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

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posted on 22.11.2019 by 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

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.

Funding

Science Foundation Ireland. Health Research Board

History

Comments

Originally Published in: Mirković B, Murray MA, Lavelle GM, Molloy K, Azim AA, Gunaratnam C, Healy F, Slattery D, McNally P, Hatch J, Wolfgang M, Tunney MM, Muhlebach MS, Devery R, Greene CM, McElvaney NG. The Role of Short-Chain Fatty Acids, Produced by Anaerobic Bacteria, in the Cystic Fibrosis Airway. American Journal of Respiratory and Critical Care Medicine. 2015 Dec 1;192(11):1314-24. doi: 10.1164/rccm.201505-0943OC. Copyright © 2015 by the American Thoracic Society. The final publication is available at http://www.atsjournals.org/

Published Citation

Mirković B, Murray MA, Lavelle GM, Molloy K, Azim AA, Gunaratnam C, Healy F, Slattery D, McNally P, Hatch J, Wolfgang M, Tunney MM, Muhlebach MS, Devery R, Greene CM, McElvaney NG. The Role of Short-Chain Fatty Acids, Produced by Anaerobic Bacteria, in the Cystic Fibrosis Airway. American Journal of Respiratory and Critical Care Medicine. 2015;192(11):1314-24.

Publication Date

01/12/2015

Publisher

American Thoracic Society

PubMed ID

26266556

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