Lung and Gut Microbiota Changes Associated with Pseudomonas aeruginosa Infection in Mouse Models of Cystic Fibrosis.

Giovanni Bacci,Lisa Cangioli,Federica Armanini,Alessio Mengoni,Ida De Fino,Nicola Segata,Alice Rossi,Alessandra Bragonzi,Annamaria Bevivino

doi:10.3390/ijms222212169

Abstract

Cystic fibrosis (CF) disease leads to altered lung and gut microbiomes compared to healthy subjects. The magnitude of this dysbiosis is influenced by organ-specific microenvironmental conditions at different stages of the disease. However, how this gut-lung dysbiosis is influenced by Pseudomonas aeruginosa chronic infection is unclear. To test the relationship between CFTR dysfunction and gut-lung microbiome under chronic infection, we established a model of P. aeruginosa infection in wild-type (WT) and gut-corrected CF mice. Using 16S ribosomal RNA gene, we compared lung, stool, and gut microbiota of C57Bl/6 Cftr tm1UNCTgN(FABPCFTR) or WT mice at the naïve state or infected with P. aeruginosa. P. aeruginosa infection influences murine health significantly changing body weight both in CF and WT mice. Both stool and gut microbiota revealed significantly higher values of alpha diversity in WT mice than in CF mice, while lung microbiota showed similar values. Infection with P. aeruginosa did not changed the diversity of the stool and gut microbiota, while a drop of diversity of the lung microbiota was observed compared to non-infected mice. However, the taxonomic composition of gut microbiota was shown to be influenced by P. aeruginosa infection in CF mice but not in WT mice. This finding indicates that P. aeruginosa chronic infection has a major impact on microbiota diversity and composition in the lung. In the gut, CFTR genotype and P. aeruginosa infection affected the overall diversity and taxonomic microbiota composition, respectively. Overall, our results suggest a cross-talk between lung and gut microbiota in relation to P. aeruginosa chronic infection and CFTR mutation.

Highlights

KO and WT congenic mice were infected with P. aeruginosa RP73 strain embedded in KO and WT congenic mice were infected with P. aeruginosa RP73 strain embedded agar beads to induce chronic infection
Empty beads reproducing the agar-induced inflammation and stress. Both KO and WT mice mice infected with P. aeruginosa lost significantly more body weight after 2–3 days from infected with P. aeruginosa lost significantly more body weight after 2–3 days from challenge challenge compared to empty beads, followed by a recovery at day 7 post-infection (Figcompared to empty beads, followed by a recovery at day 7 post-infection (Figure 1A)
Our finding indicates that the P. aeruginosa infection influences murine health both in KO and WT mice significantly changing body weight both in Cystic fibrosis (CF) and WT mice

Summary

Introduction

Cystic fibrosis (CF) is the most common autosomal recessive disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene [1]. Dysfunction of CFTR affects several organs, but primarily complications in the lung are the causes of morbidity and mortality [2]. Absence of CFTR-mediated Cl-secretion has been functionally linked to airway surface dehydration, which leads to the accumulation of concentrated mucus, airway obstruction, inflammation and infection, bronchiectasis, and death. Gastrointestinal (GI) manifestations are the most important nonpulmonary manifestations of CF and commonly complicate the care of CF patients. CF patients show altered airway microbiome, correlated to lung-specific microenvironmental conditions (e.g., viscous mucus, hyperinflammation, and infection) and altered fecal microbiomes, correlated with gastrointestinal inflammation and nutrient malabsorption [3,4]

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Discussion

Conclusion