Fecal Microbiota Transplantation and Fiber for the Treatment of Graft-versus-host Disease After Hematopoietic Cell Transplantation

粪便微生物群移植和纤维治疗造血细胞移植后移植物抗宿主病

• 批准号: 10737446
• 负责人: DAVID Neal FREDRICKS
• 金额: $ 169.95万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737446
• 关键词: Activities of Daily Living; Acute; Affect; Allogenic; Animals; Antibiotics; Area; Bacteria; Bile Acids and Salts; Biological; Biology; Blood; Blood Flow Cytometry; Butyrates; Carbohydrates; Cells; Clinical; Clinical Data; Clostridium difficile; Colon; Colonoscopy; Complication; Coupled; Data; Diarrhea; Diet; Diet Surveys; Dietary Fiber; Dietary Supplementation; Dietary intake; Disease Outcome; Engraftment; Enteral Nutrition; Environment; Exposure to; Feces; Fermentation; Fiber; Flow Cytometry; Fostering; Frequencies; Future; Gastric Acid; Genes; Goals; Health; Hematologic Neoplasms; High Prevalence; Human; Immune; Immunity; Immunologics; Immunosuppressive Agents; Impact evaluation; Injury; Intervention; Intervention Studies; Intestines; Investigation; Life; Link; Liquid substance; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Metagenomics; Methods; Microbe; Morbidity - disease rate; Mucosal Immune System; Nutrient; Nutritional; Observational Study; Oral; Oral Administration; Outcome; Participant; Patients; Pharmaceutical Preparations; Physiology; Pilot Projects; Population; Production; Publishing; Quality of life; Randomized; Randomized, Controlled Trials; Recovery; Regulatory T-Lymphocyte; Reporting; Research Personnel; Resolution; Risk; Role; Route; Shapes; Supplementation; Surveys; Symptoms; T-Lymphocyte Subsets; Testing; Transplant Recipients; Transplantation; Uncontrolled Study; Volatile Fatty Acids; attenuation; bacterial community; beneficial microorganism; burden of illness; capsule; design; dietary; disorder risk; efficacy trial; fecal microbiome; fecal transplantation; follow-up; functional loss; gastrointestinal; graft vs host disease; gut bacteria; gut colonization; gut health; gut microbiome; gut microbiota; healing; hematopoietic cell transplantation; high risk; ileum; immunoregulation; improved; insight; leukemia; liquid chromatography mass spectrometry; metagenomic sequencing; microbial; microbial colonization; microbiome; microbiota; mortality; next generation sequencing; prebiotics; primary endpoint; rRNA Genes; reconstitution; recruit; safety outcomes; sample collection; secondary endpoint; stool sample; transplantation therapy; treatment choice

