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.
Elain W Yu et al investigate the potential of fecal microbiota transplantation to improve metabolism in obese individuals.
Author summary Why was this study done? Animal studies show that body weight and glycemic regulation can be markedly altered by manipulation of the intestinal microbiota. Two prior studies in men with obesity and metabolic syndrome showed that a single nasoduodenal fecal microbiota transplantation (FMT) from lean donors led to small and transient improvements in glycemic outcomes. We hypothesized that repeated dosing with oral FMT capsules from lean donors could lead to lasting improvements in metabolic outcomes. What did the researchers do and find? We randomized adults with obesity who were at high risk for development of type 2 diabetes to receive either weekly oral FMT capsules from healthy lean donors or placebo capsules for 6 weeks. Oral FMT was safe and tolerable, and we observed durable microbial shifts in most participants receiving FMT. We found no significant differences between groups in most glycemic outcomes, weight, or body composition over a 12-week period. There was a minor improvement in HbA1c after FMT as compared to placebo. Exploratory analyses suggest possible improvement in metabolism after FMT among study participants with low baseline microbiome diversity, similar to what was observed in a prior study. What do these findings mean? Our results suggest that intestinal microbial manipulation by FMT capsules does not meaningfully alter human metabolism and weight in adults with obesity. Regional differences between study populations, differences in route of FMT administration, and differences in engrafting microbial species all might explain the overall negative findings and discordance with prior trials. Future studies should evaluate pre-selection of donors and recipients, and consider microbiome and lifestyle modifications concurrently.