Longitudinal microbial and molecular dynamics in the cystic fibrosis lung after Elexacaftor–Tezacaftor–Ivacaftor therapy

Abstract

Background Cystic fibrosis (CF) is a genetic disorder causing poor mucociliary clearance in the airways and subsequent respiratory infection. The recently approved triple therapy Elexacaftor–Tezacaftor–Ivacaftor (ETI) has significantly improved lung function and decreased airway infection in persons with CF (pwCF). This improvement has been shown to occur rapidly, within the first few weeks of treatment. The effects of longer term ETI therapy on lung infection dynamics, however, remain mostly unknown. Results Here, we applied 16S rRNA gene amplicon sequencing, untargeted metabolomics, and neutral models to high-resolution, longitudinally collected sputum samples from pwCF on ETI therapy (162 samples, 7 patients) and compared to similarly collected data set from pwCF not taking ETI (630 samples, 9 patients). Because ETI reduces sputum production, samples were collected in freezers provided in the subject’s homes at least 3 months after first taking ETI, with those on ETI collecting a sample approximately weekly. The lung function (%ppFEV1) of those in our longitudinal cohort significantly improved after ETI (6.91, SD = 7.74), indicating our study cohort was responsive to ETI. The daily variation of alpha- and beta-diversity of both the microbiome and metabolome was higher for those on ETI, reflecting a more dynamic microbial community and chemical environment during treatment. Four of the seven subjects on ETI were persistently infected with Pseudomonas or Burkholderia in their sputum throughout the sampling period while the total bacterial load significantly decreased with time (R = − 0.42, p = 0.01) in only one subject. The microbiome and metabolome dynamics on ETI were personalized, where some subjects had a progressive change with time on therapy, whereas others had no association with time on treatment. To further classify the augmented variance of the CF microbiome under therapy, we fit the microbiome data to a Hubbell neutral dynamics model in a patient-stratified manner and found that the subjects on ETI had better fit to a neutral model. Conclusion This study shows that the longitudinal microbiology and chemistry in airway secretions from subjects on ETI has become more dynamic and neutral and that after the initial improvement in lung function, many are still persistently infected with CF pathogens.

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways

“…However, ETI only shows moderate increases in ppFEV1 in subjects who were ineligible for enrollment in registration studies and those with severe airway obstruction (ppFEV1 < 40) ( Fila et al, 2023 ). Although ETI treatment reduces positive bacterial cultures in patients ( Bower et al, 2023 ), bacteria not in the CF pathogen genera persist in the sputum of patients and are not changed by ETI treatment ( Martin et al, 2023 ; Nichols et al, 2023 ). These findings may reflect the complex responses of microbiota to ETI treatment.…”

Surface-Exposed Protein Moieties of Burkholderia cenocepacia J2315 in Microaerophilic and Aerobic Conditions

“…This resistance, coupled with the patient-to-patient rapid spread of highly transmissible strains and the vast assortment of virulence factors, renders these chronic infections highly unpredictable, hazardous, and nearly untreatable [7,8]. Recently, the CFTR modulator TRIKAFTA ® , has been approved to treat CF patients with one copy of the F508del mutation and revealed good results in improving patients' lung function [9]. The sputum pathogen load, including Bcc infections, was lower in the first month of treatment and was followed by a 6-month steady state of lung function and bacterial load [9].…”

“…Recently, the CFTR modulator TRIKAFTA ® , has been approved to treat CF patients with one copy of the F508del mutation and revealed good results in improving patients' lung function [9]. The sputum pathogen load, including Bcc infections, was lower in the first month of treatment and was followed by a 6-month steady state of lung function and bacterial load [9]. However, in some CF patients, Pseudomonas aeruginosa and Bcc infections were persistent after treatment, and it is still unclear if effective eradication after long-term treatment is possible.…”