PROJECT SUMMARY Allogeneic hematopoietic cell transplantation (HCT) is a life-saving treatment for hematologic malignancies that remains the treatment of choice for conditions such as high risk leukemias. Graft-versus-host disease (GvHD) is a common complication of allogeneic HCT, affecting >50% of patients. Despite decades of progress in transplantation biology, we have limited treatment options for this common condition associated with substantial morbidity and mortality. GvHD has been linked to loss of gut bacterial diversity and changes in bacterial community composition after HCT. There is compelling evidence from antibiotic intervention studies in animals and humans that manipulation of the gut microbiota influences subsequent risk of GvHD. Observational studies of fecal microbiota transplantation (FMT) have generated intriguing data suggesting that FMT is a promising intervention for safely repopulating the gut microbiota in HCT recipients with GvHD. However, the effect of FMT delivery route on microbial reconstitution has not been investigated in a controlled manner, the role of dietary supplementation on maintaining a beneficial gut microbiota after FMT remains unexplored in this population, and there is limited insight into mechanisms for how the microbiota may impact clinical outcomes after FMT. For example, administering FMT via oral capsules may seed a larger area of the intestinal tract yielding more durable changes in gut microbial colonization, but conversely could lead to loss of functionally important bacterial species through killing by gastric acid and bile salts in the upper tract. Similarly, colonization efficiency may be enhanced by providing bacteria with key nutrients such as dietary fiber. In addition, dietary fiber is a substrate for bacterial production of short chain fatty acids such as butyrate linked to immune modulation and intestinal health. It is unknown if dietary fiber supplementation enhances microbiological engraftment after FMT in these patients or fosters a metabolic environment that promotes healing after HCT related gut injury. There are no published randomized controlled trials of FMT for treatment of GvHD. Our proposed F2 study (FMT x Fiber) in patients with gut GvHD will investigate how route of FMT (oral capsule, upper vs. colonic instillation, lower) and dietary fiber supplementation influence reconstitution of a beneficial microbiota. This study will feature frequent stool sampling, robust analysis of bacterial community composition and metagenomic content in stool, evaluation of the impact of the interventions on recovery of T-cell subsets in blood with known associations with GvHD, assessment of metabolites such as short chain fatty acids produced by the gut microbiota that may ameliorate GvHD, and follow-up to assess resolution of GvHD symptoms, stage, and grade. These in-depth longitudinal microbial, metabolic, nutritional, immunological, and clinical data will allow a much-needed, mechanistic investigation of how a beneficial gut microbiome can be optimally restored and maintained through FMT for treatment of GvHD.

项目摘要 同种异体造血细胞移植（HCT）是一种挽救血液学恶性肿瘤的疗法 对于高风险白血病等条件，仍然是选择的治疗方法。移植物抗宿主病（GVHD）是 同种异体HCT的常见并发症，影响> 50％的患者。尽管进步了数十年 移植生物学，我们对这种常见状况的治疗选择有限 发病率和死亡率。 GVHD与肠道细菌多样性的丧失和细菌的变化有关 HCT之后的社区组成。来自动物的抗生素干预研究有令人信服的证据 操纵肠道菌群的人类会影响GVHD的随后风险。观察性研究 粪便微生物群移植（FMT）产生了有趣的数据，这表明FMT是一个有前途的 干预措施，以GVHD的HCT受体中肠道菌群的安全再现。但是，FMT的影响 尚未以受控的方式研究微生物重构的交付路线，饮食的作用 在FMT之后保持有益的肠道菌群的补充，在该人群中仍未探索，并且 人们对微生物群如何影响FMT后临床结果的机制有限。为了 例如，通过口腔胶囊施用FMT可能播种较大的肠道区域，从而更耐用 肠道微生物定植的变化，但相反可能导致功能上重要的细菌丧失 通过胃酸和上层胆汁盐杀死。同样，可以提高定殖效率 通过为细菌提供关键营养素，例如饮食纤维。此外，饮食纤维是细菌的底物 与免疫调节和肠道健康相关的短链脂肪酸（例如丁酸酯）等短链脂肪酸。这是 未知的饮食纤维补充剂是否会增强这些患者FMT后的微生物植入或 促进了一种代谢环境，可在与HCT相关的肠道损伤后促进愈合。没有出版 FMT治疗GVHD的随机对照试验。我们拟议的F2研究（FMT X纤维） 肠道GVHD将研究FMT（口服胶囊，上囊和结肠滴注，下部）和饮食纤维的路线 补充会影响有益微生物群的重建。这项研究将具有频繁的粪便 对粪便中细菌群落组成和宏基因组含量的采样，可靠分析，评估 干预措施对血液中T细胞子集恢复的影响与已知与GVHD的关联， 评估代谢物，例如肠道菌群产生的短链脂肪酸，可能会改善 GVHD和随访，以评估GVHD症状，阶段和等级的分辨率。这些深入的纵向 微生物，代谢，营养，免疫学和临床数据将允许急需的机械 研究如何通过FMT对有益的肠道微生物组进行最佳恢复和维护 GVHD的处理。