# Microbiota Regulation of Pulmonary Complications Post-HCT

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $390,000

## Abstract

Project Summary
Hematopoietic cell transplantation (HCT) is a potentially curative therapy for a variety of neoplastic disorders.
However, the composition of the microbiota is often disturbed during the process of HCT. Alterations or dysbiosis
of the lung microbiome post-HCT are associated with poor clinical outcomes, including lung injury. Pulmonary
complications commonly occur among HCT recipients and are a leading cause of post-HCT morbidity and
mortality. These pulmonary complications include both pathologies generated by infectious agents and also the
so called “non-infectious” disorders. Non-infectious pulmonary complications are associated with irreversible
pulmonary dysfunction and considerable mortality. No cure exists for these progressive disorders such as
idiopathic pneumonia syndrome (IPS) which is characterized by pneumonitis, lung injury and often fibrosis. The
etiology and pathogenesis of non-infectious post-HCT pulmonary disorders is poorly understood and research
in this area is a critical need within the NIH mission. Our long-term goal is to improve outcomes for HCT recipients
by developing microbiome-informed therapeutic strategies to manage post-HCT pulmonary complications.
We have shown that primary infection or reactivation of latent herpesviruses increases the risk of post-HCT lung
injury such as IPS and that these lung injuries are associated with dysbiosis of lung microbiota in human HCT
recipients. We have developed novel animal models that recapitulate the pathologic features of IPS to allow for
mechanistic studies. We have shown that a loss in abundance of Lactobacillus species and the Lachnospiraceae
family in mice is associated with developing IPS-like pneumonitis and fibrosis, and that the development of
pneumonitis and fibrosis post-HCT and herpesviral infection is IL-17-dependent. Importantly, microbiota isolated
from the lungs of HCT mice stimulate pro-IL-17 responses by lung dendritic cells (DCs) potentially through
impairing the expression of Notch ligand, delta like ligand 4 (DLL4). Thus, we hypothesize that HCT-altered
lung microbiota facilitate lung DC modifications/priming so that DCs promote pathogenic IL-17 responses to
herpes virus infection leading to lung pathology and the development of pulmonary complications like IPS. We
will pursue the following three specific aims in this proposed project.
Aim 1. Identify key lung microbiota associated with post-HCT pulmonary complications
Aim 2. Determine the mechanism(s) through which lung microbiota regulate lung DC function
Aim 3. Determine the role of Lactobacillus species and the Lachnospiraceae family in the development
of post-HCT pulmonary complications

## Key facts

- **NIH application ID:** 10910901
- **Project number:** 5R01HL153028-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Xiaofeng Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2021-09-20 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910901

## Citation

> US National Institutes of Health, RePORTER application 10910901, Microbiota Regulation of Pulmonary Complications Post-HCT (5R01HL153028-04). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10910901. Licensed CC0.

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