SCFAs Switch Stem Cell Fate Through HDAC Inhibition to Improve Barrier Integrity in 3D Intestinal Organoids from Patients with Obesity

Overview

Journal iScience

Publisher Cell Press

Date 2023 Dec 21

PMID 38125020

Authors

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

Soon will be listed here.

Abstract

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.

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