Tezacaftor/Ivacaftor therapy has negligible effects on the cystic fibrosis gut microbiome

Abstract

People with cystic fibrosis (pwCF) experience a range of persistent gastrointestinal symptoms throughout life. There is evidence indicating interaction between the microbiota and gut pathophysiology in CF. However, there is a paucity of knowledge on the potential effects of CF transmembrane conductance regulator (CFTR) modulator therapies on the gut microbiome. In a pilot study, we investigated the impact of Tezacaftor/Ivacaftor dual combination CFTR modulator therapy on the gut microbiota and metabolomic functioning in pwCF. Fecal samples from 12 pwCF taken at baseline and following placebo or Tezacaftor/Ivacaftor administration were subjected to microbiota sequencing and to targeted metabolomics to assess the short-chain fatty acid (SCFA) composition. Ten healthy matched controls were included as a comparison. Inflammatory calprotectin levels and patient symptoms were also investigated. No significant differences were observed in overall gut microbiota characteristics between any of the study stages, extended also across intestinal inflammation, gut symptoms, and SCFA-targeted metabolomics. However, microbiota and SCFA metabolomic compositions, in pwCF, were significantly different from controls in all study treatment stages. CFTR modulator therapy with Tezacaftor/Ivacaftor had negligible effects on both the gut microbiota and SCFA composition across the course of the study and did not alter toward compositions observed in healthy controls. Future longitudinal CFTR modulator studies will investigate more effective CFTR modulators and should use prolonged sampling periods, to determine whether longer-term changes occur in the CF gut microbiome. IMPORTANCE People with cystic fibrosis (pwCF) experience persistent gastrointestinal (GI) symptoms throughout life. The research question “how can we relieve gastrointestinal symptoms, such as stomach pain, bloating, and nausea?” remains a top priority for clinical research in CF. While CF transmembrane conductance regulator (CFTR) modulator therapies are understood to correct underlying issues of CF disease and increasing the numbers of pwCF are now receiving some form of CFTR modulator treatment. It is not known how these therapies affect the gut microbiome or GI system. In this pilot study, we investigated, for the first time, effects of the dual combination CFTR modulator medicine, Tezacaftor/Ivacaftor. We found it had negligible effects on patient GI symptoms, intestinal inflammation, or gut microbiome composition and functioning. Our findings are important as they fill important knowledge gaps on the relative effectiveness of these widely used treatments. We are now investigating triple combination CFTR modulators with prolonged sampling periods.

Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis

“…With respect to microbiota diversity, we demonstrate a significant shift in the core taxa of pwCF following extended ETI therapy, which translated into a positive trajectory of whole microbiota diversity by the end of the study period. Despite this, diversity was not significantly different following ETI, as shown previously with less efficacious CFTR modulator treatments encompassing shorter administration periods [15–17,19]. Interestingly, Kristensen et al did observe significant increases in faecal microbiota diversity [18], but only following extended (12 month) Ivacaftor therapy in a group of pwCF harbouring the S1251N mutation.…”

“…Results for the frequently observed inflammation in the gut following modulator treatment are also contrasting. Some studies observed a reduction in faecal calprotectin following modulator usage [15,20,21], whilst others [16] and our own group [19], did not measure any notable reduction.…”

“…GC-MS analysis was carried out using an Agilent 7890B/5977 Single Quadrupole Mass Selective Detector (MSD) (Agilent Technologies) equipped with a non-polar HP-5ms Ultra Inert capillary column (30 m × 0.25 mm × 0.25 µm) (Agilent Technologies). Faecal sample processing to obtain, and then to derivatise SCFAs prior to GC-MS analysis, was carried out as previously described [19]. Following derivatisation, samples were loaded onto the GC-MS and injected using an Agilent 7693 Autosampler.…”

“…Previous studies investigating CFTR modulators and microbiota within the gastrointestinal tract have been mostly limited to Ivacaftor [15–18] and a couple of dual-modulator studies [17], including our previous work investigating the impact of Tezacaftor/Ivacaftor [19]. With respect to the microbiota structure, previous findings vary across studies incorporating different modulators, patient demographics, and treatment lengths [15–18].…”

Bicarbonate secretion and acid/base sensing by the intestine

“…These suboptimal strategies to improve CF-associated intestinal disease are now being successfully replaced by CFTR targeted therapy which improves not only the pulmonary but also the intestinal symptoms [ 54 , 88 , 112 ]. Preliminary results suggest that this improvement is not reached via an alteration of the dysbiotic gut microbiota seen in patients with CF [ 108 ]. Recent studies in CFTR null mice aimed to explore strategies to increase the alkalinity and fluidity in an intestine that expressed no functional CFTR protein at all and therefore is not a candidate for CFTR-targeted therapy.…”