| Abstract|| |
One year before the close of the 19th century it was recognized that intestinal peristalsis was controlled by nerve plexuses in the wall of the gut independent of the central nervous system (CNS). This concept was developed further during the first quarter of the 20th century but was almost forgotten during the next 50 years until it was revived by the early 1970s. It is now recognized that the myenteric and submucous plexuses, referrred to as the enteric nervous system (ENS), contain as many neurons as in the spinal cord. In addition to autonomy from the CNS, the ENS employs not only noradrenaline and acetylcholine but also serotonin (5-HT), ATP, peptides and nitric oxide as neurotransmitters, and controls gut movements, exocrine and endocrine secretions and the microcirculation, thus qualifying for being considered the brain of the gut. Reflexes involving the ENS may be entirely intrinsic such as that controlling peristalsis, between parts of the gut through prevertebral ganglia e.g. the enterogastric reflex, or between the gut and the CNS as examplified by the vago-vagal reflexes. Absent, defective or dysfunctional enteric neurons may result in achalasia, infantile hypertrophic pyloric stenosis, paralytic ileus, intestinal pseudo-obstruction, Hirschsprung's disease or idiopathic chronic constipation. Further, the ENS may be involved in the pathogenesis of secretory diarrhoea and inflammatory bowel disease. More research on the gut brain will deepen our understanding of the physiology and pathophysiology of the gastrointestinal tract.
Keywords: Entric nervous system; neuropeptides; gastrointestinal hormones; nitric oxide; gastrointestinal motility; esophageal sphincter; pyloric stenosis; intestinal pseudoobstruction; Hirschsprung disease; secretory diarrhoea; inflammatory bowel disease.
|How to cite this article:|
El Munshid HA. The brain of the gut. Saudi J Gastroenterol 2000;6:18-26
In 1899 Bayliss and Starling proposed that intestinal peristalsis was controlled by coordinated reflexes within the local nervous apparatus independent of the central nervous system (CNS). They demonstrated the peristaltic reflex in vivo but in 1917 Trendelenburg showed that the reflex could be elicited in vitro, thus establishing its independence from the CNS. The nerve plexuses in the wall of the gut came to be known as the enteric nervous system (ENS). Langley was impressed by the observation that while enteric neurons numbered about 100 million, the preganglionic fibres in the vagus nerve reaching the gut numbered only about 2000. This suggested to him that most enteric neurons do not receive input from the CNS and cannot as such be fitted into the sympathetic and parasympathetic divisions of the autonomic nervous system which have well defined CNS connections. He therefore proposed in 1921 that the ENS should be considered a third major division of the autonomic nervous system, in addition to the sympathetic and parasympathetic divisions.
Unfortunately during the next 50 years the perception of the enteric plexuses as a nervous system that can function independent of the CNS declined and was almost forgotten until the early 1970s when emergence of some new observations induced reawakening of the original concept proposed by Bayliss and Starling,. In addition to the fact that there are as many neurons in the ENS as in the spinal cord, evidence started to emerge that a considerable proportion of gut neurons contained neurotransmitters that were neither adrenergic nor cholinergic. Furthermore, it was shown that enteric neurons could actually "talk back" to the ganglia relaying impulses from the CNS. It is now established that the ENS qualifies for being considered the "brain" or "minibrain" of the gut. This brain controls: movement, exocrine glandular secretions, secretions from endocrine cells and the microcirculation; in addition it is involved in immune and inflammatory processes. This review deals with the anatomy and physiology of the ENS and its role in the pathophysiology of a number of gastrointestinal disorders.
| Structure of the ENS|| |
ENS is constituted by two plexuses in the wall of the gut: the myenteric or Auerbach's plexus lying between the inner circular and outer longitudenal layers of the muscularis extema, and the submucous or Meissner's plexus between circular layer and the muscularis mucosa. The myenteric plexus provides motor innervation to the smooth muscle of the muscularis externa and secretomotor fibres to the mucosal cells. The submucous plexus is especially prominent in the small intestine; it innervates the glandular epithelium, endocrine cells, the muscularis mucosa and blood vessels in the submucosa; in addition, many sensory signals from the epithelium are integrated in the submucous plexus. Extrinsic autonomic nerves connect the ENS with the brain and spinal cord. Sympathetic nerves arise in the spinal cord and synapse in the prevertebral ganglia so that the sympathetic fibres reaching the gut are postganglionic. They may end on enteric neurons, smooth muscle cells, sphincters or submucosal blood vessels. Preganglionic parasympathetic fibres are found in the vagus and pelvic splanchnic nerves: the vagus provides innervation from the esophagus up to about the middle of the transverse colon while the rest of the colon, rectum and anal canal are innervated by the pelvic splanchnic nerves. These preganlionic fibres synapse with enteric neurons which exert their effects on smooth muscle, gland cells or blood vessels either directly or through intermediate cells e.g. endocrine cells. It should be noted that there are afferent fibres from the gut to the CNS. About 80% of the fibres in the vagus nerve are afferent conveying distention and chemical changes in luminal contents relating to concentrations of glucose, aminoacids, or long-chain fatty acids. Affferents in the splanchnic nerve signal pain which may result from intense potentially damaging mechanical, thermal or chemical stimuli to the CNS. Up to 9 morphologic types of neurons have been identified in the ENS, , based on size, distribution of organelles and location. Out of these, 2 main types of neurons have been defined in accordance with morphologic, electrophysiological and functional criteria,:
