Metformin as a Multifaceted Therapeutic Agent for Gastrointestinal Diseases: Mechanisms, Clinical Efficacy, and Future Directions

The high prevalence of gastrointestinal (GI) diseases and their significant impact on the quality of life require new therapeutic strategies. The development of novel therapeutic strategies should prioritize targeting the fundamental pathophysiological mechanisms underlying these diseases, including inflammation, cellular proliferation, and gut microbiota dysregulation. Metformin, a first-line antidiabetic agent, exhibits pleiotropic pharmacological properties beyond its glucose-lowering effects, such as anti-inflammatory, antiproliferative, and microbiota-modulating activities. These multifaceted mechanisms position metformin as a promising therapeutic candidate for a spectrum of disorders, from IBS to liver disorders. This review synthesizes preclinical and clinical evidence supporting the therapeutic potential of metformin across GI pathologies-such as Helicobacter pylori infection, inflammatory bowel disease, colorectal cancer, and hepatocellular carcinoma-while elucidating its molecular mechanisms, such as AMPK/mTOR modulation, NF-κB inhibition, and gut barrier stabilization. We critically evaluate combination therapies, ongoing clinical trials, and challenges, including lactic acidosis risk and GI intolerance to position metformin as a repurposed agent for GI disease management.