Microbial–purine metabolic crosstalk regulates colitis-related intestinal fibrosis: A multiomics and cohort analysis approach

Intestinal fibrosis (IF) is a severe complication of inflammatory bowel disease (IBD), often requiring surgical interventions. The modulating role of the microbial-metabolic link in IF remains unclear. We aimed to identify disturbances in microbiome–metabolome interactions during IF progression and recognize potential metabolic biomarkers. Compositional and functional signatures, along with murine IF progression, were determined through 16S rRNA sequencing and widely targeted metabolomics. Overall, 109 patients with IBD and 111 healthy controls (HCs) were enrolled and clinically evaluated. Correlations analyses were performed to reveal the relationship between microbial–purine metabolic alterations and disease markers. Gut microbiome analysis identified structural disruptions, including a reduction in uric acid (UA)-decomposed microbes and an increase in hyperuricemia-associated taxa (P<.05), which contributed to impaired purine metabolism (P<.05). Metabolomic profiling further indicated reprogramming of purine metabolism in fibrogenesis, as evidenced by elevated UA levels in fecal, colonic, and serum samples that correlated with inflammatory and fibrotic markers. In IBD patients, compared to HCs, serum UA (342.55±95.69 vs. 294.78±66.58 µmol/L) and UA/creatinine (UA/Cr) levels (5.17±1.57 vs. 4.40±1.28) were greatly increased (P<.001) and positively correlated with the clinical and endoscopic activities, especially in CD patients. Serial measurements demonstrated elevated UA during stenosis formation. UA/Cr may be an independent risk factor (P=.006) for stenosis prognosis. Abnormal purine metabolism may regulate IF, as reflected in purine metabolism-related microbes and metabolites. Elevated serum UA and UA/Cr levels are promising biomarkers for detecting disease activity and predicting stenosis in IBD.