Stem cell transplants are a double-edged sword for patients: they can cure blood cancers like leukemia but also bring high mortality rates and the risk of deadly complications and infections.
Now, a new clinical study of 174 transplant recipients illustrates why having more diverse gut bacteria can improve survival rates and clinical outcomes in patients receiving stem cell transplants. The study revealed that diverse microbiomes fueled two types of immune cells that reduce the risk of infections and dangerous transplant complications.
The research was published in the May 25 issue of Science Translational Medicine.
"There is a growing body of evidence that loss of microbial diversity is associated with adverse transplant outcomes," said Hana Andrlová, a postdoctoral researcher at Memorial Sloan Kettering Institute in New York City and lead author of the new study.
"Therefore, strategies aiming to prevent or reduce this loss will hopefully improve our patients' survival," said Andrlová.
A Life-Saving But Potentially Dangerous Procedure
Stem cell transplants are a type of operation usually performed in patients with leukemia, lymphoma, or bone marrow diseases. Clinicians transplant healthy stem cells from a donor to the patient, where the cells travel to the bone marrow and start replacing diseased blood cells.
Yet transplants are usually given only after other treatments have failed. In addition to the potential for relapse of the cancer, transplantees face side effects such as graft-versus-host disease, which appears when the donated stem cells start to attack the recipient of the transplant. The transplanted cells need to be able to recognize and destroy any remaining cancer cells to prevent relapse, but this raises the risk of the cells turning against the patient's body.
Graft-versus-host disease can be life-threatening, and in its most-feared form it can inflict serious damage on the intestines of patients, according to Andrlová.
Stem cell transplant recipients must also watch out for other complications such as infections. As a result, patients still face a three-year mortality rate that approaches 50%, according to one 2020 estimate.
Scientists who study stem cell transplants have noticed a recurring pattern: patients who have a more diverse array of beneficial gut bacteria immediately after transplant tend to have better survival rates. Research points to benefits including a lower risk of infection and graft-versus-host disease and even fewer relapses.
"Loss of diversity of the bacterial community in the gut has been linked with poor survival for patients, but we don't know exactly why this is the case," Andrlová said when discussing the motivations behind her research.
Turning to the Immune System
Since these microbes frequently interact with immune cells, Andrlová's research group theorized that the immune system could potentially explain some of the difference in transplant outcomes.
In their new study, the team assembled a group of 174 patients who were slated for stem cell transplants at their clinical center at Memorial Sloan. The group included patients with leukemia, lymphoma, multiple myeloma, or other blood cancers.
As the patients received and recovered from their transplants, the scientists analyzed both the patients' immune cells and the bacteria in their stool. They gathered data from the patients 30 days after transplantation and again at 100 days after the procedure.
The experiments revealed a new connection between microbiome diversity and two types of T cells: innate-like mucosal-associated invariant T (MAIT) cells and V-delta-2 cells. These immune cells are a type of unconventional T cell, a broad group of T cells that quickly respond to bacterial infections, Andrlová said.
The researchers first observed that some of the patients possessed more diverse microbiomes, as they harbored a wider variety of beneficial bacteria in their stool samples. At the 30-day mark, these patients had higher amounts of both MAIT cells and V-delta-2 cells than patients who had less diverse microbiomes.
These high-diversity and high-MAIT patients ended up experiencing better outcomes in the long run. Two years later, those with higher numbers of MAIT cells at the 30-day mark had a higher overall survival rate than patients with fewer MAIT cells.
To understand the role of these T cells, Andrlová's team then examined specific bacterial species and the metabolic molecules that they produce. With these data, they concluded that the MAIT and V-delta-2 cells depended on a range of these bacterial molecules to persist after the stem cell transplant.
Although the research doesn't define exactly how the MAIT cells and V-delta-2 cells protect against side effects, the scientists say that their data suggests that both types of cells underwent some changes after transplants and became better at killing other cells.
Andrlová said that her team is the first to show that MAIT and V-delta-2 cells correlate in blood samples after transplant, and that the latter can be influenced by a binding molecule produced by gut bacteria. "We were also able to, for the first time, detect this metabolite in stool of the patients with high blood V-delta-2 numbers," she added.
However, Andrlová cautioned that their data were collected as part of broader efforts to gather patient samples rather than in a prospective study involving multiple clinical centers. More research with larger groups of patients will be necessary to validate the link between T cells and clinical outcomes in transplantees, she said.
Fortunately, there are several ongoing trials in the field that are testing therapies aimed at supporting the microbiome in transplant recipients, she added. These approaches include using prebiotic and probiotic therapies, adjusting antibiotic treatment regimens, and making dietary changes.