The role of the enteroendocrine system [3–5] is to detect the components of the intestinal lumen, to monitor the energy status of the body, and to elicit appropriate responses to control metabolic homeostasis in response to ingested food. The GI tract’s endocrine system produces more than 20 different hormones which mediate effects via neuro-, auto-, and paracrine mechanisms from at least 10 distinct EEC populations.

At least 15 gut neuroendocrine cells exist, all of which produce various bioactive peptides or amines, including serotonin, somatostatin, histamine and gastrin. These secretory products are stored in vesicles. Enteroendocrine cells are characterized by the presence of secretory vesicles, either large or smaller, synaptic-like or similar to those found in neurons [6, 7]. Other general markers for EECs include neuron-specific enolase and protein gene product 9.5, both located in the cellular cytoplasm [8]. As the most specific feature of EEC subtypes, the peptide⁄amine(s) contained within secretory vesicles has formed the basis for the classification of EECs [9].

Gut hormones are responsible for glycemic control, appetite stimulation and suppression, regulation of gastric emptying, and trophic effects on the intestinal epithelium. Additionally, EECs have unique direct connections to the enteric nervous system enabling precise transmission of sensory data and communication with the central nervous system [10]. These hormones (Table 1.2), identified in the late 70s, include cholecystokinin (CCK) that is responsible for stimulating the digestion of dietary fat and protein, the antidiabetic hormones glucagon-like peptide 1 (GLP-1) and glucoinsulinotropic polypeptide (GIP), the pro-satiety hormone peptide YY (PYY), the hunger hormone ghrelin and the inhibitory hormone somatostatin as well as the neurotransmitter 5-hydroxytryptamine (5-HT, serotonin).

The EEC population of the large bowel is generally less diverse than in the small intestine [11]. For instance, cholecystokinin-secreting cells are found in the small bowel but are absent in the colon [12]. From duodenum to rectum, the frequency of EECs is highest proximally and falls steadily reaching a trough in the colon, before rising again within the rectum. After proximal small bowel, the rectum is the location with the next greatest frequency of EECs and the only location in the GI tract where EECs are occasionally seen adjacent to each other or in clusters [5].

More generally, GIP-secreting EECs are located in the proximal duodenal region, CCK-secreting EECs in the duodenal and jejunal regions, GLP-1-secreting EECs in the jejunal, ileal, and colonic regions, and PYY-secreting EECs appear more restricted to the ileal and colonic regions [13]. Enterochromaffin (EC) cells reside in the epithelium of the GI tract, secrete serotonin and regulate secretory and peristaltic reflexes. They also activate vagal afferents through 5-HT3 receptors to signal to the central nervous system [10]. EC cells are the most abundant EECs of the GI tract and are distributed widely, populating the gastric antrum, duodenum, jejunum, ileum and appendix as well as the colon and rectum. EC cells have been shown to make up over 70% of the EEC population in the proximal large bowel. They fall to around 40% in the rectum [5].

Other EECs such as the appetite-stimulatory ghrelin-secreting A cells in the stomach appear buried within the epithelial mucosa and make contact with the serosal blood supply only [10]. These cells are presumed to detect mechanical, neuronal, and paracrine stimulations since they do not make contact with the luminal cavity. In addition to gastric ghrelin-secreting A cells, D cells secrete somatostatin, G cells secrete the acid-releasing hormone gastrin, and P cells secrete the satiety hormone leptin.

A second population of EC cells also resides in the gastric mucosa, but does not contain 5-HT. These cells respond to gastrin secreted by G cells by releasing histamine and stimulating the secretion of gastric acid from parietal cells.

Hormone output from the EECs is also regulated by other EEC subtypes, including somatostatin released by delta cells, which inhibits GLP-1 secretion from L cells in the intestine, presumably through SSTR5.

The histamine-producing enterochromaffin-like (ECL) cells have been recognized as the leading cell type involved in the most significant alterations of gastric neuroendocrine cells. The trophic stimulus exerted by circulating gastrin has been demonstrated to have a crucial role in proliferative changes of ECL cells, through a sequence of hyperplasia-dysplasia-neoplasia.

In the pancreas, the endocrine cells constitute from 1% to 2% of the volume of the organ and most of them form well-circumscribed nests called islets of Langerhans, while a few scattered endocrine cells are also present in the main pancreatic and larger interlobular ducts, but are not observed in the smaller ducts. There are at least five types of cells with a specific hormone secretion: alpha, beta, delta, PP, Y, and epsilon cells. These cells produce several peptide hormones, including insulin, glucagon, somatostatin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP) and ghrelin. The most common cells are insulin-producing beta cells, which account for 60% to 80% of all islet cells and are centrally located in the islets, while glucagon-producing alpha cells are located at the periphery of islets and constitute from 15% to 20% of the islet volume. Somatostatin-producing delta cells and PP-producing cells constitute the remaining portions. Extrahepatic biliary epithelia also contain scattered endocrine cells in the intrapancreatic portion of the common bile duct.