The enteric nervous system. (a) Cross-sectional view. The enteric nervous system (ENS) is embedded in the wall of the GI tract. The neurons are localized in the myenteric and submucosal plexi and are connected by interneurons (depicted in grey). Extrinsic efferent innervation via autonomic sympathetic (green) and parasympathetic (blue) pathways contributes to the regulation and coordination of GI function. Extrinsic afferent sensory nerves (orange) following either vagal or spinal routes provide the central nervous system with information about GI homeostasis. (b) Longitudinal view illustrating a selection of neuronal subtypes. Secretomotor and vasodilator neurons regulate fluid and molecular exchange between gut lumen, tissue, and vasculature. Peristaltic movements (oral contraction and aboral relaxation of intestinal smooth muscle) are facilitated by intrinsic primary afferent neurons (IPANs) activating ascending and descending interneurons, which then activate upstream excitatory and downstream inhibitory motor neurons, respectively. IPANs may initially be activated, e.g., through mechanoreceptors or by acetylcholine secreted by enteric endocrine cells in the luminal epithelial cell layer upon luminal distension. In addition, ENS includes the innervation of gastroenteropancreatic endocrine cells (not shown) and gut-associated lymphoid tissue, responsible for hormone secretion and transmitter release. Although not equally represented, the juxtapositioned networks of enteric glial cells (EGCs) and interstitial cells of Cajal (ICCs) are present in all layers of the GI wall. Note that the thickness of the different tissue layers is not proportionally represented.