**4. Enteroendocrine hormones, neuropeptides and signals**

#### **4.1 Humans**

The gut–brain transmission systems involve both circulation-based endocrinelike and neuronal communication routes [205]. Neuropeptides (transmitters or neurosecretory) act as messenger molecules of enteric, sensory, autonomic and central neurons. Several peptide families have been found in both brain and gut. They act as neuropeptides and/or gut hormones and have significantly contributed to the understanding of gut brain interaction. Central and peripheral neurons together with EE cells in the GI tract and other endocrinologically active cells produce variety of peptides [206–211] including hormones peptide YY (PYY) and pancreatic polypeptide (PP); neuropeptide Y (NPY), on the other hand [212]. These and other peptide families represented by glucagon-like peptide (GLP), ghrelin, cholecystokinin (CCK), corticotropin-releasing factor (CRF), leptin, osteocalcin and insulin (the last three are extra intestinal endocrine peptides) act on specific and genetically related groups of receptors that are expressed by distinct cells in the periphery and CNS. For their functional roles, endocrine peptides and neuropeptides are relevant for the regulation of digestion, control of food intake, metabolic homeostasis, and the impact of GI signals on sensation, emotion, affect, and cognition. Disturbances of the gut microbiota–brain axis result in changes of the expression and activity of many neuropeptides and their receptors in the CNS. Neuropeptides are therefore important secondary messengers of gut microbes in cerebral neuro circuitries that mediate the alterations in brain function and behavior that take place in response to changes in the GI microbial community [212]. Together it is emerging that neuropeptide systems such as NPY, CRF, ghrelin, and brain-derived neurotrophic factor (BDNF) play a particular role in the cerebral manifestations of gut microbiota perturbations.

In rats, choleocystokinin and glutamate neuro-epithelial circuit makes the communication between the brain and intestinal lumen possible stressing on the importance of a physical gut – brain axis [213]. It has been proposed that the physical connection between vagal nodose neurons and EE cells is present in rats which leads to regulation of gastrointestinal functions [213]. Intragastric nutrient infusion and optical readings of AgRP (Agouti-related protein) neurons in live and awake mice [214] suggest AgRP neurons affect long term homesostasis and energy balance of the body and do not get altered by minute changes in nutrient levels [215]. AgRP neurons get inhibited by high levels of satiation signals such as CCK and PYY (peptide YY). Receptors for both CCK and PYY are expressed by vagal afferent neurons' terminals that innervate GI [159] suggesting a possibility of a physical connection between the gut and brain carrying the message from one point to another [216].
