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

Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4615-22. doi: 10.1073/pnas.1000082107. Epub 2010 Jul 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Cells / immunology
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / microbiology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Forkhead Transcription Factors / metabolism
  • Germ-Free Life
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / microbiology*
  • Mice
  • Mice, Inbred C57BL
  • Spinal Cord / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Th17 Cells / immunology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-17
  • Interferon-gamma