Host hepatic metabolism is modulated by gut microbiota-derived sphingolipids

Microbially-derived gut metabolites are important contributors to host phenotypes, many of which may link microbiome composition to metabolic disease. However, relatively few metabolites with known bioactivity have been traced from specific microbes to host tissues. Here, we use a labeling strategy to characterize and trace bacterial sphingolipids from the gut symbiont Bacteroides thetaiotaomicron to mouse colons and livers. We find that bacterial sphingolipid synthesis rescues excess lipid accumulation in a mouse model of hepatic steatosis and observe the transit of a previously uncharacterized bacterial sphingolipid to the liver. The addition of this sphingolipid to hepatocytes improves respiration in response to fatty-acid overload, suggesting that sphingolipid transfer to the liver could potentially contribute to microbiota-mediated liver function. This work establishes a role for bacterial sphingolipids in modulating hepatic phenotypes and defines a workflow that permits the characterization of other microbial metabolites with undefined functions in host health. [Display omitted] •Alkyne-modified lipids used to trace microbe-host metabolite transfer•Unique bacterial sphingolipid is transferred from the gut microbiome to the liver•Microbial sphingolipid improves respiration in liver cells•Bacterial sphingolipid synthesis decreases excess hepatic lipid accumulation Identifying microbial metabolites modulating metabolism can be challenging. Le et al. use bioorthogonal chemistry to identify and trace the transfer of a unique bacterial sphingolipid to colon and liver tissue. Furthermore, bacterial sphingolipid synthesis by Bacteroides was determined to ameliorate hepatic lipid accumulation in a mouse model of hepatic steatosis.