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.

项目总结