Slc26a3 deletion alters pH‐microclimate, mucin biosynthesis, microbiome composition and increases the TNFα expression in murine colon

Abstract

Aim SLC26A3 (DRA) mediates the absorption of luminal Cl− in exchange for HCO3− in the distal intestine. Its expression is lost in congenital chloride diarrhoea (CLD) and strongly decreased in the presence of intestinal inflammation. To characterize the consequences of a loss of Slc26a3 beyond disturbed electrolyte transport, colonic mucus synthesis, surface accumulation and composition, pH microclimate, microbiome composition and development of inflammation was studied in slc26a3−/− mice. Methods The epithelial surface pH microclimate and the surface mucus accumulation in vivo was assessed by two photon microscopy in exteriorized mid colon of anaesthetized slc26a3−/− and wt littermates. Mucus synthesis, composition and inflammatory markers were studied by qPCR and immunohistochemistry and microbiome composition by 16S rRNA sequencing. Results Colonic pH microclimate was significantly more acidic in slc26a3−/− and to a lesser extent in cftr−/− than in wt mice. Goblet cell thecae per crypt were decreased in slc26a3−/− and increased in cftr−/− colon. Mucus accumulation in vivo was reduced, but much less so than in cftr−/− colon, which is possibly related to the different colonic fluid balance. Slc26a3−/− colonic luminal microbiome displayed strong decrease in diversity. These alterations preceded and maybe causally related to increased mucosal TNFα mRNA expression levels and leucocyte infiltration in the mid‐distal colon of slc26a3−/− but not of cftr−/− mice. Conclusions These findings may explain the strong increase in the susceptibility of slc26a3−/− mice to DSS damage, and offer insight into the mechanisms leading to an increased incidence of intestinal inflammation in CLD patients.

The Role of pHi in Intestinal Epithelial Proliferation–Transport Mechanisms, Regulatory Pathways, and Consequences

“…Possibly the alkaline pH interferes with intracellular acidification required to trigger programmed cell death at the colonic surface epithelium (Park et al, 1999;Kniep et al, 2006). Increased crypt length, seen in Cftr −/− epithelium, is not a feature of Slc26a3 −/− colonic epithelium (Kini et al, 2020).…”

Hydrokinetic pancreatic function and insulin secretion are moduled by Cl− uniporter Slc26a9 in mice

“…The ductal dysfunction is not associated with pancreatic pathological changes by histology, or an increase in proinflammatory cytokines, which is a very sensitive marker for inflammatory events, as validated in the intestine. 34 Thus, the results delineate a ductal and islet secretory defect in the isolated absence of Slc26a9 expression.…”

Slimy partners: the mucus barrier and gut microbiome in ulcerative colitis

“…Treatment with live Bifidobacterium and its culture supernatants stimulated the expression of Slc26a3, a Cl − /HCO 3 − exchanger 81 . Inflammation in the mid-distal 82 or distal colon 83 in Slc26a3-deficient mice was related to the loss of mucus secretion resulting from a remarkably low surface pH microclimate 83 , a more aggressive microbiota 82 and/or reduced microbiome diversity 83 . A luminal microenvironment with higher oxygen and lower pH could change the gut microbiota composition and drive an uncontrolled luminal expansion of E. coli and Salmonella 84 .…”