PR002557 (Project)

Description:The role of the gut microbiome in mediating steatotic liver disease is poorly understood. Here, we developed a model to deplete the gut microbiome in adult zebrafish and discovered that it led to steatotic liver disease in animals on standard diets. Using metabolomics and isotope tracing, we found that dietary glucose is transformed into sorbitol within the intestine. While bacteria degrade the sorbitol in control animals, sorbitol is passed to the livers of fish in which the gut microbiome has been depleted. Within the liver, sorbitol is converted into fructose 1-phosphate, which subsequently activates glucokinase. The result is increased hepatic metabolism of glucose, leading to elevated glycogen and fat content. Inhibition of sorbitol production in microbiome-depleted animals was sufficient to prevent the development of steatotic liver, and colonizing sorbitol-degrading bacteria in the intestines of microbiome-depleted fish reversed the steatotic liver phenotype. Taken together, these findings show that sorbitol-degrading bacteria in the gut protect against steatotic liver disease.