Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway

doi:10.1016/j.chom.2025.05.007

. 2025 Jun 11;33(6):901-914.e6.

doi: 10.1016/j.chom.2025.05.007. Epub 2025 May 30.

Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: erbrown@broadinstitute.org.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

PMID: 40449488
PMCID: PMC12169427 (available on 2026-06-11)
DOI: 10.1016/j.chom.2025.05.007

Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway

Eric M Brown et al. Cell Host Microbe. 2025.

. 2025 Jun 11;33(6):901-914.e6.

doi: 10.1016/j.chom.2025.05.007. Epub 2025 May 30.

Authors

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: erbrown@broadinstitute.org.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

PMID: 40449488
PMCID: PMC12169427 (available on 2026-06-11)
DOI: 10.1016/j.chom.2025.05.007

Abstract

Sphingolipids derived from Bacteroides species are associated with changes in host inflammation and metabolic syndrome; however, the signaling mechanisms within host cells are unknown. We utilize outer membrane vesicles (OMVs) from wild-type and sphingolipid-deficient Bacteroides strains to understand how these lipids modulate host inflammation. Characterization of the lipidome of B. thetaiotaomicron OMVs revealed enrichment of dihydroceramide phosphoethanolamine (CerPE). OMVs deliver bacterial sphingolipids into host dendritic and epithelial cells, where a subset of lipids, including CerPE, stably persist. Similarly, B. thetaiotaomicron colonization results in sphingolipid persistence in murine tissues and host lipidome alterations that are not observed with the sphingolipid-deficient strain. OMVs induce a potent, sphingolipid-dependent interleukin-10 (IL-10) anti-inflammatory response in dendritic cells, which depends on mevalonate pathway activation. Adding a CerPE fraction to sphingolipid-deficient OMVs rescued IL-10 secretion, similarly dependent on mevalonate pathway activation. These data highlight the essential roles of sphingolipids in stimulating anti-inflammatory responses mediated by mevalonate pathway induction.

Keywords: Bacteroides; CerPE; IL-10; OMVs; anti-inflammatory signaling; dendritic cells; immunometabolism; mevalonate pathway; microbiome; outer membrane vesicles; sphingolipids.

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Conflict of interest statement

Declaration of interests R.J.X. is co-founder of Jnana Therapeutics, Board Director at MoonLake Immunotherapeutics, and scientific advisory board member at Nestle, Magnet Biomedicine, and Arena BioWorks. These organizations had no role in this study.

References

1. Integrative HMP (iHMP) Research Network Consortium (2019). The Integrative Human Microbiome Project. Nature 569, 641–648. 10.1038/s41586-019-1238-8. - DOI - PMC - PubMed
1. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, et al. (2012). Human gut microbiome viewed across age and geography. Nature 486, 222–227. 10.1038/nature11053. - DOI - PMC - PubMed
1. Wexler AG, and Goodman AL (2017). An insider’s perspective: Bacteroides as a window into the microbiome. Nat. Microbiol 2, 17026. 10.1038/nmicrobiol.2017.26. - DOI - PMC - PubMed
1. Heaver SL, Johnson EL, and Ley RE (2018). Sphingolipids in host-microbial interactions. Curr. Opin. Microbiol 43, 92–99. 10.1016/j.mib.2017.12.011. - DOI - PubMed
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[1] Integrative HMP (iHMP) Research Network Consortium (2019). The Integrative Human Microbiome Project. Nature 569, 641–648. 10.1038/s41586-019-1238-8. - DOI - PMC - PubMed

[2] Integrative HMP (iHMP) Research Network Consortium (2019). The Integrative Human Microbiome Project. Nature 569, 641–648. 10.1038/s41586-019-1238-8. - DOI - PMC - PubMed

[3] Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, et al. (2012). Human gut microbiome viewed across age and geography. Nature 486, 222–227. 10.1038/nature11053. - DOI - PMC - PubMed

[4] Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, et al. (2012). Human gut microbiome viewed across age and geography. Nature 486, 222–227. 10.1038/nature11053. - DOI - PMC - PubMed

[5] Wexler AG, and Goodman AL (2017). An insider’s perspective: Bacteroides as a window into the microbiome. Nat. Microbiol 2, 17026. 10.1038/nmicrobiol.2017.26. - DOI - PMC - PubMed

[6] Wexler AG, and Goodman AL (2017). An insider’s perspective: Bacteroides as a window into the microbiome. Nat. Microbiol 2, 17026. 10.1038/nmicrobiol.2017.26. - DOI - PMC - PubMed

[7] Heaver SL, Johnson EL, and Ley RE (2018). Sphingolipids in host-microbial interactions. Curr. Opin. Microbiol 43, 92–99. 10.1016/j.mib.2017.12.011. - DOI - PubMed

[8] Heaver SL, Johnson EL, and Ley RE (2018). Sphingolipids in host-microbial interactions. Curr. Opin. Microbiol 43, 92–99. 10.1016/j.mib.2017.12.011. - DOI - PubMed

[9] Brown EM, Clardy J, and Xavier RJ (2023). Gut microbiome lipid metabolism and its impact on host physiology. Cell Host Microbe 31, 173–186. 10.1016/j.chom.2023.01.009. - DOI - PMC - PubMed

[10] Brown EM, Clardy J, and Xavier RJ (2023). Gut microbiome lipid metabolism and its impact on host physiology. Cell Host Microbe 31, 173–186. 10.1016/j.chom.2023.01.009. - DOI - PMC - PubMed

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Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway

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Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway

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