Donor factors influence success of fecal microbiota transplant

It’s sometimes easier to understand when the body isn’t healthy than to figure out what makes us healthy. Take, for example, the gut microbiome. This ecosystem is made of trillions of microbes living in the 30 (or so) feet of our digestive system and can become unbalanced and unhealthy if subjected to sufficient disruptions. But what makes a gut microbiome healthy? The answer is: it’s complicated. It’s simpler to know when we are in dysbiosis—a loss of homeostasis or microbiome balance—which can lead to inflammation, increased rates of intestinal cancers, and potentially other immune-mediated diseases.

Things that can cause dysbiosis are antibiotics, intravenous nutrition, chemotherapies, and radiation therapy. This of course is bad news for cancer patients receiving hematopoietic cell transplants (HCT), who often require all four. Transplant recipients with dysbiosis are at higher risk of pathogen outgrowth, otherwise commensal bacteria wreaking unintended havoc, immunosuppression increasing risk of other infections, and graft-versus-host disease (GVHD). There are many facets of GVHD development, but how the host’s microbiota interacts with the donor’s immune system has been shown (a few times) to play a role.

One strategy to fix dysbiosis is microbiota restoration, which isn’t as simple as it sounds. We know some people have healthy gut microbiomes and some people don’t, but teasing out the many differences between the two, and which ones are clinically relevant, is very difficult with our current knowledge. So, some doctors have taken to transplanting the microbes—all of them—straight from a healthy person’s stool to an unhealthy person’s gut, a process called fecal microbiota transplant (FMT). This can be done in a few ways, some less appealing than others: via colonoscopy or enema, or through oral delivery using either a diluted stool prep or processed capsules containing purified microbiota.

Physicians are interested in using FMT for HCT recipients for obvious reasons; however, most research on FMT has been in the context of other conditions. To address this gap, a Fred Hutch investigator is currently enrolling patients in an phase II double-blind, placebo controlled clinical trial to study FMT efficacy in GVHD prevention. This work is a follow-up to a previous randomized phase II trial that looked at FMT safety for HCT recipients. "These are patients that are at the highest possible risk of infection," explains trial lead Dr. Armin Rashidi, who published his results in the Journal of Clinical Oncology in 2023. In that study, they found that FMT was not only safe in transplant recipients ("we could say confidently that there was no increased risk of infection," says Dr. Rashidi), but it also may have a protective role against GVHD. The data were promising, but the group only observed sustained engraftment of beneficial microbes 25% of the time. The question became: “if we can improve engraftment of donor microbiota, can we decrease GVHD rates?”

In the first phase of the new trial, published this year in in Nature Communications, Dr. Rashidi and his team wanted to answer fundamental questions about why some FMTs work better than others. "What predicts the engraftment of the microbiome? Is it all about the donor? Is it all about the patient?" Dr. Rashidi asks. The purpose of the “run-in” phase was to identify donor-specific effects and pick the best donor for the remainder of the trial. Twenty patients received microbiota—in pill form—from one of three healthy donors. The dose of microbes was increased from 4 pills to 21 to ensure more complete engraftment, a >5-fold boost from the pilot study.

Consistent with prior studies, HCT recipients before FMT had less diverse microbiomes than donors due to extended antibiotic use and chemotherapy. After FMT, diversity rebounded and started to approach levels seen in healthy donors. Some patients engrafted better than others: notably, those with less diverse microbiomes pre-FMT rebounded better. This is likely because a less diverse microbiome can accept newcomers while a diverse microbiome has fewer open niches that new species can fill.

Donor-specific effects played a large role in engraftment success and potentially GVHD risk in this study. Three patients developed acute GVHD; all received FMT from Donor 1. In contrast, “donor 3 engrafted the best,” says Dr. Rashidi. There was a remarkable increase in microbiome diversity in patients that received FMTs from Donor 3—in many cases, this was primarily due to the expansion of strains unique to the donor that were not detected in the recipient prior to FMT. This shows that the donation was responsible for the recovery of the microbiome, not a decline in antibiotic use or resumption of a normal diet. “It's not enough to say we have a healthy donor … the exact characteristics of their microbiome matters in how they can engraft a patient,” Dr. Rashidi concludes.

Now that the winning donor has been identified, the next phase of the trial will use only donor 3 material for FMT to compare to a placebo control. "One goal in the new phase is to figure out the beneficial aspects of this person's microbiome," Dr. Rashidi says. This is crucial, as there may be a limited supply of material from Donor 3. "What happens after the conclusion of this trial, when we sooner or later will run out of product from this donor?" he asks.

One surprise from this study was that sex matching in FMT may have an impact on microbiome engraftment. Dr. Rashidi hypothesizes that hormones likely influence the microbiome and is excited to look more closely in the next trial. He’s also excited about teasing apart other patient factors that may impact FMT success such as intensity of the transplant conditioning regimen, antibiotic use, and diet. “The thing about these trials is that every time you finish you think 'I wish I had looked at that',” he says. “I can’t wait to look at that information.”

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Ted Gooley, Geoffrey Hill, Stephanie Lee, and Armin Rashidi contributed to this research.

The spotlighted research was funded by the Leukemia & Lymphoma Society and the Fred Hutchinson Cancer Center/University of Washington/Seattle Children’s Cancer Consortium.

Reddi, S., Senyshyn, L., Ebadi, M., Podlesny, D., Minot, S. S., Gooley, T., Kabage, A. J., Hill, G. R., Lee, S. J., Khoruts, A., & Rashidi, A. 2025. Fecal microbiota transplantation to prevent acute graft-versus-host disease: pre-planned interim analysis of donor effect. Nat Commun, 16(1), 1034.