FMT-Based Therapies for GI Disease: What to Consider

This transcript has been edited for clarity.

Researchers and physicians have been studying dysbiosis (or alterations of the gut flora) and its relationship with many disease processes, including inflammatory bowel disease, irritable bowel syndrome, rheumatoid arthritis, depression, diabetes, metabolic syndrome, multiple sclerosis, Parkinson's disease, chronic fatigue syndrome, and heart disease. In recent years, much of this research has focused on fecal microbiota transplant (FMT) as a potential therapy for disease prevention and to treat numerous medical conditions beyond Clostridium difficile infection.

For those unfamiliar with FMT, stool can be transplanted by colonoscopy, enema, frozen pills, and nasoenteric tube.

Because several conditions can contribute to dysbiosis, as well as antibiotics and diet, our ultimate goal is to use FMT to improve the microbiome and cure a variety of disease processes.

Advantages, Disadvantages of FDA Regulation

Although we lack data about the long-term side effects of FMT, animal models have shown that it can unintentionally transfer disease phenotype, including metabolic disorders and obesity. Gut bacteria have also been accused of increasing the rate of both colon cancer and heart disease in patients, so it's very important that FMT be regulated properly.

The US Food and Drug Administration (FDA) works to ensure that patients have safe access to treatments that are proven effective through research and evidence-based medicine.

As explained in a recent editorial in [Clinical and Translational Gastroenterology], which I helped contribute to as a member of the American College of Gastroenterology's FDA Committee, "In the United States, drugs and bioactive agents including MBTs [microbiome-based treatments] used with therapeutic intent for specific disease states falls under the jurisdiction of the US Food and Drug Administration."

The Center for Biologics Evaluation and Research is the part of the FDA that regulates biologic products, which includes blood as well as blood products, vaccines, gene therapies, allergenics, and human cells and tissue products.

The FDA previously decided that FMT is both a drug and a biological product and should be regulated as a drug.

Interestingly, the Federal Food, Drug, and Cosmetic Act defines drugs as "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease" and articles (other than foods) that are intended to affect the structure and function of the body of man or other animals. In addition, the Public Health Service Act says that a biological product is a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product applicable to the prevention, treatment, or cure of disease or condition in human beings. As such, biologic products in the United States can be regulated as drugs under the Federal Food, Drug, and Cosmetic Act, or as biological products under the Public Health Service Act, or under both laws.

Clinical trials of microbiome-based treatments require an investigational new drug application be submitted to the FDA for permission to give a potentially therapeutic microbiome donation to humans.

One of the advantages of having the FDA regulate FMT is that the industry can more easily navigate their medical-legal responsibilities through a uniform, organized process when bringing fecal microbiome products to market. The FDA can also help physicians more successfully treat patients by providing guidance.

However, it's difficult for the FDA to regulate potential do-it-yourself treatments when hospitals and scientists run their own stool banks or utilize donor stool from patients. Unlike medications that are produced with strict standards in a factory using controlled amounts of standardized ingredients, each human stool has a unique microbiome makeup, which can also evolve over time as donors age. Therefore, it's harder to regulate donor stool for FMT.

It's also difficult to regulate FMT due to its complexity (eg, number of bacteria in the microbiome) and because the microbiome of each donor is different. When hospitals or stool banks create FMT product, the unique microbiome components of each FMT product would need to be identified, purified, and tested.

Successful Microbiome-Based Interventions

FMT is a very effective treatment for recurrent C difficile colitis when antibiotics aren't resolving the infection. FMT's use in this indication has been supported by multiple society guidelines, including those from the American College of Gastroenterology, Infectious Diseases Society of America, and Society for Healthcare Epidemiology of America. The introduction of standardized stool banks has made fully screened donor stool [for this indication] tremendously accessible for physicians nationally. However, because FMT is still considered investigational by many regulatory agencies, insurance payment for C difficile treatment can be hindered sometimes.

Additionally, the FDA has approved two new microbiome-based therapies. In 2022, Rebyota (Ferring Pharmaceuticals) was approved, and is designed to prevent C difficile recurrences in patients 18 years of age or older. Many patients experience a recurrence after their first antibiotic for C difficile treatment, possibly due to dysbiosis. Rebyota helps restore gut flora and can't be used until after the first episode of C difficile. Rebyota is delivered rectally from donor stool. Rebyota was given priority review, orphan drug, and breakthrough therapy FDA designations. In April 2023, Vowst (Seres Therapeutics) was FDA approved. Vowst's approval is important, given that it's the first oral microbiome-based therapy used to prevent C difficile. Patients take four pills per day for a total of 3 days.

