# Host microbiota and airway mucus: a novel paradigm for lung defense and immune homeostasis during early post-natal development

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $388,750

## Abstract

Airway mucus clearance is a primary lung defense mechanism and the early neonatal period
represents a critical “window of susceptibility” for lung health. Perinatal changes in key components of the
mucus clearance system have been qualitatively described, but the details and functional significance of these
changes are unknown. Our preliminary data in mice and humans indicate that: 1) airway mucus composition is
developmentally regulated; and 2) components of the mucus clearance system are affected by the status of
the host microbiota in early life. We have identified a testable mechanism to link the host microbiota with
neonatal airway mucus biology and lung homeostasis, i.e., the IL-22+ILC3-mediated gut-lung axis. We also
posit that humans exhibit age-dependent changes in key elements contributing to airway mucus clearance,
e.g., MUC5AC levels. To test these hypotheses, we propose the following aims: 1) To test whether host
microbiota dysbiosis or blockade of the IL-22+ILC3-mediated gut-lung axis affect the abundance,
composition, and function of airway mucus in neonatal vs. adult mice. Congenic mice raised in germ-free
or specific-pathogen free conditions, either naïve or treated with antibiotics, will be assessed at post natal day
(PND)10 and PND66 for: 1) bronchoalveolar lavage (BAL) protein composition, mucus concentration, and
secreted mucins quantification; 2) airway mucociliary clearance; and 3) lung mRNA sequencing. Specific
contributions of IL-22 signaling and outcomes in the context of airway surface dehydration will be assessed
using IL-22 KO mice and Scnn1b-Tg mice, respectively. Changes in host microbiota will be determined by
bacterial 16S ribosomal RNA gene quantification. 2) To test whether CF-like host microbiota dysbiosis
affects the establishment of the normal, IL-22+ILC3-mediated gut-lung axis in neonatal mice. Congenic
∆F508 CF mice and WT littermates, either naïve or treated with antibiotics, will be used at PND10 to study the
influx of IL22+ILC3 cells into the lung referenced to quantitative analysis of their gut microbiota. In parallel, lung
and BAL samples will be collected to assess the effect of CF gut dysbiosis on the early lung transcriptome and
the composition of neonatal airway secretions. Crosses with Scnn1b-Tg mice will be used to exacerbate the
∆F508 CF lung phenotype. 3) To test whether the composition of “healthy” airway mucus presents age-
dependent, quantitative differences in humans. Airway mucus samples harvested from endotracheal tubes
used in neonates/infants/children (0-5 years old) and adults (25-40 years old) with no history or symptoms of
respiratory diseases will be analyzed for mucin and protein composition. Histologic specimens obtained from
the LungMAP
Biorepository (BRINDL)
will be probed for mRNA and protein expression of specific mucus
markers. Completion of these aims will establish a new conceptual framework and provide much needed
experimental evidence to study the pathogenesis, develop th...

## Key facts

- **NIH application ID:** 10104531
- **Project number:** 5R01HL150541-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Alessandra Maria Livraghi-Butrico
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2020-02-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104531

## Citation

> US National Institutes of Health, RePORTER application 10104531, Host microbiota and airway mucus: a novel paradigm for lung defense and immune homeostasis during early post-natal development (5R01HL150541-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10104531. Licensed CC0.

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