A look at fecal microbiota transplants in universities and biotech companies

Trillions of bacteria, along with some fungi, viruses, and archaea, make up our gut microbiome. These bacteria greatly outnumber our own cells and play a crucial role in our bodies. Researchers are exploring gut microbiome interventions to improve human health. In the last several years, fecal microbiota transplants (FMTs) have garnered much attention.

Dysbiosis (or an unbalanced microbiome) can oftentimes be a result of antibiotic treatment. Antibiotics cause a sharp decrease in microbial diversity and alter the relative abundance of various bacteria. An imbalance of the gut microbiota (a term often used interchangeably with the gut microbiome) can result in chronic inflammation, predisposing one to various illnesses and infections.

An FMT is a procedure used to restore a patient’s microbiome by repopulating the gut with bacteria from prepared donor stool. The recipient’s restored microbiota ideally produces antimicrobial compounds, inhibits the growth of various pathogens, metabolizes drugs and micronutrients, and improves the integrity of the gut barrier, among other beneficial actions.

FMTs are now being explored as therapies for multiple sclerosis, liver disease, and even cancer. Normally, our gut microbiota facilitates a symbiotic relationship, helping to maintain appropriate nutritional status and fight off infections. For a patient with cancer, a balanced microbiota helps moderate the side effects of chemotherapy. Microbial dysbiosis can, on the other hand, promote carcinogenesis by promoting inflammation. For neurological conditions such multiple sclerosis or autism, FMTs can restore normal function for the gut-brain axis, the portal by which microbiota can impact brain function.

Despite their promising potential, FDA approval for FMTs has lagged due to safety concerns. Nevertheless, a variety of actors are at work to push this field forward. Physicians and academic researchers have worked to optimize this therapy for the past 60 plus years. More recently, biotech companies are joining the ranks to produce the latest products that can earn FDA approval and treat patients.

FMT in universities and hospitals: the founding fathers

 In 1958, a team of surgeons in Colorado performed the first FMT to treat a patient with a Clostridium difficile (C. difficile) infection. C. difficile infections cause colitis, severe diarrhea, and fevers, and they often occur following antibiotic treatment. While many patients recover after one round of antibiotics, some develop a recurrent or refractory C. difficile infection, which becomes difficult to treat with antibiotics. C. difficile infections were the main target of FMTs for years, but it was not until 25 years later that an FMT was validated in a living patient. In 1983, the first case study was published on a successful transplant for a patient with a C. difficile infection.

Despite the success, FMTs were still slow to gain popularity and extensive adoption. Cases of FMT causing bloodstream infections, leading to hospitalization and even death in a few rare cases, caused hesitancy among caregivers and regulators. Even when a patient and caregiver agreed to pursue the therapy, it was difficult to obtain. Patients had to recruit their own donors (oftentimes a family member or roommate), and hospitals were required to file investigational new drug (IND) applications for the transplants.

In the early 2010s, the rise in antibiotic resistant bacteria—which are very difficult to treat—caused a shift. Without other options, more physicians began suggesting and offering FMTs for their patients with stubborn infectious diseases. In 2013, FMT implementation soared, and the FDA pulled the requirement of INDs for FMTs used to treat recurrent C. difficile infections. Around the same time, doctors began to use OpenBiome to obtain donor microbiota. OpenBiome is a nonprofit that offers a carefully screened stool bank for physicians and hospitals to use. Although the COVID-19 pandemic temporarily halted their donor collection and screening services, the company is providing its services once again.

UCSF gastroenterologist Dr. Najwa El-Nachef reports that many hospitals are back to using OpenBiome to obtain donor microbiota. But the FDA requires many costly tests for donor samples, and companies have had to seek partnerships to remain viable. OpenBiome has teamed up with University of Minnesota’s stool bank. The FMT materials are supplied and prepped by University of Minnesota, and then OpenBiome handles the manufacturing and shipping end. UCSF also partners with companies looking at FMTs and microbial cocktails for clinical trials.

These partnerships are mutually beneficial. A small portion of UCSF’s FMT researchers’ donor material is obtained through clinical trials. After successfully using FMT to treat a patient with C. difficile infections in 2015, Dr. El-Nachef now leads clinical trials investigating FMT for inflammatory bowel disease. When asked about the future of FMTs to treat various diseases, Dr. El-Nachef notes, “People are rightfully excited for this therapeutic, but there remain a few hurdles. We should approach this thoroughly as we would any other medicine.”

Significant progress has been made on some challenges already. The transfers themselves previously raised concerns with harmful bacteria causing severe infections and complications. However, the screening protocols and techniques have since improved, making this a rare occurrence these days.

According to Dr. El-Nachef, one particular challenge that remains with FMT is that donor samples can be high variable. Genetic material can differ greatly, and scientists are navigating new territory in standardizing the way FMT is made. Dr. El-Nachef and her team, as well as physicians across the country, are working to overcome these hurdles and refine FMTs further.

The FMT Biotech Boom

In the last ten years, biotech companies have also seized the opportunity to play a role in the FMT world. Several companies are currently working to improve their therapeutics and obtain FDA approval to widely distribute their products.

