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

异基因造血细胞移植（allo-HCT）是一种重要的治疗方法 血液系统恶性肿瘤。肠道微生物群由多种微生物组成 存在于肠道中的微生物对于宿主发育、体内平衡和 免疫调节。在人体分析和动物实验中，我们和其他人已经表明 肠道微生物群对所有三种主要并发症的病理生理学都有贡献 allo-HCT：感染、GVHD 和复发。使用下一代 16S 核糖体 RNA 测序后，我们检查了异基因 HCT 患者的肠道微生物群，发现了 移植“微生物群损伤”。这种生态失调可能是由于（a）广泛的综合影响 用于治疗移植后发热性中性粒细胞减少症的谱抗生素和 (b) 这些患者经历的营养改变。我们发现两者之间存在反比关系 allo-HCT 和 GVHD 死亡率导致 Blautia 属丧失。我们观察到，广泛 针对厌氧共生菌群的谱抗生素与 在我们的动物模型中，GVHD 相关死亡率增加，事实上肠道 GVHD 恶化。 通常有助于屏障功能的肠粘液保护层是 患有 GVHD 并用针对厌氧菌的抗生素治疗的动物体内的 GVHD 已被耗尽。最后， 我们和其他人观察到肠球菌与以下疾病的发展之间存在关联 小鼠和人的 GVHD。因此，我们推测肠道菌群可以调节 GVHD 的发展，可以有针对性地预防或治疗 GVHD。我们建议学习 目标 1 微生物群（特别是布劳特氏菌和肠球菌）及其微生物的机制 使用无菌小鼠代谢物调节 GVHD。在目标 2 中，我们将研究营养的作用 人类和小鼠模型中 GVHD 的发展。在同种异体 HCT 患者中，我们将 将营养摄入量、微生物群组成和 GVHD 关联起来。我们将在小鼠模型中研究 a) 饮食对粘液层的影响，b) 唾液酸酶抑制剂阻止粘液层 降解，c) 益生元减轻对微生物群和粘液层的损害，以及 d) 影响 短链脂肪酸对 GVHD 的影响。除了阐明肠道的相互作用外 GVHD 发展中的微生物群和营养，这项工作将构成临床基础 降低 GVHD 和移植相关死亡率的试验。

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.