Systems Biology and Bile Acid Signalling in Microbiome-Host Interactions in the Cystic Fibrosis Lung

Abstract

The study of the respiratory microbiota has revealed that the lungs of healthy and diseased individuals harbour distinct microbial communities. Imbalances in these communities can contribute to the pathogenesis of lung disease. How these imbalances occur and establish is largely unknown. This review is focused on the genetically inherited condition of Cystic Fibrosis (CF). Understanding the microbial and host-related factors that govern the establishment of chronic CF lung inflammation and pathogen colonisation is essential. Specifically, dissecting the interplay in the inflammation-pathogen-host axis. Bile acids are important host derived and microbially modified signal molecules that have been detected in CF lungs. These bile acids are associated with inflammation and restructuring of the lung microbiota linked to chronicity. This community remodelling involves a switch in the lung microbiota from a high biodiversity/low pathogen state to a low biodiversity/pathogen-dominated state. Bile acids are particularly associated with the dominance of Proteobacterial pathogens. The ability of bile acids to impact directly on both the lung microbiota and the host response offers a unifying principle underpinning the pathogenesis of CF. The modulating role of bile acids in lung microbiota dysbiosis and inflammation could offer new potential targets for designing innovative therapeutic approaches for respiratory disease.

Keywords: Pseudomonas aeruginosa; aspiration; bile acids; chronic infection; cystic fibrosis; gastro-oesophageal reflux; inflammation; lung; microbiota; pathogen.

Figure 1

Summary of common microbiota associated with healthy vs. CF lungs. Commonly identified taxa are illustrated and the factors governing the dynamics of these communities are presented. Microbes, such as the anaerobes Veillonella and Prevotella, are routinely isolated from healthy lungs. While Staphylococcus and Haemophilus are known to be early colonisers of the lungs of paediatric patients with CF, Pseudomonas ultimately achieves a dominant position within the lung microbiota. The balance between microbial immigration and elimination has been described as a primary influence on the community structure of a healthy lung. In contrast, regional growth conditions within the lung microenvironment have been shown to drive population diversification. Summarized in the figure are factors that shape, model and remodel the lung microbiota. These include polymicrobial interactions which can influence the survival and infection acquisition, biofilm development that can increase the persistence of infections, inflammatory responses that can both directly and indirectly affect the bacteria within the lung, antibiotic use which can directly alter the lung microbiota as well as causing alterations in inflammation and the gut microbiome, CFTR modulators which can increase airway clearance and co-morbidities that can influence the lung microbiome directly and through interconnections such as the gut–lung axis.

Figure 2

Overview of the proposed BA-microbiota axis within the CF holobiont. (A,B) The accumulation of BAs within the lungs of patients with CF as a consequence of aspiration leads to changes in the structure of the lung microbiota. This results in a transition from an (A) high diversity stable community to a (B) pathogen-dominated low diversity population. (B–D) Modulation of host signalling through the HIF-1 transcription factor by BAs and bile-induced P. aeruginosa derived Pseudomonas Quinolone Signal (PQS) serves to further promote dysregulated inflammation in CF patients. The impact of BAs on the behaviour of the key CF-associated pathogen P. aeruginosa (C) leads to a switch towards a chronic antibiotic tolerant biofilm lifestyle, with increases in PQS, the MexAB RND efflux pump and the Type Six Secretion System (T6SS), in parallel with a reduction in T3SS. (B–D) There is a dual impact of BAs on the lung microbiota, promoting chronicity and the inflammatory response. BAs also cause an FXR-dependent induction of pro-inflammatory cytokines and, consequently, the chemoattraction of neutrophils. This evidence underscores the unifying principle of BAs as a major host factor promoting the progression of chronic respiratory disease.