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Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease

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ABSTRACT

SLC26 family members are multifunctional transporters of small anions, including Cl, HCO3, sulfate, oxalate, and formate. Most SLC26 isoforms act as secondary (coupled) anion transporters, while others mediate uncoupled electrogenic transport resembling Cl channels. Of the 11 described SLC26 isoforms, the SLC26A1,2,3,6,7,9,11 are expressed in the gastrointestinal tract, where they participate in salt and water transport, surface pH‐microclimate regulation, affect the microbiome composition, the absorption, and secretion of oxalate and sulfate, and other functions that require further study. Several intestinal or extra‐intestinal diseases are related to SLC26A mutations. Patients with congenital chloride diarrhea (CLD) suffer from Cl‐rich acidic diarrhea and systemic alkalosis due to SLC26A3 mutations. Patients with osteochondrodysplastic syndromes experience skeletal defects due to SLC26A2 mutations, resulting in defective sulfate absorption in enterocytes and sulfate uptake in chondrocytes. Because of functional interactions between SLC26 and other proteins, such as the Cl channel CFTR, some of the intestinal cystic fibrosis manifestations may be attributed to impaired SLC26 isoform localization and function. The altered expression of SLC26 members due to inflammation or operative procedures have important consequences on intestinal transport and barrier function in common diseases as inflammatory bowel disease or bariatric surgery. The present review gives an overview on the current state of knowledge of the intestinally expressed SLC26A isoforms (SLC26A1,2,3,6,7,9,11) from the history of their functional identification, cloning and expression, the insights into their function, interaction partners and regulation gained in heterologous expression systems and Slc26a‐deficient mice, to information about their transcriptional regulation and roles in gastrointestinal disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:839‐872, 2019.

