EPS5.02 Faecal microbiota changes in patients with cystic fibrosis with 6 months of elexacaftor/tezacaftor/ivacaftor: preliminary findings from the PROMISE study

Objectives: Patients with CF often have fecal dysbioses relative to those without CF that correlate with increased fecal inflammation and altered bile acids (BAs). Intestinal bacteria encode bile salt hydrolases (BSHs) that modify BAs, impacting BA receptor signaling and multiple GI functions. The interplay between fecal dysbiosis, fecal BA content, and markers of GI function and inflammation is not well studied in CF. We previously found that treatment with elexacaftor/tezacaftor/ivacaftor (ETI) is associated with decreased fecal calprotectin, a biomarker of GI inflammation. The goal of this analysis is to characterize the relative dynamics of fecal microbiota constituency, BA content, BSH gene abundance, and calprotectin pre- and post-ETI initiation. Methods: This is an interim, ancillary analysis of stool samples from subjects in PROMISE, a prospective observational study of children (6–11 y/o) and adults (≥12 y/o) with CF (NCT04613128, NCT04038047). Fecal microbiota were defined by shotgun metagenomic sequencing. Results: We analyzed 140 samples from 70 children (pre- and 1 month post-ETI) and 111 samples from 41 adults (pre-, 1 month, and 6 months post-ETI). Among all subjects, we found no statistically significant differences in fecal microbiota pre- versus post-ETI. We then analyzed the fecal microbiota in subjects with initially abnormal calprotectin that normalized with ETI. Calprotectin significantly decreased in 40 children and 31 adults after 1 and 6 months of ETI, respectively. Among these, 8 children and 10 adults had initially abnormal calprotectin that normalized. In this subset of subjects, we found no statistically significant differences in fecal microbiota pre- versus post-ETI. Conclusions: In this analysis of 70 children and 41 adults with CF, we detected no significant changes in fecal microbiota after 1 (pediatric) and 6 (adult) months of ETI. Ongoing analysis includes later timepoints (2 years post-ETI), BA content, and BSH gene abundances.