Enteric nervous system
The enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal tract. It contains complete reflex circuits that detect the physiological condition of the gastrointestinal tract, integrate information about the state of the gastrointestinal tract, and provide outputs to control gut movement, fluid exchange between the gut and its lumen, and local blood flow (Gershon 2005; Furness 2006). It is the only part of the peripheral nervous system that contains extensive neural circuits that are capable of local, autonomous function. The ENS has extensive, two-way, connections with the central nervous system (CNS), and works in concert with the CNS to control the digestive system in the context of local and whole body physiological demands. Because of its extent and its degree of autonomy, the ENS has been referred to as a second brain. The roles of the ENS are much more restricted than the actual brain, and so this analogy has limited utility.
The ENS is a division of the autonomic nervous system, the other divisions being the sympathetic and parasympathetic, with which it has extensive connections.
Organisation and relationships
The enteric nervous system is composed of thousands of small ganglia that lie within the walls of the esophagus, stomach, small and large intestines, pancreas, gallbladder and biliary tree, the nerve fibres that connect these ganglia, and nerve fibres that supply the muscle of the gut wall, the mucosal epithelium, arterioles and other effector tissues. Large numbers of neurons are contained in the enteric nervous system, about 200-600 million in human. This is far more neurons than occurs in any other peripheral organ and is similar to the number of neurons in the spinal cord.
The ganglia contain neurons and glial cells, but not connective tissue elements, and in many respects they are similar in structure to the CNS, except that there is no significant blood-enteric nervous system barrier. Nerve fibre bundles within the enteric nervous system consist of the axons of enteric neurons, axons of extrinsic neurons that project to the gut wall, and glial cells. Two major sets of ganglia are found, the myenteric ganglia between the external muscle layers, and the submucosal ganglia (Fig.1). The myenteric plexus forms a continuous network, around the circumference of the gut and extending from the upper esophagus to the internal anal sphincter. The ganglionated submucosal plexus is present in the small and large intestines, but is absent from the esophagus and contains only very few ganglia in the stomach.
The enteric nervous system originates from neural crest cells that colonise the gut during intra-uterine life. It becomes functional in the last third of gestation in human, and continues to develop following birth.
The enteric nervous system receives inputs from the parasympathetic and sympathetic parts of the nervous system, and the gastrointestinal tract also receives a plentiful supply of afferent nerve fibres, through the vagus nerves and spinal afferent pathways. Thus, there is a rich interaction, in both directions, between the enteric nervous system, sympathetic prevertebral ganglia and the CNS.
The gastrointestinal tract also harbors an extensive endocrine signaling system, and many gastrointestinal functions are under dual neuronal and endocrine control (Furness et al. 1999). Enteric neurons also interact with the extensive intrinsic immune system of the gastrointestinal tract.
Types of Enteric Neurons
Approximately 20 types of enteric neurons can be defined by their functions (Brookes and Costa 2002; Furness 2006). Combinations of features (morphology, neurochemical properties, cell physiology and projections to targets) help to define each type. Amongst the 20 types, three classes can be identified, intrinsic primary afferent neurons (IPANs, also referred to as intrinsic sensory neurons), interneurons and motor neurons. IPANs detect the physical state of the organs (for example, tension in the gut wall) and chemical features of the luminal contents (Furness et al. 2004). They react to these signals to initiate appropriate reflex control of motility, secretion and blood flow. IPANs connect with each other, with interneurons and directly with motor neurons. Interneurons connect with other interneurons and with motor neurons. Amongst the motor neurons are muscle motor neurons, secretomotor neurons, secretomotor/ vasodilator neurons and vasodilator neurons.
Functions of the enteric nervous system
Control of Motility
The gastrointestinal tract has an external muscle coat whose purposes are to mix the food so that it is exposed to digestive enzymes and to the absorptive lining of the intestine, and to propel the contents of the digestive tube. The muscle also relaxes to accommodate increased bulk of contents, notably in the stomach. In human, in particular, the colon also has an important reservoir function to retain the feces until defecation. The enteric reflex circuits regulate movement by controlling the activity of both excitatory and inhibitory neurons that innervate the muscle. These neurons have co-transmitters, for the excitatory neurons, acetylcholine and tachykinins, and for the inhibitory neurons nitric oxide, vasoactive intestinal peptide (VIP) and ATP. There is also evidence that pituitary adenylate cyclase activating peptide (PACAP) and carbon monoxide (CO) contribute to inhibitory transmission.
