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

• Published in: Mucosal immunology Vol. 12; no. 2; pp. 457 - 467
• Main Authors: 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 P. B., Salzman, Nita, Borneman, James, Xavier, Ramnik, Huttenhower, Curtis, Braun, Jonathan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2019; Elsevier Limited
• Subjects: Allergology; Antibodies; Apoptosis; Ascorbic acid; Ascorbic Acid - metabolism; Biological activity; Biomedical and Life Sciences; Biomedicine; CD4 antigen; Cell Differentiation; Cell Respiration; Cells, Cultured; Crohn Disease - immunology; Crohn Disease - microbiology; Crohn's disease; Effector cells; Energy Metabolism; Gastroenterology; Helper cells; Humans; Immunology; Interferon-gamma - metabolism; Interleukin 4; Interleukin-17 - metabolism; Interleukin-4 - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mass Screening; Metabolism; Metabolites; Microbiota - immunology; Th17 Cells - immunology; γ-Interferon
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/s41385-018-0022-7

Microbial metabolites are an emerging class of mediators influencing CD4
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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
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T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4
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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
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effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4
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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.