Ferring Pharmaceutical’s company Rebiotix is working on a drug platform using live, screened microbiota to restore disrupted bacterial communities in the gut. The product, called Rebyota or RBX2660, is given as a pre-packaged, 150-milliliter suspension of microbiota collected from an individual donor. Rebiotix also runs a stool donor program based in their Roseville, Minnesota location. The company presently has multiple clinical trials underway investigating their drug platform for microbiota restoration in patients with C. difficile infections.

In 2014, Rebiotix received an FDA orphan drug designation, which makes it easier to give the FMT therapy via clinical trials. More recently, in September of this year, an FDA committee voted in support of recommending a Biologics License Application (BLA) for RBX2660. A BLA would enable Rebiotix to administer RBX2660 across state lines—a big step in expanding clinical trials to the requisite number of participants for full approval.

Seres Therapeutics, another biotech company competing on the FMT front, is not far behind. The company is working on two FMT therapeutics: SER-109 (for recurrent C. difficile infection) and the more recently developed SER-155 (to lower the risk of antimicrobial-resistant bacterial infections and graft versus host disease). Both products are administered orally and aimed at reducing bacterial infections by enriching the gut with a more balanced microbiota. SER-109 and SER-155 are composed of “a multifunctional consortium of commensal bacteria based on human clinical insights.”

Just as Rebiotix secured its BLA approval in September, Seres Therapeutics recently filed for a BLA of their own for their SER-109 candidate therapeutic. The drug has since been accepted for priority review. With BLA approval, Seres’ Chief Medical Officer Lisa von Moltke is confident that SER-109 will be well on its way to advancing care for the hundreds of thousands of patients who suffer from recurrent C. difficile infections every year in the United States. Seres anticipates that SER-109 could launch by June 2023 and become the first ever FDA-approved FMT therapeutic.

There are challenges that still lie ahead for Seres. Dr. Jack Jia, a Seres scientist on the Microbiology and Functional Screening team, notes “There are still a lot of bacterial species that are not cultivable, which makes it difficult to further characterize and study them.” Regardless, Dr. Jia seems hopeful that these microbiota therapies will be able to effectively address the disrupted microbiome in a number of diseases. Although infectious diseases are the main focus for these therapeutics, ulcerative colitis and oncology programs are also in the pipeline for Seres.

Other biotech companies investigating the gut microbiome are not far behind. Finch Therapeutics, Mikrobiomik, and Maat Pharma are also working to produce drugs aimed at restoring symbiosis in the microbiome.

A Revolutionary Alternative to FMT

 Although biotech companies are making progress on FMTs, sourcing microbiota from donors remains a challenge. OpenBiome has an extensive screening and monitoring process for donors. This includes numerous tests for infectious pathogens and screening donors for things like recent antibiotic treatment, certain medications, and an unhealthy BMI. The number of donors actually selected is quite low, and the selection process is both labor- and time-intensive, as well as costly.

FMT alternatives—to circumvent the difficulties associated with donor selection—are now being explored. For instance, researchers are exploring the creation of synthetically produced microbiota with various bacterial species carefully selected and cultivated in a lab.

Currently, researchers at Stanford University’s Fischbach lab are using this approach to create a culture of over 100 bacterial species to be transplanted into germ-free mice and eventually humans. In a recently published paper, Fischbach and his team were able to engraft a 119 species colony of bacteria into mice. The introduced colony afforded resistance against harmful, infectious bacteria, including E. coli.

To create a synthetic microbiome, researchers have to ensure a delicate balance is established. The final mixture of species must be stable, with no single species overpowering the rest. At the same time, it needs to function normally, working as a natural microbiome would. But it can be difficult to define normal function. There is natural variation in the microbiome between any two given individuals. Finding that perfect balance takes lots of tedious work, but ultimately, it would eliminate the need for stool donors and allow for more control over the final microbiome.

Synthetically produced microbiomes are already in commercial development. Vedanta Biosciences is working on candidate drugs made up of multiple different cloned human bacterial strains. The company stores these strains in an established bacterial cell bank, which allows more consistency in their product. One of their therapeutics, called VE303, targets recurrent C. difficile infections, and Vedanta expects a phase III clinical trial for that drug to begin soon. Some of their other microbiota products target inflammatory bowel disease, food allergies, and hepatic encephalopathy.

Where Will We Go Next?

There’s been lots of movement and exciting news in the FMT world as of late. Universities and physicians are regularly treating patients who have recurrent C. difficile with great success. While it’s unclear where the microbiota transplant field will be in five years, the future of FMTs looks promising. Patients are getting the treatments they need to alleviate the severe symptoms and frustrations associated with recurrent C. difficile infections. The use of FMT for other diseases is also gaining attention. There are trials underway to determine the effectiveness of FMTs in treating inflammatory bowel disease, multiple sclerosis, autism, and more. There are even thoughts of using FMT to treat cancer.

FMTs may become even more effective with the rise of precision or personalized medicine. After all, scientists are already sequencing the gut microbiota for a personalized approach into what individuals should eat. Researchers are also looking at the microbiome to be used as a biomarker for disease diagnosis, phenotype, and even response to therapy. Expanding FMTs to be used for optimizing individual health could bring lots of attention to the field. With a little more work, a therapeutic targeting the microbiome could change the game for human health.

Photo credit: Darryl Leja, NHGRI. Flickr / Creative Commons