The post-hematopoietic cell transplantation microbiome: relationships with transplant outcome and potential therapeutic targets

Abstract

Microbiota injury occurs in many patients undergoing allogeneic hematopoietic cell transplantation, likely as a consequence of conditioning regimens involving chemo- and radiotherapy, the widespread use of both prophylactic and therapeutic antibiotics, and profound dietary changes during the peri-transplant period. Peri-transplant dysbiosis is characterized by a decrease in bacterial diversity, loss of commensal bacteria and single-taxon domination (e.g., with Enterococcal strains). Clinically, deviation of the post-transplant microbiota from a normal, high-diversity, healthy state has been associated with increased risk of bacteremia, development of graft-versus-host disease and decreases in overall survival. A number of recent clinical trials have attempted to target the microbiota in allogeneic hematopoietic cell transplantation patients via dietary interventions, selection of therapeutic antibiotics, administration of pre- or pro-biotics, or by performing fecal microbiota transplantation. These strategies have yielded promising results but the mechanisms by which these interventions influence transplant-related complications remain largely unknown. In this review we summarize the current approaches to targeting the microbiota, discuss potential underlying mechanisms and highlight the key outstanding areas that require further investigation in order to advance microbiota- targeting therapies.

The contribution of the intestinal microbiome to immune recovery after HCT

“…Allogenic hematopoietic stem-cell transplantation (allo-HCT) is a curative-intent immunotherapy for hematological malignancies and immune disorders, performed for over 25,000 patients annually ( 1 , 2 ). Successful HCT delivers a robustly reconstituted new donor immune system which is a) capable of exerting graft-versus-tumor effects to prevent relapse, b) minimally alloreactive to minimize Graft-vs-Host Disease (GVHD), c) able to generate adequate responses to control viral, bacterial and fungal infections ( 3 , 4 ).…”

“…The process of allo-HCT involves administration of a cytotoxic conditioning regimen which leads to intensity-dependent damage of the gut epithelium ( 4 , 5 ), with concurrent translocation of damage and pathogen-associated molecular patterns (DAMPS/PAMPS) into the circulation ( 4 ). Following conditioning, infusion of the donor graft and subsequent multilineage repopulation of immune cells are key for successful patient outcomes.…”

“…aGVHD occurs when incoming donor immune cells recognize recipient antigen as foreign and respond in a way that results in tissue damage ( 5 ). The terminal effectors of aGVHD are alloantigen-specific T cells, which produce pro-inflammatory cytokines and cause host tissue apoptosis in an uncontrolled positive feedback loop ( 4 , 5 ). aGVHD pathogenesis has three key stages: Firstly, initial conditioning-related host tissue damage results in the release of DAMPS from host cells as well as the release of bacterial products such as lipopolysaccharide (LPS) into systemic circulation ( 4 ).…”

“…The terminal effectors of aGVHD are alloantigen-specific T cells, which produce pro-inflammatory cytokines and cause host tissue apoptosis in an uncontrolled positive feedback loop ( 4 , 5 ). aGVHD pathogenesis has three key stages: Firstly, initial conditioning-related host tissue damage results in the release of DAMPS from host cells as well as the release of bacterial products such as lipopolysaccharide (LPS) into systemic circulation ( 4 ). This first stage is followed by production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 ( 4 ).…”

“…aGVHD pathogenesis has three key stages: Firstly, initial conditioning-related host tissue damage results in the release of DAMPS from host cells as well as the release of bacterial products such as lipopolysaccharide (LPS) into systemic circulation ( 4 ). This first stage is followed by production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 ( 4 ). This pro-inflammatory cytokine milieu, coupled with the recruitment, priming, and expansion of donor T cells, results in the third stage: prolific cytokine production [interferon-gamma (IFN-γ), IL-17] and cytotoxic activity by CD8+ T cell subsets which cause further direct tissue damage ( 4 , 5 ).…”