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

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

Author information

1
Molecular Biology IDP, University of California, Los Angeles, CA, 90095, USA.
2
Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA.
3
The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
4
Washington University School of Medicine, St. Louis, MO, 63110, USA.
5
College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
6
Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
7
Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
8
Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
9
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
10
The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
11
Department of Pediatrics, Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
12
Department of Plant Pathology and Microbiology, University of California, Riverside, CA, 92521, USA.
13
Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA. jbraun@mednet.ucla.edu.

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.

PMID:
29695840
PMCID:
PMC6202286
DOI:
10.1038/s41385-018-0022-7
[Indexed for MEDLINE]
Free PMC Article

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