Unraveling the Mechanisms Behind FMT Efficacy Needed to Expand Its Use

Jennifer Lubell

June 07, 2023

A deeper understanding of the mechanisms underlying the success of fecal microbiota transplantation (FMT) is needed to further improve its effectiveness, according to two recent reviews published in Cell Host and Microbe.

Both research teams agree that more needs to be known about how various underexplored factors ― such as the patient's diet and genetic background, how closely the donor's microbial composition matches the patient's existing microbiome, and the presence of nonbacterial gut inhabitants like viruses and fungi ― affect FMT success, according to a press release.

FMT is most often used to treat recurrent Clostridioides difficile infections, which don't always respond to antibiotics. Success rates range from 60% to 90%, depending on the administration route and study design, notes an international research team led by Abbas Yadegar, PhD, a medical bacteriologist at the Shahid Beheshti University of Medical Sciences in Tehran, Iran.

Dr Abbas Yadegar

The understanding of how FMT works is incomplete, however, and the reasons some patients fail to benefit is unclear, note Yadegar and colleagues. Little attention has been paid to the role that other components of the patient's microbiome, along with outside factors, play in the treatment's success, they add.

"We wanted other researchers to look beyond changes in stool microbial composition and function, which have been the focus of research in the past few years," Yadegar's team said in a statement provided to Medscape Medical News.

Yadegar and colleagues' review of more than 130 studies summarizes recent evidence on the mechanisms contributing to FMT success against recurrent C difficile infection, highlights knowledge gaps, and proposes future research directions in the field.

Factors that influence FMT's effectiveness and the potential the procedure holds for treatment of other diseases associated with gut dysbiosis are the subject of a review of 149 studies by a team of researchers led by Serena Porcari, MD, a gastroenterologist at the Fondazione Policlinico Universitario Gemelli and Università Cattolica del Sacro Cuore, in Rome.

Dr Gianluca Ianiro

"Our main goal was not only to unravel the different mechanisms of FMT efficacy but also to introduce some mindset shifts that are needed to bring FMT forward, mainly covering the gap that exists between basic scientists and clinicians," Gianluca Ianiro, MD, PhD, a senior researcher in digestive diseases who works with Porcari and is the review's lead author, told Medscape Medical News.

Engraftment May Influence Success

Engraftment of donor microbial strains in recipients appears to be key to the therapeutic success of FMT, both reviews note.

Three factors influence engraftment: the donor's bacteria fitness relative to the recipient, the bacteria already present in the recipient, and whether antibiotics are used prior to FMT to open a niche for the incoming donor microbes, according to Yadegar and colleagues.

How to calculate strain engraftment has not yet been standardized in the field, and the number of strains detected in the recipient's fecal sample is dependent on the depth of sequencing techniques, Porcari and colleagues note.

The use of whole-genome sequencing has enabled more precise evaluation of engraftment, they add.

"With this approach, microbial engraftment has been associated with clinical success, regardless of the disease, in a large metagenomic metanalysis of 24 FMT trials and almost 1400 fecal samples," Porcari and colleagues write. However, these results have not been replicated, likely because of differences between the studies.

More study on the topic is needed, both articles note.

"Because the recent metagenomics studies compared pre- and post-FMT only in cases with successful treatment outcomes, it is not possible to link engraftment to clinical outcomes," Yadegar and colleagues write in their statement to Medscape Medical News.

A Closer Look at Donor-Recipient Pairings

Clinicians usually enlist healthy, carefully screened individuals as FMT donors.

However, both research groups conclude that fine-scale taxonomic and metabolic analyses of donor and recipient microbiomes would better inform clinical decisions, especially when treating diseases other than C difficile.

This may call for a more personalized approach to choosing donor-recipient pairings. Investigators should assess the patient's diet and genetic background and how closely the donor's microbiome matches that of the patient.

"Most studies focused on profiling stool samples before and after FMT without also including functional analyses; therefore, there are still a lot of aspects of host microbial interactions that remain unknown," write Yadegar and colleagues in their statement.

Ecologic factors, including diet and host genetics, are often not included in clinical studies of C difficile, but they "may potentially be the missing links" to treatment failure in the small portion of patients whose condition doesn't respond to FMT, they write.

Pairing donor-recipient combinations on the basis of dietary patterns and preferences could improve FMT efficacy because the donor microbiota would be preadapted to the recipient's diet, Yadegar and colleagues write. The team is examining how donor and recipient diet may affect outcomes.

Porcari and colleagues add that while some studies support the existence of shared characteristics that make up super-donors, others found that the optimal donor is more patient specific. They call for personalized selection strategies that employ microbiome sequencing tools rather than a "one stool fits all" approach.

Currently, many clinicians aren't familiar with microbiome sequencing and analysis, but they'll need to be in the near future, note Porcari and colleagues.

"Identifying microbiome characteristics that maximize strain engraftment in the FMT will allow clinicians to select the best donor for each single patient," they write.

The Possible Role of Viruses and Fungi

In FMT research, investigators tend to focus on the bacteria in the human microbiome. However, viruses and fungi also appear to play a role, both articles note.

"Other microbial kingdoms that inhabit the intestine should be taken into account when considering predictors of post-FMT microbial transfer," write Porcari and colleagues.

