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 异基因造血细胞移植（HCT）是一种挽救生命的治疗血液恶性肿瘤， 仍然是诸如高风险白血病的病症的治疗选择。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。尽管几十年来， 移植生物学，我们有有限的治疗选择，这种常见的条件相关的实质性 发病率和死亡率。GvHD与肠道细菌多样性的丧失和细菌内毒素的变化有关。 HCT后的群落组成。动物抗生素干预研究有令人信服的证据 和人类，肠道微生物群的操纵影响随后的GvHD风险。观察性研究 粪便微生物群移植（FMT）产生了有趣的数据，表明FMT是一种有前途的 在具有GvHD的HCT接受者中安全地重新填充肠道微生物群的干预。然而，裂变材料条约的影响 还没有以受控的方式研究递送途径对微生物重构的作用， 在该人群中，在FMT后维持有益的肠道微生物群的补充剂仍然未被探索， 对于微生物群如何影响FMT后的临床结果的机制的了解有限。为 例如，通过口服胶囊给予FMT可以在更大的肠道区域接种， 肠道微生物定植的变化，但反过来可能导致功能重要的细菌种类的丧失 通过胃酸和上消化道的胆盐杀死类似地，可以提高定殖效率， 通过为细菌提供关键的营养物质，如膳食纤维。此外，膳食纤维是细菌的底物， 短链脂肪酸如丁酸的产生与免疫调节和肠道健康有关。是 尚不清楚膳食纤维补充剂是否能增强这些患者FMT后的微生物植入， 促进代谢环境，促进HCT相关肠道损伤后的愈合。当前公开报道中还没有 FMT治疗GvHD的随机对照试验。我们提出的F2研究（FMT x Fiber）在以下患者中进行： 肠道GvHD将研究FMT（口服胶囊，上部vs.结肠滴注，下部）和膳食纤维的途径 补充剂影响有益微生物群的重建。本研究将以频繁排便为特征 采样，粪便中细菌群落组成和宏基因组含量的稳健分析， 干预措施对已知与GvHD相关的血液中T细胞亚群恢复的影响， 评估肠道微生物群产生的代谢物，如短链脂肪酸， GvHD，并随访以评估GvHD症状、分期和分级的消退。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一个急需的、机械的 研究如何通过FMT最佳恢复和维持有益的肠道微生物组， GVHD的治疗