The impact of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the pulmonary microbiota

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has significantly changed the course of the disease in people with cystic fibrosis (CF) (pwCF). The approved triple therapy of elexacaftor, tezacaftor and ivacaftor (ETI), commercially known as Trikafta, increases CFTR channel function, leading to improvements in sweat chloride concentration, exercise capacity, body mass index, lung function and chronic respiratory symptoms. Because of this, the majority of pwCF are living longer and having fewer CF exacerbations. However, colonization with the common CF respiratory pathogens persists and remains a major cause of morbidity and mortality. Here, we review the current literature on the effect of ETI on the respiratory microbiota and discuss the challenges in addressing CF lung infections in the era of these new life-extending therapies.

Keywords: Trikafta; cystic fibrosis; cystic fibrosis transmembrane conductance regulator (CFTR) modulators; elexacaftor, tezacaftor and ivacaftor (ETI); highly effective modulator therapy; microbiology; respiratory infections; sputum cultures.

Fig. 1.. Sites of inhibition by Trikafta (ETI). Adapted from Zaher et al. [4]. TEZ and EXA are two CFTR correctors that increase the amount of CFTR protein that reaches the cell membrane by acting on protein trafficking and modification. IVA is a potentiator that acts on gating mutations and improves the opening of the CFTR protein and thereby increases ion transport.

Fig. 2.. Proposed mechanism of Trikafta increasing microbial diversity and improving lung function. The down arrow indicates a decrease in abundance and the up arrow indicates an increase in abundance.

Fig. 3.. Effect of Trikafta on pathogen abundance in CF-associated infection sites. Sinuses, lungs and gut are pictured from top to bottom. A species or genus name listed with a down arrow indicates a decrease in relative abundance, a straight line indicates no change and an up arrow indicates an increase after ETI.