In patient with cystic fibrosis (CF), the administration of tezacaftor/ivacaftor therapy is not associated with any significant effect on gut microbiota composition or on relative levels of fecal short-chain fatty acid (SCFA), according to findings from a randomized, crossover pilot study published in the journal Microbiology Spectrum.
Throughout their lives, individuals with CF experience a variety of persistent gastrointestinal (GI) symptoms. The research question, “How can we relieve GI symptoms, such as stomach pain, bloating, and nausea?” continues to be a high priority of clinical research in the field of CF. Although evidence supports a role for the interaction between the microbiota and gut pathophysiology among patients with CF, a paucity of information is available on the possible impact of CF transmembrane conductance regulator (CFTR) modulator treatments in individuals with the disorder.
Recognizing that more than two-thirds of patients with CF in the United Kingdom currently receive CFTR modulator therapies, the researchers sought to explore the impact of treatment with tezacaftor/ivacaftor dual combination modulator therapy on the gut microbiota and metabolomic functioning in persons with CF.
In an effort to evaluate SCFA composition, fecal samples obtained at baseline and following tezacaftor/ivacaftor or placebo administration from 12 patients with CF underwent microbiota sequencing and targeted metabolomics. Ten healthy matched controls were included in the study as a comparator group. The investigators also assessed inflammatory calprotectin concentration and patients’ symptoms.
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After plotting distribution-abundance relationships for all sample groups—from the baseline, tezacaftor/ ivacaftor, and placebo treatment periods, as well as the healthy controls—bacterial taxa from within the entire gut microbiota were partitioned into common core and rare satellite taxa.
Results of the study revealed no statistically significant differences in overall gut microbiota characteristics among any of the study stages, including in gut symptoms, intestinal inflammation, or SCFA-directed metabolomics. In all treatment stages, however, microbiota and SCFA metabolomic compositions in persons with CF differed significantly from those in controls.
There were significant differences in diversity reported in core taxa between baseline and placebo (P =.007), as well as between the placebo and tezacaftor/ivacaftor treatment groups (P =.039). Core taxa diversity, however, did not differ significantly between the baseline and tezacaftor/ivacaftor groups (P >.05). In addition, for the satellite taxa, no statistically significant differences in diversity were seen between the treatment periods (P >.05 for all).
When diversity and composition of the microbiota, core taxa, and satellite taxa between each treatment period and the healthy controls were compared, diversity in the control group was significantly higher compared with each treatment period (P <.05 for all). In a similar fashion, the microbiota, satellite taxa, and core taxa compositions of the control samples differed significantly from those of the patients with CF for all treatment periods (P <.05 throughout).
“Tezacaftor/ivacaftor had negligible effects on patient GI symptoms, intestinal inflammation, or gut microbiome composition and functioning,” the researchers noted. “Our findings are important as they fill knowledge gaps on the relative effectiveness of these widely used treatments. We are now investigating triple combination CFTR modulators with prolonged sampling periods,” they concluded.
Reference
Marsh R, Dos Santos C, Hanson L, et al. Tezacaftor/ivacaftor therapy has negligible effects on the cystic fibrosis gut microbiome. Microbiol Spectr. Published online August 21, 2023. doi:10.1128/spectrum.01175-23
