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

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.

journal_name

Mucosal Immunol

journal_title

Mucosal immunology

authors

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,Braun J

doi

10.1038/s41385-018-0022-7

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

457-467

issue

2

eissn

1933-0219

issn

1935-3456

pii

10.1038/s41385-018-0022-7

journal_volume

12

pub_type

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