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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.

Human hematopoiesis is critically dependent on the transcription factor GATA2. Patients with GATA2 deficiency typically present with myelodysplastic syndrome, reduced numbers of monocytes, NK cells and B cells, and/or opportunistic infections. Here, we present two families that harbor distinct GATA2 mutations with highly variable onset and course of disease. We discuss the use of allogeneic hematopoietic cell transplantation in these patients, especially as treatment for pulmonary alveolar proteinosis.

Disruption of the intestinal microbiota occurs frequently in allogeneic hematopoietic cell transplantation (allo-HCT) recipients and predisposes them to development of graft-versus-host disease (GvHD). In a prospective, single-center, single-arm study, we investigated the effect of donor fecal microbiota transplantation (FMT) on symptoms of steroid-refractory or steroid-dependent, acute or late-onset acute intestinal GvHD in 15 individuals who had undergone allo-HCT. Study participants received a fecal suspension from an unrelated healthy donor via nasoduodenal infusion. Donor FMT was well tolerated, and infection-related adverse events did not seem to be related to the FMT procedure. In 10 of 15 study participants, a complete clinical response was observed within 1 month after FMT, without additional interventions to alleviate GvHD symptoms. This response was accompanied by an increase in gut microbial a-diversity, a partial engraft-ment of donor bacterial species, and increased abundance of butyrate-producing bacteria, including Clostridiales and Blautia species. In 6 of the 10 responding donor FMT recipients, immunosuppressant drug therapy was successfully tapered. Durable remission of steroid-refractory or steroid-dependent GvHD after donor FMT was associated with improved survival at 24 weeks after donor FMT. This study highlights the potential of donor FMT as a treatment for steroid-refractory or steroid-dependent GvHD, but larger clinical trials are needed to confirm the safety and efficacy of this procedure.

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.