Vital functions of the gut are under the control of nerves. These nerves belong to the enteric nervous system (ENS) which is a truly autonomous nervous system able to act independently from inputs of the central nervous system. The ENS is located within the wall of the gut and consists of two ganglionated plexus referred to as the myenteric and the submucous plexus. While the former is primarily responsible for regulation of muscle activity the latter is mainly concerned with the regulation of epithelial functions. Nerves of both plexus interact with the enteric immune system and are therefore important components from ensuring an intact gut barrier system as a first line of defence against noxious stimuli. Although the ENS is structurally and functionally very similar to the brain and able to conduct complex functions, ENS activity is heavily modulated by signals from non-neuronal cells. Among them are smooth muscle cells, epithelial cells, immune competent cells and glia, all of which influence ENS activity via endocrine and/or paracrine routes.

One of the most important neuroendocrine interactions is the signalling from enterochromaffine cells (EC cells) to enteric nerves. EC cells are strategically located in the epithelial layer to have relatively close contact to nerve endings. Their role is to code chemical and/or mechanical stimuli and transmit them to nerves. That means that if there is distortion of the epithelium or chemicals in the lumen, the EC cells will release serotonin, which in turn activates nerve endings in the ENS. These nerve endings belong to sensory nerves, also referred to as intrinsic primary afferents. Beside this serotonin also excites vagal or spinal afferents which are part of the extrinsic nerve supply to the gut. Serotonergic transmission in the ENS involves complex pharmacology since 5-HT1P, 5-HT3 and 5-HT4 receptor have been demonstrated post as well as presynaptically. At least in the stomach, 5-HT1P-mediated activation occurs in inhibitory neurones whereas 5-HT3-mediated activation is confined to excitatory neurones. This explains in part the differential effects of serotonin which may inhibit or activate smooth muscle activity. 5-HT4 receptors play a role in the presynaptic facilitation of acetylcholine release and activation of this receptor increases motility as well as chloride secretion. In the human submucous plexus 5-HT excites neurones and this effect is almost entirely mediated by 5-HT3 receptors, yet the finding that activation of 5-HT3 receptors do not affect secretion in the human colon was unexpected. Serotonin and its mode of action has gained a lot of attention recently because it is not only crucial for the physiological behaviour of the gut but is involved in the pathophysiology of functional bowel disease, in particular in irritable bowel.

Nutritive signalling molecules like fatty acids or glycine exert direct postsynaptic effects in the enteric nervous system. Application of butyrate, even in doses less than 1 mM, exert excitation of enteric nerves. Many of them have been identified as sensory neurones with multipolar morphology. The excitatory effect of glycine is mediated by strychnine-sensitive receptors. The basis of this unusual excitatory glycine effect is the relatively high intracellular chloride concentration in enteric neurones. Very likely glycine is not a transmitter in the ENS because no glycinergic neurones and no glycine-mediated synaptic transmission could be demonstrated. Functionally, we could identify a glycine-evoked activation of colonic motility, an effect which requires intact nerves.

Other important molecules involved in interaction between non-neuronal cells and nerves are inflammatory mediators like histamine or prostaglandins. Prostaglandins have a powerful postsynaptic excitatory effect in the ENS and they often evoke long term excitation of the nerve cells with oscillations in their excitability. This is paralleled by an activation of mucosal chloride secretion thereby favouring diarrhoea. Prostaglandin-evoked secretion is to about 70 % mediated by nerves and only a small components of their pro-secretory effects is direct activation of epithelial cells. In this way harmful antigen attacks in the gut are antagonised by dilution of the irritant and by rapid expulsion because motility is also enhanced. The ENS is a crucial part of such an alarm system and inflammatory mediators are integral parts of neuro-immune-interactions in the gut. Histamine has a similar excitatory effect though a presynaptic inhibition of acetylcholine release has been observed in addition to its powerful postsynaptic activation of enteric nerves. The prominent effect of inflammatory mediators has been supported by the finding that application of a mediator cocktail contained in the supernatant of stimulated human mast cells excites enteric nerves. In summary, although the ENS is vital for normal gastrointestinal functions one has to consider that changes in the environment of the ENS have powerful influences on enteric nerves. A substantial number of mediators from non-neuronal cells are important to maintain signalling in the ENS. Identification of their mode of action will advance our knowledge on the physiology of gut functions but is also crucial to understand malfunctions in the diseased gut.