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

Nature Metabolism volume 7, pages 1614–1629 (2025)Cite this article

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Abstract

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.

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Fig. 1: Study design and flow.
Fig. 2: Daily total energy, macronutrient, FODMAP intake and physical activity.
Fig. 3: Averaged 24-h sensor glucose profiles captured by CGM.
Fig. 4: PG, late-phase insulin and total GLP-1 response during OGTTs in each intervention period.
Fig. 5: Diversity comparisons of gut microbiome between M-M and L-M.
Fig. 6: Metabolic pathway prediction of gut microbiome between baseline, M-M and L-M.

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Data availability

The individual de-identified participant microbiota sequencing data can be accessed at https://doi.org/10.6084/m9.figshare.28123295.v1 (ref. 70). Other de-identified participant data are not openly available due to participant confidentiality and will be shared with the corresponding author upon reasonable request, and requests will be responded to within 4 weeks. The study protocol is available in the Supplementary Information. Source data are provided with this paper.

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Acknowledgements

This study was supported by a Merck KGaA investigator-initiated study grant to E.C. (MS200084_0060). The funder approved the final protocol and the manuscript but had no role in the design, collection, analyses or interpretation of data, decision to publish or preparation of the manuscript. Dexcom supported provision of Dexcom G6 CGM devices for the trial but had no role in the study design, data collection, interpretation, final decision to publish or preparation of the manuscript. N.H.S.C. was supported by the Chinese University of Hong Kong Research Fellowship scheme (RFS2223/0621/23) and an Innovation and Technology Commission Grant (MRP 029/21). We thank A. Lai, M. Lee, A. Chan and the 3M Clinical Trial Unit, Prince of Wales Hospital, for their support during the study.

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Authors and Affiliations

  1. Department of Medicine and Therapeutics, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong SAR, China

    Natural H. S. Chu, James Ling, Emily W. M. Poon, Juliana C. N. Chan & Elaine Chow

  2. Department of Gastroenterology, School of Translational Medicine, Monash University and Alfred Health, Melbourne, Victoria, Australia

    Jimmy Y. S. Lee & Jane Muir

  3. School of Pharmacy, the Chinese University of Hong Kong, Hong Kong SAR, China

    Qianbo Song & Zhong Zuo

  4. Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong SAR, China

    Juliana C. N. Chan & Elaine Chow

  5. Hong Kong Institute of Diabetes and Obesity, the Chinese University of Hong Kong, Hong Kong SAR, China

    Juliana C. N. Chan & Elaine Chow

  6. Phase 1 Clinical Trial Centre, Prince of Wales Hospital, the Chinese University of Hong Kong, Hong Kong SAR, China

    Elaine Chow

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Contributions

N.H.S.C. and E.C. conceived the idea of the study; N.H.S.C., E.W.M.P., Q.S. and J.Y.S.L. were involved in data collection and examination, which Z.Z., J.M. and J.C.N.C. supported; E.C., N.H.S.C. and J.L. analysed the data. N.H.S.C. wrote the first draft of the paper. All authors critically reviewed the paper and agreed to the final published version.

Corresponding author

Correspondence to Elaine Chow.

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Competing interests

E.C. has received speaker honoraria from AstraZeneca, Procter & Gamble and ZP Therapeutics and institutional research support from Merck KGaA, Hua Medicine, Medtronic Diabetes, Powder Pharmaceuticals and Sanofi. J.C.N.C. has received research grants and/or honoraria for consultancy or giving lectures from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Hua Medicine, Lee Powder, Merck Serono, Merck Sharp & Dohme, Pfizer, Servier, Sanofi and Viatris Pharmaceutical. Monash University financially benefits from the sales of digital applications and booklets associated with the low-FODMAP diet. The other authors declare no competing interests.

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Nature Metabolism thanks Holly Willis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Jean Nakhle and Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Changes in Gastrointestinal symptoms (a-j) between moderate M-M) and low FODMAP (L-M) interventions.a) Abdominal pain/discomfort, b) Abdominal distension, c) Belching, d) Bloating, e)Flatuence, f) Dissatidfaction of bowel habits, g) Epigastric pain/discomfort, H) Epigastric distension, i) Early satiety, j)Fatigue.

Abbreviation: VAS: visual analogue scale. Differences between interventions are compared using paired t-tests. Sample size n= moderate FODMAP intervention: 25 and low FODMAP intervention: 26 participants.

Source data

Extended Data Fig. 2 Comparisons of species. Volcano diagram in comparing a) the baseline and M-M intervention, b) L-M intervention in the species levels (T-test, adjusted p-value) and (c) Bar plot comparing the M-M and L-M interventions in the species levels.

Bar plot comparing the M-M and L-M interventions in the species levels. A volcano plot is a presentation of a scatter plot, which usually consists of several parts, including significantly up-regulated different species and significantly down-regulated different species. The horizontal axis is the fold difference of the different species in the comparison group. In contrast, the vertical axis is the p-value of the significant between-group difference test for the different species. Statistical significance was assessed using two-sided two-sample t-tests. Each point in the graph represents a differential species. (Total fecal sample size n= baseline:26, M-M:23 and L-M:24 samples.) Up (red points) represents the higher abundance of that differential species in the M-M than the L-M intervention; grey points indicate no significant change, while Down (blue points) is the opposite. Abbreviation: B: baseline, L-M: low FODMAP diet with metformin, M-M: moderate FODMAP diet with metformin.

Source data

Extended Data Fig. 3 Beta-Diversity comparisons of gut microbiome. Principal Coordinates Analysis (PCoA) between a) the baseline and interventions from Jaccard, b) unweighted_unifrac and c) weighted_unifrac.

Each point represents a sample, plotted by a principal component on the X-axis and another principal component on the Y-axis, which was colored by group. (Total fecal sample size n= baseline:26, M-M:23 and L-M:24 samples.) The percentage on each axis indicates the contribution value to discrepancy among samples.

Source data

Extended Data Table 1 Interventional diets provided to subjects
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Extended Data Table 2 Comparison in CGM metrics between interventions
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Extended Data Table 3 Inflammatory and lipid profiles at the baseline and end of each intervention period
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Extended Data Table 4 Gastrointestinal symptoms during metformin only or in combination with moderate or low FODMAP diets
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Extended Data Table 5 SCFA /Bile Acids following low or moderate FODMAPs and metformin
Full size table

Supplementary information

Supplementary Information

Supplementary Tables 1–4, Fig. 1 and Note, including the consort checklist, study protocol and statistical analysis plan.

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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. Nat Metab 7, 1614–1629 (2025). https://doi.org/10.1038/s42255-025-01336-4

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