Researchers working at Harvard University and collaborators in Brazil have identified metabolites produced by gut bacteria that travel through the portal vein to the liver and appear to influence energy use and insulin sensitivity in mice. The findings, published in Cell Metabolism, suggest possible new strategies for preventing or treating obesity and type 2 diabetes by targeting gut–liver communication.([sciencedaily.com](https://www.sciencedaily.com/releases/2025/12/251214100926.htm?utm_source=openai))
A research project carried out at Harvard University in the United States and supported by Brazil's São Paulo Research Foundation (FAPESP) has identified a set of metabolites derived from the gut microbiome that move from the intestine to the liver and then into the wider circulation, where they appear to affect key metabolic pathways and insulin sensitivity in mice. The work, reported in Cell Metabolism, involved analyzing blood from the hepatic portal vein, which carries blood from the intestine directly to the liver, and from peripheral blood that circulates throughout the body.(sciencedaily.com)
In healthy, obesity-resistant C57BL/6J mice, the team detected 111 metabolites that were enriched in portal blood and 74 that were enriched in peripheral blood. When mice genetically prone to obesity and type 2 diabetes were fed a high-fat, hyperlipidemic diet, the number of metabolites enriched in the hepatic portal vein fell from 111 to 48, indicating that diet strongly alters the profile of gut-derived molecules reaching the liver. Comparisons with a strain of mice naturally resistant to metabolic syndrome (129S1/129S6) showed that genetic background also shaped which metabolites appeared in the portal circulation.(sciencedaily.com)
"The hepatic portal vein drains much of the blood from the intestine to the liver. Therefore, it's the first place to receive products from the gut microbiome. In the liver, they can be conjugated, transformed, or eliminated, and then enter the systemic circulation," said Vitor Rosetto Muñoz, the study's first author and a postdoctoral researcher at the Ribeirão Preto School of Physical Education and Sports at the University of São Paulo (EEFERP-USP) in Brazil, in comments reported by FAPESP. He conducted the work during an internship at the Joslin Diabetes Center at Harvard Medical School under the supervision of C. Ronald Kahn.(sciencedaily.com)
To probe causal links between the microbiome and these circulating compounds, the researchers treated obesity- and diabetes-prone mice with the antibiotic vancomycin to selectively disrupt intestinal bacteria. This intervention reshaped the microbiome and changed the balance of metabolites in both portal and peripheral blood, including an increase in metabolites related to the tricarboxylic acid (Krebs) cycle such as mesaconate.(sciencedaily.com)
Follow-up experiments exposed isolated hepatocytes (liver cells) to mesaconate and related isomers itaconate and citraconate. According to the Cell Metabolism paper, these treatments improved insulin signaling and altered the expression of genes involved in gluconeogenesis, fatty acid oxidation, and lipogenesis, processes that are central to metabolic health. In mouse models, modulating these metabolites was associated with changes in insulin resistance.(pubmed.ncbi.nlm.nih.gov)
"This shows that both the environment and the host's genetics can interact in complex ways with the gut microbiome. As a result of these interactions, different combinations of metabolites may be sent to the liver and subsequently to the peripheral circulation. These metabolites likely play an important role in mediating the conditions that lead to obesity, diabetes, and metabolic syndrome," Muñoz said in statements released by FAPESP and partner outlets.(sciencedaily.com)
The study adds to a growing body of evidence that people and animals with obesity, type 2 diabetes, glucose intolerance, or insulin resistance often have distinct gut microbiomes compared with metabolically healthy individuals, but that pinpointing the key microbial products has been challenging. By focusing on metabolites enriched specifically in portal blood, the authors argue, it is possible to better understand which microbial molecules reach the liver first and how they may help drive or protect against metabolic disease.(sciencedaily.com)
The researchers now aim to characterize individual metabolites in more detail and map how they are produced by gut microbes and processed by the host. Over time, they suggest, identifying portal vein–enriched metabolites that improve insulin signaling or lipid handling in the liver could point to new microbiome-based or metabolite-based therapies to prevent or manage obesity, insulin resistance, and type 2 diabetes. The current findings, however, are based on mouse models, and experts note that further studies will be needed to determine whether the same mechanisms operate in humans and how they might be translated into clinical treatments.(sciencedaily.com)
