Control of GVHD by Probiotics with individual Commensal Bacteria

摘要 异基因造血细胞移植(allo-HCT)治疗多种良恶性疾病 造血障碍，但移植物抗宿主病(GVHD)仍然是移植的重要原因- 相关死亡率和发病率。胃肠道在移植物抗宿主病发病机制中的作用 通过临床前研究和临床研究的翻译得到证实。肠道微生物区系由一个 栖息在肠道中的各种微生物群落，对宿主的发育、动态平衡、 和免疫调节。新出现的证据表明，微生物区系多样性的扰动导致 异常的系统免疫反应以及病原体的定植和粘膜侵袭，促进了 移植物抗宿主病的发展。以微生物区系为目标以造福患者的目标是有明确的理由的 在allo-hct之后。几种干预策略已经被探索，通过抗生素，饮食和 益生菌、益生菌、微生物代谢产物和粪便微生物移植(FMT)。然而， 为免疫低下患者确定最佳FMT供体和适当的粪便筛查是一项重要的工作 这是相当大的挑战。鉴定和应用一种或多种安全有效的活微生物 在改善HCT患者的健康方面具有很高的价值。在初步研究中，我们观察到 肠道微生物区系中的巴氏杆菌与allo-HCT后小鼠移植物抗宿主病的减少有关。 此外，注射单一的巴氏杆菌菌株肠人巴氏杆菌(BI)是安全的和 在临床前小鼠模型中有效预防急性和慢性移植物抗宿主病。我们的初步研究 提供初步支持，认为巴氏杆菌可能是一种益生菌手段，可在异基因移植后使患者受益- 诊所里的红细胞压积。事实上，BI已经被证明可以清除肠道中对万古霉素耐药的肠球菌 Allo-HCT后患者GVHD的严重程度与GVHD的严重程度呈正相关。在这项提案中，我们将把我们令人兴奋的 通过进一步追求两个具体目标进行初步研究：1)确定BI和ITS 衍生代谢产物通过维持肠道内环境平衡来调节移植物抗宿主病；2)通过 BI及其衍生代谢产物通过调节供体T细胞来调节GVH/GVL反应。我们 期望坚定地确认巴氏杆菌是一种安全有效的益生菌，用于预防和治疗GVHD 损害了GVL效应。此外，我们希望了解细胞和分子机制。 巴氏杆菌通过其调节微生物区系、适应性免疫和肠道屏障功能。如果建议的 研究如预期成功执行，我们将提供一个令人信服的理由，即巴氏杆菌 益生菌可以是一种治疗方法，使患者在allo-HCT后受益。

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) can cure a variety of benign and malignant hematopoietic disorders, but graft-versus-host disease (GVHD) remains a significant cause of transplant- related mortality and morbidity. Involvement of the gastrointestinal (GI) tract in the pathogenesis of GVHD has been substantiated by the translation of pre-clinical and clinical studies. The intestinal microbiota consists of a community of diverse microbes that reside in the gut and are critical for the host development, homeostasis, and immune regulation. Emerging evidence suggests that perturbations in the microbiota diversity result in aberrant systemic immune responses as well as pathogen colonization and mucosal invasion, fostering the development of GVHD. A clear rationale exists for targeting the microbiota with the goal to benefit patients after allo-HCT. Several interventional strategies have been explored by means of antibiotics, diet and prebiotics, probiotics, microbial metabolites, and fecal microbial transplantation (FMT). However, the identification of optimal FMT donors and appropriate stool screening for immune compromised patients is of a considerable challenge. Identifying and applying one or more live microorganisms that are safe and effective in improving health of HCT patients are of high merit. In the preliminary studies, we observed that abundance of Barnesiella in gut microbiota was associated with the reduction of GVHD in mice after allo-HCT. Furthermore, administration of a single Barnesiella strain, Barnesiella intestinihominis (BI), was safe and effective in preventing both acute and chronic GVHD in preclinical murine models. Our preliminary studies provide initial support that Barnesiella may be a means of probiotics that could benefit to patients after allo- HCT in the clinic. In fact, BI has been shown to clear of intestinal vancomycin-resistance Enterococcus that positively associates with GVHD severity in patients after allo-HCT. In this proposal, we will extend our exciting preliminary studies by further pursuing two Specific Aims: 1) to define the mechanisms by which BI and its derived metabolites modulate GVHD through maintaining gut homeostasis; 2) to determine the mechanisms by which BI and its derived metabolites modulate GVH/GVL responses through regulating donor T cells. We expect to firmly validate Barnesiella as a safe and efficacious probiotic to prevent and treat GVHD without compromising the GVL effect. Furthermore, we expect to understand the cellular and molecular mechanisms by which Barnesiella regulates microbiota, adaptive immunity, and intestinal barrier functions. If the proposed studies are successfully executed as expected, we will provide a compelling rationale that Barnesiella probiotics can be a therapeutic approach that benefits to patients after allo-HCT.