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

  • Author(s): Chang, Yu-Ling;
  • Rossetti, Maura;
  • Vlamakis, Hera;
  • Casero, David;
  • Sunga, Gemalene;
  • Harre, Nicholas;
  • Miller, Shelley;
  • Humphries, Romney;
  • Stappenbeck, Thaddeus;
  • Simpson, Kenneth W;
  • Sartor, R Balfour;
  • Wu, Gary;
  • Lewis, James;
  • Bushman, Frederic;
  • McGovern, Dermot PB;
  • Salzman, Nita;
  • Borneman, James;
  • Xavier, Ramnik;
  • Huttenhower, Curtis;
  • Braun, Jonathan
  • et al.
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.

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