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Cathelicidin Modulates Clostridium difficile Toxin a-Mediated Enteritis
AGA Abstracts
Mo1714
Mo1716
Cathelicidin Modulates Clostridium difficile Toxin a-Mediated Enteritis Tressia C. Hing, David Q. Shih, Xinhua Chen, Ciaran P. Kelly, Stephan R. Targan, Charalabos Pothoulakis, Hon Wai Koon
Yersinia Pseudotuberculosis Effector Yopj Subverts TAK1 and NOD2 Functions to Elicit Intestinal Barrier Dysfunction Ulrich Meinzer, Frédérick Barreau, Camille Jung, Sophie Esmiol-Welterlin, Dominique Berrebi, Monique Dussaillant, Stéphane Bonacorsi, Hans Wolf-watz, Julie Perroy, Vincent Ollendorff, Jean-Pierre Hugot
Background and Aims: Clostridium difficile infection is the major cause of nosocomial antibiotic-associated colitis. C. difficile produces toxin A, a proinflammatory enterotoxin involved in the pathophysiology of C. difficile infection. Cathelicidin is an endogenous antimicrobial peptide that protects the host from infections. Recent findings also support the ability of cathelicidin to modulate innate immunity and alter the development of intestinal inflammation. Here we explored whether toxin A modifies the expression of cathelicidin in mouse ileum and cultured human colonocytes. We also determined the anti-inflammatory mechanism of cathelicidin in toxin A-mediated intestinal inflammation using a mouse model of enteritis and human primary peripheral blood monocytes. Methods: Ileal loops were prepared in anesthetized mice and injected with either toxin A (10 microg/20g mouse) or saline (control) (n= 6 loops per group). A separate group was treated with cathelicidin (200 microg/mouse) administered into the ileal loops. After 4 hrs, levels of cathelicidin and TNFalpha and mucosal histological changes of ileal loops were evaluated. Results: Toxin A significantly increased cathelicidin mRNA and protein expression (up to 5 fold, P=0.005) in mouse ileum. In human colonic epithelial NCM460 cells, toxin A induced cathelicidin protein (by ~2 fold, P<0.001), but not mRNA expression. Exogenous cathelicidin administration into ileal loops also significantly reduced toxin A mediated intestinal inflammation and reduced of mucosal neutrophil infiltration (>50%, P<0.01), edema (>50%, P<0.01) and TNFalpha levels (>80%, P<0.001), suggesting an anti-inflammatory role for exogenous cathelicidin in toxin A-mediated enteritis. In addition, cathelicidin, dose-dependently (1-10 microM), reduced toxin A- induced TNFalpha secretion (>50%, P<0.001) from human primary peripheral blood monocytes and mouse RAW 264.3 macrophages. This anti-inflammatory pathway was NFkappaB dependent since cathelicidin-induced inhibition of TNFalpha expression was augmented by the NF-kappaB inhibitor CAPE and reversed by the NF-kappaB activator PMA. In addition, cathelicidin (5 microM) reduced toxin A mediated NF-kappaB p65 phosphorylation in human monocytes, indicating that cathelicidin exerts its anti-inflammatory effects by inhibiting NF-kappaB. Conclusion: Toxin A induces cathelicidin mRNA and protein expression in mouse intestine and only protein expression in human colonocytes. Administration of exogenous cathelicidin reduces toxin A- mediated intestinal inflammation, suggesting that this approach may be beneficial in controlling C. difficile-associated diarrhea and colitis. Supported by a Pilot and Feasibility Study grant from UCLA-CURE Center, a Career Development Award from Crohn's and Colitis Foundation of America and K01DK084256 from National Institute of Health to HWK.
