Brown Eric M, Temple Emily R, Jeanfavre Sarah, Avila-Pacheco Julian, Taylor Noel, Liu Kai, Nguyen Phuong N U, Mohamed Ahmed M T, Ung Panhasith, Walker Rebecca A, Graham Daniel B, Clish Clary B, Xavier Ramnik J
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.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell Host Microbe. 2025 Jun 11;33(6):901-914.e6. doi: 10.1016/j.chom.2025.05.007. Epub 2025 May 30.
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.
来自拟杆菌属的鞘脂与宿主炎症和代谢综合征的变化有关；然而，宿主细胞内的信号传导机制尚不清楚。我们利用野生型和鞘脂缺陷型拟杆菌菌株的外膜囊泡（OMV）来了解这些脂质如何调节宿主炎症。对多形拟杆菌OMV脂质组的表征揭示了二氢神经酰胺磷酸乙醇胺（CerPE）的富集。OMV将细菌鞘脂递送至宿主树突状细胞和上皮细胞，其中包括CerPE在内的一部分脂质稳定存在。同样，多形拟杆菌的定殖导致鞘脂在小鼠组织中持续存在，以及宿主脂质组改变，而鞘脂缺陷型菌株则未观察到这种情况。OMV在树突状细胞中诱导一种强效的、依赖鞘脂的白细胞介素-10（IL-10）抗炎反应，这取决于甲羟戊酸途径的激活。向鞘脂缺陷型OMV中添加CerPE组分可挽救IL-10分泌，同样依赖于甲羟戊酸途径的激活。这些数据突出了鞘脂在刺激由甲羟戊酸途径诱导介导的抗炎反应中的重要作用。
