Integrative analysis revealed novel putative therapeutic targets of ulcerative colitis: Role of creatine.

ABSTRACT

BACKGROUND: Ulcerative colitis (UC) is becoming a global burden. Previous observational studies have unveiled associations between serum metabolites and UC, but their causal relationship remains unclear. METHODS: Serum samples from patients and mice with UC were utilized for untargeted metabolomics to identify UC-associated metabolites. Then, a two-sample mendelian randomization (MR) analysis was employed to estimate their causal relationship. Finally, mice with chronic colitis induced by dextran sodium sulfate (DSS) and macrophages were used to evaluate the protective role of creatine and underlying mechanism. RESULTS: 16 serum metabolites showed associations with UC after adjusting for confounders and multiple testing. Among them, creatine exhibited a robust protective effect against UC (OR=0.39; 95 % CI=0.27-0.56). Significant reduction of creatine was also observed in mice with acute UC induced by DSS. The inverse variance weighted (IVW) MR analysis further confirmed a causal effect of creatine on UC risk (OR IVW=0.45; 95 % CI 0.27-0.76). Furthermore, creatine supplementation could significantly suppress weight loss, disease activity index, mucosal damage and the infiltration of macrophages in mice with chronic colitis. Remarkably, creatine promoted the polarization of bone marrow-derived macrophage (BMDM) towards M2 phenotype and upregulated the expression of il-10, il-12 and arg-1. CONCLUSIONS: This study revealed a causal relationship between creatine and UC. Creatine supplementation ameliorated chronic colitis by inhibiting the colonic infiltration of macrophages and promoting its polarization towards M2 phenotype. These results offer new insight into the pathogenesis of UC, emphasizing a potential protective role of creatine for UC.