Microbiota-regulation of the hepatic sphingolipid synthesis pathway

Introduction: The gut microbiota has emerged as a significant modulator of sphingolipid metabolism and angiogenesis in hepatic endothelium, which are both critical factors in the development of atherosclerosis [1]. Since sphingolipid metabolism plays a central role in the pathogenesis of atherosclerosis [2], and the liver is the primary organ responsible for processing bacterial metabolites from the gut, understanding the specific contributions of sphingolipids is essential. Additionally, diet is one of the key factors influencing the progression of atherosclerosis [3]. This study aims to investigate the diet-dependent effects on the liver sinusoidal endothelial cell (LSEC) transcriptome during both early and late stages of atherosclerosis, with a specific focus on the roles of gut microbiota and sphingolipid metabolism.

Method: Low-density lipoprotein receptor-deficient (Ldlr^-/-) mice were raised under germ-free (GF) or conventional (CONV-R) conditions and fed either a high-cholesterol Western diet (WD) or normal chow diet (ND) for 16 weeks. Wild-type (WT) mice were used as controls. LSECs were isolated using magnetic cell separation and for a whole-transcriptome sequencing. The effects of diet and the microbiome at earlier stages were also explored after 8 weeks of feeding, along with histological analysis of aortic lesions. Monocolonization with E. coli was performed to assess the impact of a specific bacterium on sphingolipid metabolism, and age-related changes were examined by comparing WT mice aged 15 and 86 weeks.

Results: Comprehensive transcriptome analyses revealed that diet significantly influenced overall gene expression, particularly when comparing CONV-R mice on ND with those on a 16-week WD. However, sphingolipid regulation and angiogenesis-related genes were more strongly influenced by the microbiome than by diet when comparing GF and CONV-R mice. Monocolonization with E. coli regulated sphingolipid-related genes, underlining the role of gut bacteria in sphingolipid metabolism. Additionally, age-related shifts in sphingolipid homeostasis highlighted the importance of these lipids in endothelial function and atherosclerosis progression.

Conclusion: In summary, this study proposes that gut microbiota, rather than diet alone, is a key regulator of sphingolipid-related gene expression in LSECs. The results highlight the pivotal role of gut bacteria in sphingolipid metabolism and angiogenesis, supporting previous studies that emphasize the importance of maintaining sphingolipid homeostasis in endothelial function and atherosclerosis. However, to gain a deeper understanding of the link between sphingolipid metabolism and the progression of atherosclerosis, further functional studies are necessary, aiming to unravel the specific mechanisms by which bacterial metabolites influence sphingolipid metabolism and angiogenesis.

Publication History

Article published online:
13 February 2025

• References

• 1 Formes H. et al. “The gut microbiota instructs the hepatic endothelial cell transcriptome.”. iScience vol. 24 (10) 103092 2021;
• 2 Hornemann T, Tilla SW. “Sphingolipids and atherosclerosis.”. Atherosclerosis vol. 226 (01) 2013; 16-28
• 3 Greenhill C. “Effects of diet on atherosclerotic plaque development.”. Nature reviews. Endocrinology vol. 20 (11) 2024; 631