Hyperuricemia aggravates acute colitis through NLRP3-associated macrophage-lineage inflammatory responses

Inflammatory bowel diseases (IBDs) are chronic, relapsing inflammatory disorders of the gastrointestinal tract with rising prevalence. Hyperuricemia has been associated with IBD, but whether elevated uric acid (UA) directly aggravates intestinal inflammation and how it affects immune responses remain unclear.

We used hepatocyte-specific Glut9 knockout mice, allopurinol intervention, and acute UA administration in wild-type mice to assess dextran sulfate sodium (DSS)-induced acute colitis. Lamina propria immune cells were profiled by expanded flow cytometry; phagocytic/macrophage-lineage and NLRP3 pathways were perturbed with clodronate liposomes, MCC950, and Nlrp3 siRNA. Bone marrow-derived macrophages (BMDMs) and public human IBD mucosal transcriptomic datasets were analyzed.

Glut9 HKO mice developed higher serum UA and more severe DSS-induced colitis than controls, whereas allopurinol reduced serum UA and ameliorated disease. Acute UA administration during DSS exposure similarly worsened colitis in wild-type mice. Hyperuricemia expanded colonic monocyte/macrophage-lineage cells during DSS challenge, increased pro-inflammatory cells, and enhanced NLRP3 inflammasome-associated signaling. Clodronate-sensitive macrophage depletion and MCC950 attenuated disease severity. In BMDMs, soluble UA enhanced LPS-primed inflammatory activation and inflammasome-associated readouts, which were reduced by NLRP3 inhibition or knockdown. In human IBD mucosal transcriptomic datasets, purine metabolism scores positively correlated with inflammatory macrophage and NLRP3 inflammasome signatures.

Elevated UA aggravates DSS-induced acute colitis and amplifies inflammatory monocyte/macrophage-lineage responses associated with NLRP3 inflammasome signaling. These findings identify hyperuricemia as a metabolic modifier of acute intestinal injury and support further investigation of UA-linked innate immune activation in IBD.