l-Glutamate drives porcine intestinal epithelial renewal by increasing stem cell activity via upregulation of the EGFR-ERK-mTORC1 pathway.

l-Glutamate (Glu) is a nutritionally functional amino acid for pigs. In addition, intestinal stem cells (ISCs) maintain epithelial renewal and homeostasis by dynamically regulating proliferation and differentiation to cope with environmental cues. The rapid renewal of the intestinal epithelium requires a continuous supply of energy sources such as Glu. However, the effects of Glu on ISCs and epithelial renewal are poorly understood. In this study, we found that dietary Glu accelerated intestinal epithelial renewal and gut growth. The epidermal growth factor receptor (EGFR)/extracellular regulated protein kinase (ERK) pathway and mechanistic target of rapamycin complex 1 (mTORC1) signaling were involved in this response in piglets. Subsequent cellular assessment suggested that the EGFR/ERK pathway was upstream of Glu-induced mTORC1 signaling activation. Furthermore, we found that Glu activated the EGFR/ERK pathway and promoted ISC proliferation and differentiation in porcine intestinal organoids. Collectively, our findings suggest that Glu drives intestinal epithelial renewal by increasing ISC activity via the EGFR/ERK/mTORC1 pathway. The present study provides direct evidence that mTORC1 is activated by extracellular Glu through EGFR and that Glu acts as a nutritionally functional amino acid for piglets to maintain intestinal growth and health.