The secretion of gut hormones from EECs is stimulated by the sensing of luminal factors (i), (e.g., nutrients, bile acids, microbial products) predominantly via apical GPRCs (G_q/G_s) and transporters. Gut hormones secreted into the subepithelial space mediate their local and systemic effects via a number of signaling pathways. These include absorption into the circulation to act in the classical (ii) endocrine manner; (iii) paracrine signaling involving activation of surface receptors (e.g. NPY1R on enterocytes; SSTR5 on L cells; immunoglobulin-like domain containing receptor 1 [ILDR1] on I cells) on the basolateral surface of neighboring enterocytes and/or other EECs (iv); and activation of GPCRs (e.g. GLP1R, NPY2R, CCK1R) on vagal afferents (v) to relay information centrally, or on enteric neurons to modulate intestinal function. Enteric neurons are also capable of sensing certain absorbed nutrients directly (vi). For example, subsets of enteric neurons express the SCFA receptor FFAR3. In turn, the ENS fine-tunes the function of EECs (vii), as evident from their expression of a number of neuropeptide receptors (e.g., galanin receptor [GALR1], bombesin receptors [BB2R], vasoactive intestinal peptide receptor 1 [VPAC1R]).