- This double-blind, randomized, placebo-controlled pilot trial (n=24) tested the safety of repeatedly administering encapsulated fecal microbiota transplantation (FMT) microbes, derived from lean donors, to adults with obesity
- Other goals were to investigate whether repeated FMT administration is a feasible strategy for durably modifying the gut microbiome and improving systemic metabolism
- Six weeks of FMT capsule administration sustainably altered gut microbiome composition in most participants without serious adverse effects
- However, there were no significant differences between the FMT and placebo groups in insulin resistance, body weight or most other metabolic markers
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Recent animal studies have created keen interest in the possibility of manipulating the gut microbiome to influence the development of diabetes and other cardiometabolic disorders. That excitement was heightened by clinical research, reported in Cell, in which fecal microbiota transplantation (FMT) from lean donors improved insulin sensitivity in men with obesity and metabolic syndrome.
The effect was short-lived, though, lasting only 12 to 18 weeks after a single FMT. In addition, fresh stool was administered via endoscopy, which is unappealing to patients and limits the potential for repeated dosing.
In previous work published in JAMA, researchers at Massachusetts General Hospital pioneered a novel technique to deliver frozen FMT via orally administered capsules. In a clinical trial dubbed FMT-TRIM, Elaine W. Yu, MD, MMSc, director of the Mass General Bone Density Center, Elizabeth L. Hohmann, MD, staff physician in the Infectious Diseases Division, and colleagues recently investigated how weekly dosing of FMT capsules might affect systemic metabolism in patients with obesity.
In PLOS Medicine, they report mixed results: The capsules altered gut microbiome composition but did not change most metabolic markers.
Between August 25, 2016, and April 4, 2018, the researchers studied 24 patients, age 25 to 60, who had a body mass index ≥30 kg/m2 and mild or moderate insulin resistance. They were randomly assigned to receive FMT or placebo capsules in a double-blind fashion.
The participants took the capsules under supervision by study staff, without bowel preparation. At week 0, they took 15 capsules on each of two consecutive days, followed by 15 capsules once a week for the next five weeks. Follow-up continued for another six weeks. The donors were four metabolically healthy and lean adults; each FMT participant received capsules from a single donor.
There were no significant differences between the FMT and placebo groups in the rate of adverse events (10 vs. 5; P = .09). No related serious adverse events were reported.
After FMT dosing, the microbiomes of recipients were more similar in composition to the donor material and less similar in composition to their baseline samples, compared with placebo participants (based upon DNA analysis of fecal samples). All FMT recipients exhibited engraftment of donor-specific microbes, although the relative abundance of the engrafting microbes was highly variable.
Compared with the placebo group, the FMT group did not show significant improvement in the primary outcome, change in insulin-stimulated glucose uptake (a marker of insulin sensitivity) between week 0 and week 6 (−3 vs. +5%; P = .16).
Over 12 weeks the FMT and placebo groups did not differ in terms of change in body weight, fat mass, lean mass, fasting lipids or insulin resistance.
Changes in two metabolic markers in the FMT group were statistically significant compared with the placebo group but were clinically minor:
- Average difference between groups in reduction in HbA1c at 12 weeks: −0.1%; P = .04
- Average difference between groups in increase in C-reactive protein at 6 weeks: 1.8 mg/L; P = .02
Building on the Results
It seems unlikely that FMT-induced change in microbiome composition will be sufficient to treat or prevent metabolic disorders in humans. However, it remains possible that a greater magnitude of FMT engraftment might produce systemic metabolic changes, or that certain subsets of individuals might respond.
Possibilities for future research in this field include specifying different selection criteria for donors and/or recipients, using specifically designed microbial compositions and combining a microbiome intervention with a dietary/exercise intervention.
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