Introduction: The gut epithelium efficiently protects against invasion and systemic dissemination of the commensal flora and pathogens. Yersinia pseudotuberculosis is an enteropathogenic bacteria able to disrupt the intestinal barrier function and to invade its host through gut associated lymphoid tissue. Recently, we have shown that Nod2 plays a role in the Y. pseudotuberculosis infection. However, the molecular mechanisms that link bacterial invasion and the host barrier dysfunction remain to be explored, Methods: To identify the role of the different Yop in the bacterial invasion and the PP homeostasis disruption, C57BL/6 wild type mice and PP from wild type mice were infected with wild type and single- or multi-Yop mutant Yersinia strains and, the permeability and the bacterial translocation were assessed by Ussing-chamber experiments, bacterial quantification by serial plating respectively. The study of the Nod2 downstream partners and pathways involved in the Y. pseudotuberculosis virulence were investigated by using C57BL/6, Nod2+/+, Nod2-/- Tak1-/and IL-1R-/- mice, Ussing-chamber experiments, bacterial quantification by serial plating, survival curves, co-immunoprecipitations, BRET analyses, ELISA-Assays, transient transfections experiments, reporter gene assays and chemical inhibition and stimulation of Tak1 and Rick. Results: In ex vivo and In Vivo experiments showed that in wild-type mice, the bacterial effector YopJ is responsible of the intestinal barrier dysfunction. This effect is Nod2 dependent. In Vivo, YopJ contributes to the dissemination of Yersinia together with commensal bacteria from PP to deeper organs. From the molecular point of view, In Vitro, YopJ was able to acetylate Tak1 on its functional loop and to reduce the affinity between Nod2 and its downstream effector Rick. In Vivo, YopJ induced a Nod2- and caspase-1-dependent IL1β secretion, which was related with the intestinal barrier dysfunction. A chemical inhibition of TAK1 or RICK mimicked the effect of YopJ. Finally, Crohn's disease associated Nod2 mutant mice display a similar phenotype as the Nod2-/- mice. Conclusion: This study shows that the Yersinia pseudotuberculosis effector YopJ subverts Tak1 and Nod2 functions to elicit intestinal barrier dysfunction mediated by IL1b production. Thus, at the early phase of the infection, Yersinia pseudotuberculosis exploits the inflammatory host response to its own advantage. Mo1717 TLR-2/IL-1β Pathway Disrupts the Peyer's Patches Barrier Function by Modulating the Myosin Light Chain Kinase in Response to Yersinia Pseudotuberculosis Camille Jung, Ulrich Meinzer, Nicolas Montcuquet, Raphaële Thiébaut, Maryline Roy, Monique Dussaillant, Nadine Cerf-Bensussan, Jean-Pierre Hugot, Frédérick Barreau
Mo1715 Increased Expression of Autotaxin / Lysophospholipase D on Intestinal Vessels Involves in Aggravation of Intestinal Damage Through Lymphocytes Migration Hideaki Hozumi, Ryota Hokari, Shingo Sato, Toshihide Ueda, Masaaki Higashiyama, Yoshikiyo Okada, Chie Kurihara, Chikako Watanabe, Shunsuke Komoto, Mitsuyasu Nakamura, Kengo Tomita, Atsushi Kawaguchi, Shigeaki Nagao, Soichiro Miura
Background and aims: In human, Yersinia pseudotuberculosis is known to invade the Peyer's patches (PP) and to increase the transcellular permeability. Although toll-like-receptor 2 (TLR-2) controls the innate immune response against pathogens notably by inducing IL-1β expression, its exact role in the alterations of PP permeability in response to Y. pseudotuberculosis has not been investigated. The aims of the present study were to investigate the role of TLR-2 in Y. pseudotuberculosis induced barrier dysfunctions and to dissect the its mechanisms of action. Methods: In Vivo models consisted in TLR-2, MyD88 or IL-1 receptor invalidated mice and the wild type (WT) C57B6 control mice were orally inoculated with 107 cfu of the Y. Pseudotuberculosis strain pIB102. To investigate the respective roles of the epithelial and/or immune compartments within the PP, chimeric mice were generated by irradiating and grafting WT or TLR2-/- mice with bone marrow stem cells from WT or TLR2-/- mice. To dissect the interplay between the immune and epithelial compartments of the PP, we also developed an original In Vitro model consisting in Caco2 cells co-cultured with THP1 cells previously infected with Yersinia pIB102. On this model, specific TLR2 SiRNA, neutralizing anti-IL1β antibodies or caspase 1 inhibitors were tested. PP and Caco-2 paracellular (FITC-dextran (4kD) flux) and transcellular (FITC-dextran (40kD) flux) permeabilities were tested in Ussing and Transwell chambers respectively. IL-1β and MLCK concentrations within PP or THP1 or Caco-2 cells lines were analysed by QPCR and ELISA methods. The role of MLCK was studied by treating mice or Caco-2 cells line with ML-7, a MLCK inhibitor before Yersinia infection. Results: In Vivo and ex vivo data confirmed that Y. pseudotuberculosis altered both the paracellular and transcellular routes within PP. This effect was TLR-2 and MyD88 dependent. It was driven by the immune compartment of the PPs. In Vivo and In Vitro experiments showed that it was related with pro-IL1β expression, caspase 1 activation and IL1β secretion. IL1 receptor was required on the epithelial cells to promote the increased permeability. Finally, MLK was overexpressed in epithelial cells after Yersinia infection and a treatment by ML7 reversed the effect of Yersinia on gut permeability. Conclusions: TLR2 is a key pathway involved in the epithelial barrier dysfunction of PP after Yersinia pseudotuberculosis infection. After TLR2 stimulation, immune cells secrete IL-1β which in turn alters the PP permeability by up-regulating the MLCK expression and activity within the epithelial cells.
