Becoming infected with bacteria and other pathogens is a serious concern for people being treated for cancer. Chemotherapy and radiation therapy used to destroy cancer cells also can destroy white blood cells, one of the body’s main defenses against infections.
This complication is especially severe in patients undergoing stem cell or bone marrow transplantation (BMT), because with such treatments the patient’s own blood-forming system, including white blood cells, is often wiped out before the patient receives a transplant of stem cells.
In addition to the loss of immune cells, another problem may arise: The antibiotics given to patients to either prevent or treat infections can destroy the healthy bacteria in people’s bodies, especially in their gastrointestinal tracts, allowing dangerous pathogens to take over.
“One of the first things we see in patients undergoing transplantation is a loss of diversity in their intestinal microbiota,” says Eric G. Pamer, Chief of Memorial Sloan Kettering’s Infectious Diseases Service. “After that, we see the emergence of bacteria that can cause serious infections in patients.”
Characterizing the Microbiota
The term microbiota refers collectively to all of the microorganisms that inhabit the human body. Microbiome refers to all of the genes that make up those microorganisms.
Last summer, researchers involved in the Human Microbiome Project, a multi-institutional initiative funded by the National Institutes of Health that aims to characterize all of the microorganisms in the human body, announced that they had mapped the normal microbial makeup of healthy humans. The study offered the most detailed insight to date into the complexity of microorganisms inhabiting the human body, including microbes that likely provide functions vital to the human body, such as aiding in digestion and manufacturing vitamins, and when absent can cause sickness.
“The Human Microbiome Project looked at normal, healthy individuals,” Dr. Pamer explains. “Memorial Sloan Kettering is using the same DNA sequencing platforms and software to characterize the changing microbial makeup of patients undergoing bone marrow transplantation. For the past four years, we have been analyzing the microbiota of these patients before, during, and after transplant.”
Disrupting the Healthy Balance
Research published last year and led by Dr. Pamer and Marcel R. M. van den Brink, Head of Memorial Sloan Kettering’s Division of Hematologic Oncology, focused on how the balance between beneficial and harmful bacteria can shift in patients undergoing transplants. In particular, the team discovered how Vancomycin-resistant Enterococcus, or VRE, a major cause of complications in hospitalized patients including a dangerous bloodstream infection called sepsis, can come to dominate the microbiota.
Advances in DNA sequencing technology and computational biology have made this kind of research possible. Analyzing a microbiome involves sequencing DNA fragments from all of the microorganisms in a person’s body, resulting in millions of DNA sequences.
Using this technology, researchers from Memorial Sloan Kettering’s Computational Biology Program have been able to analyze the DNA sequences from the bacteria of patients undergoing BMT to determine which species of bacteria were most prevalent and to find out how certain components of the microbiota contribute to the development of sepsis and other infections.
New Approaches for Treatment
Memorial Sloan Kettering’s infectious disease experts are now collaborating with transplant specialists to assess potential new treatments.
One approach will evaluate the use of fecal microbiota transplantation (FMT) in patients undergoing BMT. The use of FMT has grown over the past decade as a method of restoring the balance of a healthy microbiota in patients whose gastrointestinal tracts have been taken over by another infectious agent, Clostridium difficile. In this technique, patients are infused with feces from a healthy donor — usually a family member with whom the patient lives.
In a trial currently being developed at Memorial Sloan Kettering, patients undergoing BMT will have their fecal microbiota stored before beginning therapy. After receiving their transplants and before returning home, the patients will be infused with their own pretransplant fecal microbiota. The goal is to re-establish the normal, diverse balance of bacteria they had before treatment.
“Our protocol is unique in that we will perform an FMT with the patient’s own microbiota, called an autologous transplant,” Dr. Pamer says. “One of the concerns with performing an FMT in an immunocompromised patient using material from a donor is that we can’t know the total composition of the transplanted material. We hope that using patients’ own material will spare them from exposure to bacterial species that may be harmful to them.”
Investigators at Memorial Sloan Kettering and elsewhere are also using information gained from DNA analysis of the microbiome to look for new kinds of probiotics— beneficial bacteria sometimes used as supplements. “There are certain types of bacteria that healthy humans carry in their bodies that confer a high level of resistance against of range of pathogenic organisms,” Dr. Pamer says.
However, researchers have found that the most powerful of these probiotics are anaerobic, meaning that they cannot survive in the presence of oxygen. In addition, these bacteria often produce foul-smelling by-products, which could limit their use.
“There is interest in trying to develop some of these probiotics so that they could be given to patients,” Dr. Pamer says. “The challenge is determining which ones are most protective, learning how they mediate that protection, and figuring out how to administer them to patients so that they can colonize the intestine.”