Inflammatory Bowel Disease in Patients with Congenital Chloride Diarrhoea

Norsa, Lorenzo; Canani, Roberto Berni; Duclaux-Loras, Rémi; Bequet, Emeline; Köglmeier, Jutta; Russell, Richard K.; Uhlig, Holm H.; Travis, Simon; Hollis, Jennifer; Koletzko, Sibylle; Grimaldi, Giusi; Castaldo, Giuseppe; Rodrigues, Astor; Deflandre, Jaques; Dembiński, Łukasz; Shah, Neil; Heinz‐Erian, Peter; Janecke, Andreas; Leskinen, Saara; Wedenoja, Satu; Koskela, Ritva; Lachaux, A.; Kolho, Kaija‐Leena; Ruemmele, Frank M

doi:10.1093/ecco-jcc/jjab056

Cited by 14 publications

(10 citation statements)

References 40 publications

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“…CLD patients are prone to IBD, including acute and chronic intestinal inflammation. The incidence of IBD in CLD patients is higher than that in healthy individuals, as verified in the latest research [ 42 ]. A large amount of evidence shows that IBD is related to intestinal barrier damage [ 43 – 45 ].…”

Section: − /Hco 3 − Exchangersmentioning

confidence: 71%

Pathophysiological role of ion channels and transporters in gastrointestinal mucosal diseases

Deng

Zhao

et al. 2021

Cell. Mol. Life Sci.

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The incidence of gastrointestinal (GI) mucosal diseases, including various types of gastritis, ulcers, inflammatory bowel disease and GI cancer, is increasing. Therefore, it is necessary to identify new therapeutic targets. Ion channels/transporters are located on cell membranes, and tight junctions (TJs) affect acid–base balance, the mucus layer, permeability, the microbiota and mucosal blood flow, which are essential for maintaining GI mucosal integrity. As ion channel/transporter dysfunction results in various GI mucosal diseases, this review focuses on understanding the contribution of ion channels/transporters to protecting the GI mucosal barrier and the relationship between GI mucosal disease and ion channels/transporters, including Cl−/HCO3− exchangers, Cl− channels, aquaporins, Na+/H+ exchangers, and K+ channels. Here, we provide novel prospects for the treatment of GI mucosal diseases.

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Section: − /Hco 3 − Exchangersmentioning

confidence: 71%

Pathophysiological role of ion channels and transporters in gastrointestinal mucosal diseases

Deng

Zhao

et al. 2021

Cell. Mol. Life Sci.

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“…While the disease need not be lethal any more, the substitution of electrolytes and fluid, which is the current mainstay of therapy, permits survival but does not attenuate the diarrhea. Moreover, many centers report a high percentage of grave complications, such as inflammatory bowel disease 2 , 24 or chronic renal failure, 25 both likely direct sequelae of the intestinal manifestations of CLD. It is therefore important to find causes that may aggravate the diarrheal, and/or the inflammatory intestinal phenotype in CLD patients, and to design treatment and preventive strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Most likely because of the dramatic upregulation of a panel of antimicrobial proteins in the slc26a3 −/− colon of these immunocompetent mice, colonic inflammation was found only distally, and was mild, even in the presence of a very marked barrier defect as well as a pro-inflammatory microbiota. CLD patients have a dramatically increased risk of developing IBD, 2 and it will be a task for the future to study whether the risk of CLD patients to develop IBD may be related to their genetically or environmentally determined ability to mount an antimicrobial defense.…”

Section: Discussionmentioning

confidence: 99%

“… 1 The disease is characterized by lifelong watery, acidic, and Cl-rich diarrhea, systemic alkalosis, male subfertility, a high propensity for development of inflammatory bowel disease (IBD), and a variable rate of kidney disease, which is likely secondary to fluid loss and electrolyte imbalance. 2 SLC26A3 is also strongly downregulated in the ileocolon of patients with inflammatory bowel disease, 3 , 4 and in mice with ileocolonic inflammation, 5 , 6 suggesting that defective SLC26A3 function may play a role in the pathophysiology of IBD.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of antimicrobial peptide expression in slc26a3-/- mice with colonic dysbiosis and barrier defect