Although few studies have examined the gut virome's impact on FMT effectiveness against C difficile, the existing research, although limited, indicates that bacteriophage viruses could play a role, Yadegar and colleagues note. For example, high levels of donor-derived Caudoviralesbacteriophages in recipients were associated with FMT efficacy in one preliminary study, they write.

In a small human study, fecal filtrate from healthy donors who had bacteriophages but no live bacteria successfully treated five patients with recurrent C difficile infection, Yadegar and colleagues write.

"Therefore, the idea that viruses may play a role is very provocative," write Yadegar's team in their statement.

It's important to note that these studies are associative, which means they can't definitively answer the question of how or whether viruses play a role, Yadegar's team added.

Researchers "know even less about how fungi may or may not play a role," write Yadegar and colleagues. However, in early research that involved patients who had successfulfly undergone FMT for C difficile, there was higher relative abundance of Saccharomyces and Aspergillus, whereas Candida, if prominent, may impede response, they write in their article.

Additionally, to explore whether live bacteria are necessary for FMT to work, Yadegar and colleagues informed Medscape Medical News that they are conducting a study "comparing traditional FMT to a fecal filtrate that contains no live bacteria, but has all other components, to see if we can achieve similar success rates in recurrent C difficile infection."

Repeat Treatment for Sustained Response

Yadegar's team offered another important takeaway: a single FMT treatment will not sustain a positive response, especially when treating chronic noncommunicable conditions in which intestinal dysbiosis may play a role. Repeat treatment will be needed, as with other chronic conditions. This has been shown even in C difficile infection.

"Recent studies have documented a significant advantage of repeated FMT over single FMT on the cure rates of recurrent C difficile," especially for patients with inflammatory bowel disorder, Yadegar's team told Medscape Medical News.

"What we don't know is which patient is likely to respond to microbial-based therapy, or what the dose or frequency should be, or which bacteria are responsible for the effects," Yadegar and team said in their statement to Medscape Medical News.

Porcari and colleagues are examining whether FMT could be refined to improve its success against other diseases. This may involve selecting specific donors, monitoring the gut microbiome of both donors and recipients, or using a specific means of delivery, such as lyophilized capsules, Ianiro said.

A response to FMT for chronic, noncommunicable disorders typically is not sustained long term, note Porcari and colleagues. However, they add that "sequential transplants have been applied in this setting with promising results, suggesting that chronic modulation of the patient microbiome may be beneficial in noncommunicable chronic disorders." Porcari and colleagues point to the success of repeated, long-term FMT in studies of patients with ulcerative colitis and irritable bowel syndrome.

The use of cutting-edge technologies for microbiome assessment and a change in the view of FMT as only an acute, single-use therapy could improve FMT protocols and outcomes for noncommunicable conditions, they write.

Expanding FMT Beyond C difficile

Yadegar and colleagues' article "really breaks down what is known about the mechanisms of FMT in C difficile infection, which is important as other live biotherapeutic products are developed," Colleen Kelly, MD, an associate professor of medicine at Brown University in Providence, Rhode Island, who was not involved with the reviews, told Medscape Medical News.

Yadegar and colleagues concur. They note in a press release that as the mechanisms behind FMT success are understood, that information should be used to design new standardized therapies.

"Although highly effective, there are substantial drawbacks with [FMT], including infectious risks and sparse long-term safety data," they write. "Better treatment options for recurrent C difficile infections that are targeted, safe, and donor-independent are thus desired."

In December 2022, the US Food and Drug Administration (FDA) approved the first fecal microbiota product, Rebyota, to prevent recurrence of C difficile. More recently, in April 2023, the FDA approved Vowst, a pill for treating recurrent C difficile infections.

Kelly also noted that the article by Yadegar and colleagues "may help us understand why a small percentage of patients fail to achieve cure after FMT."

Regarding Porcari and colleagues' article, Kelly said, "There is a lot of hope that FMT or other gut microbiome therapies will be beneficial for conditions outside of C difficile.

"They do a good job reviewing the state of the science of FMT and highlight the many unknowns around the use of FMT in conditions outside of C difficile," added Kelly, who has been using FMT to treat C difficile for more than 15 years.

Data supporting FMT for conditions such as ulcerative colitis and autism are compelling, Kelly acknowledged. But in her view, FMT isn't ready for "prime time" outside of C difficile ― at least not yet.

"Academic investigators and those in industry are actively conducting research in many non–C difficile indications, and I predict we will see the emergence of gut microbiome-based therapies for other indications within the next 5–10 years," Kelly said.

Yadegar reports no relevant financial relationships. One co-author of the Yadegar study has served on the adjudication board for Finch Therapeutics and has received consulting fees and a speaking honorarium from Rebiotix/Ferring Pharmaceuticals. Ianiro reports no relevant financial relationships. Kelly has consulted for Sebela Pharmaceuticals and is one of the principal investigators for the FMT National Patient Registry funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Cell Host Microbe. Published online May 10, 2023. Yadegar et al, Full text; Porcari et al, Full text

Jennifer Lubell is a freelance medical writer in the Washington, DC, metropolitan area.

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