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.

辅助 T 17 (Th17) 细胞的细菌激活会加剧小鼠自身免疫模型，但人类相关细菌如何影响 Th17 驱动的疾病仍然难以捉摸。我们发现，人肠道 Actinobacter Eggerthella lenta通过细胞和抗原独立机制解除对 Th17 转录因子 Rorγt 的抑制，从而诱导肠道 Th17 激活。E. _ lenta在炎症性肠病 (IBD) 患者中含量丰富，并以Rorc依赖性方式使小鼠结肠炎恶化。Th17 激活在不同的E中有所不同。慢菌株，归因于强心苷还原酶 2 (Cgr2) 酶。Cgr2 足以诱导白细胞介素 (IL)-17a（一种主要的 Th17 细胞因子）。cgr2+ E . lenta消耗纯培养物中假定的甾体糖苷；相关化合物与人类 IBD 严重程度呈负相关。最后，利用 Cgr2 对膳食精氨酸的敏感性，我们预防了大肠杆菌。慢病毒引起的小鼠肠道炎症。总之，这些结果支持人类肠道细菌代谢在驱动 Th17 依赖性自身免疫中的作用。