Restoring harmony Exploring the benefits of gut microbiome repair in hematopoietic cell transplantation recipients

Steroid-refractory graft-versus-host disease (GvHD) is a life-threatening complication that presents a significant clinical challenge in the care of allogeneic hematopoietic cell transplantation (HCT) recipients. Disruption of the intestinal microbiota is frequently observed in allogeneic HCT recipients and is particularly pronounced in patients who develop GvHD. Therapies targeting the microbiome, such as fecal microbiota transplantation (FMT), could contribute to preserving or restoring intestinal homeostasis by providing resistance to colonization, enhancing mucosal healing, or dampening the inflammatory immune response and may offer an attractive target in GvHD treatment. The first part of this thesis presents promising findings from a phase-I trial studying the impact of donor FMT on symptoms in patients with steroid-refractory or steroid-dependent intestinal GvHD, reports the effects of FMT therapy on the bacterial and fungal microbiome composition of these patients, and discusses the possible role of microbiome-targeted therapies in future clinical practice. The second part of this thesis focuses on patients with congenital GATA2 haploinsufficiency, a genetic immunodeficiency disorder associated with a predisposition to hematological malignancies. We describe the clinical heterogeneity between families with this genetic defect and study the immune cell reconstitution in GATA2 haploinsufficient patients undergoing allogeneic HCT, with a particular interest in innate lymphoid cells (ILC). The work in this thesis suggests gut microbiome repair presents a promising strategy for improving transplant outcomes and provides a solid foundation for future interventional studies for microbiome-modulating therapies in GvHD.