Anti-hyperuricemia therapy alleviates diet-induced gut inflammation via AhR-IL-22-signalling.

High-fat diets (HFD) are implicated in metabolic disorders through mechanisms involving hyperuricemia, gut dysbiosis, and intestinal barrier dysfunction. This study investigated the effects of pharmacological uric acid reduction on gut homeostasis in HFD-fed mice. We assessed serum uric acid, gut microbial composition, pro- and anti-inflammatory cytokine expression, intestinal barrier dysfunction markers, and tryptophan metabolism in mice subjected to HFD with or without allopurinol treatment. AhR antagonist CH-223191 was used to provide functional evidence for the role of AhR activation in mediating the observed effects. HFD induced hyperuricemia, microbial dysbiosis characterized by increased Proteobacteria and altered Firmicutes/Bacteroidetes ratios, and elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). These changes correlated with decreased IL-10 and IL-22, increased serum LPS, and systemic inflammation (IL-6, CRP). Allopurinol treatment normalized uric acid levels, restored microbial balance, reduced gut and systemic inflammation, improved intestinal barrier function, and modulated tryptophan metabolism by decreasing IDO1 activity and restoring indole production. Pharmacological blockade of AhR with CH-223191 reversed the anti-inflammatory and barrier-protective effects of allopurinol treatment, providing functional evidence for the role of AhR/IL22 axis in mediating gut protection. Targeting hyperuricemia effectively reverses HFD-induced gut dysbiosis, inflammation, and barrier dysfunction through metabolite-mediated immunoregulatory mechanisms involving the AhR-IL-22 axis. These findings propose uric acid modulation as a promising therapeutic strategy for metabolic and inflammatory gut diseases.