The times for passage of the contents through the gastrointestinal tract vary depending on the nature of the food, including its amount and nutrient content. The peristaltic activity of the esophagus takes food from the mouth to stomach in about 10 seconds, where the food is mixed with digestive juices. Gastric emptying proceeds over periods of approximately 1-2 hours after a meal, the liquefied contents being propelled by gastric peristaltic waves as small aspirates into the jejunum during this time. The fluid from the stomach is mixed with pancreatic and biliary secretions to form the liquid content of the small intestine, known as chyme. Chyme is mixed and moves slowly along the intestine, under the control of mixing and propulsive movements orchestrated by the ENS, while digestion and absorption of nutrients occurs. The average transit time through the human small intestine is 3-4 hours. Colonic transit in healthy humans takes 1-2 days.
Intrinsic reflexes of the enteric nervous system are essential to the generation of the patterns of motility of the small and large intestines. The major muscle movements in the small intestine are: mixing activity; propulsive reflexes that travel for only small distances; the migrating myoelectric complex; peristaltic rushes; and retropulsion associated with vomiting. The enteric nervous system is programmed to produce these different outcomes. In contrast to the intestine, peristalsis in the stomach is a consequence of conducted electrical events (slow waves) that are generated in the muscle. The intensity of gastric contraction is determined by the actions of the vagus nerves, which form connections with enteric neurons in the myenteric ganglia. The proximal stomach relaxes to accommodate the arrival of food. This relaxation is also mediated through vagus nerve connections with enteric neurons. Thus, the primary integrative centres for control of gastric motility are in the brainstem, whereas those for control of the small and large intestines are in the enteric nervous system. In most mammals, the contractile tissue of the external wall of the esophagus is striated muscle, and in others, including humans, the proximal half or more is striated muscle. The striated muscle part of the esophagus is controlled, via the vagus, by an integrative circuitry in the brainstem. Thus, although the myenteric ganglia are prominent in the striated muscle part of the esophagus, they are modifiers, not essential control centres, for esophageal peristalsis.
The smooth muscle sphincters restrict and regulate the passage of the luminal contents between regions. In general, reflexes that are initiated proximal to the sphincters relax the sphincter muscle and facilitate the passage of the contents, whereas reflexes that are initiated distally restrict retrograde passage of contents into more proximal parts of the digestive tract.
The progress of the contents in an oral to anal direction is inhibited when sympathetic nerve activity increases. To achieve this, transmission from enteric excitatory reflexes to the muscle is inhibited and the sphincters are contracted. The post-ganglionic sympathetic neurons utilise noradrenaline as the primary transmitter. Under resting conditions, the sympathetic pathways exert little influence on motility. They come into action when protective reflexes are activated.
Regulation of fluid exchange and local blood flow
The enteric nervous system regulates the movement of water and electrolytes between the gut lumen and tissue fluid compartments. It does this by directing the activity of secretomotor neurons that innervate the mucosa in the small and large intestines and control its permeability to ions. Neurotransmitters of secretomotor neurons are vasoactive intestinal peptide (VIP) and acetylcholine. Secretion is integrated with vasodilatation, which provides some of the fluid that is secreted. Most secretomotor neurons have cell bodies in submucosal ganglia.
Fluxes of fluid, greater than the total blood volume of the body, cross the epithelial surfaces of the gastrointestinal tract each day. Control of this fluid movement via the enteric nervous system is of prime importance for the maintenance of whole-body fluid and electrolyte balance. The largest fluxes are across the epithelium of the small intestine, with significant fluid movement also occurring in the large intestine, stomach, pancreas and gall-bladder. Water moves between the lumens of digestive organs and body fluid compartments in response to transfer of osmotically active molecules. The greatest absorption of water, 8-9 litres per day, accompanies inward flux of nutrient molecules and Na+ through the activation of nutrient co-transporters, and the greatest secretion accompanies outward fluxes of Cl¯ and HCO3¯ in the small and large intestine, gall-bladder and pancreas. In each of these organs, fluid secretion is controlled by enteric reflexes. In the small intestine and most of the colon the reflexes circuits are intrinsic, in the enteric nervous system. They balance secretion with absorptive fluxes, and draw water from the absorbed fluid and from the circulation. The activity of the secretomotor reflexes is under a physiologically important control from inhibitory sympathetic nerve pathways that respond to changes in blood pressure and blood volume through central reflex centres.
