Fiber supplementation appeared to modulate the response to fecal microbiota transplantation in patients with severe obesity and metabolic syndrome, researchers have found.
The proof-of-concept trial found that a single, oral dose form of FMT, supplemented with daily nonfermentable fiber, successfully improved insulin resistance in this patient population on optimized medical therapy.
“Since the first landmark European trial demonstrated improved short-term metabolic benefits in patients with metabolic syndrome receiving fecal microbiota transplantation from lean donors, subsequent research has been largely inconclusive,” said Valentin Mocanu, MD, a resident in general surgery at the University of Alberta, in Edmonton. “In addition, although the idea of using dietary or fiber supplementation to improve the effects of FMT has been discussed extensively in the literature, no human trial has yet to examine this concept clinically.”
To fill this gap, the investigators sought to determine whether fiber supplementation following FMT might enhance or sustain FMT-mediated metabolic benefits. As part of the randomized, double-blind, placebo-controlled trial, they enrolled 68 men and women with severe obesity and metabolic syndrome, who presented to the institution’s bariatric clinic between 2018 and 2019.
The participants were stratified by sex and then randomized to one of four treatment groups: placebo oral FMT plus nonfermentable fiber; placebo oral FMT plus fermentable fiber; oral FMT plus nonfermentable fiber; or oral FMT plus fermentable fiber.
Patients in the FMT groups received a single dose of donor stool, 50 g in 20 capsules, followed by six weeks of either fermentable or nonfermentable daily fiber supplementation. The study’s primary outcome was the mean difference in insulin sensitivity from baseline to six weeks, measured by the homeostatic model assessment of insulin resistance (HOMA2-IR).
“One of the unique aspects of our trial was that patients were all given extensive concurrent standardized medical and behavioral therapy,” Dr. Mocanu told Gastroenterology & Endoscopy News. “As part of that, they were each seen by an endocrinologist, by psychologists and nutritionists, and by a physiotherapist.”
As Dr. Mocanu reported at the 2021 Canadian Digestive Diseases Week (abstract A16), 61 patients were evaluated using a modified intention-to-treat analysis. These participants had a mean body mass index of 45 kg/m2, were predominantly female (83.6%), and had an initial HOMA2-IR score of 3.43. The four groups were similar with respect to baseline clinical characteristics, metabolic parameters, medications and dietary intake, according to the researchers.
Improvement in Insulin Sensitivity
Participants who received FMT and nonfermentable fiber saw their HOMA2-IR scores fall by a mean of 24% over the study period (P=0.02), the most of any group. These patients also demonstrated significant improvements in insulin sensitivity (mean difference, an increase of 27.6%; P=0.02) and insulinemia (mean difference, a reduction of 25.4%; P=0.02).
“We anticipated that fermentable fibers would drive the improvements in insulin sensitivity and metabolic benefit, because they’re the ones thought to be preferentially utilized by the gut microbes,” Dr. Mocanu said. “Instead, the only group of patients who showed benefit were those who received FMT and nonfermentable fiber. This combination was an interesting finding that nobody has previously shown.”
The investigators also examined levels of insulin and glucagon-like peptide-1 (or GLP-1, a blood sugar regulator). Once again, patients in the FMT with nonfermentable fiber group showed the greatest improvements in both parameters. “As such, the second novel aspect of our study is that we were able to demonstrate a potential mechanism through the enteroendocrine axis of how this intervention may work,” Dr. Mocanu said.
These benefits were associated with increased microbial quantity. Regression analyses revealed notable microbiome changes in levels of several bacteria that have been previously associated with improved metabolism, including Phascolarctobacterium faecium, Ruminococcaeceae and Bifidobacterium stercoris. “These taxa were predictive of how patients responded metabolically,” Dr. Mocanu said.
The investigators also conducted an engraftment analysis to assess the durability of FMT improvements in the four treatment groups. Only patients who received FMT and nonfermentable fiber demonstrated durable engraftment at the six-week follow-up, through the presence of donor bacterial taxa that were not present in recipients at baseline.
“That was quite exciting, because for the first time we were able to show that donor microbial engraftment in these patients was potentially associated with improved metabolic benefits,” Dr. Mocanu said. “But once we stopped the fiber, none of these metabolic improvements remained. This suggests that you need ongoing fiber supplementation after the fecal transplant to be able to sustain metabolic improvements. This is really just a proof-of-concept study. Now we need to see if we can target those bacteria specifically and whether or not that may provide a more tailored pathway to improving insulin resistance.”
Elaine W. Yu, MD, MMSc, an assistant professor at Harvard Medical School, in Boston, called the study “a welcome addition” to a field that up to now has found mixed efficacy of FMT on human metabolism.
“Strategies such as fecal transplantation and prebiotics have the capacity to alter the gut microbiome, and animal studies have highlighted the outsized influence of dietary factors on the success of microbiome transfer in shaping metabolic phenotypes,” Dr. Yu said. “All in all, these findings suggest that dietary modifications may be required as an adjunct to microbiome manipulation to have an impact on clinical outcomes such as insulin resistance. I would caution that the magnitude of clinical improvement found in this trial was minor, and yet I think this is an important study as it provides physiologic insights into the regulation of human metabolism by gut microbiota.”
—Michael Vlessides
Dr. Mocanu reported no relevant financial disclosures. Dr. Yu reported research funding from Amgen and Seres Therapeutics. The trial was funded by the W. Garfield Weston Foundation.
This article is from the July 2021 print issue.