Infection and the microbiome in bronchiectasis

Abstract

Bronchiectasis is marked by bronchial dilatation, recurrent infections and significant morbidity, underpinned by a complex interplay between microbial dysbiosis and immune dysregulation. The identification of distinct endophenotypes have refined our understanding of its pathogenesis, including its heterogeneous disease mechanisms that influence treatment and prognosis responses. Next-generation sequencing (NGS) has revolutionised the way we view airway microbiology, allowing insights into the "unculturable". Understanding the bronchiectasis microbiome through targeted amplicon sequencing and/or shotgun metagenomics has provided key information on the interplay of the microbiome and host immunity, a central feature of disease progression. The rapid increase in translational and clinical studies in bronchiectasis now provides scope for the application of precision medicine and a better understanding of the efficacy of interventions aimed at restoring microbial balance and/or modulating immune responses. Holistic integration of these insights is driving an evolving paradigm shift in our understanding of bronchiectasis, which includes the critical role of the microbiome and its unique interplay with clinical, inflammatory, immunological and metabolic factors. Here, we review the current state of infection and the microbiome in bronchiectasis and provide views on the future directions in this field.

FIGURE 1

Overview of bronchiectasis pathogenesis. A complex interaction between infection and inflammation results in a self-perpetuating cycle initially triggered by various conditions (indicated on the left). This cycle is primarily driven by bacterial infections, with growing evidence of significant contributions from viruses and fungi. The progression from acute to chronic infection hinges on factors such as pathogen virulence, adaptability and the selective pressures within the host environment. Identifying the exact stage of infection (acute or chronic) is crucial, as it influences the effectiveness of eradication efforts (broken rectangle). Central to this process is an excessive (usually neutrophilic) inflammatory response that leads to further tissue damage and impairs mucociliary clearance. This infection-driven inflammation can increase the likelihood of acute exacerbations. Therapeutic strategies aim to mitigate both infection and inflammation. This is achieved through conventional antibiotics and newer pharmacological interventions targeting neutrophilic inflammation, such as dipeptidyl peptidase 1 (DPP1)/cathepsin C (CatC) inhibitors. Despite these efforts, the structural lung damage and the conditions present at the onset of infection and inflammation preclude a reversal to the pre-disease state. Figure created with BioRender.com.

FIGURE 2

Increasing scale of culture-based and airway microbiome studies in bronchiectasis. a) Table illustrating prevalence of key bacterial taxa from several major bronchiectasis registries. b) Visual timeline of microbiological and microbiome research outputs in bronchiectasis (2000–2024) comparing culture-based and sequencing-based (microbiome) studies. Each point on the chart indicates an individual study with the size of the circle and the length of the associated vertical lines reflecting study size. Points on the chart are colour-coded by the type of analysis conducted (grey: culture based; red: bacterial 16S rRNA analysis; green: fungal internal transcribed spacer (ITS) analysis; purple: metagenomics (MG)). Selected studies specifically discussed in the review are indicated by black borders surrounding dots and have accompanying citations. A broken line demarcates the beginning of the “microbiome era” in bronchiectasis. The complete list of studies illustrated in the figure is detailed in supplementary appendix 1. A.: Aspergillus; H.: Haemophilus; P.: Pseudomonas; Sta.: Staphylococcus; Ste.: Stenotrophomonas; Str: Streptococcus.

FIGURE 3

Microbiome and microbial interactions in the vicious vortex of bronchiectasis pathogenesis, adapted from the vicious vortex hypothesis of Flume et al. [3]. NET: neutrophil extracellular trap; ROS: reactive oxygen species. Figure created with BioRender.com.