Cystic fibrosis is a complex genetic disease that slowly takes the breath of those who have it by eroding the function of their lungs over time. At the core of this erosion is a diverse community of bacteria competing to assert dominance in the lung, inflicting chronic exacerbations that need continual attention through treatment and antibiotics. A significant obstacle in treating CF is understanding the interaction among this community of bacteria to better treat infections and preserve lung function.
The lungs of those with CF provide an environment that allow bacteria to take up residence and thrive. A normal lung has a layer in its airways called the airway surface liquid (ASL), which hydrates the tissue, allowing mucous to be easily swept away. In CF, however, the ASL becomes reduced and prevents the lungs from effectively moving the mucous out.
The mucous, which serves to trap foreign particles and bacteria, becomes trapped forming plaques thereby enabling bacteria to take hold and grow. This bacterial growth then leads to infection, contributing to chronic inflammation and bronchiectasis. Overtime the accumulative effect of chronic infection and inflammation reduces the function of the lung.
A core group of bacteria have been identified that are commonly identified in the CF lung. In particular Staphylococcus aureus and Hemophilus influenzae are common in adolescence followed by the emergence of Pseudomonas aeruginosa and Burkholderia cepacia in later years entering adulthood.
The ability to detect the presence of various species of bacteria during an exacerbation is a common tool used by doctors to determine the set of antibiotics best suited to clear the infection. In clinics, sputum cultures have been the standard in which sputum from a patient is used to grow bacteria on a culture dish. One of the problems with using this technique is that it is does not provide a true description of the bacteria in the patient’s lung because not all bacteria can be grown through this method. This has long left doctors in the dark concerning the number and kinds of bacteria grown during times of infection.
In recent years, advances in DNA sequencing has slowly begun to create a more robust picture of the microbial community characteristic of CF. Rather than detecting bacteria by those that are grown on a culture, sequencing is a more sensitive technique that identifies bacteria based on the presence of its DNA. One common sequencing technique allows for the identification of bacteria through analysis of the 16s ribosomal subunit gene.
The use of DNA sequencing has quickly identified the weaknesses of past culturing techniques. In a recent article in the Journal of Clinical Microbiology, John LiPuma discusses the advantage of sequencing noting, “it is now clear that CF airways typically harbor a greater number of bacterial species than the relatively small number of species reported by standard culture.” He continues noting a weakness of clinics that, “although DNA sequence analyses are increasingly finding their way into the clinical microbiology laboratory, methods requiring detailed analysis of the large data sets resulting from deep sequencing remain primarily in the domain of research laboratories.”
DNA sequencing has demonstrated that the CF lung houses a high number of diverse bacteria beyond the common pathogens previously recognized through culturing methods. Studies have recognized that adolescents have a more diverse bacterial community than older patients who have smaller number of bacterial species commonly with one dominating the community. Although seemingly counterintuitive, this insight suggests that a greater number of bacteria may be beneficial in preventing the dominance of one species that will contribute to a more severe progression in lung disease.
The correlation of decreasing lung function with decreasing bacterial diversity was noted by Paganin and colleagues in a recent study published in PLOS ONE. “The reduced Evenness observed in SD (substantial decline in lung function) respect to S (stable lung function) group of patients revealed an impaired ecology of the bacterial community in SD patients, which in turn can be associated with lung function decline experienced by those patients.”
Paganin makes the point that, “as suggested by Zhao and colleagues, other factors, such as antibiotic use, rather than lung function or patient age have been found to be the primary drivers of the decreasing bacterial diversity in CF patients with progressive lung disease.”
Considerable progress is left to be made by researchers and doctors to understand the composition of the bacterial community in the CF lung and the role that it plays in the progression of lung disease in CF. A new class of CF drugs, such as ivacaftor, which repair the function of the defective protein in CF have been shown to decrease the number of exacerbations in patients over extended periods of time. New studies are being conducted to understand what effect these new class of drugs may have on the composition of bacterial communities in the lung relating to this decrease in number of exacerbations.
A recent study published in PLOS ONE by Bernarde and colleagues examined the change in the composition of bacterial communities in three G551D patients treated with ivacaftor by analysis of DNA sequencing. One observation noted by the study was that there was a greater bacterial diversity in patients after treatment with ivacaftor. “Ivacaftor may disrupt the CF microbiota, even if no significant differences were observed on the Colin White test.” Bernarde notes, “this tendency corroborates the hypothesis made by Rower et al., who suggested increased microbial diversity resulting from ivacaftor administration. As for other clinical situations in CF increased biodiversity may be supposed to be associated with improved respiratory function, as well as other clinical endpoints in phase-3 studies of ivacaftor.”
A great deal is left to better understand the role of bacteria in CF infection and lung disease. However, even though the study by Bernarde and colleagues was limited in its sample size it shows promise that icavaftor and other CFTR modulator drugs may help to improve lung function in patients through altering the bacterial communities within in the lung.
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