FMT in IBS: ‘We’ve Been Targeting Wrong Part of the Intestine’

VIENNA — Fecal microbiota transplantation (FMT) into the small intestine led to a better response rate of longer duration in patients with irritable bowel syndrome (IBS), vs it being administered into the large intestine, according to a new study.

Patients also reported an improvement in symptoms and quality of life with repeated doses of FMT (two doses, given one week apart) compared with a single dose in the small intestine, although statistical significance was not met.

“Administering a fecal transplant to the small intestine leads to long-term — up to 1 year in this analysis — colonization of beneficial bacteria, whereas administrating the fecal transplant to the large intestine results in the effect only lasting for the first 3 months,” said Magdy El-Salhy, MD, from the University of Bergen, Bergen, Norway.

El-Salhy presented the results at the United European Gastroenterology (UEG) 2022 meeting.

“It seems that bacteria in the small intestine play a more central role in IBS, as well as its associated fatigue, than bacteria in the large intestine,” said El-Salhy, speaking to Medscape Medical News after his presentation.

“Until now, we’ve been targeting the wrong part of the intestine,” he said.

The findings are the first to show that the small intestine is a more effective location for administering FMT than the large intestine for IBS. “It would be worthwhile doing similar [studies] in other diseases, especially in inflammatory bowel diseases,” said El-Salhy.

Researchers also didn’t expect the repeated dose to improve symptoms for a longer duration. “It really was revolutionary to see,” he added.

Some of El-Salhy’s patients have had up to 5 years of follow-up, although these results were not presented at this year’s UEG, he said.

“Around 75% of my patients have shown duration of response up to 3 years, and a few up to five years, on a 60-g dose from an earlier study group,” he said. “It’s an incredible result after a 10-minute treatment.”

In El-Salhy’s previous work, he found that increasing the dose from 30 g to 60 g increased the response from about 75% to about 90%. However, in this study presented, he found that increasing the dose to 90 g did not further increase the response. He also noted that while repeating the FMT dose improved symptoms and quality of life more than a single transplantation, it did not increase the response.

Targeting the Small Intestine

FMT has been widely investigated for the treatment of such conditions as psoriatic arthritis, Clostridioides difficile infection, and ulcerative colitis.

In this study, El-Salhy built on prior work (seven randomized controlled studies with varied outcomes) by asking whether the transplant dose increases FMT efficacy, which route of administration is more effective, and whether repeating FMT increases efficacy in patients with IBS.

A total of 186 patients were randomized to one of three groups: 90 g of frozen transplant into the large intestine (n = 62), 90 g of frozen transplant into the small intestine (n = 62), or 90 g of frozen transplant into the small intestine twice (with a 1-week interval, n = 62). FMT was administered via nasoduodenal tube and colonoscopy into the small and large intestines, respectively.

Outcomes were measured at 3, 6, and 12 months. The 12-month analysis of outcomes via patient questionnaire included 60, 61, and 60 patients, respectively.

The patient questionnaires included in the study were the IBS-SSS (a composite score of abdominal pain, duration of abdominal pain, bloating/distention, satisfaction with bowel habits, and IBS-related quality of life), the Birmingham IBS Symptom questionnaire, the Fatigue Assessment Scale questionnaire, the IBS-Quality of Life assessment, and the Short-Form Nepean Dyspepsia Index.

Fecal samples were taken and tested for bacterial loads. The bacterial profile and dysbiosis index were determined using the 16S rRNA gene.

At 3 months, patients had similar response rates, around 80%, across single dose in large intestine, single dose in small intestine, and repeat doses in small intestine.

At 6 months, the differences in response rates started to become noticeable, with 67.9% for single dose in large intestine, 71.4% for single dose in small intestine, and 86% for repeat doses in small intestine.

By 12 months, the difference in response rate between the single dose in the large and small intestines was statistically significant at 51.9% and 75.5%, respectively. The response rate to the repeat doses in the small intestine at 12 months (80.9%) was similar to that at 3 months (80.8%).

