FFAR4 drives stem cell fate toward lipid- and iron-storing enterocytes protecting human enteroids from ferroptosis

Intestinal stem cell (ISC) fate is directed by microenvironmental cues, partly regulated through surface receptors, many of which remain incompletely characterized. Here, we investigated the functional role of the lipid-sensing receptor free fatty acid receptor 4 (FFAR4) in regulating ISC fate in normal-weight individuals, and hypothesized that its function may be affected in the lipid-rich environment of patients with obesity.

Human-derived small intestinal organoids (enteroids) were developed from normal-weight multi-organ donors and from patients with obesity who underwent a Roux-en Y gastric bypass.

In enteroids derived from normal-weight individuals, FFAR4 activation in ISCs promoted differentiation toward lipid-processing absorptive enterocytes while reducing secretory goblet cell formation. Functionally, mucin production was not affected but lipid droplet formation and iron storage were increased and blocked by a MEK1/2 inhibitor. This crosstalk reduced lipid peroxidation and hence the susceptibility to ferroptosis in the presence of environmental stressors. In contrast, FFAR4 activation in enteroids from patients with obesity failed to rewire the composition and function of the enteroid epithelium, suggesting impaired FFAR4 signaling in the obese ISC compartment.

Altogether, our findings show that chemosensory receptors on stem cells play a more influential role than previously appreciated in modulating gut epithelial composition and function in response to environmental cues.