Deciphering the Ecology of Cystic Fibrosis Bacterial Communities: Towards Systems-Level Integration (original) (raw)

2019, Trends in Molecular Medicine

Despite over a decade of cystic fibrosis (CF) microbiome research, much remains to be learned about the overall composition, metabolic activities, and pathogenicity of the microbes in CF airways, limiting our understanding of the respiratory microbiome's relation to disease. Systemslevel integration and modeling of host-microbiome interactions may allow us to better define the relationships between microbiological characteristics, disease status, and treatment response. In this way, modeling could pave the way for microbiome-based development of predictive models, individualized treatment plans, and novel therapeutic approaches, potentially serving as a paradigm for approaching other chronic infections. In this review, we describe the challenges facing this effort and propose research priorities for a systems biology approach to CF lung disease. The CF Microbiota: Where Are We Now? CF (OMIM 219700) is the most common life-shortening Mendelian disease in the white populations of Europe and North America, with an incidence of approximately one in 2500-6000 live births and a prevalence of more than 70 000 people living with CF worldwide [1,2]. Disease is caused by mutations in the CF transmembrane conductance regulator (cftr) gene, which encodes an anion channel (CFTR) found in both secretory and absorbing epithelia. This defect results in abnormal sodium, chloride, and bicarbonate transport across these epithelia, altering the composition of secretions in the lung, gastrointestinal tract, pancreas, biliary ducts, and other secretory glands. In the airways, absent or dysfunctional CFTR results in thick and tenacious mucus that compromises mucociliary clearance. This condition predisposes individuals to chronic bacterial infections and airway inflammation. During chronic infection, bacterial pathogens adapt to the microenvironment of CF airways [3,4], such as a thickened mucus layer and steep hypoxic gradients [5,6], possibly also modulating virulence mechanisms and resulting in damage to the airways and consequent chronic lung disease. Bacterial lung infections are associated with reduced quality and length of life in CF (median predicted survival age of 43.6 years between 2013 and 2017, according to the Annual Data Report 2017 of US Patient Registry Data [7]). These infections are key drivers of a pathophysiological cascade that leads to progressive and irreversible airway damage [8]. Affected individuals consistently maintain high bacterial loads in their airways both during periods of clinical stability and episodic increases in symptoms known as pulmonary exacerbations (PEx), (see Glossary). Standard clinical microbiology of CF, both during stability and PEx, usually identifies a relatively low number of bacterial species that are often thought to be important for driving PEx (Table 1), occasionally also including nontuberculous mycobacteria (NTM) and fungi, such as Candida spp., Aspergillus spp., and Scedosporium spp. [9,10]. Subsequent studies utilizing culture-independent analysis demonstrated that a complex mix of bacteria, fungi, and viruses form the airway microbiota (i.e., the communities of microorganisms that inhabit a given environment) of chronically infected individuals with CF [11]. Pioneering studies by Rogers and colleagues [12,13] identified bacterial species not previously associated with CF airways in many CF sputum samples, expanding the list of potential CF pathogens and chronic airway colonizers, and establishing the polymicrobial nature of most CF respiratory infections (Table 1). Research during the past decade using next-generation sequencing confirmed and broadened this list of CF