Background: Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Recently, lysophosphatidic acid (LPA) is reported to play a critical role in lymphocyte migration to the second lymph organization. In addition, autotaxin(ATX)/ lysophospholipase D in the vascular endothelium is the main enzyme in the production of LPA. Although significant role of ATX on the lymphocyte recruitment in the physiological condition was established, there have been no studies whether ATX is involved in the aberrant lymphocyte migration to the inflamed mucosa of IBD. In this study we investigated the expression of ATX and its relation to the clinical activity of patients with IBD. The role of ATX was also assessed by using murine IBD models, CD4 transferred SCID mice model and dextran sulfate sodium(DSS) mice model. Method:Tissue samples were obtained by colonic and ileal biopsies from patients with CD, ulcerative colitis(UC) with informed consent. Lymphocytes infiltration was studied immunohistochemically using anti-CD3 and anti beta7-integrin. Vascular endothelium was assessed by anti-CD34. Highendothelium venule was stained with ATX and anti-mucosal vascular adressin(MAdCAM1). Degree of expression of mRNA ATX and MAdCAM-1 were determined by using quantitative RT-PCR. In murine study, tissue samples were obtained from ileum of SCID mice transferred with CD4 cells of spleen, and colon of BALB/c mouse provided with drinking water containing DSS. The inhibitory effect of bithionol (ATX inhibitor) on aberrant lymphocytes migration to the intestinal mucosa as well as intestinal damages were evaluated. Result: Enhanced expression of ATX mRNA was observed in the inflamed mucosa from CD and UC patients. ATX expression was co-localized with the MAdCAM-1 positive high-endothelial venules, close to lymphocytes infiltration. The degree of ATX mRNA expression was significantly higher in the actively inflamed mucosa than in the quiescent mucosa in the same patients. In CD4 transferred SCID mice model, degree of expression of ATX mRNA was gradually increased as colitis developed. In DSS mice model, degree of expression of ATX mRNA was significantly higher in colonic mucosa of chronicically developed colitis than that of acute colitis. Administration of bithionol significantly ameliorated both DSS-induced colitis and CD4-induced ileocolitis with decrease in inflammatory cells infiltration. Conclusion: ATX expression on the high endothelium within the lymphocytes aggregates suggests possible involvement of ATX in the aberrant lymphocyte migration to the inflamed mucosa of IBD patients. Blocking of ATX ameliorates intestinal damage by decreasing lymphocyte migration. Enhanced expression of ATX in the active mucosa suggests that autotaxin/ lysophospholipase D becomes a new target for IBD treatment.
