In healthy mice, the portal vein carried more than 110 distinct gut-derived metabolites, while obese/diabetes-prone mice on a high-fat diet showed a marked reduction in enriched metabolites reaching the liver.

Genetics and environment shape metabolite profiles, with differences observed between obesity/diabetes-prone and metabolically resilient mice.

On a high-fat diet, portal-vein–enriched metabolites dropped from 111 to 48 in obese-prone mice, highlighting how diet and genetics influence which microbial products reach the liver.

Future therapies could target microbiome-derived chemical signals to rewire fat and glucose handling, rather than focusing solely on appetite control or blood sugar.,

Future work will aim to better characterize individual metabolites and how they’re formed to harness microbiome-derived molecules for metabolic disease treatment.

Specific gut-derived metabolites like mesaconate enhanced insulin signaling and modulated fat storage in liver cells, illustrating a direct gut–liver–metabolism pathway suitable for targeting.

A Harvard-backed study advances beyond correlation by identifying specific gut-derived metabolites and tracing their journey from the gut to the liver and then into the bloodstream, linking them to metabolic effects.

The liver emerges as a central hub that receives gut metabolites via the portal vein and then distributes signals throughout the body, influencing metabolism and offering a potential new angle for treating obesity and type 2 diabetes.

The team mapped metabolites traveling from the gut to the liver through the hepatic portal vein and onward to the heart, with impacts on hepatic metabolism and systemic insulin response.

Publication details: Cell Metabolism, published September 5, 2025, Muñoz et al., DOI: 10.1016/j.cmet.2025.08.005.

Funding for the work comes from the São Paulo Research Foundation (FAPESP).

Modifying the gut microbiome with antibiotics altered the distribution of metabolites between portal and peripheral blood, confirming the microbiome’s role in metabolite production.

The research points toward developing drugs or dietary strategies that mimic or promote protective microbial metabolites to reprogram metabolism for diabetes and obesity management.

Mesaconate, a Krebs-cycle–related metabolite, rose after antibiotic treatment and, when applied to hepatocytes, improved insulin signaling and regulated fat metabolism genes, suggesting therapeutic potential.