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Related Experiment Video

Updated: May 23, 2025

Rectal Organoid Morphology Analysis ROMA: A Diagnostic Assay in Cystic Fibrosis
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Intestinal current measurement detects age-dependent differences in CFTR function in rectal epithelium.

Simon Y Graeber1,2,3, Olaf Sommerburg4,5, Yin Yu4,5

  • 1Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität, Berlin, Germany.

Frontiers in Pharmacology
|March 11, 2025
PubMed
Summary

Cystic fibrosis transmembrane conductance regulator (CFTR) function in the rectal epithelium declines with age, likely due to fewer secretory colonocytes. This age-related decline may explain why children respond better to CFTR modulator therapies than adults.

Keywords:
CFTRCFTR modulator therapyage-dependencyintestinal current measurementrectal epitheliumsecretory diarrhea

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Area of Science:

  • Gastroenterology
  • Pulmonology
  • Genetics

Background:

  • Intestinal current measurement (ICM) assesses cystic fibrosis transmembrane conductance regulator (CFTR) function in rectal biopsies, aiding cystic fibrosis (CF) diagnosis and evaluating CFTR modulator efficacy.
  • Clinical trials suggest CFTR function in sweat ducts is age-dependent, with children exhibiting higher levels than adults, but intestinal CFTR function's age dependency is less understood.

Purpose of the Study:

  • To investigate the age-related changes in CFTR-mediated chloride secretion in the rectal epithelium.
  • To explore the underlying mechanisms, including gene expression and cell density, of age-dependent CFTR function.
  • To correlate age with CFTR function responses to CFTR modulators in individuals with CF.

Main Methods:

  • Assessed CFTR-mediated chloride secretion using intestinal current measurement (ICM) in rectal biopsies from individuals with and without CF, aged 1 month to 68 years.
  • Stimulated chloride secretion via cAMP-mediated (IBMX, forskolin) and cholinergic (carbachol) pathways.
  • Performed quantitative real-time PCR for CFTR mRNA expression and morphometric analysis of epithelial cells.

Main Results:

  • CFTR-mediated chloride secretion was highest in infancy and early childhood, declining with age in individuals without CF.
  • While cAMP-mediated currents did not differ in individuals with CF, cholinergic-induced potassium secretion decreased with age.
  • CFTR mRNA expression slightly increased with age in individuals without CF, but CFTR-expressing colonocyte numbers at the crypt base decreased.
  • A secondary analysis showed correlations between age and the response to CFTR modulators (lumacaftor/ivacaftor) in individuals with CF.

Conclusions:

  • CFTR function in the rectal epithelium diminishes with age, primarily due to a reduction in secretory colonocytes at the crypt base.
  • These age-related cellular changes in CFTR expression likely contribute to the observed differences in functional responses to CFTR modulator therapies between children and adults with CF.