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Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial

Nature Medicine volume 27, pages 1272–1279 (2021)Cite this article

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Abstract

Fecal microbial transplantation (FMT) from lean donors to patients with obesity has been associated with metabolic benefits, yet results so far have been inconsistent. In this study, we tested the application of daily fiber supplementation as an adjunct to FMT therapy to modulate cardiometabolic outcomes. We performed a double-blind randomized trial in patients with severe obesity and metabolic syndrome receiving oral FMT, to test high-fermentable (HF) and low-fermentable (LF) fiber supplements (NCT03477916). Seventy participants were randomized to the FMT-HF (n = 17), FMT-LF (n = 17), HF (n = 17) and LF (n = 19) groups. The primary outcome was the assessment of change in insulin sensitivity from baseline to 6 weeks using the homeostatic model assessment (HOMA2-IR/IS). After 6 weeks, only patients in the FMT-LF group had significant improvements in HOMA2-IR (3.16 ± 3.01 at 6 weeks versus 3.77 ± 3.57 at baseline; P = 0.02). No difference in HOMA2-IR was observed over this period for those in the FMT-HF group (3.25 ± 1.70 at 6 weeks versus 3.17 ± 1.72 at baseline; P = 0.8), the HF group (3.49 ± 1.43 at 6 weeks versus 3.26 ± 1.33 at baseline; P = 0.8) or the LF group (3.76 ± 2.01 at 6 weeks versus 3.56 ± 1.81 at baseline; P = 0.8). Interventions were safe and well-tolerated with no treatment-attributed serious adverse events. We provide proof of concept for the use of a single-dose oral FMT combined with daily low-fermentable fiber supplementation to improve insulin sensitivity in patients with severe obesity and metabolic syndrome.

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Fig. 1
Fig. 2: Changes in glycemic parameters across the intervention groups.
Fig. 3: Changes in GLP-1 and insulin during 75 g oral glucose tolerance test at 0, 1 and 2 h by intervention group at baseline and week 6.
Fig. 4: Changes in gut microbiome and associated predictors of improved HOMA2-IR and insulin sensitivity from baseline to week 12.

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Data availability

The data generated or analyzed during this study are included in this article along with the supplementary information files. The raw sequencing data have been deposited into the Sequence Read Archive (SRA) of the NCBI (http://www.ncbi.nlm.nih.gov/sra) under BioProject PRJNA708262. All other relevant data related to the current study are freely available from the corresponding author (K.L.M.) upon request, which does not include confidential patient information. Source data are provided with this paper.

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Acknowledgements

We thank the Center of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR) for the infrastructure and support provided throughout the project. We also thank M. Emberg for his support with FMT preparation, R. Odsen for his help with trial coordination, and T. Dang for his help with fecal 16s rRNA extraction. We acknowledge S. Jamieson and D. Turner-Crerar as members of the University of Alberta Quality Management in Clinical Research Department (QMCR) for providing safety oversight. V.M. is the recipient of scholarships from the Canadian Institutes of Health Research (CIHR), Alberta Innovates, and the Clinical Investigator Program. Last, we thank the W. Garfield Weston Foundation (RES0048879) for the funding that made this project possible. The funders had no role in the study design, data collection and analysis, decision to publish or the preparation of the paper.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada

    Valentin Mocanu, Shahzeer Karmali & Daniel W. Birch

  2. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Zhengxiao Zhang, Edward C. Deehan & Naomi Hotte

  3. College of Food and Biological Engineering, Jimei University, Xiamen, China

    Zhengxiao Zhang

  4. Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Dina H. Kao & Karen L. Madsen

  5. Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

    Kalutota K. Samarasinghe

  6. APC Microbiome Ireland, School of Microbiology and Department of Medicine, University College Cork, Cork, Ireland

    Jens Walter

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Contributions

K.L.M. conceived the project. K.L.M., J.W., Z.Z., E.C.D., D.H.K., N.H. and V.M. designed the proof-of-concept study. K.L.M., J.W. and E.C.D. designed the fiber mixture. K.L.M. and D.H.K. supervised the clinical aspect of the study. D.H.K. supervised the FMT donor program. D.W.B. and S.K. helped identify patients enrolled in the bariatric clinic for study inclusion. V.M. and K.K.S. recruited, coordinated and conducted clinical visits. N.H. performed study randomization and created the fiber sachets. V.M. performed the analysis and interpretation of anthropometric, biochemical, immunologic and enteroendocrine results. E.C.D. conducted the analysis and interpretation of dietary data. Z.Z. performed the fecal microbiome sequencing and bioinformatics analysis. All authors discussed the study findings, interpretations and approved the final version of the paper.

Corresponding author

Correspondence to Karen L. Madsen.

