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Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome

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Abstract

Mice with a null mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene show intestinal structure alterations and bacterial overgrowth. To determine whether these changes are model-dependent and whether the intestinal microbiome is altered in cystic fibrosis (CF) mouse models, we characterized the ileal tissue and intestinal microbiome of mice with the clinically common ΔF508 Cftr mutation (FVB/N Cftr tm1Eur) and with Cftr null mutations (BALB/c Cftr tm1UNC and C57BL/6 Cftr tm1UNC). Intestinal disease in 12-week-old CF mice, relative to wild-type strain controls, was measured histologically. The microbiome was characterized by pyrosequencing of the V4–V6 region of the 16S rRNA gene and intestinal load was measured by RT-PCR of the 16S rRNA gene. The CF-associated increases in ileal crypt to villus axis distention, goblet cell hyperplasia, and muscularis externa thickness were more severe in the BALB/c and C57BL/6 Cftr tm1UNC mice than in the FVB/N Cftr tm1Eur mice. Intestinal bacterial load was significantly increased in all CF models, compared to levels in controls, and positively correlated with circular muscle thickness in CF, but not wild-type, mice. Microbiome profiling identified Bifidobacterium and groups of Lactobacillus to be of altered abundance in the CF mice but overall bacterial frequencies were not common to the three CF strains and were not correlative of major histological changes. In conclusion, intestinal structure alterations, bacterial overgrowth, and dysbiosis were each more severe in BALB/c and C57BL/6 Cftr tm1UNC mice than in the FVB/N Cftr tm1Eur mice. The intestinal microbiome differed among the three CF mouse models.

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Acknowledgments

This work was supported by Cystic Fibrosis Canada and the National Institutes of Health (P30 DK089507 and K02 HL105543). Maintenance of the Cftr tm1Eur mouse colony at Erasmus MC was supported by the EUROCAFECF EU concerted action program and the Dutch CF Foundation (NCFS).

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Authors and Affiliations

  1. Meakins-Christie Laboratories, Departments of Medicine and Human Genetics, McGill University, 3626 St. Urbain, Montreal, QC, H2X 2P2, Canada

    Mark Bazett, Lisa Honeyman, Anguel N. Stefanov & Christina K. Haston

  2. Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

    Christopher E. Pope & Lucas R. Hoffman

  3. Department of Microbiology, University of Washington School of Medicine, Seattle, WA, USA

    Lucas R. Hoffman

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  1. Mark Bazett
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  2. Lisa Honeyman
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  3. Anguel N. Stefanov
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  4. Christopher E. Pope
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  5. Lucas R. Hoffman
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  6. Christina K. Haston
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Correspondence to Christina K. Haston.

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Bazett, M., Honeyman, L., Stefanov, A.N. et al. Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome. Mamm Genome 26, 222–234 (2015). https://doi.org/10.1007/s00335-015-9560-4

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