# The role of bile acid metabolomics in graft-versus-host disease

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2024 · $555,619

## Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a therapy with curative intent for a variety of malignant
and non-malignant diseases. One of the major complications after allo-HCT is graft-versus-host disease (GVHD),
especially of the gastrointestinal tract. Our group was one of the first to explore the role of the intestinal
microbiome in allo-HCT in patients and preclinical models by combining next-generation sequencing with
immunological, microbial and metabolomic approaches. We found relationships between the intestinal
microbiome and GVHD, relapse, infections, engraftment, and immune reconstitution. The clinical and preclinical
studies we performed in the previous funding period resulted in 19 manuscripts (including NEJM, Nature,
Science, and Nature Med). We observed in large multi-center studies that higher diversity of intestinal microbiota
was associated with better overall survival, reconstitution of CD4, mucosal-associated invariant and V2 T cells.
Expansion of particular Enterococci was not only associated with GVHD in patients but exacerbated disease in
mice. We showed that loss of Clostridia was associated with the onset of acute GVHD, whereas lower serum
levels of butyrate were associated with an increased risk for chronic GVHD.
In addition to their role in digestive physiology, bile acids (BAs) exert wide-ranging biological effects, including
antimicrobial activity, intestinal epithelial homeostasis, and modulation of immunity. Primary BAs (PBA) are
synthesized in the liver and transformed by the intestinal microbiota into a diverse pool of secondary bile acids
(SBAs) with unique biochemical properties. BAs can bind to Farnesoid X Receptor (FXR), a nuclear receptor
that is a critical regulator of BA homeostasis, inflammation, and GI barrier function. Our preliminary preclinical
studies demonstrate that allo-HCT recipients with GVHD have: a) a decrease in unconjugated BAs and SBAs
in cecal contents and plasma, b) a reduced abundance of bile salt hydrolase genes (critical for SBA
transformation) in the intestinal microbiome, and c) decreased BA synthesis in the liver. In addition, we found
that a) most BAs can counteract FXR activation by the PBA chenodeoxycholic acid and b) donor T cells
deficient of FXR induce less GVHD. Our preliminary clinical studies corroborate the experimental results in that
fecal α-diversity is associated with increased abundance of SBAs, which are in turn correlated to less acute
GVHD and better overall survival. Based on studies demonstrating that BAs can inhibit Th17 polarization and
enhance Treg generation and our preliminary data in mouse models and allo-HCT patients, we hypothesize
that BA metabolism is an important modulator of alloreactive donor T cells and GVHD in allo-HCT recipients.
All our research is performed through perpetual dialogue between investigation in mice and humans.
Therefore, we propose to study the role of bile acids in GVHD after allo-HCT in preclinical models (Aim 1)...

## Key facts

- **NIH application ID:** 11055674
- **Project number:** 7R01CA228308-07
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Justin Cross
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,619
- **Award type:** 7
- **Project period:** 2024-03-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11055674

## Citation

> US National Institutes of Health, RePORTER application 11055674, The role of bile acid metabolomics in graft-versus-host disease (7R01CA228308-07). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/11055674. Licensed CC0.

---

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