Figure 1. Figure 1. In 1970, Turnberg and co‐workers described their view on ileal salt and water absorption in a cartoon that best explained their findings obtained in double balloon intestinal perfusion studies in normal subjects. Na+ is absorbed from the lumen in exchange for protons, Cl is absorbed in exchange for HCO3 , luminal H+, and HCO3 form CO2 and water, CO2 permeates back into the enterocyte, water follows the absorbed electrolytes following the osmotic gradient. Based on Turnberg et al., 1970 () with permission.
Figure 2. Figure 2. (A) In 1985, Knickelbein, Aronson and co‐workers described their model of the coupling of the ileal brush border membrane Na+/H+ and the Cl/HCO3 exchanger during intestinal salt absorption. They isolated brush border membrane vesicles from rabbit ileum, loaded the vesicles with buffers of defined ionic conditions, and utilized isotope flux studies and a rapid filtration technique to determine pH‐gradient driven, carbonic anhydrase (CA)‐dependent vesicular Cl uptake. They were able to localize CA activity to the apical membrane. The cartoon is reproduced from the original report by Knickelbein et al., with permission of the publisher (). (B) We now know that cytoplasmic CAII is tethered close to the intracellular transport site of many acid/base transporters, and membrane‐bound CAs are found at the luminal membranes of enterocytes, with their catalytic domain in the extracellular space. The rapid generation of H+ or HCO3 destined for transport, as well as the rapid removal of protons or base from the ion‐binding site, will allow a rapid movement of protons or base through an acid/base transport system and has been shown to increase the transport rate several fold.
Figure 3. Figure 3. Dendrogram of the SLC26A family of multifunctional anion transporters. The first members of the family were cloned by different strategies, either by expression cloning like SLC26A1 (SAT‐1), by fine‐structure linkage disequilibrium mapping and positional cloning like SLC26A2 (DSDTS), 4 (Pendrin) and 5 (Prestin), by subtraction analysis of DNA libraries like SLC26A3 (DRA), etc. and therefore have alternative names, which are still preferentially used. CFEX, chloride‐formate exchange; CLD, chloride‐losing diarrhea; DRA, downregulated in adenoma; DTDST, diastrophic dysplasia sulfate transporter; KBAT, kidney brain anion transporter; PAT1, putative anion transporter 1; PDS, Pendred syndrome; SAT1, sulfate anion transporter 1. Other members were cloned by computer‐assisted search of EST sequences and have only the SLC26A names. The green text indicates human diseases linked to mutations or polymorphisms in the respective SLC26A gene, the magenta text described phenotypes observed in Slc26a knockout or mutant mice.
Figure 4. Figure 4. Schematic diagram of the intestinal/renal sulfate absorption and oxalate secretion. The electrogenic Na+‐sulfate cotransporter Slc13a1 (NaS1) is highly expressed in the brush border membrane of small intestinal and proximal tubule epithelial cells, while Slc26a1 (Sat1) is expressed in the basolateral membrane. Mice that are defective for either transporter are hyposulfatemic, indicating that NaS1 is responsible for uptake of sulfate from the lumen and Sat1 for export into the circulation. Interestingly, Sat1 knockout mice are also hyperoxalemic and develop oxalate kidney stones, irrespective of the oxalate in the diet. The apically located Slc26a6 (PAT1, CFEX) also transports oxalate, and Slc26a6−/− mice also develop oxalate kidney stones, but only on a high oxalate diet. One explanation for these findings may be that Slc26a1 imports oxalate from the circulation into the intestinal/proximal tubule cells and Slc26a6 exports it into the lumen. The counter ions are most likely Cl or HCO3 , depending on the pH in the lumen. The cartoon is from Markovich 2012, with permission from the author and the publisher ().
Figure 5. Figure 5. Involvement of PDZ‐domain proteins in the membrane trafficking of SLC26A3. SLC26A3 is endocytosed in a PDZ‐independent manner and sorted in Rab5‐positive early endosomes (EE) where it interacts with Sorting Nexin 27 (SNX27). The initially presumed recycling pathway of SLC26A3 via Rab11‐positive recycling endosomes (RE) requires additional PDZ adapter proteins. Additionally, SNX27 is involved in an alternative, direct recycling pathway and the association of SLC26A3 with lipid rafts. SLC26A3 can also be sorted into Rab7‐positive late endosomes (LE) followed by lysosomal degradation (courtesy of Karen Bannert, University of Rostock).
Figure 6. Figure 6. Loss of firmly adherent mucus layer, altered HCO3 and fluid transport, and high intracellular pH in the enterocytes of the Slc26a3−/− mid‐distal murine colon. (A) Muc2A immunostaining of mucus granules within the goblet cells and at the mucosal surface of wt and Slc26a3−/− mid‐distal murine colon. (B) Time course of JHCO3 in the mid‐distal colon of anaesthetized wt and Slc26a3−/− mice before and after treatment with 100 µmol/L FSK. (C) Colonic fluid absorption measured in vivo was robust in wt colon and strongly inhibited by FSK. In contrast, no fluid absorption was observed in Slc26a3−/− colon. (D) Distribution of enterocytes and goblet cells at the cryptal surface of wt mid‐distal murine colon. Goblet cells (yellow cells) produce and release mucus granules (blue circles) accumulated further in continuous stratified mucus layer that adheres to the epithelium of the wt colon and an outer mucus layer. Fluid absorption is directed by NHE3, while HCO3 secretion is conducted via Slc26a3 (DRA). (E) In Slc26a3−/− mid‐distal murine colon the adherent mucus layer is absent and the outer mucus flows into the lumen of the colon. Due to absence of the Slc26a3 (DRA) the HCO3 secretion is diminished. No fluid absorption was observed in Slc26a3−/− colon, despite a strong upregulation of the expression of the sodium absorptive transporters NHE3 and ENaC. One reason for this may be the high intracellular pH (pHi) in the Slc26a3−/− colonic surface cells (pHi∼7.5), resulting in lack of NHE3 activation. See text for further details. Image based on observations from Xiao et al. () with permission.
