Oral fecal microbiota transplant (FMT) can increase the allergic threshold in some adults with peanut allergy, based on results of a phase 1 trial.

Six of 15 highly peanut-allergic adults responded to the transplant, with their reaction threshold rising from approximately half a peanut to one to two peanuts, reported lead author Rima Rachid, MD, associate professor of pediatrics at Harvard Medical School and co-director of the Food Allergy Program at Boston Children’s Hospital in Boston.

These data show how reshaping the gut microbiome can blunt food allergy, and may even point to a potential cure, Rachid told Medscape Medical News.

The study was published in Science Translational Medicine.

Background and Trial Design

Accumulating evidence has implicated the gut microbiome in the development of food allergy, and studies in mice have shown that transferring gut bacteria from healthy donors can protect against allergic responses, the investigators wrote.

Those findings prompted Rachid to test whether an oral FMT from healthy, nonallergic donors could shift the allergic response in people.

The open-label trial enrolled 15 adults with peanut allergy who reacted to 100 mg or less of peanut protein in a baseline food challenge.

Participants swallowed 36 capsules containing FMT prepared from stool donated by healthy, nonatopic donors through the nonprofit stool bank OpenBiome. All but one patient consumed the capsules in 1 day, whereas one patient consumed the capsules over a 2-day period.

In the first part of the trial, 10 participants received a single FMT with no other preparation. In the second part, five participants took a 4-day course of oral antibiotics before FMT.

Response was defined as an increase in reaction threshold from 100 mg or less to 300 or 600 mg of peanut protein at both 1 and 4 months, measured by a double-blind, placebo-controlled food challenge.

40% Responded, With No Serious Events

Overall, 40% of patients responded, including 30% of patients in the group that did not receive antibiotics and 60% in the group that did. In all responders, the higher allergic threshold was still present after 4 months and remained present in all responders who participated in an optional 1-year follow-up.

Three participants had grade 1 or 2 adverse events considered possibly or probably related to treatment, but no serious adverse events were linked to the transplant.

In responders, but not nonresponders, FMT was associated with an increased population of tolerance-promoting regulatory T cells marked by the transcription factor RORγt, alongside a decrease in allergy-associated type 2 immune cells.

In addition, stool from responders, but not nonresponders, protected allergy-prone mice against anaphylaxis. This protection paralleled expansion of Bacteroides species and their bile acid metabolites. Deleting a bacterial enzyme involved in bile acid metabolism abolished the effect, suggesting that bile acids play a key role in the therapeutic response.

An Important Step, With Caveats

Cathryn R. Nagler, PhD, the Bunning Family Professor at The University of Chicago in Chicago, who was first to suggest a role for the gut microbiome in regulating allergic responses to food, welcomed the findings.

“This is an important and exciting study because it provides proof of concept that modulating the microbiome can protect against food allergy in patients with this disease,” said Nagler, who was not involved in the study.

Still, she cautioned that FMT itself will be challenging to develop into a therapy for the millions of people with food allergies, as it cannot be scaled or standardized. Nagler also noted that the study did not show the transferred microbes remained engrafted in recipients, leaving it unclear whether the benefit would last.

Although Nagler’s own research has underscored the role of Clostridia and the short-chain fatty acid butyrate in food allergy protection, she suggested that these new findings, which highlight Bacteroides and bile acids, represent continuity, not conflict.

“I think that multiple microbial metabolites contribute to tolerance to dietary antigens, and that butyrate and secondary bile acids are two of these — not competing but synergistic — mechanisms, perhaps modulating different host responses,” Nagler told Medscape Medical News.

Looking ahead, Nagler predicted that real-world application will draw on such findings, yielding a more targeted approach than FMT.

“Ideally we would want to transfer defined consortia of bacteria that can stably engraft and produce key functional metabolites, including both butyrate and secondary bile acids,” Nagler said.

What This Means for Patients

The most important findings from the study are the mechanistic insights, as these may lead to novel therapeutics, said Edwin Kim, MD, division chief of pediatric allergy and immunology and director of the UNC Food Allergy Initiative at The University of North Carolina at Chapel Hill, who was not involved in the study.

“At the broadest level it demonstrates efficacy of a completely new treatment approach for food allergy,” he told Medscape Medical News. Because FMT works through the microbiome and immune system rather than a single food, it could potentially treat several food allergies through a shared therapeutic approach, he added.

For the present regimen, the raised allergic threshold is “clearly not enough to eat peanut butter sandwiches or to incorporate the food into the diet in any real way,” Kim said. Still, “even a four times increase in threshold may be the difference in having a reaction from an unintentional bite of something or a cross-contamination.”

The Path to the Clinic

Rachid is already developing more refined approaches based on the present findings.

For example, an ongoing phase 2 trial is evaluating a purified, concentrated form of FMT called microbiota transplantation therapy (MTT) in adolescents with peanut allergy. MTT contains less than 1% nonmicrobial material, can be stored in a home refrigerator for months, and is taken at home over 28 days after an initial supervised dose. A second trial is combining MTT with peanut oral immunotherapy in patients who have completed a year of maintenance immunotherapy.

More multisite studies, and eventually phase 3 trials, are anticipated, Rachid said, with the longer-term goal of identifying microbial or metabolic signatures to develop specific bacterial consortia or small-molecule drugs to treat allergy.

The trial was funded by the Translational Research Program at Boston Children’s Hospital, the MIT Broad Institute-Boston Children’s Hospital Precision Medicine Program, several food allergy foundations, and the National Institute of Allergy and Infectious Diseases; it received no industry funding. Rachid disclosed holding patents on methods for preventing and treating food allergy and being a cofounder of, and holding equity in, Belcanto Bio; several coauthors reported related patents, equity, or consulting arrangements. Nagler was a co-founder of ClostraBio. She separated from the company in 2023 and had no ongoing scientific affiliation with ClostraBio other than the university-licensed patents on which she appears as an inventor. Kim reported no conflicts related to this treatment and disclosed consulting relationships with ALK, Allergy Therapeutics, DBV Technologies, and others.