Abstract
Cystic fibrosis (CF) is a congenital disorder resulting in a multisystemic impairment in ion homeostasis. The subsequent alteration of electrochemical gradients severely compromises the function of the airway epithelia. These functional changes are accompanied by recurrent cycles of inflammation–infection that progressively lead to pulmonary insufficiency. Recent developments have pointed to the existence of a gut–lung axis connection, which may modulate the progression of lung disease. Molecular signals governing the interplay between these two organs are therefore candidate molecules requiring further clinical evaluation as potential biomarkers. We demonstrate a temporal association between bile acid (BA) metabolites and inflammatory markers in bronchoalveolar lavage fluid (BALF) from clinically stable children with CF. By modelling the BALF-associated microbial communities, we demonstrate that profiles enriched in operational taxonomic units assigned to supraglottic taxa and opportunistic pathogens are closely associated with inflammatory biomarkers. Applying regression analyses, we also confirmed a linear link between BA concentration and pathogen abundance in BALF. Analysis of the time series data suggests that the continuous detection of BAs in BALF is linked to differential ecological succession trajectories of the lung microbiota. Our data provide further evidence supporting a role for BAs in the early pathogenesis and progression of CF lung disease.
Highlights
Cystic fibrosis (CF, OMIM 219700) is a monogenetic autosomal recessive condition caused by biallelic pathogenic variants in the Cystic Fibrosis Conductance Transmembrane Regulator (CFTR) gene [1]
The gut–lung axis is an emerging concept that is capturing broad interest in respiratory disease because of its potential involvement in the progression of chronic lung disease [8,9]. This communication axis has been highlighted based on the role played by the gut microbiota and its associated metabolites in the maintenance of homeostasis in the host immune system [9]
The exacerbated and uncontrolled immune responses typically observed in patients with chronic lung disorders could be mediated in part by the disruption of the host-microbiota crosstalk in the gut
Summary
Cystic fibrosis (CF, OMIM 219700) is a monogenetic autosomal recessive condition caused by biallelic pathogenic variants in the Cystic Fibrosis Conductance Transmembrane Regulator (CFTR) gene [1]. The most recent evidence suggests that this initial damage of the lungs is driven by neutrophilic inflammation [5] Secondary to this exacerbated inflammatory response, colonisation of the lower airways by opportunistic pathogens initiates the self-reinforcing cycles of inflammation–infection that mediate the progressive functional deterioration of the CF lung epithelia [6,7]. Based on these evidence sets, early childhood interventions should be the focus of attention. The molecular mechanisms involved in the initiation of these pathological processes, as well as their implications in disease progression remain largely unknown
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