Abstract

Commensal microbes in the gastrointestinal tract are central to host health, yet they must adapt to frequent perturbations such as intestinal inflammation that challenges microbial homeostasis. A major challenge during inflammation is exposure to host-derived reactive nitrogen species (RNS), which damage macromolecules and impair microbial fitness, but how commensals orchestrate defense against nitrosative stress remains poorly defined. Here, we show that Bacteroides thetaiotaomicron mounts a protective RNS-defense program centered on the hybrid cluster protein Hcp, which is required for fitness under nitrosative stress. We identify a nitrite-responsive SnoA locus (Stress-responsive Nitric Oxide regulator A) that promotes HcpR-dependent hcp expression. In vivo, this pathway promotes commensal resilience in both an antibiotic-perturbed, Nos2-dependent model of intestinal nitrosative stress and during Salmonella-induced gut inflammation. Together, our findings identify a regulatory pathway that enables a dominant gut commensal to withstand host-derived nitrosative stress and persist during intestinal inflammation.