Preclinical and limited clinical evidence for metformin in ulcerative colitis: a systematic review and meta-analysis

This study systematically evaluated the preclinical efficacy and limited clinical evidence of metformin as a potential repurposed therapy for ulcerative colitis (UC) and explored candidate mechanisms using multi-omics and in silico analyses. Controlled animal studies were quantitatively synthesized using random-effects meta-analysis. Human randomized controlled trials (RCTs) were summarized narratively because of the limited number of trials and heterogeneity in clinical endpoints. Exploratory 3D response surface modeling, network pharmacology, molecular docking, molecular dynamics (MD) simulations, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) were integrated to prioritize potential dose-duration patterns and candidate mechanistic pathways. Eight preclinical animal studies and three human RCTs involving 232 patients were included. In animal models, metformin was associated with improvements in core colitis-related outcomes, including disease activity index, colon length, body weight change, and histopathological score. However, the magnitude of the pooled standardized mean differences should be interpreted cautiously because of small sample sizes, methodological heterogeneity, and potential small-study effects. Exploratory response surface modeling suggested a potential association between low-dose, long-duration regimens and larger preclinical effect estimates, but this pattern should not be interpreted as a validated dosing recommendation. Multi-omics and in silico analyses prioritized Xanthine dehydrogenase (XDH)-associated epithelial inflammatory programs and predicted epithelial-immune-vascular communication as plausible mechanistic hypotheses. The available RCTs provided limited supportive clinical signals but did not establish mechanistic causality. Metformin may ameliorate experimental colitis and shows preliminary supportive clinical signals as an adjunctive therapy in UC. The proposed XDH-associated epithelial inflammatory program remains exploratory and requires direct biochemical, functional, and large-scale clinical validation.