Local blood flow to the mucosa is regulated through enteric vasodilator neurons so that the mucosal blood flow is appropriate to balance the nutritive needs of the mucosa and to accommodate the fluid exchange between the vasculature, interstitial fluid and gut lumen. There are no intrinsic vasoconstrictor neurons. Overall blood flow to the gut is regulated from the CNS, via sympathetic vasoconstrictor neurons. The sympathetic vasoconstrictor neurons act in concert with the autonomic control of other vascular beds, to distribute cardiac output in relation to the relative needs of all organs. Thus in times of need, even during digestion, the sympathetic can divert blood flow away from the gastrointestinal tract.
Regulation of gastric and pancreatic secretion
Gastric acid secretion is regulated both by neurons and by hormones. Neural regulation is through cholinergic neurons with cell bodies in the wall of the stomach. These receive excitatory inputs both from enteric sources and from the vagus nerves.
Gastric secretion of HCl and pepsinogen in the stomach, and secretion of pancreatic enzymes, is largely dependent on vago-vagal reflexes. Enteric motor neurons are the final common pathway, but the roles of intrinsic reflexes are minor. Pancreatic secretion of bicarbonate, to neutralise the duodenal contents, is controlled secretin, a hormone released from the duodenum, in synergy with activity of cholinergic and non-cholinergic enteric neurons. Secretion into the gall-bladder and bicarbonate secretion in the distal stomach are also nerve controlled.
Regulation of gastrointestinal endocrine cells
Nerve fibres run close to endocrine cells of the mucosa of the gastro-intestinal tract, some of which are under neural control. For example, gastrin cells in the antrum of the stomach are innervated by excitatory neurons that utilize gastrin releasing peptide as the primary neurotransmitter. Conversely, hormones released by gastrointestinal endocrine cells influence the endings of enteric neurons. In a sense, the endocrine cells act like taste cells, that sample the luminal environment, and release messenger molecules into the tissue of the mucosa, where the nerve endings are found. This is a necessary communication, because the nerve endings are separated from the lumen by the mucosal epithelium. An important communication is with serotonin (5-hydroxytryptamine, 5-HT) containing endocrine cells which activate motility reflexes. Excessive release of serotonin can cause nausea and vomiting, and antagonists of the 5-HT3 receptor are anti-nauseants.
Enteric neurons are involved in a number of defense reactions of the gut. Defense reactions include diarrhea to dilute and eliminate toxins, exaggerated colonic propulsive activity that occurs when there are pathogens in the gut, and vomiting.
Fluid secretion is provoked by noxious stimuli, particularly by the intraluminal presence of certain viruses, bacteria and bacterial toxins. This secretion is due in large part to the stimulation of enteric secretomotor reflexes. The physiological purpose is undoubtedly to rid the body of pathogens and their products. However, if the pathogens overwhelm the body’s ability to cope, the loss of fluid (diarrhoea) can become a serious threat to the organism.
Signals between gut regions are carried both by hormones (such as cholecystokinin, gastrin and secretin) and by nerve circuits. Entero-enteric reflexes regulate one region in relation to others. For example, when nutrients enter the small intestine, secretion of digestive enzymes from the pancreas occurs. A series of nerve circuits that carry signals from one region of intestine, to sympathetic ganglia, and back to the gut wall provide a regulatory system that is unique to the gastrointestinal tract. Neurons with cell bodies in enteric ganglia and terminals in pre-vertebral sympathetic ganglia form the afferent limbs of these reflexes. These are known as intestinofugal afferent neurons (IFANs) (Szurszewski et al. 2002).
