Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain

Abstract

Background & aims: We evaluated the efficacy and safety of diet-modulated autologous fecal microbiota transplantation (aFMT) for treatment of weight regain after the weight-loss phase.

Methods: In the DIRECT PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols-Unprocessed) weight-loss trial (May 2017 through July 2018), abdominally obese or dyslipidemic participants in Israel were randomly assigned to healthy dietary guidelines, Mediterranean diet, and green-Mediterranean diet weight-loss groups. All groups received free gym membership and physical activity guidelines. Both isocaloric Mediterranean groups consumed 28 g/d walnuts (+440 mg/d polyphenols provided). The green-Mediterranean dieters also consumed green tea (3-4 cups/d) and a Wolffia globosa (Mankai strain, 100 g/d) green shake (+800 mg/d polyphenols provided). After 6 months (weight-loss phase), 90 eligible participants (mean age, 52 years; mean weight loss, 8.3 kg) provided a fecal sample that was processed into aFMT by frozen, opaque, and odorless capsules. The participants were then randomly assigned to groups that received 100 capsules containing their own fecal microbiota or placebo until month 14. The primary outcome was regain of the lost weight over the expected weight-regain phase (months 6-14). Secondary outcomes were gastrointestinal symptoms, waist circumference, glycemic status, and changes in the gut microbiome, as measured by metagenomic sequencing and 16s ribosomal RNA. We validated the results in a parallel in vivo study of mice specifically fed with Mankai compared with control chow diet.

Results: Of the 90 participants in the aFMT trial, 96% ingested at least 80 of 100 oral aFMT or placebo frozen capsules during the transplantation period. No aFMT-related adverse events or symptoms were observed. For the primary outcome, although no significant differences in weight regain were observed among the participants in the different lifestyle interventions during months 6-14 (aFMT, 30.4% vs placebo, 40.6%; P = .28), aFMT significantly attenuated weight regain in the green-Mediterranean group (aFMT, 17.1%, vs placebo, 50%; P = .02), but not in the dietary guidelines (P = .57) or Mediterranean diet (P = .64) groups (P for the interaction = .03). Accordingly, aFMT attenuated waist circumference gain (aFMT, 1.89 cm vs placebo, 5.05 cm; P = .01) and insulin rebound (aFMT, -1.46 ± 3.6 μIU/mL vs placebo, 1.64 ± 4.7 μIU/mL; P = .04) in the green-Mediterranean group but not in the dietary guidelines or Mediterranean diet (P for the interaction = .04 and .03, respectively). The green-Mediterranean diet was the only intervention to induce a significant change in microbiome composition during the weight-loss phase, and to prompt preservation of weight-loss-associated specific bacteria and microbial metabolic pathways (mainly microbial sugar transport) after the aFMT. In mice, Mankai-modulated aFMT in the weight-loss phase compared with control diet aFMT, significantly prevented weight regain and resulted in better glucose tolerance during a high-fat diet-induced regain phase (all, P < .05).

Conclusions: Autologous FMT, collected during the weight-loss phase and administrated in the regain phase, might preserve weight loss and glycemic control, and is associated with specific microbiome signatures. A high-polyphenols, green plant-based or Mankai diet better optimizes the microbiome for an aFMT procedure. ClinicalTrials.gov number, NCT03020186.

Keywords: Autologous FMT; Diabetes; Obesity; Weight Regain After Diet.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:. Study design, enrollment of the participants and completion of the Study

Panel A: Experimental design; Panel B: Trial flowchart.

Figure 2:. Symptom monitoring

Comparison between aFMT and placebo treatment groups in monitored symptoms. P values represent comparisons between treatment groups at each timepoint.

Figure 3:. aFMT effect across lifestyle interventions; 6-14 months changes in anthropometric measures and glycemic state

Body weight (A), waist circumference (B) and insulin (C) changes between 6 and 14-months. * Regain % was calculated as 100 * (14-months – 6-months) / (6-months – 0-months).

Figure 4:. Microbiome composition and species-level changes

Panel A: Principal coordinate analysis (PCoA) of weighted UniFrac distances of microbiome composition measured by 16s rRNA sequencing. Each sub-plot displays the distances between individual microbiome samples within the distances of the indicated lifestyle intervention, at baseline and 6-months. Panel B: Principal coordinate analysis (PCoA) of Bray-Curtis distances of microbiome composition, each sub-plot displays the distances between individual microbiome samples within the indicated lifestyle intervention and treatment group, at 6 and 14-months. 95% standard error ellipses are shown for each sub-group; Panel C: Shotgun metagenomics assessed species (B) that were significantly changed by weight loss and maintained by the aFMT treatment, across lifestyle intervention groups.

Figure 5:. KEGG pathway - changes and association with insulin rebound

Panel A: Shotgun metagenomics assessed metabolic pathways (KEGG modules) that were significantly changed by weight loss and maintained by the aFMT treatment, across lifestyle intervention groups. Panel B: Fold change of the same metabolic pathways as in ‘A’, comparing individuals with and without insulin rebound (defined as the median change between 6 and 14-months) among the aFMT+green Mediterranean group participants.

Figure 6:. Mankai supplementation during weight-loss and aFMT efficacy in mice

Experimental design (A); Mankai enrichment during weight-loss and weight change during following the weight-loss period (B); Weight regain by high fat diet+aFMT following weight-loss with added Mankai/saline gavage (C+D) Intraperitoneal glucose tolerance test (IPGTT) following the weight regain phase (week 12) (E). Weighted UniFrac distances to the weight-nadir timepoint during the weight regain phase (F). *P ≤.05, **P ≤.01, ***P ≤.001.