Bacterial activation of T helper 17 (Th17) cells exacerbates mouse models of autoimmunity, but how human-associated bacteria impact Th17-driven disease remains elusive. We show that human gut Actinobacterium Eggerthella lenta induces intestinal Th17 activation by lifting inhibition of the Th17 transcription factor Rorγt through cell- and antigen-independent mechanisms. E. lenta is enriched in inflammatory bowel disease (IBD) patients and worsens colitis in a Rorc-dependent manner in mice. Th17 activation varies across E. lenta strains, which is attributable to the cardiac glycoside reductase 2 (Cgr2) enzyme. Cgr2 is sufficient to induce interleukin (IL)-17a, a major Th17 cytokine. cgr2+ E. lenta deplete putative steroidal glycosides in pure culture; related compounds are negatively associated with human IBD severity. Finally, leveraging the sensitivity of Cgr2 to dietary arginine, we prevented E. lenta-induced intestinal inflammation in mice. Together, these results support a role for human gut bacterial metabolism in driving Th17-dependent autoimmunity.
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Date of publication: 24 November 2021; Cell Host & Microbe (2021)
Author information: Margaret Alexander(1); Qi Yan Ang(1); Renuka R. Nayak(1)(2); Annamarie E. Bustion(3); Moriah Sandy(1)(2); Bing Zhang(2); Vaibhav Upadhyay(1)(2); Katherine S. Pollard(3)(4)(5); Susan V. Lynch(2); Peter J. Turnbaugh (1)
(1) Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
(2) Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
(3) Gladstone Institutes, San Francisco, CA 94158, USA
(4) Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
(5) Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA