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Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation

Nature volume 504, pages 451–455 (2013)Cite this article

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Abstract

Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine1. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells2,3,4,5,6, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation1,7. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.

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Figure 1: SCFAs produced by commensal bacteria stimulate in vitro generation of Treg cells.
Figure 2: Butyrate provision promotes extrathymic Treg-cell generation in vivo.
Figure 3: Butyrate acts within T cells to enhance acetylation of the Foxp3 locus and Foxp3 protein.
Figure 4: HDAC-inhibitory activity of butyrate decreases pro-inflammatory cytokine expression within dendritic cells to promote Treg induction.

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Gene Expression Omnibus

Data deposits

Microarray data have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE51263.

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Acknowledgements

This work was supported by the Robert Black Fellowship of the Damon Runyon Cancer Research Foundation DRG-2143-13 (N.A.), Ludwig Center at Memorial Sloan Kettering Cancer Center and the US National Institutes of Health (NIH) grant T32 A1007621 (N.A.) and R37 AI034206 (A.Y.R.). A.Y.R. is an investigator with the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA

    Nicholas Arpaia, Clarissa Campbell, Xiying Fan, Stanislav Dikiy, Joris van der Veeken, Paul deRoos, Paul J. Coffer & Alexander Y. Rudensky

  2. Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA

    Nicholas Arpaia, Clarissa Campbell, Xiying Fan, Stanislav Dikiy, Joris van der Veeken, Paul deRoos, Paul J. Coffer & Alexander Y. Rudensky

  3. Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USA

    Hui Liu & Justin R. Cross

  4. Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany ,

    Klaus Pfeffer

  5. Department of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands,

    Paul J. Coffer

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Contributions

N.A., C.C. and X.F. performed experiments and analysed data, with general assistance from S.D. and assistance from P.d. for HPLC, P.J.C. for immunoprecipitation of acetylated Foxp3 and J.v.d.V. for ChIP–qPCR experiments. H.L. and J.R.C. performed LC–MS. N.A., C.C., X.F. and A.Y.R. designed and interpreted experiments. K.P. provided Gpr109a mice. N.A. and A.Y.R. wrote the paper.

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Correspondence to Alexander Y. Rudensky.

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The authors declare no competing financial interests.

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Arpaia, N., Campbell, C., Fan, X. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013). https://doi.org/10.1038/nature12726

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