Impaired distal colonic pH in adults with cystic fibrosis

Patel, Dhiren; Mathews, Stacy; Unen, Vincent van; Chan, Joshua E; Al-Hammadi, Noor; Borowitz, Drucy; Gelfond, Daniel; Sellers, Zachary M.

doi:10.1016/j.jcf.2022.12.011

“…The CFTR channel permits transepithelial movement of bicarbonate (HCO3 − ) and chloride (Cl − ) ( 5 ). Intestinal pH is lower in patients with CF due to the lack of neutralizing bicarbonate ( 86 ) yet increases with CFTR modulator treatment, consistent with increased CFTR activity in the intestinal tract ( 87 ). We observed a reduced abundance of microbial protein groups associated with acid tolerance ( Fig.…”

Section: Discussionmentioning

confidence: 93%

Longitudinal profiling of the intestinal microbiome in children with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor

Reasoner,

Bernard,

Waalkes

et al. 2024

mBio

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The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores the function of the pathogenic mutated CF transmembrane conductance regulator (CFTR) channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in body mass index and percent predicted forced expiratory volume in one second, and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus , the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA. IMPORTANCE Cystic fibrosis (CF) is an autosomal recessive disease with significant gastrointestinal symptoms in addition to pulmonary complications. Recently approved treatments for CF, CF transmembrane conductance regulator (CFTR) modulators, are anticipated to substantially improve the care of people with CF and extend their lifespans. Prior work has shown that the intestinal microbiome correlates with health outcomes in CF, particularly in children. Here, we study the intestinal microbiome of children with CF before and after the CFTR modulator, ELX/TEZ/IVA. We identify promising improvements in microbiome diversity, reduced measures of intestinal inflammation, and reduced antibiotic resistance genes. We present specific bacterial taxa and protein groups which change following ELX/TEZ/IVA. These results will inform future mechanistic studies to understand the microbial improvements associated with CFTR modulator treatment. This study demonstrates how the microbiome can change in response to a targeted medication that corrects a genetic disease.

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“…The CFTR channel permits transepithelial movement of bicarbonate (HCO3 - ) and chloride (Cl - ) (5). Intestinal pH is lower in patients with CF due to the lack of neutralizing bicarbonate (85) yet increases with CFTR modulator treatment, consistent with increased CFTR activity in the intestinal tract (86). We observed a reduced abundance of microbial protein groups associated with acid tolerance (Fig.…”

Section: Discussionmentioning

confidence: 93%

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor

Reasoner,

Bernard,

Waalkes

et al. 2023

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The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores function of the pathogenic mutated CFTR channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in BMI, ppFEV1 and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus, the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic-resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.

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Neurogastroenterology and Motility Disorders of the Gastrointestinal Tract in Cystic Fibrosis

Patel,

Jose,

Baker

et al. 2023

Curr Gastroenterol Rep

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Impaired distal colonic pH in adults with cystic fibrosis

Cited by 4 publications

References 21 publications

Longitudinal profiling of the intestinal microbiome in children with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor

Longitudinal profiling of the intestinal microbiome in children with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor

Neurogastroenterology and Motility Disorders of the Gastrointestinal Tract in Cystic Fibrosis

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