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This prospective, post-approval study investigated the impact of 15-week ETI therapy on sinonasal microbiota of pwCF aged 12 years and older. Whole-genome shotgun sequencing was performed on total DNA from 24 paired nasal lavage samples, with synthetic spike-in controls enabling absolute abundance normalization. Taxonomic profiling was conducted using the Wochenende pipeline. ETI did not induce major shifts in alpha or beta diversity. Instead, the overall microbial community became further dominated by the skin commensals\n                      <jats:italic toggle=\"yes\">Staphylococcus epidermidis<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Cutibacterium acnes<\/jats:italic>\n                      , accompanied by a more than twofold increase in total bacterial load. Classical CF pathogens showed divergent trajectories:\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      tended to decrease, whereas\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      exhibited a tendency toward increased abundance. Co-occurrence network analysis revealed a transition from a dense, multicomponent baseline network to a single, fully connected, but less densely integrated network following treatment initiation.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The nasal cavity represents the primary entry point of microorganisms into the respiratory tract and a potential reservoir for lower airway infection, the major cause of CF disease progression. Using shotgun metagenomics with spike-in controls, this study provides the first genome-wide characterization of how ETI alters microbial load and pathogen dynamics in CF nasal airways. Treatment with ETI strengthened the dominance of skin commensals in the nares while reducing\n                        <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                        . Given the observed increase in\n                        <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                        , further work is needed to determine whether this represents expansion of a typical nasal colonizer or a clinically relevant rise of a key CF pathogen that could act as a reservoir for future lower airway infection.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00601-26","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:00:26Z","timestamp":1783947626000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Effects of elexacaftor\/tezacaftor\/ivacaftor on the nasal microbial metagenome in cystic fibrosis"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5423-7950","authenticated-orcid":true,"given":"Tom 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