Folic acid enhances intestinal stem cell-mediated epithelial regeneration depending on β-adrenergic receptor signaling

Abstract

Folic acid, a water-soluble B vitamin, is well known for its critical roles in neural tube development and its contributions to neonatal gut maturation and overall gut health. However, the specific mechanisms by which folic acid influences the intestinal mucosa remain incompletely understood. In this study, we aimed to explore the effects of folic acid on the proliferation and differentiation of intestinal stem cells (ISCs). A mouse model of intestinal mucosal injury was established by intraperitoneal injection of 5-fluorouracil (5-FU) at 50 mg kg-1 body weight once daily for five consecutive days. Our results demonstrated that folic acid enhanced epithelial barrier integrity and modulated epithelial function through the upregulation expression of tight junction components and nutrient transporters. Additionally, folic acid promoted the differentiation of intestinal epithelial cells and accelerated ISC renewal. Mechanistically, folic acid increased the expression of β-adrenergic receptors, whereas its stimulatory effects on enteroid growth and budding were attenuated by the β-adrenergic receptor antagonist propranolol, suggesting the involvement of β-adrenergic receptor signaling in folic acid-mediated epithelial regeneration. Collectively, these findings indicate that folic acid enhances ISC-driven epithelial regeneration in a β-adrenergic signaling-dependent manner, providing new insights into intestinal homeostasis and potential therapeutic strategies for mucosal injury.