Trial Report Faecal microbiota transplantation in [IBS] (REFIT2): a randomised, double-blind, placebo-controlled, phase 3 trial, 2026, Johnsen et al

Utsikt

Utsikt

Senior Member (Voting Rights)
Faecal microbiota transplantation in irritable bowel syndrome (REFIT2): a randomised, double-blind, placebo-controlled, phase 3 trial

Johnsen, Peter Holger; Juul, Frederik Emil; Hoff, Dag Arne Lihaug; Hillestad, Eline Randulff; Holme, Øyvind; Skjevling, Linn Kallbekken; Hansen, Hege Marie; Rasmus, Marthe H; Barnett, Lauren; Barry, Sarah J E; Hjerde, Erik; Lindstedt, Kenneth; Buczek, Dorota J; Hatlebakk, Jan G; Steinsvik, Elisabeth K; Berentsen, Birgitte; Garborg, Kjetil Kjeldstad; Valeur, Jørgen; Valle, Per Christian; Løberg, Magnus; Kalager, Mette; Bretthauer, Michael; Goll, Rasmus

Abstract

Background​

Gut microbiota composition might have a role in the pathogenesis of irritable bowel syndrome (IBS), and faecal microbiota transplantation has been proposed as a means of restoring healthy gut microbiota for individuals with this condition. We aimed to investigate the efficacy and safety of faecal microbiota transplantation in patients with IBS.

Methods​

In this parallel-group, randomised, double-blind, placebo-controlled, phase 3 trial, conducted at five hospitals in Norway, we enrolled men and women aged 18–65 years with moderate-to-severe IBS.

IBS diagnosis was defined by the Rome IV criteria and an IBS-Severity Scoring System (IBS-SSS) score of 175 points or higher. A colonoscopy within 5 years before study enrolment was required for all participants aged 50 years or older to rule out colorectal cancer, and participants with IBS with predominantly diarrhoea required negative biopsies to exclude microscopic colitis.

Participants were randomly assigned 2:1 to faecal microbiota transplantation with faeces samples from either healthy donors (intervention) or the participants themselves (placebo group).

All investigators, participants, and study personnel involved in treatment administration, patient care, and outcome assessment were masked to treatment allocation throughout the study.

Treatments were delivered as a once-only rectal enema.

The primary endpoint was the proportion of participants with a reduction of 75 points or more in IBS-SSS score at 90 days after treatment compared with baseline, assessed in all patients who received their allocated treatment.

All participants were advised to report any adverse event during follow-up to their study contact, preferably by telephone.

A patient representative was involved in the planning of the trial.

The trial was registered at ClinicalTrials.gov (NCT04691544).

Findings​

Between May 5, 2021, and July 14, 2022, we assessed 2304 individuals for eligibility, and 450 participants were enrolled and randomly assigned to the intervention group (299) or placebo group (151); two randomly assigned participants were excluded from analyses because their allocated treatments were switched. 293 (65%) of 448 participants were women, 155 (35%) were men, and the median age was 36 years (IQR 29–44).

119 (40%) participants in the donor faecal microbiota transplantation group and 57 (38%) in the placebo group showed an improvement of at least 75 points on the IBS-SSS at 90 days after treatment. The absolute difference was 1·9 percentage points (95% CI –8·1 to 12·0; p=0·76).

The proportion of participants with adverse events was similar in the two study groups.

Interpretation​

The trial did not show a clinical benefit of faecal microbiota transplantation in patients with IBS. These findings suggest that microbiota modulation alone might be insufficient for symptom improvement in IBS.

Web | DOI | The Lancet
 
Utsikt said:
The trial did not show a clinical benefit of faecal microbiota transplantation in patients with IBS. These findings suggest that microbiota modulation alone might be insufficient for symptom improvement in IBS.
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You know, there are certainly worse things in life, but I’m happy that I don’t have to consider that as a treatment option.

I wonder if this puts a hole in the idea that gut microbiome has a role to play in IBS pathology? I have no idea how successful FMT is at changing someone’s microbiome, but it does feel like it strengthens the gut-brain axis hypothesis. Which, I know I don’t need to say this here but I want to get it off my chest, does not mean positive thinking and therapy will improve IBS.
 
I don’t have strong views either way on the role of the gut microbiodome in various health issues, but though this study clearly suggests adding ‘healthy’ bacteria alone is not helpful in treating IBS, there are potential problems with totally rejecting this approach unless it can be shown that they had successfully restored a ‘normal’ microbiota balance without changing the IBS symptoms.

Way back in the last century when I was at the trying everything and anything stage of my ME I saw a very enthusiastic nutritionalist, who argued for rebalancing gut flora and fauna by getting rid of the ‘harmful’ bacteria, yeasts, etc, replacing them with ‘healthy’ ones and sustaining this change by significant dietary change. If he was correct, this study could have failed because they only included one of the three stages required.

At the time I was under the nutritionalist I attempted to address eliminating harmful microbes and replacing them via both ends of the gut, radically altered my diet and consumed a very expensive quantity of dietary supplements. I did ‘recover’ under this regime however I was also trying out other things, and subsequently established I had a relapsing and remitting form of ME. I now believe that it was only because I was already experiencing spontaneous recovery that I was able to even participate in such a gruelling regimen. And only because I was still working that I could afford the various ‘treatments’ and supplementation.

Also it is not clear in ME/CFS that a one off acute viral infection would overnight radically imbalance the gut biodome. Both my initial onset with EBV and my first relapse with presumed seasonal flue were sudden switches from active and apparently healthy to moderate/severe ME/CFS with associated IBS symptoms.

Subsequent more half hearted ventures into rebalancing my gut microbiome have not been associated with any dramatic change in my ME, though healthy eating can not be a bad thing. I suspect that like my vitamin deficiency (B12) and my food intolerances, addressing any serious imbalance in the gut biodome if the individual has such, may address any negative symptoms associated with those issues, but does not directly address any other underlying medical issue such as IBS or ME/CFS.
 
I’m surprised they didn’t find them useful, as they were very effective for me. Perhaps IBS is too broad a category or there was an issue with implementation.

My ME onset was following antibiotic treatment for Giardiasis. GI disturbances have been a significant feature ever since, manifesting in significant food intolerances, most intractably to soy, nuts, and fructose. Provided I avoided problematic categories, my GI was manifestly normal, but with severe gas, bloating, and diarrhea when I didn’t. I tried a number of rounds of DIY FMT a few years in hoping they would help both ME and GI function. The impacts were generally profoundly negative in terms of ME function. Cognitively, I haven’t regained some of the lost function even 13 years later. In terms of GI function, though, they were a miracle. All my tolerances at the time disappeared. The effect only lasted about 7 months, however. In the years since, I’ve been able to reintroduce problematic foods very gradually, but that tolerance hasn’t ultimately been durable and weakens when I’m sick with a cold. I just lost tolerance to nuts after 4 years and soy after 3 years.

One other wrinkle regarding the transplants is that my wife was my donor and she developed ME many years later.
 
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