Control of GVHD by Probiotics with individual Commensal Bacteria

益生菌与单个共生细菌控制 GVHD

• 批准号: 10617324
• 负责人: Xue-Zhong Yu
• 金额: $ 61.35万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617324
• 关键词: Acute; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Antibiotics; Bacteria; Bacteroides fragilis; Benign; Biological Response Modifiers; Bone Marrow Transplantation; Clinic; Clinical; Clinical Research; Clinical Trials; Communities; Complication; Consensus; Decontamination; Development; Diet; Diet Modification; Disease; Donor person; Enterococcus; Epithelium; Feces; Fostering; Gastrointestinal tract structure; Goals; Habits; Health; Hematopoietic; Hematopoietic Neoplasms; Homeostasis; Human; Immune; Immune response; Immunosuppression; Individual; Injury; Intervention; Intestinal permeability; Intestines; Invaded; Lactobacillus; Malignant - descriptor; Mediating; Microbe; Modeling; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Outcome; Pathogenesis; Patients; Probiotics; Research; Role; Severities; Severity of illness; T cell response; T-Lymphocyte; Testing; Therapeutic; Translations; Transplant Recipients; Transplantation; Vancomycin Resistance; Xenograft Model; adaptive immunity; bacterial community; chronic graft versus host disease; commensal bacteria; experimental study; fecal transplantation; graft vs host disease; graft vs leukemia effect; gut homeostasis; gut microbiota; hematopoietic cell transplantation; immunoregulation; improved; intestinal barrier; leukemia; member; microbial; microbiota; microorganism; mortality; mouse model; pathogen; pre-clinical; prebiotics; preclinical study; preservation; prevent; response; screening; transplant model

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.

抽象的 异基因造血细胞移植（allo-HCT）可治愈多种良性和恶性疾病 造血系统疾病，但移植物抗宿主病（GVHD）仍然是移植后发生的重要原因 相关的死亡率和发病率。胃肠道 (GI) 参与 GVHD 的发病机制 已通过临床前和临床研究的转化得到证实。肠道微生物群由 肠道内存在多种微生物群落，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会导致 异常的全身免疫反应以及病原体定植和粘膜侵袭，促进 GVHD 的发展。以微生物群为目标，以造福患者为目标，有明确的理由 allo-HCT 后。通过抗生素、饮食和治疗等手段探索了几种干预策略 益生元、益生菌、微生物代谢物和粪便微生物移植（FMT）。然而， 确定最佳 FMT 供体以及对免疫受损患者进行适当的粪便筛查至关重要 相当大的挑战。识别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，我们观察到丰度 肠道微生物群中巴尼氏菌的数量与异基因 HCT 后小鼠 GVHD 的减少有关。 此外，单一巴尼氏菌菌株——肠巴尼氏菌（BI）的施用是安全且有效的。 在临床前小鼠模型中可有效预防急性和慢性 GVHD。我们的初步研究 提供初步支持，巴尼氏菌可能是益生菌的一种手段，可以使患者受益 诊所中的 HCT。事实上，BI 已被证明可以清除肠道耐万古霉素肠球菌， 与 allo-HCT 后患者的 GVHD 严重程度呈正相关。在这个提案中，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）定义 BI 及其 衍生代谢物通过维持肠道稳态来调节 GVHD； 2) 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 反应。我们 期望坚定地验证 Barnesiella 是一种安全有效的益生菌，可预防和治疗 GVHD，且无需 损害 GVL 效果。此外，我们希望了解细胞和分子机制 巴尼氏菌通过其调节微生物群、适应性免疫和肠道屏障功能。如果建议 研究如预期成功执行，我们将提供令人信服的理由证明 Barnesiella 益生菌可以成为一种对异基因 HCT 后患者有益的治疗方法。