Harvard researchers uncover gut link that may transform obesity and diabetes treatment

The research, led by Harvard University in collaboration with the University of São Paulo (USP) and the University of Eastern Finland, explored how nutrients processed by gut bacteria interact with the liver—our central metabolic hub. When food is digested, it releases microbial byproducts into the hepatic portal vein, a blood vessel that directly connects the gut and the liver. This pathway makes the liver the body’s first responder to signals from the microbiome.

Using sophisticated metabolic profiling, scientists compared blood samples from healthy mice and those genetically prone to obesity and diabetes. Samples were taken from both the hepatic portal vein (blood exiting the intestine) and peripheral circulation (blood moving through the body). In healthy mice, researchers found 111 unique metabolites enriched in the hepatic vein, but this number dropped dramatically to 48 when the animals were fed a high-fat diet. The sharp decline suggests that poor diet alters which gut-produced chemicals reach the liver—and how effectively the body handles energy.

To test whether these molecules affect metabolism, the team looked at one standout compound: mesaconate, a metabolite involved in the Krebs cycle, the fundamental energy-producing process in cells. When liver cells were exposed to mesaconate in the lab, insulin signaling improved, and genes that regulate fat production and oxidation were better balanced.

The study also revealed that both genetics and environment shape how microbes produce these metabolites. When susceptible mice were treated with antibiotics to disrupt gut bacteria, metabolite profiles changed again, confirming the microbiome’s critical influence.

Lead author Dr. Vitor Rosetto Muñoz explains, “This is the first evidence that specific gut-to-liver metabolites directly influence insulin sensitivity.” The team is now identifying which bacterial strains generate these molecules. Their ultimate goal: to use these findings to design microbiome-based therapies that restore healthy metabolic function and prevent diseases such as diabetes.

REFERENCE: Vitor Rosetto Muñoz, Francois Moreau, Marion Soto, Yoshiyuki Watanabe, Loc-Duyen Pham, Jimmy Zhong, Sam Zimmerman, Bruna B. Brandao, Khyati Girdhar, Julian Avila, Hui Pan, Jonathan M. Dreyfuss, Michael Y. Mi, Robert E. Gerszten, Emrah Altindis, Aleksandar Kostic, Clary B. Clish, C. Ronald Kahn. Portal vein-enriched metabolites as intermediate regulators of the gut microbiome in insulin resistance. Cell Metabolism, 2025; 37 (10): 2048 DOI: 10.1016/j.cmet.2025.08.005