Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial
Authors: Elaine W Yu
Jasmin Mahabamunuge
Matthew R Henn
Elizabeth L Hohmann
Petr Stastka
Jessica A Bryant
Mariam Torres Soto
Christopher B Ford
Michael C Cheney
Liu Gao
Journal: PLoS medicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: gut microbiota; fecal microbiota transplantation; obesity; insulin sensitivity; metabolic outcomes
Affiliations: Endocrine Unit, Division of Endocrinology and Metabolism, Massachusetts General Hospital, Boston, Massachusetts, United States of America., Harvard Medical School, Boston, Massachusetts, United States of America., Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America., Seres Therapeutics, Cambridge, Massachusetts, United States of America.

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. 

Retracted: No

PubPeer comments:
 I am disappointed by some of these definitive statements made without regards to potential confounders. Such as:  Our results suggest that intestinal microbial manipulation by FMT capsules does not meaningfully alter human metabolism and weight in adults with obesity  Thus, it seems unlikely that FMT-induced microbiome compositional changes alone will be sufficient to treat or prevent metabolic disorders in humans These statements will be extremely misleading for the vast majority of laypeople and even professionals not well versed in FMT. There is no accounting for donor quality, or things like clearing the mucosa, and thus, such statements are totally inappropriate, misleading, and erroneous. It came as no surprise that the listed donor criteria were inadequate deficient. I think it s extremely unfortunate (and puzzling) that this neglect for donor quality seems to be the standard among people doing FMT clinical trials. Discussion and references on donor quality here: https: archive.fo I3wSb#selection-1891.2-1891.53 ,