Mo1718 Role of NHE3 in the Maintenance of Intestinal Barrier Integrity in IL-10Deficient Mice Claire B. Larmonier, Daniel Laubitz, Alexis L. Bucknam, Robert D. Thurston, Faihza M. Hill, Monica T. Midura-Kiela, Rajalakshmy Ramalingam, Pawel R. Kiela, Fayez K. Ghishan Background: Crohn's disease, one of the most common types of Inflammatory Bowel Disease (IBD) is a spontaneously relapsing, immunologically mediated disorder of the gastrointestinal tract characterized by intestinal inflammation and mucosal damage. NHE3 (Intestinal Na+/ H+ exchanger) has been shown to be downregulated and/or inhibited in patients with active UC and CD; this phenomenon has been believed to contribute to inflammation-associated diarrhea. Our group recently demonstrated spontaneous colitis in NHE3-/- mice and the
AGA Abstracts
S-634
Mo1714
Mo1716
Cathelicidin Modulates Clostridium difficile Toxin a-Mediated Enteritis Tressia C. Hing, David Q. Shih, Xinhua Chen, Ciaran P. Kelly, Stephan R. Targan, Charalabos Pothoulakis, Hon Wai Koon
Yersinia Pseudotuberculosis Effector Yopj Subverts TAK1 and NOD2 Functions to Elicit Intestinal Barrier Dysfunction Ulrich Meinzer, Frédérick Barreau, Camille Jung, Sophie Esmiol-Welterlin, Dominique Berrebi, Monique Dussaillant, Stéphane Bonacorsi, Hans Wolf-watz, Julie Perroy, Vincent Ollendorff, Jean-Pierre Hugot
Background and Aims: Clostridium difficile infection is the major cause of nosocomial antibiotic-associated colitis. C. difficile produces toxin A, a proinflammatory enterotoxin involved in the pathophysiology of C. difficile infection. Cathelicidin is an endogenous antimicrobial peptide that protects the host from infections. Recent findings also support the ability of cathelicidin to modulate innate immunity and alter the development of intestinal inflammation. Here we explored whether toxin A modifies the expression of cathelicidin in mouse ileum and cultured human colonocytes. We also determined the anti-inflammatory mechanism of cathelicidin in toxin A-mediated intestinal inflammation using a mouse model of enteritis and human primary peripheral blood monocytes. Methods: Ileal loops were prepared in anesthetized mice and injected with either toxin A (10 microg/20g mouse) or saline (control) (n= 6 loops per group). A separate group was treated with cathelicidin (200 microg/mouse) administered into the ileal loops. After 4 hrs, levels of cathelicidin and TNFalpha and mucosal histological changes of ileal loops were evaluated. Results: Toxin A significantly increased cathelicidin mRNA and protein expression (up to 5 fold, P=0.005) in mouse ileum. In human colonic epithelial NCM460 cells, toxin A induced cathelicidin protein (by ~2 fold, P<0.001), but not mRNA expression. Exogenous cathelicidin administration into ileal loops also significantly reduced toxin A mediated intestinal inflammation and reduced of mucosal neutrophil infiltration (>50%, P<0.01), edema (>50%, P<0.01) and TNFalpha levels (>80%, P<0.001), suggesting an anti-inflammatory role for exogenous cathelicidin in toxin A-mediated enteritis. In addition, cathelicidin, dose-dependently (1-10 microM), reduced toxin A- induced TNFalpha secretion (>50%, P<0.001) from human primary peripheral blood monocytes and mouse RAW 264.3 macrophages. This anti-inflammatory pathway was NFkappaB dependent since cathelicidin-induced inhibition of TNFalpha expression was augmented by the NF-kappaB inhibitor CAPE and reversed by the NF-kappaB activator PMA. In addition, cathelicidin (5 microM) reduced toxin A mediated NF-kappaB p65 phosphorylation in human monocytes, indicating that cathelicidin exerts its anti-inflammatory effects by inhibiting NF-kappaB. Conclusion: Toxin A induces cathelicidin mRNA and protein expression in mouse intestine and only protein expression in human colonocytes. Administration of exogenous cathelicidin reduces toxin A- mediated intestinal inflammation, suggesting that this approach may be beneficial in controlling C. difficile-associated diarrhea and colitis. Supported by a Pilot and Feasibility Study grant from UCLA-CURE Center, a Career Development Award from Crohn's and Colitis Foundation of America and K01DK084256 from National Institute of Health to HWK.
