Abstract 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. Citation Format: Julie Reygner, Margaux De Seilhac, Cyrielle Gasc, Emmanuel Prestat, Charlotte Petitjean, Sophie Declomesnil, Carole Schwintner, Nathalie Corvaia, Sheri Simmons, Ernst Holler, Robert R. Jenq, Bastien Laperrousaz. MaaT013 pooled fecal microbiotherapy improves gastrointestinal physiology and controls inflammation which delays GvHD in a proof-of-concept humanized mouse study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2868.
Reygner et al. (Fri,) studied this question.