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: 10434993
• 负责人: Xue-Zhong Yu
• 金额: $ 62.39万
• 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/10434993
• 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; Epithelial; Feces; Fostering; Gastrointestinal tract structure; Goals; Habits; Health; Hematopoietic; Hematopoietic Neoplasms; Homeostasis; Human; Immune; Immune response; Immunosuppression; Individual; Injury; Intervention; Intestinal permeability; Intestines; 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; base; 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; 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; Epithelial; Feces; Fostering; Gastrointestinal tract structure; Goals; Habits; Health; Hematopoietic; Hematopoietic Neoplasms; Homeostasis; Human; Immune; Immune response; Immunosuppression; Individual; Injury; Intervention; Intestinal permeability; Intestines; 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; base; 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 同种异体造血细胞移植（Allo-HCT）可以治愈多种良性和恶性肿瘤 造血疾病，但移植抗宿主病（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）的参与GVHD的发病机理 通过临床前和临床研究的翻译来证实。肠道菌群由 居住在肠道中的各种微生物的社区，对于宿主发展至关重要，体内平衡， 和免疫调节。新兴证据表明，微生物群多样性的扰动导致 异常的系统性免疫反应以及病原体定植和粘膜侵袭，促进 GVHD的发展。针对以使患者有益的目标，存在明确的靶向微生物群的理由 在Allo-HCT之后。通过抗生素，饮食和 益生元，益生菌，微生物代谢产物和粪便微生物移植（FMT）。但是， 鉴定最佳FMT供体和免疫损害患者的适当的粪便筛查是 巨大的挑战。识别和应用一种或多种安全有效的生物生物 在改善HCT患者的健康方面具有很高的优点。在初步研究中，我们观察到丰度 肠道微生物群中的barnesiella的含量与Allo-HCT后小鼠的GVHD减少有关。 此外，施用单一的barnesiella菌株，Barnesiella intestinihominis（BI），是安全的，并且 有效防止临床前鼠模型中的急性和慢性GVHD。我们的初步研究 提供最初的支持，即Barnesiella可能是一种益生菌的手段，可以在同疗后对患者受益 HCT在诊所中。实际上，BI已被证明避免了肠道抗霉素的肠球菌肠球菌 Allo-HCT后患者的GVHD严重程度正相关。在此提案中，我们将扩大激动人心的 初步研究通过进一步追求两个具体目标：1）定义BI及其ITS的机制 衍生的代谢产物通过维持肠道稳态来调节GVHD； 2）通过 BI及其得出的代谢产物通过调节供体T细胞来调节GVH/GVL反应。我们 期望牢固地将Barnesiella验证为一种安全有效的益生菌，以防止和治疗GVHD 损害GVL效应。此外，我们期望理解细胞和分子机制 Barnesiella调节微生物群，适应性免疫和肠屏障功能。如果提议 根据预期，研究成功执行，我们将提供令人信服的理由，即Barnesiella 益生菌可以是一种治疗方法，可对Allo-HCT后患者受益。