Introduction: The gut epithelium efficiently protects against invasion and systemic dissemination of the commensal flora and pathogens. Yersinia pseudotuberculosis is an enteropathogenic bacteria able to disrupt the intestinal barrier function and to invade its host through gut associated lymphoid tissue. Recently, we have shown that Nod2 plays a role in the Y. pseudotuberculosis infection. However, the molecular mechanisms that link bacterial invasion and the host barrier dysfunction remain to be explored, Methods: To identify the role of the different Yop in the bacterial invasion and the PP homeostasis disruption, C57BL/6 wild type mice and PP from wild type mice were infected with wild type and single- or multi-Yop mutant Yersinia strains and, the permeability and the bacterial translocation were assessed by Ussing-chamber experiments, bacterial quantification by serial plating respectively. The study of the Nod2 downstream partners and pathways involved in the Y. pseudotuberculosis virulence were investigated by using C57BL/6, Nod2+/+, Nod2-/- Tak1-/and IL-1R-/- mice, Ussing-chamber experiments, bacterial quantification by serial plating, survival curves, co-immunoprecipitations, BRET analyses, ELISA-Assays, transient transfections experiments, reporter gene assays and chemical inhibition and stimulation of Tak1 and Rick. Results: In ex vivo and In Vivo experiments showed that in wild-type mice, the bacterial effector YopJ is responsible of the intestinal barrier dysfunction. This effect is Nod2 dependent. In Vivo, YopJ contributes to the dissemination of Yersinia together with commensal bacteria from PP to deeper organs. From the molecular point of view, In Vitro, YopJ was able to acetylate Tak1 on its functional loop and to reduce the affinity between Nod2 and its downstream effector Rick. In Vivo, YopJ induced a Nod2- and caspase-1-dependent IL1β secretion, which was related with the intestinal barrier dysfunction. A chemical inhibition of TAK1 or RICK mimicked the effect of YopJ. Finally, Crohn's disease associated Nod2 mutant mice display a similar phenotype as the Nod2-/- mice. Conclusion: This study shows that the Yersinia pseudotuberculosis effector YopJ subverts Tak1 and Nod2 functions to elicit intestinal barrier dysfunction mediated by IL1b production. Thus, at the early phase of the infection, Yersinia pseudotuberculosis exploits the inflammatory host response to its own advantage. Mo1717 TLR-2/IL-1β Pathway Disrupts the Peyer's Patches Barrier Function by Modulating the Myosin Light Chain Kinase in Response to Yersinia Pseudotuberculosis Camille Jung, Ulrich Meinzer, Nicolas Montcuquet, Raphaële Thiébaut, Maryline Roy, Monique Dussaillant, Nadine Cerf-Bensussan, Jean-Pierre Hugot, Frédérick Barreau
Mo1715 Increased Expression of Autotaxin / Lysophospholipase D on Intestinal Vessels Involves in Aggravation of Intestinal Damage Through Lymphocytes Migration Hideaki Hozumi, Ryota Hokari, Shingo Sato, Toshihide Ueda, Masaaki Higashiyama, Yoshikiyo Okada, Chie Kurihara, Chikako Watanabe, Shunsuke Komoto, Mitsuyasu Nakamura, Kengo Tomita, Atsushi Kawaguchi, Shigeaki Nagao, Soichiro Miura
Background and aims: In human, Yersinia pseudotuberculosis is known to invade the Peyer's patches (PP) and to increase the transcellular permeability. Although toll-like-receptor 2 (TLR-2) controls the innate immune response against pathogens notably by inducing IL-1β expression, its exact role in the alterations of PP permeability in response to Y. pseudotuberculosis has not been investigated. The aims of the present study were to investigate the role of TLR-2 in Y. pseudotuberculosis induced barrier dysfunctions and to dissect the its mechanisms of action. Methods: In Vivo models consisted in TLR-2, MyD88 or IL-1 receptor invalidated mice and the wild type (WT) C57B6 control mice were orally inoculated with 107 cfu of the Y. Pseudotuberculosis strain pIB102. To investigate the respective roles of the epithelial and/or immune compartments within the PP, chimeric mice were generated by irradiating and grafting WT or TLR2-/- mice with bone marrow stem cells from WT or TLR2-/- mice. To dissect the interplay between the immune and epithelial compartments of the PP, we also developed an original In Vitro model consisting in Caco2 cells co-cultured with THP1 cells previously infected with Yersinia pIB102. On this model, specific TLR2 SiRNA, neutralizing anti-IL1β antibodies or caspase 1 inhibitors were tested. PP and Caco-2 paracellular (FITC-dextran (4kD) flux) and transcellular (FITC-dextran (40kD) flux) permeabilities were tested in Ussing and Transwell chambers respectively. IL-1β and MLCK concentrations within PP or THP1 or Caco-2 cells lines were analysed by QPCR and ELISA methods. The role of MLCK was studied by treating mice or Caco-2 cells line with ML-7, a MLCK inhibitor before Yersinia infection. Results: In Vivo and ex vivo data confirmed that Y. pseudotuberculosis altered both the paracellular and transcellular routes within PP. This effect was TLR-2 and MyD88 dependent. It was driven by the immune compartment of the PPs. In Vivo and In Vitro experiments showed that it was related with pro-IL1β expression, caspase 1 activation and IL1β secretion. IL1 receptor was required on the epithelial cells to promote the increased permeability. Finally, MLK was overexpressed in epithelial cells after Yersinia infection and a treatment by ML7 reversed the effect of Yersinia on gut permeability. Conclusions: TLR2 is a key pathway involved in the epithelial barrier dysfunction of PP after Yersinia pseudotuberculosis infection. After TLR2 stimulation, immune cells secrete IL-1β which in turn alters the PP permeability by up-regulating the MLCK expression and activity within the epithelial cells.
