Microbiome Diversity Key To Survival After Allogeneic Hematopoietic Cell Transplantation
The Audio Journal of Oncology Podcast
SAN DIEGO—Overall survival after allogeneic hematopoietic cell transplantation (allo-HCT) was found to be adversely influenced by a lack of diversity in the intestinal microbiota—before, during and after the transplant—in a study from four research centers in three countries reported at the 2018 annual meeting of the American Society of Hematology.
The study found patterns of “microbiome injury” were strikingly comparable from country to country and from one transplant center to another—even when patients had different baseline microbiomes and the centers had different antibiotic practices, Jonathan Peled MD PhD, a bone marrow transplant physician at Memorial Sloan Kettering Cancer Center, New York told the Audio Journal of Oncology. “The implication is that associations observed in one center—or interventions that are observed to work in a trial at one center—are likely to be applicable broadly,” he said.
“We hypothesize that the injury we observed during transplant is attributable to antibiotic exposures and to not eating much during the transplant—although the chemotherapy conditioning and other drugs could be playing a role too.”
“We’ve known from animal studies that intestinal microbiota has a really important impact on how an individual who has received a bone marrow transplant does,” said Peled. And so the aim of the study had been to investigate this in humans: “And not just in a single-center observational fashion but in a multi-center large cohort so that we could really try to answer these questions definitively,” he said. The study had been designed to find out whether the pre-transplant microbiome diversity in the intestine could predict patient outcome.
Peled explained that intestinal diversity was a measures “richness”—how many unique bacterial species were present in a sample, and also “even-ness”—how evenly each species was distributed in the sample. Typically, healthy bacterial communities in the gut had very high diversities, he said. And one microbiome injury pattern—or dysbiosis—they had observed in transplant patients had been a severe loss of this diversity. “In transplant patients a loss of diversity is seen that’s more severe than in most so-called dysbiotic states in other clinical settings” he said.
The study found that low diversity—either pre-transplant or post transplant—predicted for poor outcomes with shorter overall survival, increased transplant-related mortality, and—in some sub-sets of patients—more graft versus host disease, said Peled. “The number one implication is that we need clinical trials to design or test strategies to remediate damage. And number two: It may well be that bacteria have a pathogenic role in the pathophysiology of graft versus host disease,” he said.
The researchers collected 1922 stool samples from 991 patients having allo-HCT—in the United States, Germany and Japan—at four transplant centers. Patients varied in their underlying diagnoses, donor-graft sources, conditioning intensities, and graft versus host disease (GVHD) prophylaxis. “This is the largest such cohort that’s been assembled to ask these kinds of questions to date. And a critical feature of the study is that although we collected samples from all over the world we analyzed them all in one laboratory to try to overcome some of the potential biases,” Peled said.
On average patients from all four transplantation centers had reduced microbiota diversity—even before allo-HCT—than in samples from healthy volunteers. Among 753 patients those in the lowest quartile of pre-HCT microbiota diversity had lower overall survival than those in the highest quartile. The investigators concluded that microbiota injury after transplant had been preceded by bacterial “community structures” that had already been abnormal at the start of the procedure. This explained why antibiotic exposure before transplant had been found to have been a risk factor for poor outcome.
“Domination”—defined as one bacterial species populating at least thirty per cent of the microbiota—was found to be the injury most strongly associated with poor outcome. “In a bone-marrow transplant patient who is not eating, and has antibiotics “on board” for a week or more there can—in some cases—be only a single bacterium—mono-domination,” Peled said.
During transplantation the cumulative incidence of intestinal domination by any organism was more than 50 per cent at the outset and had become at least 87 per cent a month later. Such “low-diversity” states were found to be associated with exposure to broad-spectrum antibiotics, conditioning intensity, and low calorie intake.
The study concluded that microbiota configurations were similar in all four institutions as well as being distinct from those in healthy individuals. Also severe microbiota injury—including mono-domination—was commonly associated with allo-HCT. It began before allograft infusion, and microbiota injury before transplant predicted poor overall survival.
They investigators suggested that the pre-transplant period was a window of opportunity to assess microbiota injury and to inform clinicians’ choice of antibiotic prophylaxis, approaches to gut-decontamination, GVHD-prophylaxis, and conditioning regimens. They concluded it was also a priority for researchers to look into ways of intervening to prevent or remedy microbiota injury.
“Judicious use of antibiotics—following guidelines such as those articulated by the Infectious Diseases Society of America—is always a good idea,” said Peled. “We’re not yet at the point where we can recommend changes to practice. But we are evaluating a potential recommendation in a randomized clinical trial.”
His center was comparing two different antibiotic strategies—the use of piperacillin-tazobactam and cephepime, Peled said. “In a prospective randomized clinical trial we’re randomizing patients to either of those two drugs as the first-line treatment for empiric fever-neutropenia. Our hypothesis is that: Piperacillin-tazobactam will be more deleterious to the flora and more deleterious for patient outcomes because it hits anaerobic bacteria. The results of this study may have implications about guidelines in the future.”
Peled said that our immune system co-evolved with bacteria and depended on certain signals that emanated from the gut flora for its normal function. “So our microbiome and our immune system are existing in a constant dialogue—in an equilibrium—on a daily basis. You could even consider that, when you’re not sick, what your immune system is doing most of the time is maintaining this equilibrium,” he said.
On this model any immune reaction—be it auto-immune, anti-tumor, allo-immune, immune deficiency, or a response to an infection—could be viewed as a perturbation from that baseline equilibrium, he suggested. “So the more we can understand about how the host and the microbiome interact with one another at baseline, the [more] we can understand better what happens under states of perturbation,” he said.
But Peled was not impressed by over-the-counter probiotic products. “They tend to include facultative aerobes—or at least bacteria that can tolerate oxygen. Whereas in contrast we find that most of the bacteria with benefits for patients are strict anaerobes. He did not recommend patients undergoing cancer therapy to stock up on any of the probiotics that are commercially available. “I don’t have data that it’s dangerous, but I don’t have any evidence that it’s beneficial,” he said. “On the other hand what would really be great would be to design a probiotic that is rationally designed and assembles just the right strains that we think will have the right effect,” he said. And he mentioned that he is beginning a research collaboration to develop probiotics that could be made available to patients.
In daily practice cancer doctors needed to remember that everything they did had a potential downside and toxicity—and that we needed to test strategies to “dial back” the intensity and the duration of antibiotics. “So the busy cancer doctor should by all means treat fevers and infections in immune-compromised patients aggressively—according to guidelines—but we should be aware that there may be a down-side,” he said.