Deciphering the role of the Cystic Fibrosis Transmembrane Receptor (CFTR) in dietary fatty acid transport in the small intestine

Program Director/Principal Investigator (Last, First, Middle): Kohan, Alison B (PI); Hodges, CA (MPI) PROJECT SUMMARY Though cystic fibrosis (CF) is considered a lung disease, it presents in infancy as an intestinal disease leading to severe malnutrition and low body weight. These small intestinal symptoms are directly related to future respiratory failure and mortality rates. A major gap in the field, even with modulator therapy, is determining the mechanisms of intestinal CFTR dysfunction and how to reverse the persistent nutritional defects in patients with CF. Using a novel surgical model and primary intestinal organoids, identified fatty acid (FA) trafficking across the apical epithelial membrane as the step of lipid absorption that is inhibited by CFTR-/-. Our studies will test clinically relevant experimental diets and modulator therapy in gold-standard models of fat absorption and use patient- derived human intestinal organoids to directly quantify dietary fat absorption and chylomicron secretion. The outcome of our studies could have a measurable impact on patients with CF, especially in early life, as these studies will fill a persistent gap in knowledge about the activity of CFTR modulators in the intestine and mechanisms of fat malabsorption (in CF and in other malabsorptive or diarrheal diseases).