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Competing interests

J.W. has received research funding and consulting fees from industry sources involved in the manufacture and marketing of fibers, and is a co-owner of Synbiotics Health, a developer of synbiotic products. There are no conflicts pertaining to this manuscript. All other authors have no competing interests.

Additional information

Peer review information Nature Medicine thanks Bright Offorha and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Jennifer Sargent was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Changes in anthropometric parameters across intervention groups from baseline (BL) to six (T6) and twelve (T12) weeks.

a, Weight. b, Waist circumference. c, Systolic Blood Pressure (SBP). d, Diastolic Blood Pressure (DBP). Values are reported as mean ± SEM or as percent change from BL to T6 and BL to T12. Box-and-whisker plots represent the distribution of each group from baseline to week 12 by intervention group. The median is represented by the middle line while the upper and lower borders of the box plot identify the 75th and 25th percentile, respectively. The whiskers correspond to the minimal and maximal values. Pairwise comparisons between groups were conducted using Mann-Whitney U-tests without adjustment for multiple comparisons. Paired time points were compared to baseline values using the Wilcoxon signed-rank test. FMT-HF (n = 15), FMT and high-fermentable fiber group. HF (n = 15), high-fermentable fiber group. FMT-LF (n = 14), FMT and low-fermentable fiber group. LF (n = 17), low-fermentable fiber group. All tests were two-tailed with a p-value <0.05 identifying statistical significance.

Source data

Extended Data Fig. 2 Changes in lipid parameters across intervention groups from baseline (BL) to six (T6) and twelve (T12) weeks.

a, Total Cholesterol. b, High-density lipoprotein (HDL-C). c, Low-density lipoprotein (LDL-C). d, Triglycerides (Tg). Values are reported as mean ± SEM or as percent change from BL to T6 and BL to T12. Box-and-whisker plots represent the distribution of each group from baseline to week 12 by intervention group. The median is represented by the middle line while the upper and lower borders of the box plot identify the 75th and 25th percentile, respectively. The whiskers correspond to the maximal and minimal values. Pairwise comparisons between groups were conducted using Mann-Whitney U-tests without adjustment for multiple comparisons. Paired time points were compared to baseline values using the Wilcoxon signed-rank test. FMT-HF (n = 15 patients), FMT and high-fermentable fiber group. HF (n = 15 patients), high-fermentable fiber group. FMT-LF (n = 14 patients) FMT and low-fermentable fiber group. LF (n = 17 patients), low-fermentable fiber group. All tests were two-tailed with a p-value <0.05 identifying statistical significance.

Source data

Extended Data Fig. 3 Changes in HOMA2-IR across intervention groups baseline (BL) to six (T6) and twelve (T12) weeks.

a, HOMA2-IR. Values are reported as mean ± SEM or as percent change from BL to T6 and from BL to T12. Points represent raw unadjusted values at baseline, week 6, and week 12 following and/or fiber supplementation. Box-and-whisker plots represent the distribution of each group from baseline to week 12 by intervention group. The median is represented by the middle line while the upper and lower borders of the box plot identify the 75th and 25th percentile, respectively. The whiskers correspond to the maximal and minimal values. Pairwise comparisons between groups were conducted using Mann-Whitney U-tests without adjustment for multiple comparisons. Paired time points were compared to baseline values using the Wilcoxon signed-rank test. FMT-HF (n = 15 patients), FMT and high-fermentable fiber group. HF (n = 15 patients), high-fermentable fiber group. FMT-LF (n = 14 patients), FMT and low-fermentable fiber group. LF (n = 17 patients), low-fermentable fiber group. All tests were two-tailed with a p-value <0.05 identifying statistical significance.

Source data

Extended Data Fig. 4 Composite scores of 5-level EQ-5D (EQ-5D-5L) survey domains from baseline to 12 weeks.

a, Mobility domain. b, Self-Care domain. c, Usual Activity domain. d, Pain and Discomfort domain. e, Anxiety and Depression domain., f, Visual Analogue Health Scale. Data reported as mean ± SEM. Pairwise comparisons between two groups were conducted using Mann-Whitney U-tests and Kruskal-Wallis tests for four group comparisons. No adjustment was made for multiple comparisons. FMT-HF (n = 15), FMT and high-fermentable fiber group. HF (n = 15), high-fermentable fiber group. FMT-LF (n = 14), FMT and low-fermentable fiber group. LF (n = 17), low-fermentable fiber group. All tests were two-tailed with a p-value <0.05 identifying statistical significance.

