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

Mucosal Immunologyvolume 12pages457467 (2019) | Download Citation



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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This study was supported by the Crohn’s and Colitis Foundation 323814, and National Institutes of Health grants PO1-DK46763 (J.B., D.P.B.M.), P30-CA016042 (UCLA Jonsson Comprehensive Cancer Center), and NCATS UCLA CTSI UL1TR001881. We thank all the volunteers for their participation in this study. We particularly thank the Immune Assessment Core at University of California, Los Angeles, for their support in scaling up the screens and running Luminex experiments. We also thank members from Dr. Michael Teitell Laboratory, Dr. Laurent Vergnes, and Dr. Linsey Stiles from Cellular Bioenergetics Core at University of California, Los Angeles, for the help with the Seahorse experiments.

Author information


  1. Molecular Biology IDP, University of California, Los Angeles, CA, 90095, USA

    • Yu-Ling Chang
  2. Pathology and Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA

    • Yu-Ling Chang
    • , Maura Rossetti
    • , David Casero
    • , Gemalene Sunga
    • , Nicholas Harre
    • , Shelley Miller
    • , Romney Humphries
    •  & Jonathan Braun
  3. The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA

    • Hera Vlamakis
    • , Ramnik Xavier
    •  & Curtis Huttenhower
  4. Washington University School of Medicine, St. Louis, MO, 63110, USA

    • Thaddeus Stappenbeck
  5. College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA

    • Kenneth W. Simpson
  6. Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    • R. Balfour Sartor
  7. Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    • Gary Wu
  8. Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    • James Lewis
  9. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    • Frederic Bushman
  10. The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    • Dermot P. B. McGovern
  11. Department of Pediatrics, Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    • Nita Salzman
  12. Department of Plant Pathology and Microbiology, University of California, Riverside, CA, 92521, USA

    • James Borneman


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Y.-L.C., M.R. and J.B. were responsible for experimental design, data interpretation, and manuscript preparation. Y.-L.C., G.S., N.H., and S.M. performed the experiments. Y.-L.C. and D.C. contributed to data analysis, and C.H. and H.V. predicted metabolites from metagenomics analysis. R.H., K.W.S., R.B.S., G.W., J.L., F.B., D.P.B.M., N.S., and J.B. in the CCFA consortium contributed to study design. J.B., T.S., R.X., and C.H. contributed to information integration and analysis.

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The authors declare no competing interests.

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Correspondence to Jonathan Braun.

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