CF and Bacteria… How are they related?

Cystic fibrosis is a genetic disease caused by a mutation in the CFTR gene; this mutation alters the movement of chloride ions in and out of epithelial cells in the body. The disruption of these cellular functions affect normal mucus consistency which typically lines organs - our lab particularly studies the lungs and airway. 

When chloride ions cannot flow through the mutated CFTR protein to exit the cell easily (or at all), extracellular mucus develops a viscous consistency due to dehydration. Defective ion transport causes water to be drawn away from the airway surface, dehydrating the mucus layer. This dehydrated mucus layer disrupts the natural flow of mucus within the organs, and therefore interrupts the fundamental clearing mechanism known as mucociliary transport/clearance. 

In healthy individuals, mucociliary transport sweeps the thin layer of mucus coating the epithelial cells, this is to help protect the host against pathogenic bacteria and clear the airway of debris. In people with cystic fibrosis (pwCF), mucociliary transport is dampened by the sticky mucus, providing the perfect nesting ground for bacteria to grow and stay. Interestingly, pwCF are known to house unique microbiomes that are different from typical cultures.

The Game Changing Modulator

Before the three part modulator was approved in Canada back in June of 2021 (Health Canada, 2021), the big question in Cystic Fibrosis research was how to increase life expectancy of those with the disease. Now research is starting to shift its focus from survival to thrival, and part of the mystery is how Trikafta affects lung health beyond its immediate CFTR-correcting effects.

Trikafta is a combination of Elexacaftor, Tezacaftor and Ivacaftor and is thus also known as ETI treatment. Elexacaftor and Tezacaftor are both corrector modulators, working to improve the folding for CFTR protein mutation F508del, increasing the amount of CFTR proteins that reach the cell membrane. Ivacaftor complements the work of correctors by acting on CFTR channels that have reached the membrane, increasing the probability that they will remain open to enhance ion transport; Ivacaftor is known as a potentiator. 

Trikafta and the CF Lung Microbiome 

Despite inhibited pathogen clearance, pwCF often have low microbial diversity due in the airway, beleived to be caused due to the dominance of specific resilient bacteria. Recent studies have found that this diversity actually increases follwoing Trikafta initiation, suggesting that the composition of bacterial communities can change in repsonse to CFTR correction in the airway epithelia (Sosinski et al., 2022). While not all lungs with CF have the same rates of microbial differentiation post ETI initiation, all patients seem to move towards a higher level of diversity. This may be evidence to suggest that the airway microbiome shifts towards a less pathogen dominant environment and toward an increasingly even microbial community. 

Research has also been exploring the relationship between Trikafta, the lung microbiome, and the metabolome. The metabolome plays a direct role in health because it comprises of the small molecules involved in cellular processes, reflecting the biochemical activity of both the host and its microorganisms. Bacteria often use metabolome products for nutrition and so, the prevalence of particular metabolites can serve as a great indicator about what microorganisms may be present. Keeping this in mind, pwCF who demonstrate low microbial diversity often encounter imbalances in metabolites, with an increase in inflammation associated compounds. Sosinski et al. (2022) found that the change of bacterial composition in pwCF upon ETI treatment initiation influenced metabolite presence, then observed a decrease in inflammatory response related metabolites.

What Does this Mean for CF research?

As scientists push the limits and continue to search for ways to improve the lives of those with Cystic Fibrosis, more and more questions arise with regard to how things are moving and what impact these changes are really making. The question of Trikafta’s affects on the lung microbiome is not a question of whether Trikafta itself is making the change, but rather, how are the outcomes in Trikafta patients affecting other aspects of their health along the way?

While Trikafta is not an antimicrobial treatment, these findings suggest that the benefits of Trikafta extend beyond correcting a defective protein. By altering the lung environment, ETI therapy may help reshape the microbial communities and biochemical processes that contribute to disease progression. Understanding these changes could help researchers identify new ways to further improve long term health outcomes for people with cystic fibrosis.

References 

Health Canada. (2021, November 16). Question period note: Trikafta (Reference No. HC-2021-QP2-00017). Government of Canada. 

Sosinski, L. M., Martin, C. H., Neugebauer, K. A., Ghuneima, L.-A. J., Guzior, D. V., Castillo-Bahena, A., Mielke, J., Thomas, R., McClelland, M., Conrad, D., & Quinn, R. A. (2022). A restructuring of microbiome niche space is associated with elexacaftor-tezacaftor-ivacaftor therapy in the cystic fibrosis lung. Journal of Cystic Fibrosis, 21, 996–1005. https://doi.org/10.1016/j.jcf.2022.06.009

Image created by Briley Hillyard using BioRender.com