MaaT013 pooled fecal microbiotherapy improves gastrointestinal physiology and controls inflammation which delays GvHD in a proof-of-concept humanized mouse study

Background : Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), where allogeneic donor T cells recognize recipient tissues as foreign and damage them. Gut microbiota disruption following allo-HSCT has been associated with increased aGvHD incidence, severity, and mortality. The gut microbiota plays a key role in the modulation of the immune system, particularly in maintaining immune tolerance. These results prompted the development of fecal microbiotherapies to restore a healthy and diverse gut microbiota and to treat or prevent aGvHD. Growing clinical evidence supports the efficacy of fecal microbiotherapy in aGvHD mortality. MaaT013, a standardized allogeneic fecal microbiotherapy derived from pooled healthy human fecal microbiota, has demonstrated unprecedented efficacy and favorable safety profile as third-line treatment of aGvHD with gastro-intestinal (GI) involvement in the pivotal ARES trial. Method: In this study, we combined in vitro , in vivo , metagenomics, metabolomics and transcriptomics studies to elucidate the underlying mechanisms by which MaaT013 influences GvHD. Results: We demonstrate that MaaT013-derived metabolites control inflammation and prevent inflammation-induced gut barrier alteration in an in vitro leaky gut model. We also show that MaaT013 is able to modulate immunity by activating TLR and NOD sensors, stimulating DC-mediated IL-10 production and Tregs amplification in vitro . We further demonstrate that beneficial bacteria from MaaT013 safely engraft in the digestive tract of germ-free mice, leading to the production of anti-inflammatory metabolites and restoring healthy gut physiology and immune homeostasis. Transcriptomic analysis of colon tissue from MaaT013-treated germ-free mice provides further evidence that MaaT013 promotes gastrointestinal maturation and restores immune functions. Finally, we demonstrate that MaaT013 delays the appearance of GvHD symptoms in a humanized mouse model of aGvHD using highly immunodeficient mice engrafted with human Peripheral Blood Mononuclear Cells (PBMCs). Conclusion: Altogether, these results support the potential of MaaT013 to mitigate aGvHD through restoration of microbial diversity, gut barrier integrity, and immune homeostasis, leading to control of inflammation.