Uric acid promotes dietary lipid absorption through microbiome and metabolomic remodeling via a liver-gut endocrine axis

Abstract

Hyperuricemia closely correlates with obesity, yet high uric acid (UA) is largely viewed as a consequence or biomarker of obesity rather than a causal driver. Integrating human clinical analyses with animal studies, we redefine UA as a liver-derived endocrine regulator that drives obesity by modulating gut ecology. UA remodels the gut microbiota, selectively depleting Lactobacillus johnsonii by disrupting peptidoglycan synthesis. This depletion reduces microbial phenyllactic acid (PLA)—a metabolite produced by L. johnsonii lactate dehydrogenase that we identify as an endogenous suppressor of intestinal peroxisome proliferator-activated receptor alpha (PPARα) signaling. Consequently, PPARα disinhibition upregulates fatty acid transporters, accelerating lipid absorption and promoting obesity. Leveraging human genetic data, we pinpoint lysine acetyltransferase 5 (TIP60) as a master regulator of hepatic UA production. Hepatic TIP60 ablation lowers UA, restoring the L. johnsonii -PLA axis and conferring obesity resistance. These findings establish a UA-driven liver-gut axis and nominate TIP60 inhibition as a dual-target therapy for obesity and hyperuricemia.