Chang YL, Rossetti M, Vlamakis H, Casero D, Sunga G, Harre N, Miller S, Humphries R, Stappenbeck T, Simpson KW, Sartor RB, Wu G, Lewis J, Bushman F, McGovern DPB, Salzman N, Borneman J, Xavier R, Huttenhower C, and Braun J
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.