Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis
Open accessAbstract
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.
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The altered microbiota of patients could transfer the disease from a human host to a mouse host.
“Of extreme relevance, the altered microbiota of patients could transfer the disease from a human host to a mouse host (113, 116–120).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [117]
Protection from experimental autoimmune encephalomyelitis in germ-free mice was associated with a decrease of pro-inflammatory cytokine levels such as IFN-γ and IL-17A and an increase in Treg cells in the peripheral organs, gut, and spinal cord.
“Again, the protection was associated with a decrease of pro-inflammatory cytokine levels, such as IFN-γ and IL-17A, and an increase in Treg cells in the peripheral organs, the gut and the spinal cord (117).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [117]
Germ-free mice were almost completely protected from experimental autoimmune encephalomyelitis compared to conventionally colonized mice.
“Thereafter, Lee Y. and colleagues showed for the first time that GF mice were almost completely protected from EAE compared to conventionally colonized mice (117).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [117]
Germ-free mice colonized with only SFB developed experimental autoimmune encephalomyelitis and a T helper 17 pathogenic immune response in the gut and CNS.
“Strikingly, GF mice colonized with only a single bacterium, the SFB, developed EAE, and a T helper (Th)-17 pathogenic immune response in the gut and in the CNS (117).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [117]
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- Authors
- Lee, Y. K., Menezes, J. S., Umesaki, Y., & Mazmanian, S. K.
- Affiliations
- California Institute of Technology (US)
- Yakult Central Institute (JP)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-07-26
- Volume
- 108
- Issue
- supplement_1
- Pages
- 4615-4622
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3063590
- OpenAlex
- W2121968767
- Cited by
- 1,323
- References
- 48
- Citations by year
- 2026: 38 · 2025: 57 · 2024: 80 · 2023: 81 · 2022: 84 · 2021: 118 · 2020: 92 · 2019: 102 · 2018: 101 · 2017: 116 · 2016: 100 · 2015: 94 · 2014: 85 · 2013: 68 · 2012: 48
- FWCI
- 37.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- California Institute of Technology
- Weston Havens Foundation
- Edward Mallinckrodt, Jr. Foundation
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- gut microbiota, experimental autoimmune encephalomyelitis, multiple sclerosis, germ-free mice, segmented filamentous bacteria, regulatory T cells, Th17 cells, IL-17A, interferon-gamma, dendritic cells, neuroinflammation, commensal bacteria, autoimmunity
- MeSH terms
- Animals, Dendritic Cells, Encephalomyelitis, Autoimmune, Experimental, Enzyme-Linked Immunosorbent Assay, Female, Germ-Free Life, Interferon-gamma, Intestinal Mucosa, Intestines, Mice, Inbred C57BL, Spinal Cord, Interleukin-17, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Th17 Cells
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