Figure 7. Figure 7. Strong increase in the number of colonic lymphoid aggregates and reduced survival in Slc26a3 −/− mice after low concentration of dextrane sodium sulfate (DSS) exposure. (A) Slc26a3−/− mice displayed strongly reduced survival during the DSS drinking period, even though the DSS concentration was low and elicited very mild inflammatory changes in the mucosa of wt mice. (B) H&E stain of the colon of Slc26a3 −/− and wt littermates after exposure to 2% DSS in the drinking water. A strong increase in the number of large lymphoid aggregates was observed both in the mucosa and submucosa in the colon of the Slc26a3−/− mice (C). The cartoons describe the aforementioned findings in (D) wt mice and (E) Slc26a3−/− mice. Image based on observations from Xiao et al. () with permission.
Figure 8. Figure 8. Significant decrease of DRA expression in the inflamed colonic mucosa. (A) Hematoxylin and eosin staining of the mid colon of TNF‐α overexpressing mice. Although the maximal inflammation occurs in the distal ileum, the mid‐colonic mucosa shows elevated proinflammatory cytokine expression levels (B). (C) mRNA expression for DRA, CFTR, and NHE3 in the mid‐colon of TNF+/ΔARE (□) compared to TNF+/+ (▪) mid‐colon. (D) Immunofluorescence of DRA (green) in TNF+/ΔARE and TNF+/+ mice mid‐colon. DRA fluorescence is decreased in the apical membrane of colonic enterocytes of TNF+/ΔARE compared to TNF+/+ (scale bars = 10 μm). A representative of three different experiments is shown. Modified from Xiao et al., 2012, with permission of the publisher ().
Figure 9. Figure 9. Expression of Slc26a9 in the murine gastric mucosa. The cellular expression pattern and physiological function of Slc26a9 in the gastric mucosa is not fully understood. (A) Immunostaining demonstrated strong expression of Slc26a9 in the gastric surface cells, with very faint expression in the H+/K+‐positive parietal cells, and only weak overlap of Slc26a9 and H+/K+‐ATPase (B, white arrows). Reprinted from Chang et al., 2009, with permission of the publisher (). (C) Because the antibody was not tested in Slc26a9 −/− tissue and because Slc26a9 was discussed as the parietal cell Cl conductance activated during acid secretion, laser capture dissection of the total gastric glands, the upper third, and the lower third of the gland area was performed. Slc26a9 mRNA expression was quantified in these three areas, and compared with the mRNA expression of H+/K+‐ATPase (parietal cell expression), Muc5a (mucus neck and surface cell expression), and NHE2 (surface cell expression > gland expression). The mRNA expression of the total gland area was set to 1. The results are also not compatible with a predominantly parietal cell expression. See text for further details. Courtesy of Riederer, B., 2018, with permission.
Figure 10. Figure 10. Schematic diagram of cellular composition and acid/base transporter expression along the jejunal crypt‐villus axis and its effect on cellular HCO3 and fluid output. Renewal of the intestinal epithelia is driven by intestinal stem cells (ISCs). ISCs are located at the base of the crypt, either at the +4 position counting from the bottom of the crypt (yellow, Bmi‐1 stem cells) directly above the Paneth cells (blue), or as crypt base columnar (CBC) cells (red, Lgr5 + stem cells) located between the Paneth cells, whereas progenitor cells (rose) arise from the self‐renewing CBCs. As intestinal epithelial cells differentiate and move toward the villus tip, the expression profile of acid/base, electrolyte and nutrient (not shown) transporters changes dramatically. The diagram shows how this will affect CFTR‐dependent and ‐independent luminal HCO3 output. The transporter names are abbreviated as commonly used. In the crypt and “CFTR high expresser” enterocytes, high CFTR expression and no SLC26A3/6 expression is observed in the apical membrane, and high NKCC1, but no NBC expression in the basolateral membrane. These cells are capable of high Cl secretory rates, and in conjunction with cation and water permeable claudin‐2, of high NaCl and water flux into the lumen, but the HCO3 concentration in this secretion will be low. Villus enterocytes display low CFTR, but high SLC26A3/6 expression in the apical, and high NBC, but low NKCC1 expression in the basolateral membrane. In the basal state, these cells absorb Na+, Cl, and HCO3 via NHE3 and SLC26A3/6, but if secretagogues raise intracellular cyclic nucleotide and possibly Ca2+ concentrations, proton export via NHE3 is inhibited, while SLC26‐mediated HCO3 export is ongoing. The Cl is recycled into the lumen via CFTR. This type of HCO3 output into the lumen need not be accompanied by fluid secretion. If stimulation of secretion results in a strong decrease of intracellular Cl concentrations, the WNK pathway may be activated that will increase the HCO3 permeability of CFTR. See text for further details.
Figure 11. Figure 11. Schematic diagram of cellular composition and acid/base transporter expression along the colonic crypt‐villus axis and its effect on cellular HCO3 and fluid output. The ISC zone and partially differentiated enterocytes and goblet cells are located in the lower part of the colonic crypt. ISCs are presented by Bmi‐1 cells (yellow) and crypt base columnar (CBC) cells (red, Lgr5 + stem cells). Colonic cryptal cells express high levels of CFTR in the apical and NKCC1 in the basolateral membrane and therefore secrete a Cl‐rich HCO3 poor fluid. When CFTR is absent or defective, cryptal enterocyte pH is significantly increased, because the high [Cl‐]I inhibits basolateral HCO3 i/Cl o exchange via AE2 (). CFTR expression dramatically decreases toward the cryptal mouth and surface cells region, while SLC26A3 expression is upregulated. Deletion of SLC26A3 results in extremely low colonic HCO3 alkalization rates, while that of CFTR has a minor effect, suggesting that SLC26A3 is the major colonic HCO3 output pathway and its action is largely independent of CFTR expression.


