FMT Model Predicts Which Bacterial Strains Will Engraft to Recipient

Fecal microbiota transplantation (FMT), recently included for the first time in clinical practice guidelines as a recommended treatment for patients who have experienced multiple recurrences of Clostridium difficile infection (CDI), involves the transferring of stool from a healthy donor to a recipient. For this treatment to be successful, bacteria from the donor must engraft to the gut of the recipient; not much is known about the factors that control this engraftment.

However, new research published in the journal Cell Host & Microbe sheds some light on this process through the creation of a statistical model capable of predicting which bacterial strains will engraft after FMT in a given host, according to the press release. The model is “the first predictive strategy for developing a synthetic probiotic—a biologic therapy based on microorganisms acting as a drug.”

“Fecal transplant or stool transplant—harnessing bacteria from stool from one living being and putting them into another—has been around for a while,” Sahil Khanna, MBBS, MS, associate professor of medicine in the department of Gastroenterology at the Mayo Clinic in Rochester, MN, told Contagion^® in a recent interview. “In modern medicine, the first reports were in 1958, where a surgeon used stool from one person and placed them into another person with Pseudomembranous colitis. At that time, we didn’t even know that C. difficile existed as a cause of human diarrhea. In the late eighties, and now, for the last 10 years or so, we’ve seen an upsurge of fecal transplantation being used as a treatment for C. difficile infection clinically, and also being used as research for other diseases.”

Investigators postulate that mechanisms pertaining to FMT efficacy focus on the gut microbiota—trillions of bacteria that reside within the gastrointestinal tract, study authors write. FMT is believed to restore these bacteria, which could potentially “alter host metabolism, inhibit pathogens, and effect changes in host immunity.”

To avoid this, study authors worked to provide a context for understanding how to develop alternative therapeutics that could “offer the therapeutic potential of FMT without the risks associated with the use of raw fecal matter,” they write.

“We describe a model focused on 3 elements, including bacterial engraftment, growth, and mechanism of action, that need to be considered when developing these live therapies targeting the gut microogranisms, or microbiome,” co-senior author of the study Eric J. Alm, who is also co-director of the Center for Microbiome Informatics and Therapeutics at the Massachusetts Institute of Technology, commented in the press release.

To create the model, the investigators assessed 20 patients with C. difficile who were treated with therapeutic FMT. In order to get a look at the gut microbiota of both donors and recipients before and after FMT for up to 4 months, they used high-resolution deep metagenomics genetic sequencing. In donors and recipients, they measured strain types and abundance of each strain and used these measurements to create the model.

Their findings? Thirty percent of the bacteria from the donor engrafted in the recipient, and the strains that were most abundant were more likely to engraft. The investigators stress the importance of their finding, in that this tells them that “if a drug only colonizes 30% of the patients you put it in, then the maximum efficacy of your drug is 30%,” according to second co-senior author Ramnik J. Xavier, MD, PhD, chief of the Division of Gastroenterology at Massachusetts General Hospital and CMIT co-director.

In addition, donor strains within a species were found to engraft in an all or nothing manner, meaning that if the donor had 3 strains of bacteria species, then all 3 of them would transfer to the recipient. Furthermore, the investigators found that there was a higher likelihood of donor strains engrafting to the recipient if the recipient already possessed some of those strains. Lastly, the investigators found that their model allowed them to predict the amount of each engrafted strain grown in the recipient.

The investigators have applied their model to other diseases, such as metabolic syndrome.

“We are in the midst of one of the largest disease therapeutics that are being developed based on a human source—bugs within us,” Dr. Xavier said in the press release. “These bugs within us, or the microbiome, are going to have a potential impact for many diseases.”