Last January, a major milestone was reached when the world’s one millionth blood stem cell transplant was performed. Beginning in the 1970s, bone marrow and blood stem cell transplants — also known as BMTs — have offered the chance of a cure for many people with leukemias, lymphomas, and other blood disorders.
But since patients first began receiving this treatment, a major complication of allogeneic transplants, in which patients receive stem cells or bone marrow from a donor, has been graft-versus-host disease (GVHD).
GVHD occurs when newly transplanted immune cells from the donor recognize the recipient’s tissue as foreign and attack it. The condition can be temporary or chronic and can result in damage to the liver, lungs, digestive tract, or other organs. In some cases it is fatal.
Memorial Sloan Kettering physician-scientist Robert Jenq is one of many investigators studying the disease. His particular research is focused on the role of bacteria and how certain bacterial strains that are naturally found in the body may protect against GVHD. This past weekend at the BMT Tandem Meeting near Dallas, he presented a study that was selected as one of the six best abstracts of the meeting.
We spoke to Dr. Jenq about his research and how it might someday benefit patients.
Studying the Microbiota
“Since the 1970s, we’ve known that the bacteria that live in the gastrointestinal tract — the microbiota — have an impact on the risk for GVHD,” he says. “We tried to apply some of the early discoveries we made in mouse models to patients, but in the end they didn’t work.”
Fast-forward to the advent of computational biology. Advances in computing power over the past decade have made it possible to make sense of vast amounts of genetic data coming from populations of bacteria living in the human body. “New genetic sequencing technologies have helped us to characterize all the bacteria that live in the gastrointestinal tract in great detail,” Dr. Jenq explains. “This approach is something that wasn’t possible even a few years ago.”
Aiding in the development of new research is the Human Microbiome Project, an ongoing, multi-institutional initiative funded by the National Institutes of Health that aims to characterize and provide detailed insight into the complexity of all of the microorganisms that live inside us.
Previous studies from Dr. Jenq and his colleagues, including Hematologic Oncology Division Head Marcel van den Brink, began looking at how the balance of intestinal bacteria can affect GVHD. One of their areas of focus has been how antibiotics given to patients during the course of treatment to either relieve or prevent infections may have a negative effect on the so-called good or healthy bacteria that live in the body.
A Bacterium Called Blautia
The latest study, done in collaboration with Dr. van den Brink and infectious disease specialists Eric Pamer and Ying Taur, focused on a genus of bacteria called Blautia. “Using sequencing technologies to study the bacterial makeup of the gastrointestinal tracts of patients undergoing BMTs, we found that if patients had even a smidgen of Blautia left — just 0.1 percent of the total makeup of bacteria in their GI tract was Blautia — they had an almost negligible risk of GVHD,” Dr. Jenq says.
The investigators took their findings back to mouse models and found that giving Blautia to mice that had lost it could protect them against GVHD.
“Blautia is a harmless type of bacteria that every patient comes in with, but a lot of them lose it during the course of transplantation,” he adds. “It seems to be sensitive to the antibiotics that patients are given during the course of treatment, and it also declines in patients who aren’t eating, a common situation in BMT patients.”
Currently, GVHD is treated with powerful immune suppressants. “It’s necessary because GVHD can be fatal,” Dr. Jenq says, “but these drugs increase the risk that patients will develop infections and also that their cancer may come back. Our findings about Blautia open up new avenues for preventing GVHD.”
New Approaches to Preventing GVHD
One solution may be giving patients only types of antibiotics that do not affect Blautia. In addition, encouraging patients to eat during their transplants rather than providing them with their nutrition intravenously may help to keep their Blautia alive. “When you supply nutrients by IV, you’re feeding the patients but you’re not feeding their bacteria,” Dr. Jenq notes. “That may be important.”
Another approach could be finding a way to give patients beneficial bacteria such as Blautia after their transplants. (This is the basis of the idea behind the food supplements known as probiotics.)
Some studies have suggested that the role of Blautia in the gastrointestinal tract is to produce compounds called short-chain fatty acids, which researchers believe help to suppress inflammation. “If this proves to be true, we may be able to bypass the bacteria completely and just give as a treatment the compounds the bacteria are producing that mediate the beneficial effects,” he says. “We call this strategy ‘postbiotics.’”
All of these possibilities need to be evaluated further before any clinical studies can begin in patients. “Testing all of these strategies in mice will shape whatever trials we do in the future,” Dr. Jenq concludes.