Kynurenine promotes porcine intestinal epithelial cell proliferation by activating the AHR-MST1-YAP1 axis

The objective of this study was to investigate the effect of L-tryptophan (L-Trp) and its metabolite kynurenine (Kyn) on the regulation of porcine intestinal epithelial cell proliferation.

Dietary supplementation of L-Trp significantly increased villus height and decreased crypt depth in the jejunum and ileum of weaned pigs. mRNA sequencing data and qPCR analysis found that L-Trp activated the expression of cell proliferative genes and the AHR (aryl hydrocarbon receptor)-MST1 (mammalian STE20-like kinase 1)-YAP1 (Yes-associated protein 1) axis in the ileum. Further in vitro analysis revealed that L-Trp treatment significantly enhanced cell proliferation of intestinal porcine epithelial cells-jejunum 2 (IPEC-J2) cells by activating the MST1-YAP1 signaling pathway. Further targeted metabolomics analysis identified Kyn as the core Trp metabolite involved in promoting IPEC-J2 cell proliferation. Mechanistically, Kyn interacted with AHR, which in turn bound to the upstream promote region of MST1 to initiate the transcription of downstream target gene YAP1 to activate intestinal epithelial cell proliferation. Furthermore, porcine intestinal organoid model also demonstrated that Kyn promoted intestinal organoid-budding efficiency and intestinal stem cell proliferation. Importantly, by using the AHR- or YAP1-specific inhibitors, the data confirmed that the Kyn-induced intestinal epithelial cell proliferation in IPEC-J2 cells and intestinal organoids was dependent on the activation of the AHR-MST1-YAP1 axis.

Together, this study has revealed a regulatory mechanism of Trp metabolism-derived Kyn in promoting porcine intestinal epithelial cell proliferation, offering insights into the connection between nutrient metabolism and intestinal epithelial homeostasis.