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

Genetic defects in SLC26A3 (DRA), an intestinal Cl-/HCO3 (-) 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, Reg3 beta/gamma, Relm beta, 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.

Automated summary

This study investigated the changes in microbiota in the colon of mice lacking the SLC26A3 gene, as well as the inflammatory potential and host responses. The results showed that the colon microbiota of SLC26A3-deficient mice was abnormal, but the inflammatory burden in the colon was surprisingly mild, which may be explained by the upregulation of antimicrobial proteins.