Tuesday, 20 December 2016 10:35

Toward better understanding of fecal microbiota transplants

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Published in mBiosphere

In recent years, researchers have learned that gut microbiota play a role in a number of human diseases, including Clostridium difficile infection, irritable bowel syndrome, Parkinson’s disease, and autism spectrum disorder. The revelations have scientists hopeful that fecal microbiota transplantation (FMT) or other therapies that target the gut microbiome can be used to treat these diseases. A new paper investigating why FMT works is now published in mBio, an open-access journal of the American Society for Microbiology.

In the last decade, FMT has been increasingly used to treat patients who have recurrent Clostridium difficile infection, typically caused by a dysbiosis or microbial imbalance of the gut. Microbiota are integral to human physiology and health, and exposure to antibiotics can alter the composition and activity of microbiota, sparking many common health problems. The procedure involves collecting fecal matter from a healthy donor, purifying microbiota from the feces, mixing it with saline solution, and placing it in a patient, usually by colonoscopy. 

"Treating patients with recurrent C. difficile infection with microorganisms alone provides cure or reduction of symptoms at a rate many times higher than any drug or chemical that has ever been looked at. These cure rates of 94% and 96% are astronomical, and it is all due to the power of microbes, " said Michael Sadowsky, PhD, director of the BioTechnology Institute at the University of Minnesota, St. Paul, Minnesota. "I think the future of medicine in the 21st century is to use the power of microbes to cure diseases."

Eight years ago, Dr. Sadowsky and gastroenterologist Alexander Khoruts, MD, at the University of Minnesota got together to cure C. difficile infection with FMT and later established the Microbiota Therapeutics Program, through which patients can receive FMT. "We have standardized donor material and a rigorous protocol to ensure the material is safe and effective for use. It is produced under a investigational new drug application in a facility that allows us to make it under good manufacturing practices," said Dr. Sadowsky. Over the last year, roughly 420 patients have undergone a fecal transplant for recurrent C. difficile through the program.

In a recent placebo-controlled trial of patients with recurrent C. difficile infection, Dr. Sadowsky and Christopher Staley, PhD, a postdoc in the BioTechnology Institute, and colleagues identified a potential strategy for examining the true efficacy of FMT.

The trial involved 27 patients who received a FMT using fecal microbiota from healthy patients (a heterologous transplant) or, as a placebo, the patient's own stool microbes (an autologous transplant). The cure rate with the transplantation from healthy donors was 90%, which is what the researchers expected, but surprisingly several patients who received the transplant with their own stool were also cured. Those who did not respond to the autologous transplant went on to receive a heterologous transplant.

Using Illumina-based next-generation sequencing to characterize bacterial communities, the researchers found that subjects cured by what was supposed to be the placebo transplantation had a greater abundance of Clostridium Xia clade and Holdemania prior to treatment, and the relative abundance of these microorganisms significantly increased after transplantation, compared to heterologous transplant and pre-transplant samples. Additional analyses showed that the microbiota of patients cured by the autologous transplant remained distinct from that of patients cured by the heterologous transplant.

"We wanted to see whether the same groups that were potentially responsible for recovery in the placebo group were the same ones that were coming through in the heterologous material," said Dr. Staley. "What we saw was that the groups were really different."

The researchers also found that once the donor’s fecal microbiota became established in the patient, it didn’t stay static, but changed over time. Previous studies have shown that a couple weeks after a FMT from a healthy donor, a patient’s microbiota usually looks very similar to the donor’s microbiota. "As opposed to what we thought, complete engraftment of microbiota is not required to get cure," said Dr. Sadowsky. "The study provides insight into which microorganisms are the most important for cure and may allow clinicians to better tailor therapy, by improving the donor material to facilitate a more rapid, effective, and lasting cure. We have data about which microbes to supplement into our preparations."


—Kate O’Rourke

Last modified on Tuesday, 20 December 2016 13:25

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