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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.

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.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often associated with chemotherapy- and radiotherapy-induced host tissue damage, leading to graft-versus-host disease (GVHD). Innate lymphoid cells (ILC) have an essential role in tissue homeostasis and tissue repair via their production of interleukin (IL)-22, which acts on intestinal stem cells. The tissue healing capacities of ILC via IL-22 in the context of allo-HSCT and GVHD has previously been demonstrated in a mouse model for acute GVHD. We investigated potential other ways of ILC-mediated tissue protection against GVHD. Tissue injury leads to the release of danger-associated molecular patterns (DAMPs). DAMPs interact with purinergic receptors and ectoenzymes on immune cells and induce pleiotropic effects, including activation of proinflammatory antigen-presenting cells and immunosuppressive effects via the generation of adenosine. Here, we report a novel subset of human ILC3 that coexpress the ectoenzymes CD39 and CD73 (ecto(+) ILC3). Ecto(+) ILC3 express RORγt and were present in the oral-gastrointestinal tract and bone marrow. ILC3 ectoenzyme expression is modulated by the proinflammatory cytokine IL-1β. Extracellular adenosine triphosphate (eATP) stimulated ecto(+) ILC3 to produce IL-22 and adenosine. Activated ecto(+) ILC3 suppressed autologous T-cell proliferation in coculture experiments via the production of adenosine. In allo-HSCT recipients, intestinal GVHD was associated with reduced proportions of ecto(+) ILC3 and decreased levels of adenosine and its metabolite inosine. Taken together, ecto(+) ILC3 have immunosuppressive properties, but in patients with GVHD, ecto(+) ILC3 are depleted. A lack of ecto(+) ILC3 and subsequent reduced capacity to neutralize DAMPs may contribute to the development of GVHD.

Introduction Enteric dysbiosis has a negative influence on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) recipients. The presence of an imbalanced microbiome, marked by decreased gut flora diversity and intestinal pathobiont domination, is associated with an increased risk to develop graft-versus-host disease (GvHD). Objectives This prospective, single-arm pilot study tested if donor fecal microbiota transplantation (FMT) is safe and effective to treat intestinal GvHD. Methods Fifteen patients with steroid-refractory or steroid-dependent GvHD received a single FMT via nasoduodenal infusion from an unrelated, healthy donor. Results FMT was well tolerated and there were no serious adverse events observed that could be attributed to FMT. With 6-month follow-up nearly completed for all patients, 11 participants showed a complete response (CR), defined as resolution of all GvHD symptoms four weeks after FMT, without other interventions to alleviate symptoms. In six patients, the normalization of stool frequency and consistency was sustained throughout follow-up and immunosuppressants were tapered successfully. Five other responders initially showed improvement of GvHD after FMT but relapsed upon prednisolone taper (CR/sf; complete responders with secondary failure). A durable response to FMT was associated with a better prognosis (Figure 1). 16S ribosomal RNA sequencing of fecal samples from the first 13 patients revealed overall low alpha diversity in patients pre-FMT (Figure 2). One week after FMT, the fecal microbial composition of CR patients resembled that of the donor the most (Figure 3). Analysis of fecal samples from the other patients will be completed in the near future and will give more insights into the effects on microbial diversity and composition that are introduced by donor FMT. Conclusion The encouraging data from this pilot study show the potential of donor FMT as a safe therapy for steroid-refractory or steroid-dependent GvHD and promote further investigation in larger cohorts.