Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial

Abstract

Background: There is intense interest about whether modulating gut microbiota can impact systemic metabolism. We investigated the safety of weekly oral fecal microbiota transplantation (FMT) capsules from healthy lean donors and their ability to alter gut microbiota and improve metabolic outcomes in patients with obesity.

Methods and findings: FMT-TRIM was a 12-week double-blind randomized placebo-controlled pilot trial of oral FMT capsules performed at a single US academic medical center. Between August 2016 and April 2018, we randomized 24 adults with obesity and mild-moderate insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] between 2.0 and 8.0) to weekly healthy lean donor FMT versus placebo capsules for 6 weeks. The primary outcome, assessed by intention to treat, was change in insulin sensitivity between 0 and 6 weeks as measured by hyperinsulinemic euglycemic clamps. Additional metabolic parameters were evaluated at 0, 6, and 12 weeks, including HbA1c, body weight, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure by indirect calorimetry. Fecal samples were serially collected and evaluated via 16S V4 rRNA sequencing. Our study population was 71% female, with an average baseline BMI of 38.8 ± 6.7 kg/m2 and 41.3 ± 5.1 kg/m2 in the FMT and placebo groups, respectively. There were no statistically significant improvements in insulin sensitivity in the FMT group compared to the placebo group (+5% ± 12% in FMT group versus -3% ± 32% in placebo group, mean difference 9%, 95% CI -5% to 28%, p = 0.16). There were no statistically significant differences between groups for most of the other secondary metabolic outcomes, including HOMA-IR (mean difference 0.2, 95% CI -0.9 to 0.9, p = 0.96) and body composition (lean mass mean difference -0.1 kg, 95% CI -1.9 to 1.6 kg, p = 0.87; fat mass mean difference 1.2 kg, 95% CI -0.6 to 3.0 kg, p = 0.18), over the 12-week study. We observed variable engraftment of donor bacterial groups among FMT recipients, which persisted throughout the 12-week study. There were no significant differences in adverse events (AEs) (10 versus 5, p = 0.09), and no serious AEs related to FMT. Limitations of this pilot study are the small sample size, inclusion of participants with relatively mild insulin resistance, and lack of concurrent dietary intervention.

Conclusions: Weekly administration of FMT capsules in adults with obesity results in gut microbiota engraftment in most recipients for at least 12 weeks. Despite engraftment, we did not observe clinically significant metabolic effects during the study.

Trial registration: ClinicalTrials.gov NCT02530385.

Fig 1. Study flow diagram.

DXA, dual-energy X-ray absorptiometry; FMT, fecal microbiota transplantation; GI, gastrointestinal; HOMA-IR, homeostatic model assessment of insulin resistance.

Fig 2. Boxplot of percentage change in insulin sensitivity in fecal microbiota transplantation (FMT) and placebo groups from baseline to 6 weeks.

Insulin-stimulated glucose uptake (M value) was assessed by hyperinsulinemic euglycemic clamp as a measurement of insulin sensitivity.

Fig 3. Boxplot displaying the amplicon sequence variant (ASV) diversity (Shannon diversity index) identified in lean donor samples and baseline samples of participants with obesity.

Fig 4. Beta diversity boxplots displaying microbiome compositional similarity of each participant to their respective baseline or triplicate donor preps.

Microbiome similarity to baseline (a) and to donor (b) is compared between fecal microbiota transplantation (FMT) and placebo groups. Placebo results shown in (b) reflect comparisons of all combinations of placebo participant to donor prep samples. However, for Wilcoxon rank sum tests comparing similarities between FMT and placebo recipients, the similarity of each placebo participant sample to all donor prep samples was first averaged. *p < 0.05; **p < 0.01.

Fig 5. Proportion of bacterial amplicon sequence variants (ASVs) for each fecal microbiota transplantation (FMT) participant and timepoint hypothesized to originate from the participant’s or donor’s microbiome.

Each facet is labeled by participant (first line) and paired donor (second line). Red bars indicate ASVs present in participant baseline and follow-up samples, and thus thought to be native to the participant. ASVs originating from the donor and not detected in paired participant baseline samples, and thus thought to be engrafting ASVs, are shown in blue. ASVs only observed following treatment and not seen in paired donor material are categorized as newly detected and displayed in gray. ASVs shown in white were observed in both paired donor and baseline recipient samples, and thus we were unable to resolve whether the ASVs at post-dosing timepoints came from strains native to the participant or donor material. The 75th quartile of newly detected ASVs across post-dosing placebo participant samples is delineated by a dotted line for comparison.