Metformin plus low-to-moderate FODMAP diet improves glycaemic control, BMI and gut microbiota in prediabetes

A study by the Chinese University of Hong Kong (CUHK) in collaboration with Monash University, Australia, found that combining metformin therapy with a diet containing fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) in individuals with prediabetes resulted in improved glycaemic control and gut microbiome, among other benefits, with greater effects seen with moderate-FODMAP (M-M) compared with low-FODMAP (L-M) regimens.

The double-blind, randomized, crossover trial included 26 individuals with prediabetes (median age, 58 years; male, 46 percent; mean baseline body mass index [BMI], 26.4 kg/m²; mean fasting plasma glucose [FPG], 5.6 mmol/L; with hypertension, 31 percent). Participants received either a moderate-FODMAP (14 g/day) or low-FODMAP (2 g/day) diet in random order for two periods, along with extended-release metformin 1,000 mg QD on days 6–10, separated by a 2-week washout period. The primary endpoint was difference in postprandial plasma glucose (PPG) assessed by total postprandial incremental area under the curve (pp-iAUC) through continuous glucose monitoring in the 3 hours after meals during each intervention period. [Nat Metab 2025;doi:10.1038/s42255-025-01336-4]

‘‘Our findings reveal benefits of moderate- over low-FODMAP intake in altering gut microbiota [specifically Odoribacter splanchnicus, Butyricimonas virosa and Bacteroides massiliensis], enhancing the glucose-lowering effect of metformin [via an increase in postprandial glucagon-like peptide 1 (GLP-1) secretion and a decrease in inflammation] as the first-line drug for preventing type 2 diabetes [T2D],’’  said Dr Natural Chu, first author of the study.

These positive effects were observed regardless of changes in body weight, total calories and carbohydrate and fibre intake. Both M-M and L-M regimens for 10 days resulted in significant reductions in body weight, BMI, percent abdominal fat mass (all p<0.0001), systolic blood pressure and visceral fat (both p=0.001), compared with baseline.

As expected, metformin use resulted in improved FPG, PPG responses and AUC PG with both low- and moderate-FODMAP diets. FPG was lowered similarly with both diets following metformin administration, but the M-M regimen led to a 21 percent decrease in PPG vs 12 percent with the L-M regimen. Compared with L-M intervention, M-M intervention tripled the baseline level of GLP-1, and induced a 98 percent higher late-phase GLP-1 secretion, with a 80 percent higher postprandial late-phase insulin secretion. Plasma high-sensitivity C-reactive protein was also found to be lower during M-M vs L-M intervention (p=0.005).

“Soy milk, watermelon and mushrooms are suitable local food choices that are rich in FODMAPs,” added Dr Elaine Chow, another member of the research team.

Despite the proven efficacy of metformin, its associated gastrointestinal side effects such as nausea, flatulence or diarrhoea often limit its use. Of note, metformin-intolerant participants were found to have higher baseline levels of Dorea formicigenerans than metformin-tolerant participants, suggesting its role as a promising biomarker for identifying individuals susceptible to gastrointestinal side effects of metformin, paving the way for personalized treatment.

‘‘One in 10 adults in Hong Kong suffers from T2D and preventing its onset is a top priority. Introducing transformative models that integrate precision medicine with personalized diabetes care, including dietary management, is key to addressing this major global health issue,’’ noted Professor Juliana Chan, a member of the team and the Founding Director of the Hong Kong Institute of Diabetes and Obesity, CUHK.