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

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.

Longitudinal Microbial and Molecular Dynamics in the Cystic Fibrosis Lung after Elexacaftor-Tezacaftor-Ivacaftor therapy.

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 the lung function and decreased airway infection of 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, remains 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 of CF subjects 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. 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.

Garden microbiomes of Apterostigma dentigerum and Apterostigma pilosum fungus-growing ants (Hymenoptera: Formicidae).

Fungus-growing ants share a complex symbiosis with microbes, including fungal mutualists, antibiotic-producing bacteria, and fungal pathogens. The bacterial communities associated with this symbiosis are poorly understood but likely play important roles in maintaining the health and function of fungal gardens. We studied bacterial communities in gardens of two Apterostigma species, A. dentigerum, and A. pilosum, using next-generation sequencing to evaluate differences between the two ant species, their veiled and no-veiled fungal garden types, and across three collection locations. We also compared different parts of nests to test for homogeneity within nests. Enterobacteriaceae dominated gardens of both species and common OTUs were shared across both species and nest types. However, differences in community diversity were detected between ant species, and in the communities of A. dentigerum veiled and no-veiled nests within sites. Apterostigma pilosum had a higher proportion of Phyllobacteriaceae and differed from A. dentigerum in the proportions of members of the order Clostridiales. Within A. dentigerum, nests with veiled and no-veiled fungus gardens had similar taxonomic profiles but differed in the relative abundance of some groups, with veiled gardens having more Rhodospirillaceae and Hyphomicrobiaceae, and no-veiled having more Xanthomonadaceae and certain genera in the Enterobacteriaceae C. However, bacterial communities in Apterostigma fungal gardens are highly conserved and resemble those of the nests of other attine ants with dominant taxa likely playing a role in biomass degradation and defense. Further work is required to understand and explain how bacterial community composition of fungus-growing nests is maintained.