Combining a diet rich in fermentable carbohydrates with metformin improves glycaemic control and reshapes the gut microbiota in people with prediabetes.

Metformin efficiently lowers blood glucose levels but leads to gastrointestinal side effects. However, whether dietary interventions can improve metformin tolerability and glucose-lowering efficacy remains unknown. Here we investigate the effects of pretreatment with a diet rich in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) in combination with metformin on postprandial glycaemia and gut microbiota in people with prediabetes. In a double-blind, randomised, crossover trial, 26 individuals with prediabetes received an isocaloric diet with moderate or low FODMAPs for 10 d, concomitantly with metformin for 5 d, separated by a washout period of 2 weeks. The primary endpoint is the difference in postprandial glycaemia assessed by total postprandial incremental area under the curve through continuous glucose monitoring. Secondary endpoints are differences in glucose, insulin and glucagon-like peptide 1 (GLP-1) levels after an oral glucose tolerance test, gut microbiota, gastrointestinal symptoms and body weight. We show that moderate FODMAPs with metformin, as compared with low FODMAPs with metformin, result in lower postprandial glycaemia, higher GLP-1 secretion and higher Butyricimonas virosa abundance. We also show that a higher baseline abundance of Dorea formicigenerans predicts gastrointestinal intolerance to metformin. These findings have implications for personalizing nutritional and pharmacological interventions to prevent diabetes. ClinicalTrials.gov registration: NCT05628584 .