SCFAs switch stem cell fate through HDAC inhibition to improve barrier integrity in 3D intestinal organoids from patients with obesity
Mona Farhadipour,
Kaline Arnauts,
Mathias Clarysse,
Theo Thijs,
Kathrin Liszt,
Bart Van der Schueren,
Laurens J. Ceulemans,
Ellen Deleus,
Matthias Lannoo,
Marc Ferrante,
Inge Depoortere
Affiliations
Mona Farhadipour
Gut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium
Kaline Arnauts
Inflammatory Bowel Disease, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium
Mathias Clarysse
Leuven Intestinal Failure and Transplantation (LIFT) Center, University Hospitals Leuven, 3000 Leuven, Belgium
Theo Thijs
Gut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium
Kathrin Liszt
Gut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium
Bart Van der Schueren
Department of Endocrinology, University Hospitals Leuven, 3000 Leuven, Belgium
Laurens J. Ceulemans
Leuven Intestinal Failure and Transplantation (LIFT) Center, University Hospitals Leuven, 3000 Leuven, Belgium
Ellen Deleus
Department of Abdominal Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
Matthias Lannoo
Department of Abdominal Surgery, University Hospitals Leuven, 3000 Leuven, Belgium
Marc Ferrante
Inflammatory Bowel Disease, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, 3000 Leuven, Belgium
Inge Depoortere
Gut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, 3000 Leuven, Belgium; Corresponding author
Summary: Stem cells are a keystone of intestinal homeostasis, but their function could be shifted during energy imbalance or by crosstalk with microbial metabolites in the stem cell niche. This study reports the effect of obesity and microbiota-derived short-chain fatty acids (SCFAs) on intestinal stem cell (ISC) fate in human crypt-derived intestinal organoids (enteroids). ISC fate decision was impaired in obesity, resulting in smaller enteroids with less outward protruding crypts. Our key finding is that SCFAs switch ISC commitment to the absorptive enterocytes, resulting in reduced intestinal permeability in obese enteroids. Mechanistically, SCFAs act as HDAC inhibitors in stem cells to enhance Notch signaling, resulting in transcriptional activation of the Notch target gene HES1 to promote enterocyte differentiation. In summary, targeted reprogramming of ISC fate, using HDAC inhibitors, may represent a potential, robust therapeutic strategy to improve gut integrity in obesity.
