# Microbial Dysbiosis in Chronic Lung Allograft Dysfunction

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $534,403

## Abstract

PROJECT SUMMARY:
Lung transplant is the only curative treatment for end stage lung diseases such as idiopathic
pulmonary fibrosis, COPD, cystic fibrosis and pulmonary hypertension. However, long-term
survival of lung transplant recipients (LTRs) is the lowest among all organ transplantations with a
median survival of 6 years. Approximately 50% of LTR’s develop chronic rejection within 5 years
post-transplantation, a syndrome referred to as chronic lung allograft dysfunction (CLAD). CLAD
pathogenesis is poorly understood. We and others have shown that lung dysbiosis (disruption of
microbiota homeostasis) is strongly associated with CLAD, although to date it is unclear if
dysbiosis is the cause or effect of CLAD. Unlike, gut dysbiosis which is an established risk for
chronic inflammatory diseases; the role of lung dysbiosis and the mechanisms linking it to CLAD
remain to be determined, representing a critical knowledge gap. Our objectives are to use a
longitudinal approach to define the pathogenic lung microbiome that predates CLAD onset and
investigate mechanisms for microbiome-induced fibrogenesis that increase CLAD susceptibility.
Our hypothesis is that lung dysbiosis inhibits epithelial autophagic clearance of pro-fibrotic
cytokines in an IL-33 dependent manner, thereby augmenting fibrogenesis and risk for CLAD.
SA1: To investigate the role of IL-33 blockade in attenuation of lung dysbiosis related fibrogenesis
and CLAD in a murine lung transplant model. SA2: To elucidate the mechanisms of IL-33
regulation of autophagy that are linked to pro-fibrotic responses in the lung. SA3: To determine
the relationship between human lung dysbiosis, IL-33 and CLAD susceptibility. Completion of the
proposed studies will (a) define the mechanistic link between airway microbial dysbiosis in lung
transplant recipients to dysregulated epithelial responses and CLAD; (b) provide proof-of-concept
that IL-33 blockade can favorably modulate microbiome mediated pro-fibrotic response leading
to CLAD. (c) Identify specific airway microbiome signatures that identify those at risk for CLAD.

## Key facts

- **NIH application ID:** 10522586
- **Project number:** 1R01HL161620-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Nirmal S Sharma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $534,403
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522586

## Citation

> US National Institutes of Health, RePORTER application 10522586, Microbial Dysbiosis in Chronic Lung Allograft Dysfunction (1R01HL161620-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10522586. Licensed CC0.

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