New phase 3 trial finds no significant benefit over placebo at three months or one year, despite measurable changes to the gut microbiota.
A Norwegian phase 3 trial has found no significant improvement in irritable bowel syndrome (IBS) symptoms with faecal microbiota transplantation (FMT) compared with placebo, despite measurable changes to recipients’ gut microbiota.
The Recalibrating the Intestinal Microbiota by Fecal Microbiota Transplantation 2 (REFIT2) trial, conducted at five hospitals between May 2021 and October 2023, included 448 participants aged 18–65 years (median age 36) with moderate-to-severe IBS, 65% of whom were women.
Published in The Lancet, this double-blind, placebo-controlled trial randomised participants 2:1 to receive a single rectal enema containing faecal material from a healthy donor (intervention group) or material derived from their own stool (placebo group). Participants were allocated to one of three donors in the intervention group.
Exclusion criteria were comprehensive, and nearly 2000 participants were excluded due to IBD, microscopic colitis, diverticulitis, endometriosis, obesity, diabetes, previous FMT, and many more.
The primary outcome was a reduction of at least 75 points on the IBS Severity Scoring System (IBS-SSS) at 90 days. This meaningful reduction in symptom severity was achieved by 40% of the intervention group and 38% of the placebo group (absolute difference 1·9 percentage points, 95% CI –8·1 to 12·0; p=0·76).
At one year, improvement was recorded in 44% of the FMT group and 45% of the placebo group (absolute difference –1.5 percentage points, 95% CI –12.0 to 9.1).
Additional measures included stool samples, the IBS-Quality of Life (IBS-QoL) questionnaire, the Global Improvement Scale, the Hospital Anxiety and Depression Scale (HADS), the Modified Fatigue Impact Scale (MFIS), and the Patient Health Questionnaire-15 (PHQ-15).
There was no significant difference between groups in quality-of-life improvement at either 90 days or one year, or in adequate symptom relief (defined according to European Medicines Agency criteria) at 90 days. Participants with diarrhoea-predominant IBS did not show a significant improvement in stool consistency, while those with constipation-predominant IBS did not have an improvement in the number of complete spontaneous bowel movements.
Subgroup analyses of improvements in IBS-SSS at both 90 days and 365 days post-FMT found no association between treatment efficacy and sex, IBS subtype, baseline IBS-SSS severity, or diet (i.e., low FODMAP diet).
The trial also examined whether clinical outcomes differed according to which of the three donors supplied the transplant, addressing the hypothesis that certain individuals may act as “super donors” whose gut microbiota consistently produce superior clinical benefits.
The researchers said the trial was the first IBS study to randomly assign participants according to individual donors, and they found no significant differences in symptom improvement between donor groups at either 90 or 365 days, including in post-hoc analyses.
At baseline, relative microbial abundance and diversity did not differ between the FMT and placebo groups, although both groups differed significantly from the donors.
At 90 days post-treatment, recipients of donor FMT showed a significant change in microbial abundance from baseline, and the relative microbial abundance and diversity difference between the intervention and placebo groups was significant.
Related
The increased diversity was greatest for recipients of donors A (R2=0.015; adjusted p<0.001) and C (R2=0.012; adjusted p<0.001). The effect was smaller but still significant for recipients of donor B (R2=0.007; adjusted p<0.001).
Researchers concluded that their findings did not support a hypothesis of FMT efficacy being donor dependent.
“Although engraftment occurred in all three donor groups to varying degrees, the degree of engraftment did not correspond with differences in clinical outcomes between donors,” they wrote.
The proportion of participants experiencing adverse events was similar between groups, although the total number recorded was higher in the intervention group.
Up to 365 days, there were 24 adverse events in the FMT group, including six serious events, compared with eight events in the placebo group, none of which were serious. Four participants receiving FMT and three receiving placebo experienced events considered possibly or probably related to treatment; none were serious. No deaths occurred during follow-up.
In an accompanying commentary, US researchers Jacqueline Liu, a registered dietitian, and Associate Professor Andrea Shin, Co-Director of the Clinical Studies and Database Core at UCLA’s Goodman-Luskin Microbiome Center, highlighted several methodological issues requiring consideration.
They noted that FMT was delivered as a single rectal enema, leaving uncertainty about whether this route achieves microbial delivery comparable with other methods, such as colonoscopy.
They also questioned whether symptom assessments adequately captured the fluctuating nature of IBS. The primary IBS-SSS outcome was measured at a single timepoint, while other symptom measures were collected over a four-week period and did not coincide with IBS-SSS assessments.
The use of three donors also introduced biological heterogeneity, the commentators wrote. Although the researchers adjusted their analyses for donor variability, the study may have been underpowered to detect differences between donors, and combining their recipients into one intervention group could have obscured donor-specific effects.
“Finally, given the importance of diet–microbiome interactions and preclinical evidence highlighting specific dietary interventions as prerequisites for effective faecal microbiota transplantation, the absence of standardised dietary co-interventions in the study might constitute an important gap,” they wrote.
The Lancet, 24 September 2026 (article)
The Lancet, 24 September 2026 (commentary)
