The intestinal epithelium, a critical interface between the gut and the body's internal environment, plays a dual role in nutrient absorption and immune defense. Intestinal stem cells (ISCs) are essential for maintaining epithelial integrity and homeostasis throughout an individual's lifespan. Recent research has highlighted the intricate interplay between ISCs and their niche, which includes various cell types, extracellular components, and signaling molecules. This review focuses on the regulatory mechanisms governing ISC behavior, emphasizing the dynamic adaptability of the intestinal epithelium in response to environmental challenges. Key signaling pathways, such as Wnt, Notch, BMP, and Hedgehog, are crucial for maintaining ISC function. The role of Lgr5, a receptor for R-spondin, in promoting Wnt signaling and stabilizing β-catenin is particularly important. Additionally, the niche environment, including Paneth cells and mesenchymal cells, significantly influences ISC function. Aging and dietary factors, such as high-fat diets, can disrupt mucosal homeostasis by altering ISC behavior and the gut microbiome. Understanding these complex interactions is crucial for developing strategies to improve gut health and address age-related gastrointestinal disorders.The intestinal epithelium, a critical interface between the gut and the body's internal environment, plays a dual role in nutrient absorption and immune defense. Intestinal stem cells (ISCs) are essential for maintaining epithelial integrity and homeostasis throughout an individual's lifespan. Recent research has highlighted the intricate interplay between ISCs and their niche, which includes various cell types, extracellular components, and signaling molecules. This review focuses on the regulatory mechanisms governing ISC behavior, emphasizing the dynamic adaptability of the intestinal epithelium in response to environmental challenges. Key signaling pathways, such as Wnt, Notch, BMP, and Hedgehog, are crucial for maintaining ISC function. The role of Lgr5, a receptor for R-spondin, in promoting Wnt signaling and stabilizing β-catenin is particularly important. Additionally, the niche environment, including Paneth cells and mesenchymal cells, significantly influences ISC function. Aging and dietary factors, such as high-fat diets, can disrupt mucosal homeostasis by altering ISC behavior and the gut microbiome. Understanding these complex interactions is crucial for developing strategies to improve gut health and address age-related gastrointestinal disorders.