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. 2021 Nov 10;22(22):12169.
doi: 10.3390/ijms222212169.

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

Giovanni Bacci  1 , Alice Rossi  2 , Federica Armanini  3 , Lisa Cangioli  1 , Ida De Fino  2 , Nicola Segata  3 , Alessio Mengoni  1 , Alessandra Bragonzi  2 , Annamaria Bevivino  4
Affiliations

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

Giovanni Bacci et al. Int J Mol Sci. .

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.

Keywords: CFTR mice; Pseudomonas aeruginosa; animal models; cystic fibrosis; gut; gut-lung axis; lung; microbiome.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Body weight changes and P. aeruginosa load in KO and WT congenic mice. KO male and WT male mice were infected with 3–4 × 105 CFU of P. aeruginosa RP73 embedded in agar beads by intratracheal inoculation. A control group was challenged with empty beads. Mice were weighed daily, and the percentage change from the initial body weight was averaged for each group of mice (A). After day 7 post-inoculation, the mice were sacrificed, lungs were excised, homogenized and plated onto tryptic soy agar to determine the bacterial load (B). Data are presented as mean ± SEM. The data were pooled from four independent experiments (RP73 infected: KO mice n = 13 and WT mice n = 17; empty beads: KO mice n = 7 and WT mice n = 8). * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Comparisons between KO P. aeruginosa infected vs. KO mice challenged with empty beads and WT P. aeruginosa infected vs. WT mice challenged with empty beads were performed by two-way ANOVA with Bonferroni’s post-test.
Figure 2
Figure 2
Clustering of mice microbiota. Codes of samples are as those reported in Table S1.
Figure 3
Figure 3
Taxonomic composition and clustering of samples based on the most abundant ASV (top 100). The heat-map showing the abundance of the top 100 ASVs in samples is reported.
Figure 4
Figure 4
Principal component analysis (PCA) of mice microbiota. Pales shows the distribution of samples with respect to (A) infections; (B) WT mice and (C) KO mice in relation to districts. WT mice: empty beads n = 8 and RP73 infected n = 17; KO mice: empty beads n = 7 and RP73 infected n = 13.
Figure 5
Figure 5
Experimental design. Mice were intratracheally infected with 3–4 × 105 of clinical strain P. aeruginosa RP73 embedded in agar beads or empty beads and were sacrificed after seven days. Lungs, stool, and the final straight portion of the rectum (mucosae + feces) were aseptically excised and processed for metagenomic analysis. Read-outs of the disease progression were body weight changes, health status and CFUs in the lung.
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