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Outer Membrane Vesicles of a Human Commensal Mediate Immune Regulation and Disease Protection
Open accessAbstract
Commensal bacteria impact host health and immunity through various mechanisms, including the production of immunomodulatory molecules. Bacteroides fragilis produces a capsular polysaccharide (PSA), which induces regulatory T cells and mucosal tolerance. However, unlike pathogens, which employ secretion systems, the mechanisms by which commensal bacteria deliver molecules to the host remain unknown. We reveal that Bacteroides fragilis releases PSA in outer membrane vesicles (OMVs) that induce immunomodulatory effects and prevent experimental colitis. Dendritic cells (DCs) sense OMV-associated PSA through TLR2, resulting in enhanced regulatory T cells and anti-inflammatory cytokine production. OMV-induced signaling in DCs requires growth arrest and DNA-damage-inducible protein (Gadd45α). DCs treated with PSA-containing OMVs prevent experimental colitis, whereas Gadd45α(-/-) DCs are unable to promote regulatory T cell responses or suppress proinflammatory cytokine production and host pathology. These findings demonstrate that OMV-mediated delivery of a commensal molecule prevents disease, uncovering a mechanism of interkingdom communication between the microbiota and mammals.
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“Furthermore, PSA produced by Leuconostoc mesenteroides strain NTM048 or Bacteroides fragilis acts as an immunostimulant to enhance the mucosal barrier and influence systemic immune responses [111, 112] (Fig. 5G).”
From Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies (2022) · cites this paper as [112]
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“some bacterial species have been shown to drive Treg development via alternative pathways dependent on polysaccharide A and TLR signaling to dendritic cells”
From The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy (2018) · cites this paper as Shen et al., 2012
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“In addition, some bacterial species have been shown to drive Treg development via alternative pathways dependent on polysaccharide A and TLR signaling to DCs (Round and Mazmanian, 2010; Shen et al., 2012).”
BackgroundExtracellular vesicles as tools and targets in therapy for diseases
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Metadata
- Authors
- Shen, Y., Torchia, M. L. G., Lawson, G. W., Karp, C. L., Ashwell, J. D., & Mazmanian, S. K.
- Affiliations
- California Institute of Technology (US)
- National Institutes of Health (US)
- University of California, Los Angeles (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Mazmanian, Sarkis K.
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 12
- Issue
- 4
- Pages
- 509-520
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC3895402
- OpenAlex
- W2051349444
- Cited by
- 714
- References
- 41
- Citations by year
- 2026: 59 · 2025: 84 · 2024: 60 · 2023: 61 · 2022: 69 · 2021: 83 · 2020: 61 · 2019: 48 · 2018: 34 · 2017: 40 · 2016: 30 · 2015: 27 · 2014: 33 · 2013: 23 · 2012: 1
- FWCI
- 11.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM007616, GM007616)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 078938, R01DK078938, R21DK083633, R56DK078938)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- 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
- outer membrane vesicles, Bacteroides fragilis, capsular polysaccharide, commensal bacteria, regulatory T cells, dendritic cells, TLR2, GADD45A, experimental colitis, mucosal tolerance, immunomodulation, interkingdom communication, gut microbiota, anti-inflammatory cytokines
- MeSH terms
- GADD45 Proteins, Animals, Bacteroides fragilis, Dendritic Cells, Immunologic Factors, Mice, Inbred BALB C, Mice, Inbred C57BL, Nuclear Proteins, Polysaccharides, Bacterial, Cytokines, Mice, Knockout, Cell Cycle Proteins, Gene Expression Profiling, T-Lymphocytes, Regulatory, Toll-Like Receptor 2, Mice, Exosomes
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