# Project 2: Microbiota-based biomarkers and therapeutic strategies for intestinal graft vs host disease

> **NIH NIH P01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $392,922

## Abstract

Abstract
 Allogeneic hematopoietic-cell transplantation (allo-HCT) is an important treatment with
curative intent for hematological malignancies. Graft-vs-host disease (GVHD) is a major cause of
morbidity and mortality after transplantation. In human analyses and animal experiments, we and
others have shown that the intestinal microbiota contribute to the pathophysiology of GVHD, as
well as post-transplant infections and relapse. Using 16S ribosomal RNA next-generation
sequencing, we examined the intestinal microbiota of allo-HCT patients and found a post-
transplant “microbiota injury” with loss of diversity and a dramatic expansion of potentially
pathogenic bacteria that precedes bacterial sepsis with the same organisms. This dysbiosis is
likely due to the combined effects of (a) broad-spectrum antibiotics for the treatment of post-
transplant febrile neutropenia and (b) the profound nutritional alterations experienced by these
patients. We found an inverse relationship between a loss of the genus Blautia after allo-HCT and
GVHD mortality. We observed that broad-spectrum antibiotics that target the anaerobic
commensal flora are particularly associated with increases in GVHD-related mortality and in fact
worsened intestinal GVHD in our animal model. We thus hypothesize that the intestinal microbiota
has a significant role in the development of GVHD, is a potent modulator of GVHD severity, and
can be targeted to prevent or treat GVHD. We propose studies that aim to elucidate the
mechanisms by which the microbiota can regulate the pathophysiology of GVHD (and graft-vs-
tumor (GVT) activity), as well as studies to translate these findings into clinical biomarkers and
therapies for allo-HCT patients with GVHD.
 In Aim 1 we will assess the intestinal microbiota of allo-HCT patients for its relationship
with acute and chronic GVHD. We will study the relationship of a) pre-HCT intestinal microbiota
with and use as biomarkers for acute GVHD, and b) pre- and/or post-HCT microbiota with chronic
GVHD. We will also study the recovery of the intestinal microbiota after allo-HCT and its
relationship with immune reconstitution. In Aim 2 we will assess the mechanisms by which
microbiota can influence alloreactivity and graft-versus-tumor activity in preclinical models and
study the effects of individual microbes, defined bacterial ecologies and fecal microbiota
transplantation on GVHD and GVT activity. These studies form the basis for ongoing and future
trials targeting the intestinal microbiota to reduce GVHD and transplant-related mortality.

## Key facts

- **NIH application ID:** 9984296
- **Project number:** 5P01CA023766-40
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Marcel R M van den Brink
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,922
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984296

## Citation

> US National Institutes of Health, RePORTER application 9984296, Project 2: Microbiota-based biomarkers and therapeutic strategies for intestinal graft vs host disease (5P01CA023766-40). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9984296. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*