Akkermansia muciniphila phospholipid induces homeostatic immune responses
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Abstract Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging 1–3 . Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity 4–7 . Here we report the identification of a lipid from A. muciniphila ’s cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays 8 . The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure–activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2–TLR1 heterodimer 9,10 . Certain features of the phospholipid’s activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC 50 ) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2–TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila’ s ability to set immunological tone and its varied roles in health and disease.
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A lipid from Akkermansia's cell membrane can activate a non-canonical TLR2-TLR1 pathway in immune cells.
“while a lipid from Akkermansia’s cell membrane can activate a non-canonical TLR2-TLR1 pathway in immune cells42.”
From A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy (2023) · cites this paper as [42]
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- Authors
- Bae, M., Cassilly, C. D., Liu, X., Park, S.-M., Tusi, B. K., Chen, X., Kwon, J., Filipčík, P., Bolze, A. S., Liu, Z., Vlamakis, H., Graham, D. B., Buhrlage, S. J., Xavier, R. J., & Clardy, J.
- Affiliations
- Gachon University (KR)
- Harvard University (US)
- Broad Institute (US)
- Corresponding author
- Xavier, Ramnik J.
- Clardy, Jon
- ORCID
- Venue
- Nature
- Published
- 2022-07-27
- Volume
- 608
- Issue
- 7921
- Pages
- 168-173
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9328018
- OpenAlex
- W4288052200
- Cited by
- 413
- References
- 52
- Citations by year
- 2026: 72 · 2025: 126 · 2024: 102 · 2023: 95 · 2022: 18
- FWCI
- 32.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Massachusetts General Hospital
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI172147)
- National Institute of Diabetes and Digestive and Kidney Diseases (RC2DK114784, P30DK043351, R01DK131742, R01DK127171)
- National Center for Complementary and Integrative Health (F32AT010415, R01AT009708)
- 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
- Akkermansia muciniphila, immunomodulation, Toll-like receptor signaling, structure-activity relationship, gut microbiota, immune homeostasis, inflammatory cytokines, synthetic analogues
- MeSH terms
- Akkermansia, Cell Membrane, Homeostasis, Humans, Immunity, Phosphatidylethanolamines, Structure-Activity Relationship, Cytokines, Inflammation Mediators, Toll-Like Receptor 1, Toll-Like Receptor 2
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