Ceramide accumulation and microbiota-derived sphingolipids: A novel axis in obesity-linked diabetic inflammation

Abstract

Obesity and type 2 diabetes are associated with chronic low-grade inflammation and metabolic abnormalities, in which ceramide accumulation is identified as a core pathogenic factor. Ceramides are bioactive sphingolipids synthesized through both de novo and salvage pathways that repress insulin signaling, induce programmed cell death, and initiate inflammatory cascades. It was reviewed that the gut microbiota is another sphingolipid source, particularly via Bacteroides-derived metabolites, which can modulate host lipid metabolism and immune function. Obesity-associated dysbiosis disrupts sphingolipid production by the gut microbiota, leading to changes in systemic lipids and heightened inflammatory responses induced by ceramides. This ceramide–microbiome-sphingolipid axis contributes to insulin resistance, adipose tissue macrophage activation, and hepatic metabolic stress, linking the ecology of the gut microbiota to diabetic inflammation. In this review, we aim to summarize recent advances in ceramide metabolism, microbial sphingolipid production and their intersection in obesity-associated diabetes. We also addressed the potential of therapeutic interventions (ie, dietary modulation, probiotics, and pharmacological inhibitors) targeting lipid homeostasis to alleviate immunometabolic dysfunction. Deciphering this new axis provides translational chances for biomarker discovery and precision therapies of metabolic disorders.