Microbiota-regulation of endothelial phenotypes in atherosclerosis

Introduction Atherosclerosis, a chronic inflammatory disease driven by endothelial dysfunction and dysregulated lipid metabolism, involves not only cholesterol accumulation but also sphingolipid-mediated signaling. Gut microbiota, particularly Bacteroidota species, produce odd-chain sphingolipids that integrate into host metabolism, yet how these microbial lipids shape host endothelial sphingolipid metabolism in atherosclerosis remains largely unexplored. The liver, a major site of host–microbiota metabolic exchange, contains hepatic sinusoidal endothelial cells (HSECs) that may sense and regulate microbial lipid signals. Here, we demonstrate how gut microbiota control sphingolipid biosynthesis in HSECs via the intestinal epithelium–endothelium axis and how this interaction modulates vascular inflammation [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]. Method Low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice were maintained under germ-free (GF) or conventionally raised (CONV-R) conditions and fed either a high-cholesterol Western diet (WD) or normal chow diet (CD) for 8 weeks (early atherosclerosis) or 16 weeks (advanced atherosclerosis). HSECs were isolated by magnetic cell separation and subjected to whole-transcriptome sequencing and OLINK analysis. To characterize the gut–liver axis, intestinal epithelial and endothelial cells were isolated for qRT-PCR and single-cell RNA-sequencing analysis, respectively. Vascular phenotypes in the small intestine were assessed by immunofluorescence staining. Finally, monocolonization with the sphingolipid-producing Bacteroides fragilis was performed to evaluate their impact on hepatic endothelial sphingolipid metabolism. Results Comprehensive analysis of the hepatic and intestinal transcriptome from mice fed a WD for 16 weeks reveled no significant regulation of sphingolipid metabolism induced by gut microbiota, likely due to severe hyperlipidemia. However, in the early atherosclerotic stage, hepatic endothelial cells showed microbiota-dependent changes in the expression of genes involved in sphingolipid synthesis. Monocolonization with sphingolipid-producing Bacteroides fragilis led to downregulation of key sphingolipid synthesis genes, suggesting that bacterial sphingolipids modulate host hepatic pathways. Furthermore, proteomic analysis identified inflammatory mediators linking dietary, microbial, and monocolonization effects in the hepatic endothelium. Conclusion Our findings demonstrate that although diet is the dominant regulator of overall gene expression, the gut microbiota, particularly Bacteroides fragilis , plays a critical role in regulating sphingolipid metabolism and hepatic endothelial function. These microbial effects further extend to vascularization in the intestine and immune cell composition within atherosclerotic plaques, thereby linking the gut–liver axis to atherosclerosis progression. Understanding these microbiota-driven pathways opens new perspectives for targeting host–microbe interactions to prevent or treat cardiometabolic diseases. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany