https://www.cas.cn/syky/202606/t20260609_5112110.shtml
https://www.cell.com/cell-host-microbe/abstract/S1931-3128(26)00181-2
From an evolutionary perspective, humans and certain non-human primates lost the urate oxidase gene during their evolution—unlike most other mammals—resulting in elevated serum uric acid levels and a unique high-uric-acid microenvironment. In ancient times of food scarcity, this high-uric-acid trait likely conferred a survival advantage by actively facilitating energy intake and storage. In modern society, however, hyperuricemia shows a strong clinical correlation with obesity and metabolic syndrome. The medical community has generally regarded uric acid merely as an end-product of purine metabolism or a biomarker accompanying obesity, lacking mechanistic evidence that it directly drives the development of obesity.
A research team led by the CAS Shanghai Institute of Nutrition and Health and the Shanghai Institute of Materia Medica discovered that uric acid acts as a liver-derived endocrine regulator; through liver-gut crosstalk, it remodels the gut microbiota, thereby promoting dietary lipid absorption and inducing obesity.
Clinical cohort analyses revealed a significant positive correlation between serum uric acid levels and the capacity for intestinal dietary lipid absorption in humans. Using various animal models, the study confirmed that reducing hepatic uric acid synthesis inhibits dietary lipid absorption in mice, rendering them resistant to high-fat-diet-induced obesity. Mechanistically, uric acid produced in the liver enters the intestine via the bloodstream and specifically interferes with the synthesis of peptidoglycan in the cell walls of Lactobacillus johnsonii, thereby inhibiting its growth. Lactobacillus johnsonii normally inhibits the intestinal PPARαsignaling pathway and reduces the expression of fatty acid transport proteins through the synthesis of phenyllactic acid. Elevated uric acid levels lead to a reduction in Lactobacillus johnsonii and a consequent drop in intestinal phenyllactic acid levels; this relieves the inhibition of PPARα signaling, accelerating dietary lipid absorption and inducing obesity.
The study also identified the histone acetyltransferase TIP60 as a key factor regulating hepatic uric acid synthesis and evaluated its therapeutic potential. Research shows that treating obese mice with lipid nanoparticle-delivered siRNA targeting Tip60 inhibits hepatic uric acid production, restores the abundance of Lactobacillus johnsonii, and ameliorates metabolic abnormalities.