Allogeneic hematopoietic cell transplantation, the microbiome, and graft-versus-host disease

Abstract

Many patients with hematological malignancies, such as acute myeloid leukemia, receive an allogeneic hematopoietic cell transplantation (HCT) to cure their underlying condition. Allogeneic HCT recipients are exposed to various elements during the pre-, peri- and post-transplant period that can disrupt intestinal microbiota, including chemo- and radiotherapy, antibiotics, and dietary changes. The dysbiotic post-HCT microbiome is characterized by low fecal microbial diversity, loss of anaerobic commensals, and intestinal domination, particularly by Enterococcus species, and is associated with poor transplant outcomes. Graft-versus-host disease (GvHD) is a frequent complication of allogeneic HCT caused by immunologic disparity between donor and host cells and results in tissue damage and inflammation. Microbiota injury is particularly pronounced in allogeneic HCT recipients who go on to develop GvHD. At present, manipulation of the microbiome for example, via dietary interventions, antibiotic stewardship, prebiotics, probiotics, or fecal microbiota transplantation, is widely being explored to prevent or treat gastrointestinal GvHD. This review discusses current insights into the role of the microbiome in GvHD pathogenesis and summarizes interventions to prevent and treat microbiota injury.

Keywords: Allogeneic HCT; FMT; GvHD; gut microbiome; gut microbiota; mucosal immune system.

Figure 1.

The classical picture of GvHD pathophysiology. Chemotherapy and/or radiotherapy (host conditioning) results in tissue damage, translocation of bacteria, and the release of damage-associated molecular patterns (DAMP) and pathogen-associated molecular patterns (PAMP), which activate host antigen-presenting cells (APC). APCs stimulate alloreactive donor lymphocytes (e.g. T cells (t)), which in turn produce inflammatory cytokines and recruit additional effector cells (e.g. neutrophils (n)) resulting in enhanced tissue damage and inflammation. Created with BioRender.com.

Figure 2.

Peri-transplant microbiome injury. A typical schedule for the treatment of acute myeloid leukemia (AML) is depicted, with two AML remission-induction chemotherapy cycles followed by allogeneic HCT. Repeated cycles of remission-induction chemotherapy and subsequent allogeneic HCT are associated with alterations in diet and necessitate the use of antibiotics, anti-emetics, and other drugs that lead to loss of microbiome diversity. In addition, chemotherapy and radiotherapy directly damage the microbiome. Created with BioRender.com.

Figure 3.

Disruption and restoration of intestinal homeostasis in GvHD. In the healthy situation (left panel), commensals metabolize dietary fibers to short-chain fatty acids (SCFA), which are important for immunologic tolerance via induction of regulatory T cells (Treg) and the production of secretory IgA by B cells (b). SFCA enhance IL-22 production via innate lymphoid cells (ILC) thereby supporting epithelial integrity and promoting anti-microbial peptide (AMP) production that are important in shaping the microbial community and the prevention of pathogen outgrowth. Goblet cells produce mucus to hamper bacterial translocation. All of these processes are impacted by factors that are inherent in cancer treatment, such as the use of antibiotics, changes in diet, etcetera. This results in dysbiosis, low levels of SCFA, hampered mucus production, damage to epithelial cells, activation and the influx of (alloreactive) T cells (t) and neutrophils (n), and inflammation (right panel). Where classic GvHD treatment predominantly focuses on tempering immune activation via immunosuppressants, novel approaches include therapies that target the microbiota to prevent or treat dysbiosis. Created with BioRender.com.