A screen of Crohn's disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells |
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| Affiliation: | 1. Molecular Biology IDP, University of California, 90095, Los Angeles, CA, USA;2. Pathology and Laboratory Medicine, University of California, 90095, Los Angeles, CA, USA;3. The Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;4. Washington University School of Medicine, 63110, St. Louis, MO, USA;5. College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA;6. Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;7. Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;8. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;9. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;10. The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 90048, Los Angeles, CA, USA;11. Department of Pediatrics, Microbiology and Immunology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;12. Department of Plant Pathology and Microbiology, University of California, 92521, Riverside, CA, USA;1. Molecular Biology IDP, University of California, 90095, Los Angeles, CA, USA;2. Pathology and Laboratory Medicine, University of California, 90095, Los Angeles, CA, USA;3. The Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;4. Washington University School of Medicine, 63110, St. Louis, MO, USA;5. College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA;6. Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, 27599, Chapel Hill, NC, USA;7. Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;8. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;9. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;10. The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 90048, Los Angeles, CA, USA;11. Department of Pediatrics, Microbiology and Immunology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;12. Department of Plant Pathology and Microbiology, University of California, 92521, Riverside, CA, USA |
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| 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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