PR000754 (Project)

Description:Sphingolipids are structural membrane components and important eukaryotic signaling molecules. We hypothesized that sphingolipids mediate intestinal health as they were identified as the most upregulated metabolite feature in stool of inflammatory bowel disease (IBD) patients. Commensal Bacteroidetes also produce sphingolipids, but the impact of these metabolites on host pathways is largely uncharacterized. To study Bacteroidetes sphingolipids in intestinal health, we colonized germ-free mice with a sphingolipid-deficient Bacteroides thetaiotaomicron strain. A lack of Bacteroides-derived sphingolipids increased intestinal inflammation, dysregulated innate immunity and altered the host ceramide pool. Using metabolomic analysis, we described the Bacteroides sphingolipid biosynthesis pathway and revealed a greater variety of Bacteroides-derived sphingolipids than previously recognized, including ceramide phosphoinositol and deoxy-sphingolipids. We annotated Bacteroides sphingolipids in an IBD metabolomic dataset, discovering lower abundances in IBD and negative correlations with gut inflammation and host sphingolipid production. These data highlight the role of sphingolipids in maintaining host-bacterial symbiosis and intestinal homeostasis.