Control of GVHD by Probiotics with individual Commensal Bacteria

摘要 异基因造血细胞移植（allo-HCT）可治疗多种良恶性肿瘤 造血系统疾病，但移植物抗宿主病（GVHD）仍然是移植的重要原因， 相关的死亡率和发病率。胃肠道（GI）参与GVHD的发病机制， 通过临床前和临床研究的翻译得到证实。肠道微生物群由 存在于肠道中的多种微生物群落，对宿主发育，体内平衡， 和免疫调节。新出现的证据表明，微生物群多样性的扰动导致 异常的全身免疫应答以及病原体定殖和粘膜侵袭，促进了 GVHD的发展。有一个明确的理由来靶向微生物群，以使患者受益 allo-HCT后。通过抗生素、饮食、 益生元、益生菌、微生物代谢物和粪便微生物移植（FMT）。但 确定最佳的FMT供体和适当的粪便筛查免疫功能低下的患者是一个 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 肠道菌群中Barnesiella的减少与allo-HCT后小鼠GVHD的减少相关。 此外，施用单一Barnesiella菌株，Barnesiella cuminihominis（BI）是安全的， 在临床前小鼠模型中有效预防急性和慢性GVHD。我们的初步研究 提供初步支持，即Barnesiella可能是一种益生菌，可以使患者在异体移植后受益， HCT在诊所事实上，BI已被证明可以清除肠内万古霉素耐药性肠球菌， 与allo-HCT后患者的GVHD严重程度呈正相关。在本提案中，我们将扩展我们令人兴奋的 通过进一步追求两个具体目标进行初步研究：1）确定BI及其 衍生的代谢物通过维持肠道内稳态调节GVHD; 2）通过以下方式确定机制： 其中BI及其衍生代谢物通过调节供体T细胞来调节GVH/GVL应答。我们 我希望坚定地验证Barnesiella是一种安全有效的益生菌，可以预防和治疗GVHD， 影响GVL效应。此外，我们希望了解细胞和分子机制 Barnesiella通过其调节微生物群、适应性免疫和肠道屏障功能。如果拟议的 如果研究按预期成功执行，我们将提供一个令人信服的理由， 益生菌可以是一种有益于allo-HCT后患者的治疗方法。

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.