Source data

Extended Data Fig. 5 Responses to Hunger and Satiety SLIM from baseline to 12 weeks.

a, Hunger and satiety SLIM scoring upon waking. b, Hunger and satiety SLIM scoring 1-1.5 hours after a meal. c, Hunger and satiety SLIM scoring 2-2.5 hours after a meal. Data reported as mean ± SEM. Results were analyzed by fitting a random effects mixed model analysis with Dunnett’s test controlling for multiple comparisons. FMT-HF (n = 15), FMT and high-fermentable fiber group. HF (n = 15), high-fermentable fiber group. FMT-LF (n = 14), FMT and low-fermentable fiber group. LF (n = 17), low-fermentable fiber group. All tests were two-tailed with a p-value <0.05 identifying statistical significance.

Source data

Extended Data Fig. 6 Responses to Gastrointestinal Tolerance questionnaire from baseline to 12 weeks.

a, Stomach aches. b, Bloating. c, Flatulence. d, Overall Well-being. e, Consistency. f, Frequency. Data reported as mean ± SEM. Pairwise comparisons between two groups were conducted using Mann-Whitney U-tests and Kruskal-Wallis tests for four group comparisons. Paired data was analyzed by fitting a mixed model. No adjustments were made for multiple comparisons. FMT-HF (n = 15), FMT and high-fermentable fiber group. HF (n = 15), high-fermentable fiber group. FMT-LF (n = 14), FMT and low-fermentable fiber group. LF (n = 17), low-fermentable fiber group. All tests were two-tailed with a p-value <0.05 identifying statistical significance.

Source data

Extended Data Fig. 7 Donor composition at Phylum level of stool and oral capsules.

Bar chart represents proportion of ASV counts at the phylum level.

Extended Data Fig. 8 Family level microbial composition of FMT recipients and paired donors from baseline (BL) to week 6 (T6).

a, BL FMT-LF composition. b, Composition of matched FMT-donor in patients receiving FMT and low-fermentable fiber. c, T6 FMT-LF composition. d, BL FMT-HF composition. e, Composition of matched FMT-donor in patients receiving FMT and high-fermentable fiber. f, T6 FMT-HF composition.

Extended Data Fig. 9 Evidence of fecal microbial engraftment in FMT-LF patients from baseline to week 12.

a, Recipient Chao1 index from baseline to week 12 versus donor FMT. Box-and-whisker plots represent the distribution of each group’s Chao1 index from baseline to week 12. The median is represented by the middle line while the upper and lower borders of the box plot identify the 75th and 25th percentile, respectively. The whiskers correspond to the maximal and minimal values. Between-group differences were assessed by linear regression, and pairwise comparisons were conducted using unpaired t-tests. P-values were adjusted by Benjamin-Hochberg false discovery rate (FDR) method. b, Principal-coordinate analysis (PCoA) of ASVs demonstrating that at baseline, recipients have significantly different microbial clustering patterns than donors. At week 6, no significant differences in microbial structure were observed between recipients and donors. At week 12, after fiber cessation, significant differences in microbial structure between recipients and donors are again demonstrated. Significant differences were assessed by PERMANOVA based on unweighted UniFrac distances with FDR correction (* q < 0.05). c-f, PCoA grouping of patients and donors (baseline, week 2, week 6, and week 12) demonstrating substantial increases in similarity between recipient and donor microbial structure over time. g, Evidence of donor specific ASV engraftment obtained if taxa were shared between donor and recipients at week 6 but not present in recipients at baseline ASVs with the highest number of post-FMT patients received showing evidence of acquisition of the donor’s taxa. FMT-LF (n = 14 patients), FMT and low-fermentable fiber group. All tests were two-tailed with a q-value <0.05 identifying statistical significance.

Extended Data Fig. 10 Lack evidence for fecal microbial engraftment in FMT-HF patients from baseline to week 12.

a, Recipient Chao1 index from baseline to week 6 versus donor FMT. Box-and-whisker plots represent the distribution of each group’s Chao1 index from baseline to week 12. The median is represented by the middle line while the upper and lower borders of the box plot identify the 75th and 25th percentile, respectively. The whiskers correspond to the maximal and minimal values. Between-group differences were assessed by linear regression, and pairwise comparisons were conducted using unpaired t-tests. P-values were adjusted by Benjamin-Hochberg false discovery rate (FDR) method. b, Principal-coordinate analysis (PCoA) of ASVs demonstrating that at baseline, week 6 and week 12, recipients have significantly different microbial clustering patterns than donors. Significant differences were assessed by PERMANOVA based on unweighted UniFrac distances with FDR correction (* q < 0.05). c, PCoA grouping of patients and donors (baseline, week 2, week 6, and week 12) demonstrating minor increases in similarity between recipient and donor microbial structure over time. FMT-HF (n = 15 patients), FMT and high-fermentable fiber group. All tests were two-tailed with a q-value <0.05 identifying statistical significance.

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Mocanu, V., Zhang, Z., Deehan, E.C. et al. Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial. Nat Med 27, 1272–1279 (2021). https://doi.org/10.1038/s41591-021-01399-2

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