Slc26a3 (DRA) Deficient Mice Display an Acidic Colonic pH‐microclimate, Develop a Strongly Altered Microbiome and Colonic Inflammation

Abstract

BackgroundThe anion transporter Slc26a3 (DRA‐Down Regulated in Adenoma) is localized on the apical membrane of the colonic mucosa and is functionally involved in the absorption of luminal chloride (Cl−) in exchange for bicarbonate ions (HCO3−). Mutations in the dra gene result in congenital chloride diarrhoea (CLD) which is characterized by secretory diarrhoea, loss of Cl− in the stool, dehydration and metabolic alkalosis. These patients also have a higher risk of incidence of acute as well chronic intestinal inflammation (Wedenoja et al. Hum. Mut 2011). We previously reported low colonic HCO3− output rates and an increased susceptibility to Dextran Sodium Sulfate (DSS) damage in slc26a3−/− mice (Xiao, F. et al. Acta Phys. 2015).AimThe present study was undertaken to explore whether the slc26a3−/− mice develop spontaneous intestinal inflammation, and whether an altered microbiome composition may be the underlying molecular mechanism for inflammation.MethodsColonic surface pH was measured in vivo by two photon microscopy, the inflammatory state of the mucosa by Quantitative PCR (qPCR) and immunohistochemistry, the intestinal microbiome by 16S rRNA sequencing, and the effect of the microbiome of the slc26a3−/− colon on the development of inflammation in germ‐free mice by fecal crossing experiments.ResultsThe slc26a3−/− mice developed distal colonic inflammation evidenced by an increase in proinflammatory cytokine expression and the number of inflammatory cells in the colonic mucosa/submucosa at the time of sacrifice. The slc26a3−/− microbiome was significantly different from that of cohoused wild type (WT) littermates, with a strongly decreased diversity, and an increased percentage of several proinflammatory species. Transmission of this dysbiotic microbiome into germ free mice did not lead to a development of inflammation in the recipient mice. Instead, the species richness in the germ free mice gavaged with slc26a3−/− microbiome had increased, and the percentage of proinflammatory species decreased, in comparison to its donor microbiome.ConclusionsSlc26a3−/− mice display a very low colonic pH microclimate and develop spontaneous intestinal inflammation. The microbiome of slc26a3−/− colon is “dysbiotic” with strongly reduced diversity. However, transmission of this microbiome into germ‐free mice does not result in inflammation, but does result in microbiome normalization, suggesting that the reduced pH microclimate and reduced colonic transit time is necessary for the development of intestinal dysbiosis.Support or Funding InformationVolkswagen Foundation VW Vorab, DFG project SE460/17‐1 and 19‐1 and SFB621/C9This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.