Kini¹,

Zhao

Basic

et al. 2022

Gut Microbes

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Genetic defects in SLC26A3 (DRA), an intestinal Cl − /HCO 3 − exchanger, result in congenital chloride diarrhea (CLD), marked by lifelong acidic diarrhea and a high risk of inflammatory bowel disease. Slc26a3 −/− mice serve as a model to understand the pathophysiology of CLD and search for treatment options. This study investigates the microbiota changes in slc26a3 −/− colon, the genotype-related causes for the observed microbiota alterations, its inflammatory potential, as well as the corresponding host responses. The luminal and the mucosa-adherent cecal and colonic microbiota of cohoused slc26a3 −/− and wt littermates were analyzed by 16S rRNA gene sequencing. Fecal microbiota transfer from cohoused slc26a3 −/− and wt littermates to germ-free wt mice was performed to analyze the stability and the inflammatory potential of the communities. The cecal and colonic luminal and mucosa-adherent microbiota of slc26a3 −/− mice was abnormal from an early age, with a loss of diversity, of short-chain fatty acid producers, and an increase of pathobionts. The transfer of slc26a3 −/− microbiota did not result in intestinal inflammation and the microbial diversity in the recipient mice normalized over time. A strong increase in the expression of Il22, Reg3β/γ, Relmβ , and other proteins with antimicrobial functions was observed in slc26a3 −/− colon from juvenile age, while the mucosal and systemic inflammatory signature was surprisingly mild. The dysbiotic microbiota, low mucosal pH, and mucus barrier defect in slc26a3 −/− colon are accompanied by a stark upregulation of the expression of a panel of antimicrobial proteins. This may explain the low inflammatory burden in the gut of these mice.

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“…The risk for inflammatory bowel disease (IBD) is elevated both in human CLD and in slc26a3 -deficient mice [ 7 , 12 , 13 ]. Several studies have linked SLC26A3 polymorphisms or downregulation to ulcerative colitis (UC) [ 14 – 16 ], and low or absent SLC26A3 expression to intestinal adenomas and adenocarcinomas [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Fecal microbiota in congenital chloride diarrhea and inflammatory bowel disease

et al. 2022

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Background and aims Subjects with congenital chloride diarrhea (CLD; a defect in solute carrier family 26 member 3 (SLC26A3)) are prone to inflammatory bowel disease (IBD). We investigated fecal microbiota in CLD and CLD-associated IBD. We also tested whether microbiota is modulated by supplementation with the short-chain fatty acid butyrate. Subjects and methods We recruited 30 patients with CLD for an observational 3-week follow-up study. Thereafter, 16 consented to oral butyrate substitution for a 3-week observational period. Fecal samples, collected once a week, were assayed for calprotectin and potential markers of inflammation, and studied by 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing and compared to that of 19 healthy controls and 43 controls with Crohn’s disease. Data on intestinal symptoms, diet and quality of life were collected. Results Patients with CLD had increased abundances of Proteobacteria, Veillonella, and Prevotella, and lower abundances of normally dominant taxa Ruminococcaceae and Lachnospiraceae when compared with healthy controls and Crohn´s disease. No major differences in fecal microbiota were found between CLD and CLD-associated IBD (including two with yet untreated IBD). Butyrate was poorly tolerated and showed no major effects on fecal microbiota or biomarkers in CLD. Conclusions Fecal microbiota in CLD is different from that of healthy subjects or Crohn´s disease. Unexpectedly, no changes in the microbiota or fecal markers characterized CLD-associated IBD, an entity with high frequency among patients with CLD.

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Inflammatory Bowel Disease in Patients with Congenital Chloride Diarrhoea

Cited by 14 publications

References 40 publications

Pathophysiological role of ion channels and transporters in gastrointestinal mucosal diseases

Pathophysiological role of ion channels and transporters in gastrointestinal mucosal diseases

Upregulation of antimicrobial peptide expression in slc26a3-/- mice with colonic dysbiosis and barrier defect

Fecal microbiota in congenital chloride diarrhea and inflammatory bowel disease

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