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Published March 15, 2011 | Published + Supplemental Material
Journal Article Open

Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis

Abstract

Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-γ and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4^(+)CD25^(+)Foxp3^+ regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A–producing CD4^+ T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro- and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.

Additional Information

© 2011 National Academy of Sciences. Edited by Jeffrey I. Gordon, Washington University School of Medicine, St. Louis, MO, and approved June 23, 2010 (received for review January 19, 2010). Published online before print July 26, 2010. This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, "Microbes and Health" held November 2–3, 2009, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. The complete program and audio files of most presentations are available on the NAS Web site at http://www.nasonline.orgSACKLER_Microbes_and_Health. We are grateful to members of the Mazmanian laboratory for their critical review of the manuscript. We thank Rochelle A. Diamond (Caltech) for help with cell sorting. S.K.M. is a Searle Scholar. This work is supported by funding from the California Institute of Technology, the Weston Havens Foundation, and the Edward Mallinckrodt Jr. Foundation (to S.K.M.). Author contributions: Y.K.L. and S.K.M. designed research; Y.K.L. and J.S.M. performed research; Y.U. contributed new reagents/analytic tools; Y.K.L., J.S.M., and S.K.M. analyzed data; and Y.K.L., J.S.M., and S.K.M. wrote the paper.

Attached Files

Published - Lee2011p13292P_Natl_Acad_Sci_Usa.pdf

Supplemental Material - pnas.201000082SI.pdf

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