Figure 1. In 1970, Turnberg and co‐workers described their view on ileal salt and water absorption in a cartoon that best explained their findings obtained in double balloon intestinal perfusion studies in normal subjects. Na+ is absorbed from the lumen in exchange for protons, Cl is absorbed in exchange for HCO3 , luminal H+, and HCO3 form CO2 and water, CO2 permeates back into the enterocyte, water follows the absorbed electrolytes following the osmotic gradient. Based on Turnberg et al., 1970 () with permission.


Figure 2. (A) In 1985, Knickelbein, Aronson and co‐workers described their model of the coupling of the ileal brush border membrane Na+/H+ and the Cl/HCO3 exchanger during intestinal salt absorption. They isolated brush border membrane vesicles from rabbit ileum, loaded the vesicles with buffers of defined ionic conditions, and utilized isotope flux studies and a rapid filtration technique to determine pH‐gradient driven, carbonic anhydrase (CA)‐dependent vesicular Cl uptake. They were able to localize CA activity to the apical membrane. The cartoon is reproduced from the original report by Knickelbein et al., with permission of the publisher (). (B) We now know that cytoplasmic CAII is tethered close to the intracellular transport site of many acid/base transporters, and membrane‐bound CAs are found at the luminal membranes of enterocytes, with their catalytic domain in the extracellular space. The rapid generation of H+ or HCO3 destined for transport, as well as the rapid removal of protons or base from the ion‐binding site, will allow a rapid movement of protons or base through an acid/base transport system and has been shown to increase the transport rate several fold.


Figure 3. Dendrogram of the SLC26A family of multifunctional anion transporters. The first members of the family were cloned by different strategies, either by expression cloning like SLC26A1 (SAT‐1), by fine‐structure linkage disequilibrium mapping and positional cloning like SLC26A2 (DSDTS), 4 (Pendrin) and 5 (Prestin), by subtraction analysis of DNA libraries like SLC26A3 (DRA), etc. and therefore have alternative names, which are still preferentially used. CFEX, chloride‐formate exchange; CLD, chloride‐losing diarrhea; DRA, downregulated in adenoma; DTDST, diastrophic dysplasia sulfate transporter; KBAT, kidney brain anion transporter; PAT1, putative anion transporter 1; PDS, Pendred syndrome; SAT1, sulfate anion transporter 1. Other members were cloned by computer‐assisted search of EST sequences and have only the SLC26A names. The green text indicates human diseases linked to mutations or polymorphisms in the respective SLC26A gene, the magenta text described phenotypes observed in Slc26a knockout or mutant mice.


