Human gut bacterial metabolism drives Th17 activation and colitis

Cell Host Microbe. 2022 Jan 12;30(1):17-30.e9. doi: 10.1016/j.chom.2021.11.001. Epub 2021 Nov 24.


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.

Keywords: T helper 17 cells; autoimmune disease; dietary supplementation; human gut microbiome; inflammatory bowel disease; microbial metabolism.

MeSH terms

  • Actinobacteria
  • Animals
  • Bacteria / metabolism
  • Colitis / immunology
  • Colitis / metabolism*
  • Cytokines
  • Dietary Supplements
  • Disease Models, Animal
  • Female
  • Gastrointestinal Microbiome / physiology*
  • Humans
  • Inflammatory Bowel Diseases / microbiology
  • Interleukin-17 / metabolism
  • Lymphocyte Activation / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Th17 Cells / metabolism*


  • Cytokines
  • IL17A protein, human
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human

Supplementary concepts

  • Eggerthella lenta