Molecular mechanisms of stimulus detection and secretion in enteroendocrine cells

Enteroendocrine cells (EECs) secrete over 20 different gut hormones in response to changes to the gut environment. They detect a range of nutritional stimuli through activation of a host of nutrient-sensing G-protein–coupled receptors and electrogenic nutrient cotransport. These activate intracellular signalling pathways which converge on membrane depolarisation and action potential generation, which elicit secretion. Emerging evidence has demonstrated that EECs also respond to non-nutritional stimuli, including mechanosensation, pH changes, and metabolites produced by the gut microbiome. EECs are polyhormonal cells, in which hormone expression is plastic and dependent on location in the gut. Hormones and small-molecule neurotransmitters secreted by EECs can activate extrinsic vagal afferents, modulating central processes such as appetite and food preference. While neuronal afferents are sometimes found in close proximity to EECs, the extent to which EEC/neuronal connections recapitulate traditional synaptic connections remains undefined.