A nitrite-responsive regulatory RNA locus sustains commensal resilience against nitrosative stress

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.