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A microbiome makeover with fecal microbiota transplantation (FMT) proved no better -- and perhaps somewhat worse -- than placebo for easing the symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D), researchers reported.

In the double-blind, randomized, placebo-controlled crossover trial primary endpoint, IBS-Symptom Severity Scores (IBS-SSS) did not differ between FMT recipients (mean 221) and placebo recipients (236) at 12 weeks (P=0.65), after adjustment for baseline scores, according to Olga C. Aroniadis, MD, of Albert Einstein College of Medicine in New York City, and colleagues.

In secondary outcomes, there was no intergroup difference in IBS-Quality of Life scores, the Hospital Anxiety and Depression Scale (HADS), and the Bristol Stool Form Scale (BSFS) at 12 weeks after adjustment for baseline scores. Both groups showed improvement from baseline to week 12 in IBS-SSS, IBS-QoL, and BSFS, the researchers reported in the .

Additional microbiome analysis, however, showed that FMT responders had higher ratios of Bacteroidetes to Firmicutes at baseline than non-responders, with the genus Prevotella predominating in the Bacteroidetes phylum of responders.

"Bacterial profiles at baseline, might help stratify patients and shed light on the mechanistic drivers of response to FMT," the authors wrote.

From May 2015 to April 2017, the investigators recruited 48 patients with moderate-to-severe IBS-D (defined by IBS-SSS >175) from three U.S. centers. The cohort was more than 60% male and more than 80% white and ranged in age from 27 to 48 years. The median duration of disease was 6 years and many patients were on antimotility drugs and gluten-, lactose- and dairy-free diets. Baseline IBS-SSS in the population was close to 300.

The study randomly assigned patients one-to-one in blocks of four to receive FMT capsules first (n=25) followed by identical-looking placebo capsules, or placebo capsules first (n=23) followed by FMT capsules. Over 3 days, patients took either 75 FMT capsules (each containing about 0.38 g of minimally processed donor stool) or 75 placebo capsules (25 per day). All participants crossed over to the alternate treatment at 12 weeks.

The trial was stopped early after an interim analysis revealed no efficacy from FMT, with clinical responses in both groups at 59%.

Symptom severity and clinical response were similar between groups until the final 4 weeks of the trial. Participants who received placebo before FMT continued to improve from 12 weeks to 24 weeks, while scores of FMT-first patients plateaued. Placebo-first patients achieved a lower IBS-SSS at 24 weeks than their FMT-first counterparts after adjustment for baseline scores, with a mean difference of –69 (P=0.033).

The most common drug-related adverse events included abdominal pain (five FMT recipients vs four on placebo), nausea (four vs two), and exacerbated diarrhea (three vs eight). Acute cholecystitis unrelated to the study drug was reported in a patient receiving placebo.

The authors hypothesized that patients with a history of post-infection IBS might benefit most from FMT, as these are likely to develop symptoms as a direct consequence of an acutely altered gut microbial community. But in a post-hoc subgroup analysis, this outcome was not significant (P=0.87).

The authors conceded their results were not surprising because four previous trials yielded mixed results on the efficacy of FMT, with two reporting significant improvements in IBS symptoms after FMT compared with placebo and two finding no improvement. In 2018 studies, donor FMT was associated with significantly at 3 months compared with autologous FMT. An found greater symptom relief with placebo.

The authors surmised that differences in the source, composition, storage, and administration of FMT products could impact efficacy. The trials supporting the use of FMT, for example, used stool from a single donor whereas the study favoring placebo used pooled fecal material from four donors. Additionally, the pro-FMT studies used fresh stool versus the frozen stool used in the current trial, and an earlier study favoring placebo.

"Additional [randomized controlled trials] are needed to improve understanding of the therapeutic role of FMT in patients with IBS and IBS subgroups," Aroniadis and colleagues said.

Study limitations included underpowering because of early termination, the absence of testing for small intestinal bacterial overgrowth in all participants, and the absence of a washout period.

In an accompanying , Paul Moayyedi, MD, of McMaster University in Hamilton, Ontario, Canada, said the trial's negative findings indicate that FMT should not currently be offered to IBS patients in clinical practice. Nonetheless, he noted that "this intervention should still be the subject of further clinical trials in IBS. A wealth of data suggests that the gut microbiota is involved in IBS3 and FMT is still an interesting approach to try and alleviate symptoms."

Moayyedi added that future studies should recruit greater numbers of patients and donors, test different delivery methods, and delineate patient and microbiota characteristics that might predict response.

"Studies have a long way to go, but the possibility remains that particular patients with IBS might benefit from FMT," he wrote.