Figure 4. Schematic diagram of the intestinal/renal sulfate absorption and oxalate secretion. The electrogenic Na+‐sulfate cotransporter Slc13a1 (NaS1) is highly expressed in the brush border membrane of small intestinal and proximal tubule epithelial cells, while Slc26a1 (Sat1) is expressed in the basolateral membrane. Mice that are defective for either transporter are hyposulfatemic, indicating that NaS1 is responsible for uptake of sulfate from the lumen and Sat1 for export into the circulation. Interestingly, Sat1 knockout mice are also hyperoxalemic and develop oxalate kidney stones, irrespective of the oxalate in the diet. The apically located Slc26a6 (PAT1, CFEX) also transports oxalate, and Slc26a6−/− mice also develop oxalate kidney stones, but only on a high oxalate diet. One explanation for these findings may be that Slc26a1 imports oxalate from the circulation into the intestinal/proximal tubule cells and Slc26a6 exports it into the lumen. The counter ions are most likely Cl or HCO3 , depending on the pH in the lumen. The cartoon is from Markovich 2012, with permission from the author and the publisher ().


Figure 5. Involvement of PDZ‐domain proteins in the membrane trafficking of SLC26A3. SLC26A3 is endocytosed in a PDZ‐independent manner and sorted in Rab5‐positive early endosomes (EE) where it interacts with Sorting Nexin 27 (SNX27). The initially presumed recycling pathway of SLC26A3 via Rab11‐positive recycling endosomes (RE) requires additional PDZ adapter proteins. Additionally, SNX27 is involved in an alternative, direct recycling pathway and the association of SLC26A3 with lipid rafts. SLC26A3 can also be sorted into Rab7‐positive late endosomes (LE) followed by lysosomal degradation (courtesy of Karen Bannert, University of Rostock).


Figure 6. Loss of firmly adherent mucus layer, altered HCO3 and fluid transport, and high intracellular pH in the enterocytes of the Slc26a3−/− mid‐distal murine colon. (A) Muc2A immunostaining of mucus granules within the goblet cells and at the mucosal surface of wt and Slc26a3−/− mid‐distal murine colon. (B) Time course of JHCO3 in the mid‐distal colon of anaesthetized wt and Slc26a3−/− mice before and after treatment with 100 µmol/L FSK. (C) Colonic fluid absorption measured in vivo was robust in wt colon and strongly inhibited by FSK. In contrast, no fluid absorption was observed in Slc26a3−/− colon. (D) Distribution of enterocytes and goblet cells at the cryptal surface of wt mid‐distal murine colon. Goblet cells (yellow cells) produce and release mucus granules (blue circles) accumulated further in continuous stratified mucus layer that adheres to the epithelium of the wt colon and an outer mucus layer. Fluid absorption is directed by NHE3, while HCO3 secretion is conducted via Slc26a3 (DRA). (E) In Slc26a3−/− mid‐distal murine colon the adherent mucus layer is absent and the outer mucus flows into the lumen of the colon. Due to absence of the Slc26a3 (DRA) the HCO3 secretion is diminished. No fluid absorption was observed in Slc26a3−/− colon, despite a strong upregulation of the expression of the sodium absorptive transporters NHE3 and ENaC. One reason for this may be the high intracellular pH (pHi) in the Slc26a3−/− colonic surface cells (pHi∼7.5), resulting in lack of NHE3 activation. See text for further details. Image based on observations from Xiao et al. () with permission.


Figure 7. Strong increase in the number of colonic lymphoid aggregates and reduced survival in Slc26a3 −/− mice after low concentration of dextrane sodium sulfate (DSS) exposure. (A) Slc26a3−/− mice displayed strongly reduced survival during the DSS drinking period, even though the DSS concentration was low and elicited very mild inflammatory changes in the mucosa of wt mice. (B) H&E stain of the colon of Slc26a3 −/− and wt littermates after exposure to 2% DSS in the drinking water. A strong increase in the number of large lymphoid aggregates was observed both in the mucosa and submucosa in the colon of the Slc26a3−/− mice (C). The cartoons describe the aforementioned findings in (D) wt mice and (E) Slc26a3−/− mice. Image based on observations from Xiao et al. () with permission.


