Gut health is more than just gut health. Disruptions to the gut microbiota – the ecosystem of microbial organisms that inhabit the intestines – are associated with everything from susceptibility to infections, autoimmune diseases, mental health conditions, and response to cancer treatments.
Gut microbes are essential for digestion. They break down food molecules that human cells alone cannot and turn them into absorbable nutrients. This process often requires cooperation between several microbial species, each performing a critical step in the transformation from food to nutrients. While the gut microbiome is generally beneficial, some species – or combinations of species – have harmful impacts on overall health. They over-consume necessary nutrients, disrupt the flow of digestion, or cause inflammation. Thus, the species composition of the gut ecosystem has wide-ranging consequences for human health.
Could restoration of healthy gut microbiota treat depression, prevent infection, or improve cancer outcomes in people with disrupted gut ecosystems? In recent years, several studies have investigated this question using fecal microbiota transplant, a procedure involving the transfer of a non-selective colonic microbial sample from one person to another. The goal is that healthy microbes from the donor engraft in the recipient, outcompeting and replacing any harmful microbes. In practice, however, only a small fraction of total microbial species engrafts, and the results vary widely from recipient to recipient.
Dr. Armin Rashidi in the Clinical Research Division studies fecal microbiota transplant and its use in cancer care. He noted, “One particularly mysterious question is whether there are “modules” of engraftment, where several species consistently and reliably co-engraft.” Currently, fecal microbiota transplant outcomes are inconsistent and unpredictable, partially due to donor-to-donor microbiome variability. Even when engraftment is successful, the species that engraft do not always contribute to host’s health. Identification of consistent, beneficial modules of engraftment could pave a path toward a safer and more predictable fecal microbiota transplant-like therapy.
In a recent study published in iScience, Dr. Rashidi and colleagues performed a meta-analysis of fecal microbiota transplant trials to identify cohesive modules of engraftment (CMEs), groups of species that regularly engraft together and maintain consistent species ratios. Dr. Rashidi explained that cohesiveness “is important for novel therapeutic design because [it] allows us to reliably predict the resulting communities after treatment.”
The analysis included 60 donor:patient pairs across five studies investigating fecal microbiota transplant as a therapy for C. difficile infection, Crohn’s disease, or cancer. They looked for species that co-engrafted and maintained cohesiveness in at least eight of the transplant recipients. Considering all possible combinations and numbers of species, they identified 122 two-species CMEs, 70 three-species CMEs, 24 four-species CMEs, and 2 five-species CMEs.
Dr. Rashidi noted, “Not all CMEs are likely to be clinically beneficial. Some may be neutral, and some might even be harmful to the host. Our work identifies a long list of candidate CMEs to be screened mechanistically and in the specific disease context.”
The team assessed whether any of the identified CMEs were correlated with favorable treatment outcomes to hematopoietic stem cell transplantation in people with blood cancers, based on data from one of the five analyzed trials. They grouped study participants into two categories, those who were relapse-free one year post-treatment and those who relapsed or died within one year, and calculated the engraftment rates of CMEs in each group. The CME of the bacteria species Blautia massiliensis and Lachnospira eligens had highest differential engraftment in patients with relapse-free survival, suggesting it may be beneficial for the response to stem cell transplants.
Dr. Rashidi acknowledges that there is still a lot to learn about these CMEs. “Currently, we don’t know the mechanisms that bring together species of a given CME and maintain its integrity and cohesiveness.” Understanding this, along with the clinical benefit of each CME, is crucial to developing effective, consistent, and predictable therapies to restore healthy microbiota and potentially treat the myriad conditions affected by the gut microbiome.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Armin Rashidi, Stephanie Lee, and Geoffrey Hill contributed to this research.
The spotlighted research was funded by the Leukemia & Lymphoma Society and the National Institutes of Health.
Rashidi A, Minot SS, Lee SJ, Hill GR, Podlesny D. 2026. Cohesive modules of engraftment in fecal microbiota transplantation. iScience. doi: 10.1016/j.isci.2026.116025
Science Spotlight writer Ashley Person is a PhD candidate in the Cohn lab in the Vaccine and Infectious Disease Division at Fred Hutch. She studies how HIV-infected cells persist over time in people living with HIV on long term treatment.