BLOG: Microbiome’s role in outcomes, relapse risk after HSCT or cellular therapy
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The microbiome is linked to myriad processes in human health and disease.
Research seeking to understand the role of the microbiome in carcinogenesis, as well as its impact on cancer-directed therapies outcomes, has grown exponentially in the last decades.
Studies from the 1970s first described the relationship between intestinal commensal microorganisms and hematopoietic stem cell transplant, when it was noted that mice in germ-free conditions or receiving gut-decontaminating antibiotics developed less gut graft-versus-host disease. Since then, vast research has been conducted demonstrating quite the opposite: Microbiome preservation, repletion and diversity positively impact HSCT outcomes and GVHD rates.
Adult and pediatric HSCT recipients with low bacterial diversity have worse OS, treatment-related mortality, and GVHD-related and infection-related mortality in several studies. Microbiota from these individuals showed higher abundances of Enterococcaceae and Enterobacteriaceae.
On the contrary, specific taxa — such as Blautia and Clostridium — have been reported to be protective against GVHD.
Similarly, outcomes of cellular therapy have been linked to changes in the microbiome. One study showed an association between Clostridium species and day 100 complete response after chimeric antigen receptor T-cell therapy. Another study developed and validated a predictive algorithm that separates responders from nonresponders based on Bacteroides, Ruminococcus, Eubacterium and Akkermansia abundance.
Although studies are sparse, specific taxa such as Eubacterium limosum also have been noted to correlate with decreased relapse risk after HSCT.
How does the microbiota influence HSCT and cellular therapy outcomes, immune reconstitution and risk for relapse?
The answer may lie in a fundamental role for the microbiota in myelopoiesis.
Our studies in mouse models show that when the microbiota is depleted through broad spectrum antibiotic treatment, hematopoietic progenitors and granulopoiesis are suppressed via a Type I interferon-mediated pathway. Inflammatory signaling and hematopoiesis are restored upon restoration of the fecal microbiota or by oral supplementation with microbial metabolites.
Standard practices surrounding HSCT and cellular therapies — such as the use of broad-spectrum antibiotics prophylactically or therapeutically, radiation-based conditioning regimens, dietary limitations and parental nutrition — certainly alter the intestinal microbiota.
Detailing the mechanisms through which these alterations impact clinical outcomes can allow for modifications of the medical management we implement for our patients, with the goal of preserving microbiome integrity and decreasing morbidity and mortality.
Different strategies — such as dietary changes, supplementation with pre- and probiotics, precision prebiotics and symbiotics that favor the predominance of specific commensal bacteria, Clostridial-sparing antibiotic regimens, and even fecal microbiota transplantation — are the focus of multiple preclinical and clinical trials to promote earlier immune reconstitution, improve acute GVHD-related symptoms and prevent GVHD.
Picturing a clinical landscape in which we are able to orchestrate our practices in a way that preserves the microbiome, while using modern designer microbiota modulators, precision prebiotics and supplements, and detecting specific bacterial compounds that identify those individuals with low bacterial diversity who benefit the most from interventions such as FMT, is truly exciting.
References:
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