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Dysregulated immune responses to commensal intestinal bacteria, includingEscherichia coli , contribute to the development of inflammatory bowel diseases (IBDs) and experimental colitis. Reciprocally,E. coli responds to chronic intestinal inflammation by upregulating expression of stress response genes, includinggadA andgadB . GadAB encode glutamate decarboxylase and protectE. coli from the toxic effects of low pH and fermentation acids, factors present in the intestinal lumen in patients with active IBDs. We hypothesized thatE. coli upregulatesgadAB during inflammation to enhance its survival and virulence. Using real-time PCR, we determinedgadAB expression in luminalE. coli from ex-germfree wild-type (WT) and interleukin-10 (IL-10) knockout (KO) (IL-10−/− ) mice selectively colonized with a commensalE. coli isolate (NC101) that causes colitis in KO mice in isolation or in combination with 7 other commensal intestinal bacterial strains.E. coli survival and host inflammatory responses were measured in WT and KO mice colonized with NC101 or a mutant lacking thegadAB genes (NC101ΔgadAB ). The susceptibility of NC101 and NC101ΔgadAB to killing by host antimicrobial peptides and their translocation across intestinal epithelial cells were evaluated using bacterial killing assays and transwell experiments, respectively. We show that expression ofgadAB in luminalE. coli increases proportionately with intestinal inflammation in KO mice and enhances the susceptibility of NC101 to killing by the host antimicrobial peptide cryptdin-4 but decreases bacterial transmigration across intestinal epithelial cells, colonic inflammation, and mucosal immune responses. Chronic intestinal inflammation upregulates acid tolerance pathways in commensalE. coli isolates, which, contrary to our original hypothesis, limits their survival and colitogenic potential. Further investigation of microbial adaptation to immune-mediated inflammation may provide novel insights into the pathogenesis and treatment of IBDs.

Inflammation-Induced Acid Tolerance Genes gadAB in Luminal Commensal Escherichia coli Attenuate Experimental Colitis