Side effects, including mild abdominal pain, diarrhea, and constipation, after FMT were seen for the first 5 days after treatment. “People who generally suffer from constipation get diarrhea after FMT and vice versa,” El-Salhy reported.

“Long-term side effects, as monitored up to three years, were not observed,” he added.

Treatment reduced IBS symptoms in all patient groups as measured by IBS-SSS scores. By 12 months, the score fell from around 350 to around 220 in patients who received a single dose in the large intestine, from around 300 to around 200 in patients who received a single dose in the small intestine, and from around 350 to around 170 in patients who received repeat doses in the small intestine.

Quality of life showed a statistically significant difference at 3 months between single and repeated doses in the small intestine and similarly at 6 and 12 months.

Chronic fatigue, experienced by many patients with IBS, was substantially reduced after FMT, El-Salhy noted. “This surge in energy is often more important to them than the gastrointestinal symptoms.”

Location Affects Bacterial Success

Certain beneficial bacteria were found to thrive more when the donor transplant was administered to the small intestine than to the large intestine.

Of note, Lactobacillus species and Holdemanella biformis grew and then dropped off sharply after 3 months in patients who received a single-dose fecal transplant in the large intestine, while they grew after 3 months and continued to grow after 6 and 12 months in the groups who received a fecal transplant in the small intestine.

“We think bacteria in the small intestine have different characteristics to those in the large intestine,” El-Salhy said. “This is relatively new, because many years ago it was thought that bile acids prevented bacterial survival. Now we know lots can thrive in the small intestine.”

“It might be viral or some other component that is most effective here. We don’t know yet, but so far we have identified 11 bacteria of interest,” he added.

Broader Questions

“Rather than focusing on a specific, single strain microbe as a predictor of success in a disease, the global equilibrium of microbiota is more important, and microbial ecology parameters would be interesting to assess,” remarked Gianluca Ianiro, MD, from the Università Cattolica del Sacro Cuore, Rome, Italy, who co-moderated the session. “Selected survival of some bacteria through the gut may be the response.”

FMT emerged in response to the challenges posed by recurrent C difficile infections, noted Alexander Khoruts, MD, a professor of medicine in the division of gastroenterology, hepatology, and nutrition at the University of Minnesota in Minneapolis, who was not involved in the research.

“It is much harder to achieve remodeling of the gut microbiome in non-C difficile conditions where there is an intact and resilient indigenous microbiota,” he told Medscape Medical News. “Therefore, regimens using antibiotic preconditioning and repeated administrations of microbiota are generally more efficacious in achieving this objective.”

The specificity of the bacteria according to disease type targeted was important, said Khoruts, who has a special interest in gut microbiota.

“The big question in non-C difficile indications is the composition of donor microbiota. It is critical that we understand the mechanisms involved in each target disease to design appropriate microbiota-based therapeutics,” he said.

Khoruts sounded a note of caution with respect to establishing the pharmacokinetic and dynamic data related to FMT, which is classified as a drug in the United States.

“It’s imperative that we develop the pharmacology discipline appropriate for this class of therapeutics, including their pharmacokinetics and pharmacodynamics, and an understanding of their potential toxicity and drug–drug interactions,” he said.

Drug distribution data are needed to determine host-microbiota interactions.

“This includes the small bowel microbiome, which continues to be woefully understudied,” Khoruts said.

United European Gastroenterology (UEG) Week 2022: Abstract OP123. Presented October 10, 2022.

El-Salhy reports no relevant financial relationships. Ianiro reports receiving personal fees for acting as speaker for Biocodex, Sofar, Malesci, and Tillotts Pharma, and for acting as consultant/advisor for Ferring Therapeutics, Biocodex, Tillotts Pharma, Zambon. Khoruts reports he has patents pertaining to fecal microbiota separation from stool and their cryopreservation and lyopreservation.

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