Development and validation of the CF Gut Microbial Dysbiosis Index (CF-GMDI), a species-level metagenomic index, to quantify gut microbial imbalance in children with CF (ages 0–18 years) vs. healthy controls, and to assess its responsiveness to Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy.
CF-GMDI was significantly higher in children with CF vs. healthy controls (p < 0.001), inversely correlated with species richness (ρ = −0.74, p < 0.001), higher in pancreatic-insufficient vs. pancreatic-sufficient CF (p = 0.01), and decreased significantly at 6 and 12 months post-ETI treatment — while standard alpha diversity metrics showed no change.
Index was derived from a single cohort (PEARL-CF; n=70 CF, 67 controls; ages 0–6) and validated in one independent cohort (EARTH; n=56 CF, 56 controls); ETI responsiveness was assessed using publicly available data, not a purpose-designed trial. Age range of derivation cohort (0–6 years) is narrower than the validation cohort (0–18 years), which may affect generalizability.
CF-GMDI may serve as a more sensitive and CF-specific endpoint than standard diversity metrics for tracking gut microbiome changes in clinical trials, particularly for CFTR modulator therapies like ETI. Clinicians and researchers designing CF intervention studies should consider this index as a standardised, reproducible gut health measure.
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