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Gut microbial diversity before stem cell transplantation may impact survival
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SAN DIEGO — Higher gut microbial diversity was associated with improved survival in a multinational cohort of patients undergoing hematopoietic stem cell transplantation, according to findings presented at ASH Annual Meeting and Exposition.
The human intestinal microbiome harbors the highest density of bacteria in the world, according to Jonathan U. Peled, MD, PhD, assistant attending at the adult bone marrow transplant service in the department of medicine at Memorial Sloan Kettering Cancer Center.
“We are actually ecosystems walking around,” he said during his presentation. “Our immune systems are really maintaining homeostasis with the bacteria that we co-evolved with.”
Associations between gut microbiota composition and outcomes such as relapse, mortality, graft-versus-host disease, organ toxicity and survival have been explored among patients undergoing HSCT, according to Peled. However, he noted that many of the analyses demonstrating these associations were conducted during the first weeks after transplantation, and in single-center studies.
“After transplant, there is a striking drop in gut microbiota diversity,” he said. “This is a phenomenon not seen in other clinical scenarios.”
The researchers sought to assess the impact of microbial diversity in the gut earlier in the transplant course, including before stem cells are administered and before chemotherapy. Researchers hypothesized that low gut microbial diversity could predict poorer survival and higher diversity could predict better survival.
The study was conducted at four international transplant centers: Duke University, Memorial Sloan-Kettering Cancer Center and sites in Regensburg, Germany and Hokkaido, Japan. Peled suggested that gut flora is comparable regardless of the patient’s geographical location and diet.
Researchers sequenced and analyzed stool samples collected from 991 adults who underwent allogeneic HSCT at the four centers, comparing the results with samples of healthy volunteers.
Prior to transplantation, patients had gut microbiota diversity levels that were 1.7- to 2.5-fold lower than those of the volunteers.
Pretransplant microbial populations were indeed comparable among patients at the four study sites.
“No matter where you live, when you come for a bone marrow transplant, the composition of your gut flora is comparable from center to center,” Peled said.
A key finding from the Memorial Sloan Kettering cohort showed that high pretransplant microbial diversity predicted OS (HR = 0.69; P = .002) compared with low diversity.
“Even at this early time point, where patients are in the diversity plot can predict their outcome,” Peled said. “The implication is, if we can come up with a way to remediate microbiome injury, there might be time to implement it before the transplant.”
Survival curves for the Memorial Sloan Kettering (HR = 0.75; P = .024), Regensburg (HR = 0.27; P = .011) and Duke (HR = 0.37; P = .039) cohorts led the researchers to conclude that the association between OS and intestinal microbial diversity peri-neutrophil engraftment is reproducible, according to Peled.
Researchers also evaluated monodomination of the gut microbiota, defined as when one bacterium accounts for 30% or more of the population of the gut.
“Monodomination is, instead of hundreds of bacteria growing in the gut, one-third or, in some cases, 95% of bacteria growing in the intestine are all the exact same strain,” Peled said.
Incidence and prevalence of monodomination phenotype was similar at all four centers, despite the different diets and antibiotic strategies in the U.S., Europe and Japan.
“The patterns of microbial injury are nearly superimposable,” Peled said.
“Microbiota injury, including loss of diversity and enterococcal domination, occur across geography,” he added. “The association of diversity with overall survival is reproducible over time and across geography. Microbiota diversity is predictive of overall survival when sampled either pre-HSCT or peri-neutrophil engraftment.” – by Rob Volansky
Reference:
Peled J, et al. Abstract 811. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Peled reports research funding from Seres Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.
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Ran Reshef, MD
There has been a growing interest in studying the microbiome in a variety of diseases. This entered the transplant world a number of years ago with the understanding that the immune responses to transplant dictate the ultimate outcome for these patients. The recovery of the gut immune system is extremely critical in determining those outcomes.
A number of associations have been identified, mostly in single-center studies. They described how almost every patient who goes through transplant loses the diversity in their gut microbiome. We also learned that there are extreme differences in loss of diversity, in terms of increasing specific bacteria that determine risk for severe GVHD or even disease relapse. The immediate suspects are underlying issues of the individual, genomic variance, geography, nutrition and mainly antibiotics, which are used heavily in the transplant setting.
What is unique about this paper is that it examined what happened to the patients even before they came to transplant. Peled and colleagues documented differences in microbial diversity between individuals even prior to transplant that ultimately are associated with their outcomes.
Another aspect that’s unique to this paper is that it moved away from the single-center analyses that have been done so far. They showed that the geographical differences are smaller than in pre- and posttransplant patients, or in patients who take antibiotics vs. those who do not. It’s a proof-of-concept study that these findings are reproducible across cohorts.
The bottom line of this study is that, even pretransplant, you can document who is going to do worse based on their microbiome composition and the degree of diversity. This leads to a completely different set of possible interventions. Physicians who treat these patients before transplant should learn appropriate management of antibiotics that won’t hurt the microbiome using probiotics, fecal transplantation and varied nutritional interventions — all with the purpose of improving the microbiome composition in a patient prior to transplant.
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Henry Chi Hang Fung, MD, FACP, FRCPE
Investigators from Memorial Sloan Kettering Cancer Center’s transplant program have been doing this for decades. They are the only ones who collect all the stool specimens. This is the first time they extended their work to other centers and had the same conclusion that there is a high incidence of pre-HSCT microbiota injury. We can now truly say that microbiota injury is associated with subsequent survival because of the damage to the bowel before the transplant.
We have identified what we can do for these patients to improve the survival. Drugs that cause severe damage to the bowel should be avoided. There also should be monitoring and different GVHD prophylaxis therapy regimens.
This is a very interesting observation. However, no interventions have been done, so we don’t know if interventions will make any difference. We also don’t know if it’s reversible or if this is a surrogate marker, meaning that maybe the sickest patients are undergoing transplant, and so maybe they will have the worst outcome. A prospective, intervention study could help us determine this.
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Joseph Mikhael, MD
The microbiome of our guts helps us understand the prognosis of patients undergoing HSCT. One of the greatest challenges we face in that treatment modality is that patients can develop GVHD. The microbiome of patients undergoing transplant can help us appreciate the nature of GVHD. This study shows us how different microbiota diversity is in patients undergoing transplant and how that can influence their risk for GVHD. This has large data information that no one simple system could come up with.
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