Figure 8. Significant decrease of DRA expression in the inflamed colonic mucosa. (A) Hematoxylin and eosin staining of the mid colon of TNF‐α overexpressing mice. Although the maximal inflammation occurs in the distal ileum, the mid‐colonic mucosa shows elevated proinflammatory cytokine expression levels (B). (C) mRNA expression for DRA, CFTR, and NHE3 in the mid‐colon of TNF+/ΔARE (□) compared to TNF+/+ (▪) mid‐colon. (D) Immunofluorescence of DRA (green) in TNF+/ΔARE and TNF+/+ mice mid‐colon. DRA fluorescence is decreased in the apical membrane of colonic enterocytes of TNF+/ΔARE compared to TNF+/+ (scale bars = 10 μm). A representative of three different experiments is shown. Modified from Xiao et al., 2012, with permission of the publisher ().


Figure 9. Expression of Slc26a9 in the murine gastric mucosa. The cellular expression pattern and physiological function of Slc26a9 in the gastric mucosa is not fully understood. (A) Immunostaining demonstrated strong expression of Slc26a9 in the gastric surface cells, with very faint expression in the H+/K+‐positive parietal cells, and only weak overlap of Slc26a9 and H+/K+‐ATPase (B, white arrows). Reprinted from Chang et al., 2009, with permission of the publisher (). (C) Because the antibody was not tested in Slc26a9 −/− tissue and because Slc26a9 was discussed as the parietal cell Cl conductance activated during acid secretion, laser capture dissection of the total gastric glands, the upper third, and the lower third of the gland area was performed. Slc26a9 mRNA expression was quantified in these three areas, and compared with the mRNA expression of H+/K+‐ATPase (parietal cell expression), Muc5a (mucus neck and surface cell expression), and NHE2 (surface cell expression > gland expression). The mRNA expression of the total gland area was set to 1. The results are also not compatible with a predominantly parietal cell expression. See text for further details. Courtesy of Riederer, B., 2018, with permission.


Figure 10. Schematic diagram of cellular composition and acid/base transporter expression along the jejunal crypt‐villus axis and its effect on cellular HCO3 and fluid output. Renewal of the intestinal epithelia is driven by intestinal stem cells (ISCs). ISCs are located at the base of the crypt, either at the +4 position counting from the bottom of the crypt (yellow, Bmi‐1 stem cells) directly above the Paneth cells (blue), or as crypt base columnar (CBC) cells (red, Lgr5 + stem cells) located between the Paneth cells, whereas progenitor cells (rose) arise from the self‐renewing CBCs. As intestinal epithelial cells differentiate and move toward the villus tip, the expression profile of acid/base, electrolyte and nutrient (not shown) transporters changes dramatically. The diagram shows how this will affect CFTR‐dependent and ‐independent luminal HCO3 output. The transporter names are abbreviated as commonly used. In the crypt and “CFTR high expresser” enterocytes, high CFTR expression and no SLC26A3/6 expression is observed in the apical membrane, and high NKCC1, but no NBC expression in the basolateral membrane. These cells are capable of high Cl secretory rates, and in conjunction with cation and water permeable claudin‐2, of high NaCl and water flux into the lumen, but the HCO3 concentration in this secretion will be low. Villus enterocytes display low CFTR, but high SLC26A3/6 expression in the apical, and high NBC, but low NKCC1 expression in the basolateral membrane. In the basal state, these cells absorb Na+, Cl, and HCO3 via NHE3 and SLC26A3/6, but if secretagogues raise intracellular cyclic nucleotide and possibly Ca2+ concentrations, proton export via NHE3 is inhibited, while SLC26‐mediated HCO3 export is ongoing. The Cl is recycled into the lumen via CFTR. This type of HCO3 output into the lumen need not be accompanied by fluid secretion. If stimulation of secretion results in a strong decrease of intracellular Cl concentrations, the WNK pathway may be activated that will increase the HCO3 permeability of CFTR. See text for further details.


