in Ca2+, also affect paracellular permeability, cause inflammation and via brain-mediated reflexes can trigger pain and nausea.

 


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Mrinalini C. Rao. Physiology of Electrolyte Transport in the Gut: Implications for Disease. Compr Physiol 2019, 9: 947-1023. doi: 10.1002/cphy.c180011