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

Fansler, R. T.; Bak, D. W.; Langford-Butler, M.; Chen, L.; Singla, D.; Spiga, L.; Livny, J.; Karijolich, J.; Meers, C.; Zhou, Q.; Weerapana, E.; Zhu, W.

doi:10.64898/2026.07.09.736866

bioRxiv · 10.64898/2026.07.09.736866

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

Fansler, R. T.·Bak, D. W.·Langford-Butler, M.·Chen, L.·Singla, D.·Spiga, L.·Livny, J.·Karijolich, J.·Meers, C.·Zhou, Q.·Weerapana, E.·Zhu, W.

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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.

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Fansler, R. T., Bak, D. W., Langford-Butler, M., Chen, L., Singla, D., Spiga, L., Livny, J., Karijolich, J., Meers, C., Zhou, Q., Weerapana, E., Zhu, W.. 2026-07-10. A nitrite-responsive regulatory RNA locus sustains commensal resilience against nitrosative stress. https://doi.org/10.64898/2026.07.09.736866

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