Figure 11. Schematic diagram of cellular composition and acid/base transporter expression along the colonic crypt‐villus axis and its effect on cellular HCO3 and fluid output. The ISC zone and partially differentiated enterocytes and goblet cells are located in the lower part of the colonic crypt. ISCs are presented by Bmi‐1 cells (yellow) and crypt base columnar (CBC) cells (red, Lgr5 + stem cells). Colonic cryptal cells express high levels of CFTR in the apical and NKCC1 in the basolateral membrane and therefore secrete a Cl‐rich HCO3 poor fluid. When CFTR is absent or defective, cryptal enterocyte pH is significantly increased, because the high [Cl‐]I inhibits basolateral HCO3 i/Cl o exchange via AE2 (). CFTR expression dramatically decreases toward the cryptal mouth and surface cells region, while SLC26A3 expression is upregulated. Deletion of SLC26A3 results in extremely low colonic HCO3 alkalization rates, while that of CFTR has a minor effect, suggesting that SLC26A3 is the major colonic HCO3 output pathway and its action is largely independent of CFTR expression.
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Teaching Material

U. Seidler, K. Nikolovska. Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease. Compr Physiol 9: 2019, 839-872.

Didactic Synopsis

Major Teaching Points:

  • The SLC26A family of multifunctional anion transporters, represented in humans by 11 isoforms, encompasses exchangers and/or channel-like transporters of numerous monovalent/divalent anions.
  • SLC26A1,2,3,6,7,9,11 are expressed in the apical (3, 4, 8, 11) or basolateral (1, 9) membranes of the gastrointestinal epithelium. Important intestinal functions like salt/water/sulfate/bicarbonate absorption or oxalate/chloride/bicarbonate secretion involve different SLC26A isoforms. By participating in the ion transport, they contribute to intestinal surface pH-microclimate regulation, mucus hydration and microbiome composition and affect the function of distant organs like the kidney and the cartilage.
  • Mutations and polymorphisms of SLC26A isoforms expressed in the intestine are associated with inherited diseases, such as diastrophic dysplasia (SLC26A2), chloride diarrhea (SLC26A3), or cystic fibrosis-associated meconium ileus and diabetes (SLC26A9). Disrupted interaction of CFTR and SLC26A3/6/9 may contribute to other gastrointestinal manifestations in cystic fibrosis as well.
  • Disturbed SLC26A expression in inflammatory bowel disease contributes to inflammatory diarrhea and oxalate nephrolithiasis.

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 Teaching points: Electrolyte transport in ileum. The ileal villous enterocytes express both Na+/H+ and Cl/HCO3 exchangers. The import of Na+ from the lumen into the cytoplasm of the enterocyte results in export of H+ into the intestinal lumen by the Na+/H+ exchanger. Simultaneously, extracellular Cl is absorbed in exchange of HCO3 secretion in the intestinal lumen. The secreted H+ and HCO3 ions react in the lumen to form H2O and CO2, which further can perfuse in the enterocyte following the osmotic gradient.

Figure 2 Teaching points: In the brush border membrane of the ileum, the absorption rates of Cl and Na+ ions are probably synchronized via the intracellular pHi. This coupled NaCl transport involves Na+/H+ and Cl/HCO3 coupled exchangers, as well as carbonic anhydrases located on the brush boarder membrane, which assist the NaCl transport by providing HCO3 or removing H+ ions close to the internal and external transport site.

Figure 3 Teaching points: Dendrogram showing the relations between the different members of the SLC26A family and the ionic species they transport. Mutations in three human SLC26 genes are associated with congenital diseases: chondrodysplasias for SLC26A2, chloride diarrhea for SLC26A3 and deafness for SLC26A4. Additional phenotypes are observed in mouse knockout models such as oxalate urolithiasis, hypochlorhydria or male infertility.

Figure 4 Teaching points: Slc26a1 (Sat1) is an important sulfate and oxalate transporter in kidney, liver and intestinal cells, expressed in the basolateral membrane. The intestinal oxalate secretion and sulfate absorption rates are reduced in Sat1−/-mice. Slc26a6 (PAT1, CFEX) is an apically located oxalate transporter, which deficiency in mice fed on high oxalate diet results in development of oxalate kidney stones. Oxalate secretion by intestinal epithelial cells involves oxalate entry from blood via Slc26a1, and then its efflux from the cell into the lumen by Slc26a6.

