Computational biologist Joao Xavier (left) and Eric Pamer, Chief of the Infectious Diseases Service
Investigators from Memorial Sloan Kettering are studying how changes in the intestinal microbiota can influence outcomes for patients undergoing stem cell transplantation. Microbiota refers to the complex population of microorganisms that inhabit the external and internal surfaces of the human body.
Two recent studies revealed that changes in the balance of bacteria that make up the intestinal microbiota can affect patients receiving a transplant of stem cells from a donor, a process known as allogeneic hematopoietic stem cell transplantation (HSCT).
HSCT, a procedure used as a treatment for blood cancers such as leukemias and lymphomas, makes patients temporarily more susceptible to infections. Before patients receive the donor stem cells that will replace their cancerous blood cells, they must first be given large doses of radiation therapy and chemotherapy, which impair their ability to produce their own blood cells.
The loss of white blood cells leaves them unable to fight infections. Therefore, these patients are given preventive antibiotics during the transplantation procedure to help protect them.
Interest in microbiota and how it relates to human health has grown recently as scientists have developed techniques for identifying large numbers of microorganisms using next-generation DNA sequencing technologies, which can analyze thousands or even millions of sequences at the same time. A government-funded effort recently reported that the populations of bacteria that live in and on the human body vary markedly between healthy individuals.
Maintaining the Balance
The recent Memorial Sloan Kettering studies showed that the administration of antibiotics to patients following HSCT does prevent or treat some infections. However, it also creates an opportunity for other potentially harmful, antibiotic-resistant bacteria to become more abundant, particularly in the gastrointestinal tract.
The research sought to explain why patients undergoing HSCT often experience infections with antibiotic-resistant bacteria. These infections often originate in the gastrointestinal tract but can spread into the bloodstream, causing a potentially lethal side effect called sepsis.
One of the studies, published online in Clinical Infectious Diseases on June 20, focused on how the balance between beneficial and harmful bacteria can shift dramatically, and how this shift increases the risk of serious infection.
“When antibiotics are administered, certain ‘healthy’ species of bacteria are lost from the intestine’s microbiota,” explains Eric G. Pamer, Chief of the Infectious Diseases Service and the study’s senior author. “This can allow other, potentially harmful bacteria to expand and establish an unnatural state of dominance.”
The investigators, including first author Ying Taur of the Infectious Diseases Service and computational biologist Joao Xavier, characterized the intestinal microbiota from 94 patients undergoing HSCT at Memorial Sloan Kettering. They started gathering data before treatment and collected it until 35 days after the transplants.
They then used advanced gene sequencing and computational biology techniques to analyze hundreds of thousands of DNA sequences from the patients’ bacteria, with the goal of determining which species of bacteria were most prevalent and establishing correlations between the composition of the microbiota and the development of sepsis.
The researchers found that the diversity of bacteria can drop substantially, leading the intestine to be dominated by certain harmful species and increasing the likelihood that patients experience bloodstream infections.
Preventing Side Effects
Another recent study from the same team, published this spring in the Journal of Experimental Medicine, looked at how the change in bacterial balance contributes to graft-versus-host disease (GVHD), a serious complication of HSCT in which the donor’s immune cells attack the patient’s organs. The study’s first author was Robert R. Jenq of the Bone Marrow Transplant Service.
“Transplant physicians have always known that GVHD is affected by the balance of the microbiota in the gut,” says Marcel R. M. van den Brink, head of the Division of Hematologic Oncology, who was senior author of the publication. “A major message of this research is that we need to look more closely at our use of antibiotics and our patients’ diets, because they can all change the risk of GVHD in HSCT patients.”
The investigators also believe that these studies will open the door to new research on how eating certain foods or dietary supplements – such as probiotics found in yogurt – may help maintain strong populations of beneficial bacteria and thus improve outcomes for patients. Importantly, the two Memorial Sloan Kettering studies illustrate how multidisciplinary collaboration between clinicians and scientists can enable the field of human microbiota science to find its application in patient treatment.
“Our main goal is to reduce GVHD and sepsis,” Dr. van den Brink concludes. “But we hope we may also be able to speed the healing of the gut after HSCT and reduce the gastrointestinal side effects of this treatment for patients.”
Research published in Clinical Infectious Diseases was supported by the National Institutes of Health under award numbers AI095398-01, DP2OD008440, and AI42135. Research published in the Journal of Experimental Medicine was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA023766 and CA107096, and by NIH grants HL069929, AI080455, AI042135, AI039031, AI34495, and HL56067. Both studies were also funded by Memorial Sloan Kettering’s Lucille Castori Center for Microbes, Inflammation, and Cancer and the Tow Foundation.
