A new study in Cell Metabolism suggests that small molecules produced in the gut may play an important role in how the body regulates insulin, stores fat and responds to a high-fat diet. The research helps explain why diet and the gut microbiome are so closely linked to obesity and type 2 diabetes.
Researchers at Harvard University and the University of São Paulo focused on the metabolites that appear in two key places: the hepatic portal vein, which carries blood directly from the intestine to the liver, and the peripheral bloodstream, which circulates these metabolites throughout the body. By comparing these metabolites in mice with different genetic risks for metabolic disease, the team found striking differences in the chemical signals that reach the liver.
The portal vein was enriched with more than 100 gut-derived metabolites in healthy mice. But when genetically susceptible mice ate a high-fat diet, the number of these molecules dropped by more than half. According to first author Vitor Rosetto Muñoz, this suggests that diet can dramatically alter the metabolic “messages” the liver receives from the gut.
The researchers also identified specific metabolites that changed consistently when the microbiome was altered. One of them, mesaconate, is linked to the Krebs cycle, a key energy-producing pathway inside cells. When the team treated liver cells with mesaconate and related compounds, they observed improvements in insulin signaling and changes in genes involved in fat storage and fat breakdown.
These findings point to a potential mechanism for how gut microbes influence liver function and metabolic health. They also reinforce that the effects of diet on metabolism extend beyond calories or macronutrients, involving the microbial byproducts that circulate throughout the body.
The study was conducted in mice, so more research will be needed before the findings can translate to people. Still, the work adds to growing evidence that gut-derived metabolites may help explain why some individuals are more vulnerable to the metabolic effects of high-fat diets than others.
This research was supported by grants from the National Institutes of Health, the São Paulo Research Foundation and several collaborating institutions involved in the TOPMed and Jackson Heart Study programs. The authors thank the participating research teams and study volunteers.