The gastrointestinal tract is in two way communication with the CNS. Afferent neurons convey information about the state of the gastrointestinal tract. Some of this reaches consciousness, including pain and discomfort from the gut and the conscious feelings of hunger and satiety, which are integrated perceptions derived from the gastrointestinal tract and other signals (blood glucose, for example). Other afferent signals, concerning, for example, the nutrient load in the small intestine, or the acidity of the stomach, do not normally reach consciousness. In turn, the CNS provides signals to control the intestine, which are, in most cases, relayed through the ENS. For example, the sight and smell of food elicits preparatory events in the gastro-intestinal tract, including salivation and gastric acid secretion. This is termed the cephalic phase of digestion. Swallowed food stimulates the pharynx and upper esophagus, eliciting afferent signals that are integrated in the brainstem, and subsequently provide efferent signals to enteric neurons in the stomach that cause acid secretion and increased gastric volume, in preparation for the arrival of the food. At the other end of the gut, signals from the colon and rectum are relayed to defecation centres in the spinal cord, from which a programmed set of signals is conveyed to the colon, rectum and anal sphincter to cause defecation. The defecation centres are under inhibitory control from higher CNS regions, and inhibition that can be released when it is chosen to defecate. The other central influences are through sympathetic pathways, which have been discussed under the sections on control of motility and regulation of fluid exchange and local blood flow, above.
There are a large number of pathologies associated with the neural regulation of digestion, many of these arising from abnormalities of the enteric nervous system (De Giorgio and Camilleri 2004; Spiller and Grundy 2004). One neuropathology of the gut is Hirschprung’s disease, in which an agenesis of the enteric nervous system, that extends proximally from the rectum for various distances, occurs. It is fatal if untreated. Other enteric neuropathologies include hypertrophic pyloric stenosis, esophageal atresia, gastroparesis, slow transit constipation, some cases of esophageal reflux, and Chagas’ disease. The irritable bowel syndrome (IBS) is sometimes considered to be an enteric neuropathy, although IBS covers a spectrum of conditions.
Two-way communication occurs between the enteric nervous system and the immune system of the gastrointestinal tract, that is, transmitters released by the terminals of enteric neurons in the mucosa influence immune-related cells, such as mast cells, and the cells of the mucosa release active substances, including cytokines and mast cell tryptase, that act on enteric neurons (De Giorgio et al. 2004; Lomax et al. 2006). The inter-communication that occurs in disorders such as Crohn’s disease and ulcerative colitis are complex, and beyond the scope of this short review.
Brookes SJH, Costa M (2002) Cellular organisation of the mammalian enteric nervous system. In: Brookes SJH, Costa M (eds) Innervation of the gastrointestinal tract. Taylor and Frances, London & New York, pp 393-467
De Giorgio R, Camilleri M (2004) Human enteric neuropathies: morphology and molecular pathology. Neurogastroenterol. Motil. 16: 515-531
De Giorgio R, Guerrini S, Barbara G, Stanghellini V, De Ponti F, Corinaldesi R, Moses PL, Sharkey KA, Mawe GM (2004) Inflammatory neuropathies of the enteric nervous system. Gastroenterology 126: 1872-1883
Furness JB (2006) The Enteric Nervous System. Blackwell, Oxford, pp 274
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Lomax AE, Linden DR, Mawe GM, Sharkey KA (2006) Effects of gastrointestinal inflammation on enteroendocrine cells and enteric neural reflex circuits. Autonom. Neurosci. 126: 250-257
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Enteric nervous system
A division of the autonomic nervous system whose component neurons lie within the walls of the digestive organs (esophagus, stomach, intestines, pancreas, gall bladder and pancreato-biliary ducts). The enteric nervous system contains entire nerve circuits for digestive organ control, and can function autonomously.
A neuron whose cell body is in a ganglion within the wall of the digestive tract, biliary system or pancreas. Most enteric neurons make connections with other enteric neurons or with gastrointestinal tissues, such as its muscle coats, intrinsic blood vessels and glands.
A plexus of small groups of nerve cells (ganglia) and connecting nerve fibre bundles that lies between the longitudinal and circular muscle layers of the gut wall and forms a continuous network from the upper esophagus to the internal anal sphincter.
A plexus of small ganglia and connecting nerve fibre bundles that lies within the submucosal layer, between the external musculature and the mucosa of the small and large intestines, forming a continuous network from the duodenum to the internal anal sphincter.
Intrinsic primary afferent neurons
Neurons of the enteric nervous system that are detectors of the states of the digestive organs, including detection of chemical entities within the lumen of the intestine, and the tension in the gut wall. Intrinsic primary afferent neurons are the first neurons of intrinsic neural reflex circuits of the intestine.
Neurons with cell bodies in the gut wall and axons that project to and make connections with neurons in prevertebral ganglia. These are afferent neurons of reflexes between gut regions.