Neuronal regulation of intestinal stem cells dictates immune homeostasis

The intestinal epithelium undergoes continuous regeneration driven by intestinal stem cells (ISCs) residing within the crypt niche. Traditionally, this niche has been viewed as a stromal signaling compartment governed by gradients of Wnt, bone morphogenetic protein, and Notch activity. However, recent advances have revealed regulation via far more complex multicellular networks integrating stromal, immune, vascular, neuronal, and glial signals. In this review, we discuss emerging evidence positioning the enteric nervous system as a regulator of epithelial differentiation, regeneration, and mucosal immunity. Collectively, these findings support a revised model in which the ISC niche functions as an extended neuroglial-immune sensory unit. Understanding this integrated regulatory architecture may provide new therapeutic opportunities for inflammatory bowel disease, infection, impaired regeneration, and neuroimmune disorders of the gut.