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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.
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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