Figure 5 Teaching points: The endocytosis of SLC26A3 can be conducted through different pathways that involve interaction with Nexin 27 in a PDZ dependent or independent manner. SLC26A3 is trafficked to Rab5-positive early endosomes (EE) in PDZ-independent manner where it interacts with Nexin 27. SLC26A3 recycling and its later association with lipid rafts is managed via the Rab11-positive recycling endosomes (RE) (in PDZ dependent manner) or via direct interaction with Nexin 27. SLC26A3 can be subjected to lysosomal degradation when sorted into Rab7-positive late endosomes (LE).

Figure 6 Teaching points: Slc26a3−/−mice have significantly decreased colonic HCO3 secretory (JHCO3-) and fluid absorptive rates associated with high intracellular pH (pHi) in the Slc26a3−/− colonic surface cells and absence of firmly adherent mucus layer compared to wt littermates.

Figure 7 Teaching points: Slc26a3 deficient mice have markedly lower survival rate when given 2 % DSS in their drinking water compared to wt, in a period of just 5 days. The Slc26a3−/− mice treated with 2 % DSS for only 2–3 days histologically display moderate infiltration of mononuclear cells into the lamina propria, but a remarkably increased size and number of lymphoid aggregates unlike the wt, possibly indicative of high rates of pathogen invasion.

Figure 8 Teaching points: The decreased colonic bicarbonate secretion rates in the inflamed ileocolon of tumor necrosis factor alpha (TNF-α) overexpressing (TNF+/ΔARE) mice (A), which display (B) high proinflammatory cytokine levels in both ileum and colon, was predominantly due to inflammation-induced decrease in DRA expression at the (C) mRNA and (D) protein level.

Figure 9 Teaching points: To determine Slc26a9 cellular localization in the stomach, immunofluorescence co-staining with Slc26a9 antibody and H+/K+-ATPase antibody (as parietal cells marker). Slc26a9 is immunolocalized at the apical membrane of gastric surface epithelia and moderately in cells expressing the H+/K+-ATPase. When mRNA expression of Slc26a9 was analyzed by laser capture dissection in the total gastric glands, the upper third, and the lower third of the gland, the localization of Slc26a9 expression did not overlap with that for H+/K+ expression.

Figure 10 Teaching points: In the jejunum, the expression profile of different transporters is varying with the differentiation state of the cells, as they move from the crypt toward the surface of the villi. Enterocytes in the lower part of the crypt express high levels of CFTR and NKCC1, and are capable of high Cl, but low HCO3 secretory rates. Villus enterocytes absorb Na+, Cl and HCO3 via NHE3 and SLC26A3/6. When proton export via NHE3 is inhibited by cAMP/cGMP, but SLC26-mediated HCO3 export is ongoing, the Cl can be recycled into the lumen via activated CFTR and HCO3 secretion ensues. In addition, a strong decrease of intracellular Cl concentration during CFTR activation may activate the WNK pathway that will increase the HCO3 permeability of CFTR, because the basolateral membrane of villous enterocytes expresses NBCs instead of NKCC1.

Figure 11 Teaching points: The expression profile of different ion transporters varies along the colonic crypt axis, as the cells exit the proliferation zone (base of the crypt) and differentiate (surface of the crypt). Colonocytes at the base of the crypt express high levels of CFTR in the apical and NKCC1 in the basolateral membrane and secrete fluid with high Cl, but low HCO3 content. As the cells differentiate and move towards the cryptal surface, CFTR expression decreases dramatically, whereas SLC26A3 increases strongly. Colonic HCO3 output into the lumen occurs predominantly mainly via SLC26A3.

 


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How to Cite

Ursula Seidler, Katerina Nikolovska. Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease. Compr Physiol 2019, 9: 839-872. doi: 10.1002/cphy.c180027