Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control

Obesity affects millions of people in the world. The gut microbiome influences body fat accumulation, but the mechanisms remain to be investigated. Here, we show an association between microbial aromatic amino acid metabolites in serum and body fat accumulation in a large Chinese longitudinal cohort. We next identify that 4-hydroxyphenylacetic acid (4HPAA) and its analogues effectively protect male mice from high-fat-diet-induced obesity. These metabolites act on intestinal mucosa to regulate the immune response and control lipid uptake, which protects against obesity. We further demonstrate that T cells and B cells are not vital for 4HPAA-mediated obesity prevention, and innate lymphoid cells have antagonistic roles. Together, these findings reveal specific microbial metabolites as pivotal molecules to prohibit obesity through immune control, establishing mechanisms of host modulation by gut microbial metabolites. The gut-microbiota-derived aromatic amino acid metabolite 4-hydroxyphenylacetic acid (4HPAA) and its analogues have been shown to protect against obesity. In mice, 4HPAA exerts anti-obesogenic effects by modulating mucosal immunity and lipid uptake in the intestine.