The Role of Short-Chain Fatty Acids, Produced by Anaerobic Bacteria, in the Cystic Fibrosis Airway

Bojana Mirković, Michelle A Murray, Gillian M Lavelle, Kevin Molloy, Ahmed Abdul Azim, Cedric Gunaratnam, Fiona Healy, Dubhfeasa Slattery, Paul McNally, Joe Hatch, Matthew Wolfgang, Michael M Tunney, Marianne S Muhlebach, Rosaleen Devery, Catherine M Greene, Noel G McElvaney

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Rationale: Anaerobic bacteria are present in large numbers in the airways of people with cystic fibrosis (PWCF). In the gut, anaerobes produce short-chain fatty acids (SCFAs) that modulate immune and inflammatory processes.

Objectives: To investigate the capacity of anaerobes to contribute to cystic fibrosis (CF) airway pathogenesis via SCFAs.

Methods: Samples of 109 PWCF were processed using anaerobic microbiological culture with bacteria present identified by 16S RNA sequencing. SCFA levels in anaerobic supernatants and bronchoalveolar lavage (BAL) were determined by gas chromatography. The mRNA and/or protein expression of two SCFA receptors, GPR41 and GPR43, in CF and non-CF bronchial brushings and 16HBE14o− and CFBE41o− cells were evaluated using reverse transcription polymerase chain reaction, Western blot analysis, laser scanning cytometry, and confocal microscopy. SCFA-induced IL-8 secretion was monitored by ELISA.

Measurements and Main Results: Fifty-seven (52.3%) of 109 PWCF were anaerobe positive. Prevalence increased with age, from 33.3% to 57.7% in PWCF younger (n = 24) and older (n = 85) than 6 years of age. All evaluated anaerobes produced millimolar concentrations of SCFAs, including acetic, propionic, and butyric acids. SCFA levels were higher in BAL samples of adults than in those of children. GPR41 levels were elevated in CFBE41o− versus 16HBE14o− cells; CF versus non-CF bronchial brushings; and 16HBE14o− cells after treatment with cystic fibrosis transmembrane conductance regulator inhibitor CFTR(inh)-172, CF BAL, or inducers of endoplasmic reticulum stress. SCFAs induced a dose-dependent and pertussis toxin–sensitive IL-8 response in bronchial epithelial cells, with a higher production of IL-8 in CFBE41o−than in 16HBE14o− cells.

Conclusions: This study illustrates that SCFAs contribute to excessive production of IL-8 in CF airways colonized with anaerobes via up-regulated GPR41.

Original languageEnglish
Pages (from-to)1314-1324
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume192
Issue number11
Early online date12 Aug 2015
DOIs
Publication statusPublished - 01 Dec 2015

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