# The role of intestinal microbiota in graft-versus-host disease

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $550,156

## Abstract

Allogeneic hematopoietic-cell transplantation (allo-HCT) is an important treatment for
hematological malignancies. The intestinal microbiota consists of a community of diverse
microbes that reside in the intestine and are critical for host development, homeostasis, and
immune regulation. In human analyses and animal experiments, we and others have shown that
the intestinal microbiota contribute to the pathophysiology of all three major complications of
allo-HCT: infections, GVHD, 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”. 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.
The protective layer of intestinal mucus that normally contributes to barrier function was
depleted in animals suffering from GVHD and treated with anaerobe-targeted antibiotics. Finally,
we and others have observed an association between Enterococcus and the development of
GVHD in mouse and man. Therefore, we hypothesize that the intestinal microbiota can regulate
the development of GVHD and can be targeted to prevent or treat GVHD. We propose to study
in Aim 1 the mechanisms by which microbiota (in particular Blautia and Enterococcus) and their
metabolites modulate GVHD using gnotobiotic mice. In Aim 2 we will study the role of nutrition
in the development of GVHD both in humans and mouse models. In allo-HCT patients we will
correlate nutritional intake, microbiota composition and GVHD. In mouse models we will study
a) the effects of the diet on the mucus layer, b) sialidase inhibitors to prevent mucus layer
degradation, c) prebiotics to mitigate damage to the microbiota and mucus layer, and d) effects
of short chain fatty acids on GVHD. In addition to elucidating the interactions of the intestinal
microbiota and nutrition in the development of GVHD, this work will form the basis of clinical
trials to reduce GVHD and transplant-related mortality.

## Key facts

- **NIH application ID:** 10136554
- **Project number:** 5R01CA228308-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Marcel R M van den Brink
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $550,156
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136554

## Citation

> US National Institutes of Health, RePORTER application 10136554, The role of intestinal microbiota in graft-versus-host disease (5R01CA228308-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136554. Licensed CC0.

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