By Jean Balchin 15/02/2018

Gut scientists have pored over numbers and come up with a way of predicting which good bacteria can be successfully transplanted in a poo transplant.

What is a Poo Transplant?

Fecal microorganism transplant (FMT) is a process wherein fecal matter (aka poo) is collected from a tested donor, mixed with a saline solution, strained, and reintroduced to a patient, via colonoscopy, endoscopy, sigmoidoscopy, or enema. This transplant’s purpose is to replace “good” bacteria that has been killed or outnumbered by bad bacteria, specifically Clostridium difficile, or C. diff.. This bad bacteria overpopulates the colon, causing a condition called C. diff. colitis, which results in often debilitating, sometimes fatal diarrhoea. For FMT be successful, donor bacteria must attach, or engraft, to the recipient’s gut, but the forces influencing engraftment and growth have been largely unknown.
Clostridium difficile. Wikimedia Commons.

The Study

In a paper published February 14 in Cell Host & Microbe, scientists provide a statistical model predicting which bacterial strains will engraft after FMT. This paper represents the first predictive strategy for developing a synthetic probiotic—a biologic therapy based on microorganisms acting as a drug.
It was also discovered that recipients acquired new bacteria that were previously undetected in both the donor and the recipient, suggesting that the post-FMT microbiome (microbes in the recipient’s gut community) is a mixture of bacterial strains from the donor, recipient, and the environment. Moreover, it was also found that the recipient microbiome and immune state have roles in successful FMT.

“This paper provides a context for understanding how to make these live biological therapeutics as an alternative to transferring raw fecal matter,” says co-senior author Eric J. Alm, co-director of the Center for Microbiome Informatics and Therapeutics (CMIT) at MIT. “We describe a model focused on three elements, including bacterial engraftment, growth, and mechanism of action, that need to be considered when developing these live therapies targeting the gut microorganisms, or microbiome,” he says.

20 patients with C. diff infection who received therapeutic FMT were examined using high-resolution deep metagenomics genetic sequencing. The scientists thus studied the gut-level microbiota of donors and recipients before and after FMT up to 4 months.  Both the strain type and abundance of each strain in donors and recipients was measured, in order to build a predictive model of the presence and the abundance bacterial strains in the recipient after FMT.

It was found that after the FMT process, about 30% of the donor bacteria engrafted in the recipient, and the most abundant strains were more likely to engraft.

“That’s important to know when designing a microbiome-based therapeutic like this,” says the second co-senior author Ramnik J. Xavier, Chief of the Division of Gastroenterology at Massachusetts General Hospital and CMIT co-director. “If a drug only colonises 30 percent of the patients you put it in, then the maximum efficacy of your drug is 30 percent.”

It was also found that 30 percent of the engrafted strains exhibited an unusual “all of nothing” pattern of behaviour. For instance, if the donor had five different strains of a bacterial species, all five strains transferred into the patient. Moreover, if the recipient already had some of the strains found in the donor, the probability of those strains engrafting was higher.

This model has enabled the prediction of the amount of each engrafted strain grown in a recipient.

“Again, that is an essential piece of information because you want to know whether a bacterial strain will be found in trace levels or at high levels so that it can actually produce the metabolite that you want,” adds Xavier.

The team developed and applied this model not only to C. diff patients but in other studies with other diseases, including 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,” says Xavier. “These bugs within us, or the microbiome, are going to have a potential impact for many diseases.”

The genetic sequencing of the bacterial strains was conducted at the Broad Institute of MIT and Harvard, where Alm and Xavier are institutional members. You can read this study here.