R01HL166107

Fecal microbiota transplantation and fiber for the treatment of graft-versus-host disease after hematopoietic cell transplantation - 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.

Fred Hutchinson Cancer Center

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Seattle, Washington 981094433 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 202% from $1,699,475 to $5,128,451.