Gastroenterologists have welcomed both drugs as new tools in our armamentarium against C difficile, which can cause diarrhea leading to death in certain severe cases.

Potential Side Effects, Risks, and Complications

In general, FMT is safe. However, there are potential side effects, ranging from mild stomach upset to severe infection, for which being immunocompromised was identified as a risk factor. Reported gastrointestinal-related side effects include crampy abdominal pain, bloating, flatus, belching, burping, diarrhea, constipation, nausea, vomiting, and increased borborygmus (stomach rumbling).

In 2019, there was a report of a severe case of Escherichia coli infection following FMT that resulted in death. This prompted the FDA to mandate that all stool be screened for E coli infection. The patient who passed away was receiving FMT for an experimental treatment of allogeneic hematopoietic cell transplantation using a hospital-based stool bank that was not screened for multidrug-resistant organisms. This case sounded alarm bells in the medical industry. Moving forward, FMT should become safer, with standardized stool donor collection and increased screening protocols.

Administering FMT by upper gastrointestinal delivery can place patients at risk for aspiration. There has been a case reported where a patient died of fecal aspiration, so it's important to provide an antiemetic medication when delivering it via upper scope. Also, patients should not be sedated.

Delivery via colonoscopy places patients at a slightly increased risk for perforation.

It's important to have a thorough benefits-risks conversation with the patient in advance and a signed consent detailing all known potential side effects of FMT.

Despite the potential side effects and risks, many researchers and gastroenterologists hope that one day soon we may use FMT for many medical diagnoses because the potential success for disease modification is so great.

Standardized Testing, Storage, and Tracking

I recommend stricter standardized testing of donor stool and blood prior to transplantation in order to prevent any infection risk. One author has recommended that HIV testing be performed 14 days after donation to help further eliminate any risk. Perhaps a risk assessment should be performed to prevent FMT donation from individuals who are engaging in risky behaviors.

We should also consider how FMT is stored and its expiration life. For instance, there are certain organisms, such as Faecalibacterium prausnitzii (frequently found in patients with inflammatory bowel disease), that can be damaged by oxygen. Therefore, careful attention needs to be paid to how to prevent oxygen exposure to FMT donations. We may need to regulate storage conditions, including storage temperature and how stool is stored.

Future safeguard research should focus on potential side effects of FMT for recipients. Also, we need to determine whether donors who eventually develop significant medical problems, such as cancer, are impacting recipient patients through donor stool.

Another area of concern as FMT therapeutics take off is that the FDA orphan drug designation could prevent competing products from coming to market unless the drug production process is novel and completely different. Greater attention should be placed on how FMT is prepared.

Unresolved Areas of Research

As research into FMT continues, I recommend that institutional review boards work together with the FDA. Bioethicists should remain involved due to the potential downstream effects of microbiome manipulation during research. All should work together to determine which are acceptable risks for patients. Within FMT research, systems should also be placed to help track long-term health outcomes for all patients and studies.

The future of FMT being used to alter the course of disease is extremely promising, but unresolved areas of research remain. Some questions that an excellent recent article in Nature Medicine, by Kjersti Aagaard and Elizabeth Hohmann, proposed were: "What duration of follow-up is necessary? How might microbial changes be altered by future drugs, diseases, or age? At the completion of a study in which participating subjects are given live microbiome therapeutics, should these subjects receive antibiotics for eradication of the study microbe (regardless of study findings)? If so, what collateral damage might such antimicrobial therapy subsequently unleash?" These are important questions that bioethicists and the FDA will need to help regulate.

As we research the ability to alter the microbiome, it would also be important to adjust or fine-tune treatment to account for diet and host genotype. Perhaps human stool and FMT should be recategorized uniquely at the FDA and internationally for regulatory purposes. Stool banks and national registries should work together for long-term tracking of donors and recipients over time. Finally, as FMT products are brought to the market, companies should use manufacturing guidelines to help make sure that each step of the manufacturing process is uniform for patient safety.

Benjamin H. Levy III, MD, is a gastroenterologist at the University of Chicago. In 2017, Levy, a previous Fulbright Fellow in France, also started a gastroenterology clinic for refugees resettling in Chicago. His clinical projects focus on the development of colorectal cancer screening campaigns. Levy, who recently gave a TEDx Talk about building health education campaigns using music and concerts, organizes Tune It Up: A Concert To Raise Colorectal Cancer Awareness with the American College of Gastroenterology (ACG). He frequently publishes on a variety of gastroenterology topics and serves on ACG's Public Relations Committee and FDA-Related Matters Committee.

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