Multi-strain probiotic reduces gastrointestinal side effects in women with elevated HOMA-IR index treated with metformin: a 12-week randomised controlled trial

Background: Metformin is widely used as a first-line therapy for type 2 diabetes and increasingly prescribed off-label in women with elevated HOMA-IR indices, including those at risk of metabolic disorders. However, its clinical use is often limited by gastrointestinal (GI) adverse effects. The present study examined whether a multi-strain probiotic could enhance the metabolic effects of metformin and reduce GI side effects in women with newly identified elevated HOMA-IR. Methods: CFU/day) or placebo. Outcomes included metabolic markers (glucose, insulin, HOMA-IR, RBP4, lipid profile, body composition) and self-reported GI symptoms. Results: After 12 weeks, the probiotic group reported significantly fewer GI symptoms compared with placebo, including lower frequency of abnormal stool consistency during abdominal pain (26% vs. 52%, p < 0.05), abnormal stool frequency (18% vs. 51%, p < 0.05), and hard or lumpy stools (Bristol types 1-2; 14% vs. 26%, p < 0.05). No significant between-group differences were observed for metabolic or anthropometric parameters. Both groups showed significant improvements over time in fasting glucose (time effect p < 0.05), HOMA-IR (p < 0.05), RBP4 (p < 0.05), and total cholesterol (p < 0.01), with no significant group × time interactions, indicating effects attributable to metformin rather than probiotic supplementation. Conclusion: Multi-strain probiotic supplementation did not enhance the metabolic efficacy of metformin in women with elevated HOMA-IR but significantly alleviated GI side effects. Probiotic co-administration may therefore improve tolerability and adherence to metformin therapy. Clinical trial registration: https://clinicaltrials.gov/study/NCT06092060, identifier NCT06092060.