A screen of Crohn's disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells

Mucosal Immunol. 2019 Mar;12(2):457-467. doi: 10.1038/s41385-018-0022-7. Epub 2018 Apr 25.

Abstract

Microbial metabolites are an emerging class of mediators influencing CD4+ T-cell function. To advance the understanding of direct causal microbial factors contributing to Crohn's disease, we screened 139 predicted Crohn's disease-associated microbial metabolites for their bioactivity on human CD4+ T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T-cell bioactivity, 3 previously reported, and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T-cell bioactivity among Crohn's disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T-cell energy metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Ascorbic Acid / metabolism*
  • Cell Differentiation
  • Cell Respiration
  • Cells, Cultured
  • Crohn Disease / immunology
  • Crohn Disease / microbiology*
  • Energy Metabolism
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-4 / metabolism
  • Lymphocyte Activation
  • Mass Screening
  • Microbiota / immunology*
  • Th17 Cells / immunology*

Substances

  • Interleukin-17
  • Interleukin-4
  • Interferon-gamma
  • Ascorbic Acid