The role of intestinal microbiota in graft-versus-host disease

摘要(与父代R01相同) 异基因造血细胞移植(allo-hct)是一种重要的治疗方法。 恶性血液病。肠道微生物区系由不同种类的 驻留在肠道中的微生物，对宿主的发育、内稳态和 免疫调节。在人体分析和动物实验中，我们和其他人已经证明 肠道微生物区系对所有三种主要并发症的病理生理学有贡献。 异基因血细胞移植：感染、移植物抗宿主病和复发。使用16S核糖体RNA的下一代 测序，我们检测了allo-HCT患者的肠道微生物区系，发现了一种后 移植“微生物区系损伤”。这种生态失调可能是由于(A)广泛的- 光谱抗生素治疗移植后发热中性粒细胞减少症和(B) 这些患者所经历的营养变化。我们发现了一种相反的关系 异基因血细胞移植和移植物抗宿主病死亡后布劳蒂亚属的丧失。我们观察到广泛的- 针对厌氧共生菌的光谱抗生素尤其与 在我们的动物模型中，GVHD相关死亡率的增加，事实上加剧了肠道GVHD。 通常有助于屏障功能的肠道粘液保护层是 在患有移植物抗宿主病的动物体内耗尽，并使用厌氧菌靶向抗生素治疗。最后， 我们和其他人已经观察到肠球菌与肺炎的发展之间的联系 小鼠和人的GVHD。因此，我们假设肠道微生物区系可以调节 GVHD的发展，可靶向预防或治疗GVHD。我们建议研究 在目标1中，微生物区系(特别是布鲁氏菌和肠球菌)及其 代谢产物调节GVHD使用诺生菌小鼠。在目标2中，我们将研究营养的作用 在人类和小鼠模型中GVHD的发展过程中。对于allo-hct患者，我们将 营养摄入量、微生物区系组成和移植物抗宿主病之间存在相关性。在小鼠模型中，我们将研究 A)饮食对粘液层的影响，b)唾液酸酶抑制剂防止粘液层 降解，c)益生素，以减轻对微生物区系和粘液层的损害，以及d)影响 短链脂肪酸对移植物抗宿主病的影响。除了阐明肠道之间的相互作用 微生物区系与营养在移植物抗宿主病的发展中的作用，这项工作将为临床奠定基础 减少移植物抗宿主病和移植相关死亡率的试验。

Abstract (unchanged from Parent R01) Allogeneic hematopoietic-cell transplantation (allo-HCT) is an important treatment for hematological malignancies. The intestinal microbiota consists of a community of diverse microbes that reside in the intestine and are critical for host development, homeostasis, and immune regulation. In human analyses and animal experiments, we and others have shown that the intestinal microbiota contribute to the pathophysiology of all three major complications of allo-HCT: infections, GVHD, and relapse. Using 16S ribosomal RNA next-generation sequencing, we examined the intestinal microbiota of allo-HCT patients and found a post- transplant “microbiota injury”. This dysbiosis is likely due to the combined effects of (a) broad- spectrum antibiotics for the treatment of post-transplant febrile neutropenia and (b) the profound nutritional alterations experienced by these patients. We found an inverse relationship between a loss of the genus Blautia after allo-HCT and GVHD mortality. We observed that broad- spectrum antibiotics that target the anaerobic commensal flora are particularly associated with increases in GVHD-related mortality and in fact worsened intestinal GVHD in our animal model. The protective layer of intestinal mucus that normally contributes to barrier function was depleted in animals suffering from GVHD and treated with anaerobe-targeted antibiotics. Finally, we and others have observed an association between Enterococcus and the development of GVHD in mouse and man. Therefore, we hypothesize that the intestinal microbiota can regulate the development of GVHD and can be targeted to prevent or treat GVHD. We propose to study in Aim 1 the mechanisms by which microbiota (in particular Blautia and Enterococcus) and their metabolites modulate GVHD using gnotobiotic mice. In Aim 2 we will study the role of nutrition in the development of GVHD both in humans and mouse models. In allo-HCT patients we will correlate nutritional intake, microbiota composition and GVHD. In mouse models we will study a) the effects of the diet on the mucus layer, b) sialidase inhibitors to prevent mucus layer degradation, c) prebiotics to mitigate damage to the microbiota and mucus layer, and d) effects of short chain fatty acids on GVHD. In addition to elucidating the interactions of the intestinal microbiota and nutrition in the development of GVHD, this work will form the basis of clinical trials to reduce GVHD and transplant-related mortality.