Background: Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Recently, lysophosphatidic acid (LPA) is reported to play a critical role in lymphocyte migration to the second lymph organization. In addition, autotaxin(ATX)/ lysophospholipase D in the vascular endothelium is the main enzyme in the production of LPA. Although significant role of ATX on the lymphocyte recruitment in the physiological condition was established, there have been no studies whether ATX is involved in the aberrant lymphocyte migration to the inflamed mucosa of IBD. In this study we investigated the expression of ATX and its relation to the clinical activity of patients with IBD. The role of ATX was also assessed by using murine IBD models, CD4 transferred SCID mice model and dextran sulfate sodium(DSS) mice model. Method:Tissue samples were obtained by colonic and ileal biopsies from patients with CD, ulcerative colitis(UC) with informed consent. Lymphocytes infiltration was studied immunohistochemically using anti-CD3 and anti beta7-integrin. Vascular endothelium was assessed by anti-CD34. Highendothelium venule was stained with ATX and anti-mucosal vascular adressin(MAdCAM1). Degree of expression of mRNA ATX and MAdCAM-1 were determined by using quantitative RT-PCR. In murine study, tissue samples were obtained from ileum of SCID mice transferred with CD4 cells of spleen, and colon of BALB/c mouse provided with drinking water containing DSS. The inhibitory effect of bithionol (ATX inhibitor) on aberrant lymphocytes migration to the intestinal mucosa as well as intestinal damages were evaluated. Result: Enhanced expression of ATX mRNA was observed in the inflamed mucosa from CD and UC patients. ATX expression was co-localized with the MAdCAM-1 positive high-endothelial venules, close to lymphocytes infiltration. The degree of ATX mRNA expression was significantly higher in the actively inflamed mucosa than in the quiescent mucosa in the same patients. In CD4 transferred SCID mice model, degree of expression of ATX mRNA was gradually increased as colitis developed. In DSS mice model, degree of expression of ATX mRNA was significantly higher in colonic mucosa of chronicically developed colitis than that of acute colitis. Administration of bithionol significantly ameliorated both DSS-induced colitis and CD4-induced ileocolitis with decrease in inflammatory cells infiltration. Conclusion: ATX expression on the high endothelium within the lymphocytes aggregates suggests possible involvement of ATX in the aberrant lymphocyte migration to the inflamed mucosa of IBD patients. Blocking of ATX ameliorates intestinal damage by decreasing lymphocyte migration. Enhanced expression of ATX in the active mucosa suggests that autotaxin/ lysophospholipase D becomes a new target for IBD treatment.
Mo1718 Role of NHE3 in the Maintenance of Intestinal Barrier Integrity in IL-10Deficient Mice Claire B. Larmonier, Daniel Laubitz, Alexis L. Bucknam, Robert D. Thurston, Faihza M. Hill, Monica T. Midura-Kiela, Rajalakshmy Ramalingam, Pawel R. Kiela, Fayez K. Ghishan Background: Crohn's disease, one of the most common types of Inflammatory Bowel Disease (IBD) is a spontaneously relapsing, immunologically mediated disorder of the gastrointestinal tract characterized by intestinal inflammation and mucosal damage. NHE3 (Intestinal Na+/ H+ exchanger) has been shown to be downregulated and/or inhibited in patients with active UC and CD; this phenomenon has been believed to contribute to inflammation-associated diarrhea. Our group recently demonstrated spontaneous colitis in NHE3-/- mice and the
AGA Abstracts
S-634