PO.IM02.03 · 免疫学
MaaT013混合粪便微生物疗法改善胃肠道生理功能并控制炎症，从而在概念验证人源化小鼠研究中延缓GvHD
MaaT013 pooled fecal microbiotherapy improves gastrointestinal physiology and controls inflammation which delays GvHD in a proof-of-concept humanized mouse study
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摘要 Abstract
中文摘要
背景：急性移植物抗宿主病（aGvHD）是异基因造血干细胞移植（allo-HSCT）的一种危及生命的并发症，其中异基因供体T细胞将受体组织识别为异物并对其造成损害。allo-HSCT后的肠道菌群紊乱与aGvHD发生率、严重程度和死亡率的增加相关。肠道菌群在免疫系统的调节中发挥关键作用，尤其是在维持免疫耐受方面。这些结果推动了粪便微生物疗法的开发，以恢复健康且多样的肠道菌群并治疗或预防aGvHD。越来越多的临床证据支持粪便微生物疗法对aGvHD死亡率的疗效。MaaT013是一种源自混合健康人类粪便微生物群的标准化异基因粪便微生物疗法，在关键性ARES试验中作为伴有胃肠道（GI）受累的aGvHD三线治疗，已展现出前所未有的疗效和良好的安全性特征。
方法：在本研究中，我们结合了体外、体内、宏基因组学、代谢组学和转录组学研究，以阐明MaaT013影响GvHD的潜在机制。
结果：我们证明MaaT013衍生的代谢物在体外渗漏肠道模型中控制炎症并预防炎症诱导的肠道屏障改变。我们还表明MaaT013能够通过激活TLR和NOD传感器、刺激DC介导的IL-10产生和Tregs扩增在体外调节免疫。我们进一步证明，MaaT013中的有益细菌安全地在无菌小鼠的消化道中定植，导致抗炎代谢物的产生并恢复健康的肠道生理功能和免疫稳态。对MaaT013处理的无菌小鼠结肠组织的转录组学分析进一步证明，MaaT013促进胃肠道成熟并恢复免疫功能。最后，我们证明MaaT013在使用移植了人类外周血单个核细胞（PBMCs）的高度免疫缺陷小鼠的aGvHD人源化小鼠模型中延缓了GvHD症状的出现。
结论：总之，这些结果支持MaaT013通过恢复微生物多样性、肠道屏障完整性和免疫稳态来减轻aGvHD、从而控制炎症的潜力。
查看英文原文 English 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.
利益披露 Disclosure
J. Reygner, None..
M. De Seilhac, None..
C. Gasc, None..
E. Prestat, None..
C. Petitjean, None..
S. Declomesnil, None..
C. Schwintner, None..
N. Corvaia, None..
S. Simmons, None..
E. Holler, None..
R. R. Jenq, None..
B. Laperrousaz, None.