Alterations of mucosa-attached microbiome and epithelial cell numbers in the cystic fibrosis small intestine with implications for intestinal disease

Jennifer Kelly, Miran Al-Rammahi, Kristian Daly, Paul K. Flanagan, Arun Urs, Marta C. Cohen, Gabriella di Stefano, Marcel J.C. Bijvelds, David N. Sheppard, Hugo R. de Jonge, Ursula E. Seidler, Soraya P. Shirazi-Beechey*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
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Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Defective CFTR leads to accumulation of dehydrated viscous mucus within the small intestine, luminal acidification and altered intestinal motility, resulting in blockage. These changes promote gut microbial dysbiosis, adversely influencing the normal proliferation and differentiation of intestinal epithelial cells. Using Illumina 16S rRNA gene sequencing and immunohistochemistry, we assessed changes in mucosa-attached microbiome and epithelial cell profile in the small intestine of CF mice and a CF patient compared to wild-type mice and non-CF humans. We found increased abundance of pro-inflammatory Escherichia and depletion of beneficial secondary bile-acid producing bacteria in the ileal mucosa-attached microbiome of CFTR-null mice. The ileal mucosa in a CF patient was dominated by a non-aeruginosa Pseudomonas species and lacked numerous beneficial anti-inflammatory and short-chain fatty acid-producing bacteria. In the ileum of both CF mice and a CF patient, the number of absorptive enterocytes, Paneth and glucagon-like peptide 1 and 2 secreting L-type enteroendocrine cells were decreased, whereas stem and goblet cell numbers were increased. These changes in mucosa-attached microbiome and epithelial cell profile suggest that microbiota-host interactions may contribute to intestinal CF disease development with implications for therapy.

Original languageEnglish
Article number6593
JournalScientific Reports
Volume12
Issue number1
DOIs
Publication statusPublished - 21 Apr 2022

Bibliographical note

Funding Information:
This work was funded by the UK Cystic Fibrosis Trust’s Strategic Research Centre Initiative (SRC) (CFT Project No: SRC 011). We gratefully acknowledge the generous donation of the Castella family for making this research possible. We are grateful to Profs Chris Taylor and Paul McNamara for their help and clinical advice.

Publisher Copyright:
© 2022, The Author(s).

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