OR26-06 Fecal Microbiota Transplantation Trial for the Improvement of Metabolism (FMT-TRIM): A Randomized Double-Blind Placebo-Controlled Pilot Trial

Abstract Background: There is intense interest about the therapeutic potential of altering gut microbiota to improve metabolism, based primarily on intriguing animal studies. One prior trial of fecal microbiota transplantation (FMT) in obese men found that improved metabolic response after FMT was predicted by low baseline microbiome diversity. In the current trial, we investigated the safety and efficacy of weekly oral FMT capsules to improve glycemic outcomes in obese adults, and also explored determinants of successful microbiome engraftment and metabolic improvement after FMT. Methods: FMT-TRIM was a double-blind randomized placebo-controlled pilot trial of weekly oral FMT vs placebo capsules for 6 weeks in 24 obese adults with mild-moderate insulin resistance. Each participant in the FMT arm received capsules derived from one of 4 metabolically healthy lean donors (BMI 18.5-23 kg/m2). The primary outcome was change in insulin sensitivity assessed by hyperinsulinemic euglycemic clamp at 0 and 6 weeks. Secondary outcomes included body weight, metabolic labs, and body composition assessed by DXA over 12 weeks. 16SV4 rRNA sequencing was performed to assess microbiome composition and engraftment. Post-hoc exploratory analyses investigated metabolic outcomes after stratification by baseline microbiome diversity. Results: FMT and placebo groups were well balanced in terms of age (mean±SD 40±9 yrs), BMI (40±6 kg/m2), sex (72% female), and baseline metabolic measures. During the study, there were no statistically significant differences in insulin sensitivity between the FMT and placebo groups (+5 ± 12% FMT vs -3 ± 32% placebo, mean percent difference 9%, 95% CI -5% to 28%; p=0.16). There was a minor improvement in HbA1c at 12 weeks after FMT as compared to placebo (mean difference -0.1, 95% CI -0.3-0.01), but no significant differences in other metabolic labs, body weight, or body composition. Microbial engraftment varied by donor but was present in most FMT recipients, with persistence of engrafting strains throughout the 12-week study. Subgroup analyses of subjects with low microbiome diversity at baseline (FMT n=4, placebo n=7) showed a relative benefit of FMT over placebo at 12 weeks for HbA1c (mean difference -0.2, 95% CI -0.4 to -0.01), total cholesterol (-22 mg/dL, 95% CI -40 to -4 mg/dL), and fasting glucose (-10 mg/dL, 95% CI -19 to -1 mg/dL). There were no significant differences in adverse events between FMT and placebo groups. Conclusion: Weekly administration of FMT capsules results in gut microbiota engraftment for at least 12 weeks but does not meaningfully alter human metabolism in an unselected population of obese adults. Future studies are needed to elucidate the role of baseline recipient microbial diversity and other factors on the impact of FMT.