Highlight
- Combined therapy of metformin and moderate FODMAP diet significantly reduces postprandial glucose excursions and enhances GLP-1 secretion in prediabetic patients.
- Moderate FODMAP intake increases abundance of beneficial butyrate-producing bacteria and reduces systemic inflammation markers.
- No significant increase in gastrointestinal side effects observed compared to low FODMAP intake during metformin therapy.
- Baseline abundance of Dorea formicigenerans may predict metformin intolerance, highlighting gut microbiota’s role in drug response.
Study Background and Disease Burden
Prediabetes affects a substantial portion of the global population, representing a critical window for intervention to prevent or delay progression to type 2 diabetes mellitus (T2DM). Metformin is widely recommended as first-line pharmacotherapy due to its proven efficacy in lowering blood glucose via multiple mechanisms including activation of AMP-activated protein kinase (AMPK). Moreover, metformin influences gut microbiota composition and promotes secretion of incretin hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), which modulate insulin secretion, appetite, and glycemic control.
Despite its benefits, metformin use is often limited by dose-dependent gastrointestinal side effects like nausea, bloating, and diarrhea, reported in approximately 16–28% of patients with impaired glucose regulation based on data from the China Diabetes Prevention Program. Emerging evidence implicates gut microbiota composition as a determinant of metformin tolerance and efficacy. However, investigations into how diet, particularly fermentable carbohydrates, interacts with microbiota and metformin therapeutic outcomes remain sparse.
Study Design
This recent randomized, double-blind, crossover clinical trial by researchers at The Chinese University of Hong Kong enrolled 26 prediabetic patients to investigate the effects of metformin combined with different fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) dietary loads.
Participants underwent two 10-day interventions separated by at least a 2-week washout. In the first 5 days, subjects consumed either a moderate-FODMAP diet (~14 grams/day) or a low-FODMAP diet (~2 grams/day), followed by addition of metformin (standardized dose) from days 6 to 10. After washout, diet groups swapped to complete the crossover. Total daily caloric intake and macronutrient distribution were meticulously maintained constant. Physical activity was monitored using pedometers and the International Physical Activity Questionnaire (IPAQ).
Primary endpoints included postprandial glucose excursion measured by the incremental area under the curve (iAUC) over 3 hours post-meal, GLP-1 secretion during oral glucose tolerance tests (OGTT), gut microbiota composition analyzed by fecal samples, short-chain fatty acid (SCFA) levels, systemic inflammatory markers (hs-CRP), and gastrointestinal symptom scores.
Key Findings
Metformin combined with a moderate FODMAP diet resulted in significantly lower postprandial glucose iAUC compared to metformin with low FODMAP (401 vs. 458 mmol/L; p<0.05). Fasting insulin levels decreased post-intervention; however, no significant insulin sensitivity differences (HOMA2-IR and Matsuda index) were observed between diet groups.
Total and late-phase GLP-1 secretion after OGTT were significantly higher in the moderate FODMAP group (13.4 vs. 11.3 pmol/L; late-phase secretion 3.62 vs. 1.82 pmol/mmol; p<0.05), suggesting enhanced incretin effect.
Systemic inflammation measured by high-sensitivity C-reactive protein (hs-CRP) dropped significantly more in the moderate FODMAP group (478 ng/mL) compared to the low FODMAP group (861 ng/mL) from baseline (974 ng/mL).
Gastrointestinal symptoms remained mild and comparable between groups with the exception of a slight, non-clinically significant increase in flatulence in the moderate FODMAP group during metformin exposure.
Microbiota analysis showed no significant global structural differences between diet groups but revealed increased relative abundance of butyrate-producing bacteria such as Odoribacter splanchnicus and Bacteroides species with moderate FODMAP intake. Unexpectedly, Bifidobacterium longum declined, although remaining higher in the moderate FODMAP group relative to low FODMAP.
Correspondingly, fecal short-chain fatty acids (SCFAs), particularly butyrate, increased more in the moderate FODMAP group, paralleled by greater reductions in serum bile acids at 2 hours postprandial. Functional metagenomics indicated upregulation of carbohydrate degradation, SCFA metabolism, and gas production pathways in moderate FODMAP intake.
Notably, participants exhibiting poor metformin tolerance had higher baseline abundance of Dorea formicigenerans. This species remained elevated post moderate FODMAP intervention but not after low FODMAP, suggesting its potential as a biomarker for intolerance.
Expert Commentary
This pivotal trial elucidates a synergistic interaction between metformin and fermentable carbohydrate intake impacting glycemic control and gut microbiota composition in prediabetes. The modest fermentable carbohydrate load supports growth of beneficial butyrate-producing bacteria, which may enhance GLP-1 secretion and attenuate systemic inflammation contributing to improved glucose metabolism.
These findings are consistent with prior animal and human studies indicating that gut microbiome modulation can potentiate antidiabetic drug efficacy. It also underscores the importance of diet customization in optimizing pharmacotherapy outcomes, especially given the frequent GI intolerance to metformin.
Limitations include the short intervention duration and relatively small sample size, warranting larger, longer-term studies to confirm metabolic benefits and evaluate durability. Further mechanistic investigations are necessary to clarify microbiota-host interactions driving differential drug responses.
Conclusion
The combination of metformin with a moderate FODMAP diet demonstrates enhanced postprandial glycemic control, improved GLP-1 and insulin secretion, increased abundance of butyrate-producing gut bacteria, and reduced inflammation without exacerbating gastrointestinal adverse effects in prediabetic patients. Gut microbiota compositions, especially the presence of Dorea formicigenerans, may predict metformin tolerance, supporting personalized therapeutic approaches. Future research should focus on long-term clinical outcomes and mechanistic pathways underlying diet-drug-microbiome interplay to better prevent progression to type 2 diabetes.
References
[1] Chu N H S, Ling J, Poon E W M, et al. Combining a diet rich in fermentable carbohydrates with metformin improves glycaemic control and reshapes the gut microbiota in people with prediabetes. Nature Metabolism. 2025; DOI:10.1038/s42255-025-xxxx-x.
[Additional references for background and discussion should be consulted from current literature databases as appropriate.]
