乌鸦传媒

In patients who had treatment-refractory irritable bowel syndrome (IBS) with diarrhea or mixed symptoms, symptoms eased after fecal microbiota transplant (FMT) in a small, sham-controlled trial.

The effect waned over 1 year, however, but were salvaged with retransplantation, according to Tom Holvoet, MD, PhD, of the University of Ghent in Belgium, and colleagues writing in .

In patients having failed at least three conventional therapies and randomly assigned to single-dose donor stools (n=43) or to autologous "placebo" stool (n=19), the following outcomes were observed at week 12:

• 56% in the donor stool group had a response with overall improvement in IBS symptoms and bloating versus 26% of patients given placebo stool (P=0.03)
• Donor-stool patients also had significant improvements in discomfort (mean reduction of 19%) and stool frequency (mean reduction 13%), urgency (mean reduction 38%), and flatulence (mean reduction 10%)
• Mean increase of 16% from baseline in quality of life with donor stool (P<0.05) versus no significant change with sham
• Women given donor stool responded at higher rates than did men (69% vs 29%, P=0.01) -- a difference not seen with sham treatment

After a single FMT, 21% receiving donor stool reported effects lasting more than a year compared with 5% with sham transplant. A second FMT from the same original stool donor reduced symptoms in 67% of 12 patients who had shown an initial response to donor stool, but not in patients with prior non-response. In the original placebo group, retransplantation with donor stools (n=12) resulted in an overall response rate of 58% with overall improvement of abdominal bloating in 33% of patients.

"Response [was] associated with composition of the fecal microbiomes before FMT; this might be used as a biomarker to select patients for this treatment," Holvoet and colleagues wrote.

Previous studies of FMT in diarrhea-predominant IBS have had conflicting results, some disappointing and others showing efficacy.

Study details

During December 2015 to October 2017, Holvoet's group recruited patients ages 19 to 75 years with refractory diarrhea-predominant or mixed-type IBS according to Rome III criteria. Mean age in the treatment group was 40 and 31% were male; in the placebo group the mean age was 36 and 59% were male. The mean disease duration was 10 years and 7 years, respectively.

Donor stools were collected on the day of transplant from two healthy male volunteers exhibiting high microbial diversity.

Patients kept symptom diaries on daily bowel movements, stool consistency, and abdominal circumference, while IBS-related quality of life was evaluated using a standardized questionnaire (IBS-QoL). Participants followed a stable diet.

Patients and donors underwent microbiome analysis before and after treatment. Not surprisingly, microbial diversity at baseline was higher in donors than in IBS patients, but diversity significantly increased in patients after FMT. Fecal samples from responders showed higher diversity of microbiota before administration of donor material than those samples from non-responders (P=0.04) and had a distinct baseline composition (P=0.04), but no specific marker taxa were associated with response.

"Using these high-richness donors, we were able to find significant differences between FMT treatment and autologous FMT placebo. However, we observed here that high richness alone is not sufficient to select a donor. After all, we found a non-significant difference in effectiveness between both donors, with the best performing Donor 2 having a lower baseline diversity," they wrote.

Perspective

Gastroenterologist Magdy El-Salhy, MD, PhD, of the University of Norway in Bergen, told 乌鸦传媒 that the study "supports the idea that the selection of donors is important for the outcome of FMT and confirmed that administration of FMT to the upper gastrointestinal tract is successful."

He cautioned, however, that the study was restricted to IBS patients with diarrhea-predominant and mixed-type IBS, the cohort size was relatively small, and prior power calculations were lacking. "Furthermore," continued El-Salhy, who was not involved in the research, "while earlier studies administering FMT to the upper or lower gastrointestinal tract showed that increasing the dose of the transplant increases response (30 g vs 60 g), the authors of this study did not clarify what dose of transplant they used, mentioning only an infusion of 300 mL of the mixed and filtered donor feces."

He also took issue with the study's narrower criteria for donor selection. In a El-Salhy and colleagues selected donors based on a broad range of factors that might positively affect intestinal microbiota. The selected donor was a healthy, drug-free, lean, athletic, young male, born through vaginal delivery, breastfed, and having a history of only three antibiotic courses in his life, eating a varied diet, supplemented with proteins, vitamins, fiber, and minerals. He was normobiotic and had a specific microbial signature deviating from expected healthy normal abundance in 14 of 39 bacterial markers, making his feces richer than average in Lactobacilli, Lachnospiraceae, and Verrucomicrobia, and lower in Shigella and Escherichia spp.

"Although the results of this study are interesting, further studies are needed applying the recommendations proposed by especially those concerning the selection of the donor, the dose and route of FMT administration, and the characteristics of the IBS patients included," he said.

Holvoet and colleagues noted that donor stool preparation may also be an important factor in FMT efficacy. "Indeed, unpublished data from our own lab suggest that freezing stools is associated with a reduction in diversity and might explain the lack of effect in studies using frozen FMT capsules," they wrote.

As for the next step, "Studies are needed to identify which patients are most likely to respond and which components of the fecal material are responsible for the therapeutic effects," the group wrote.

They acknowledged several study limitations, including use of Rome III rather than Rome IV criteria, which focus on the presence of abdominal pain. Furthermore, the autologous "placebo" stool might negatively affect outcomes and therefore exaggerate the benefit from donor stool.

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