S/type I neurons have club-shaped processes and a single long thin process; they receive fast nicotinic synaptic input and are motor in function. AH/type II neurons are multipolar and have many long processes; they lack fast excitatory synaptic potentials and have a prominent after-hyperpolarization (AH) following the action potential; they function as intrinsic afferent neurons. The remaining morphologic types function as intemeurons. There are also glial cells that resemble astrocytes of the CNS; they produce interleukins and express MHC class II proteins in response to cytokines
| Neurotransmitters in ENS|| |
Postganglionic sympathetic fibres release noradrenaline (NA). NA relaxes intestinal smooth muscle partly through action on alpha 2 presynaptic receptors which inhibit release of acetylcholine (Ach) from enteric neurons, and partly through direct action on the smooth muscle cells. It contracts gastrointestinal sphincters and constricts submucosal blood vessels. All preganglionic vagal and sacral fibres are cholinergic. They innervate both excitatory and inhibitory enteric neurons. Excitatory cholinergic motor neurons stimulate motility and glandular secretions. By the early 1960s evidence was presented that there were nonadrenergic noncholinergic (NANC) neurotransmitters in the gut, and from the early 1970s onwards serotonin (5hydroxytryptamine or 5-HT), ATP, many peptides, and nitric oxide were discovered in the ENS. These chemical messengers may act either as neurotransmitters or neuromodulators. In addition, more than one messenger may be synthesized and released by an enteric neuron
The gut constitutes the largest store of 5-HT in the body; it is found in mucosal enterochromaffm cells and in enteric neurons,,,. Enteric neuronal 5-HT is involved in the regulation of the migrating motor complex (MMC) and the initiation of peristalsis.. ATP was proposed as the transmitter of NANC nerves that caused relaxation of intestinal smooth muscle by Burnstock and coworkers ,, ; such nerves or neurons are termed purinergic. Numerous peptides have by now been found in enteric neurons which are consequently called peptidergic. Some of these peptides were first isolated from the brain and then found in the ENS, while the sequence of discovery for others was the reverse. Some of the neuropeptides are found in gut endocrine cells as well as enteric neurons . The gut locations and actions of the peptides are summarized in [Table - 1]. Substance P (SP) was discovered in 1931 in extracts of gut and brain and was later shown to be a peptide containing 11 aminoacids. Vasoactive intestinal peptide (VIP) was isolated fro1m the intestine in 1970. It is a peptide containing 28 aminoacids . Gastrin-releasing peptide (GRP) is the mammalian equivalent of bombesin which was originally isolated from frog skin,
Cholecystokinin (CCK), the hormone that primarily contracts the gall bladder and stimulates pancreatic enzyme secretion, is also found in enteric neurons. Only its effect when released from enteric neurons is given in [Table - 1].
Met-and leu-enkephalins are opioid peptides each containing 5 aminoacids. Somatostatin was first isolated from the hypothalamus and later found in the gut. It exists in two forms: one containing 14 aminoacids and the other containing 28 aminoacids. Neurotensin is a peptide with 13 aminoacids originally isolated from the hypothalamus and later found in the gut. Its physiological effects are unclear but its known actions are given in [Table - 1].
Neuropeptide Y (NPY) and peptide YY (PYY) were discovered in 1982,. The actions of NPY and PYY are given in [Table - 1] but their physiological significance remains to be determined. Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide which may be involved the regulation of gastrin release . Galanin is a peptide which is emerging as a neural regulator of intestinal motility and gastric acid secretion.
The advent of nitric oxide (NO) as a transmitter, represents a significant addition to NANC neurotransmitters in the gut and elsewhere. NO is formed from the aminoacid L arginine by the enzyme nitric oxide synthase (NOS), The role of nitric oxide as a neurotransmitter of NANC nerves in the gastrointestinal tract has recently been comprehensively reviewed, In general, NO mediates smooth muscle relaxation in many gut locations; it is also involved in stimulation of pancreatic exocrine and endocrine secretions [Table 2]. Furthermore, NO has cytotoxic properties and is likely to participate in nonspecific immunological and inflammatory reactions when released by activated macrophages
| Functional Classification of Neurons in ENS|| |
Intrinsic afferent neurons: are AH/type II neurons. They are located in both plexuses. They characteristically exhibit prominent afterhyperpolarization following the end of the action potential. They are all cholinergic and may or may not contain substance P as well.
Interneurons: Connet primary afferent neurons to motor or secretomotor neurons. In motor reflexes interneurons may be ascending i.e. directed orally, or descending i.e. directed anally. In the peristaltic reflex interneurons form multisynaptic pathways over considerable distances in the gut. Subgroups of interneurons may be identified according to their neurotransmitter content.
Motor neurons: are S/type I neurons that receive fast nicotinic synaptic input. Those supplying circular smooth muscle may be either excitatory, employing mainly acetylcholine and substance P as transmitters, or inhibitory, releasing vasoactive intestinal peptide or nitric oxide. Enteric neurons may target smooth muscle cells, glandular exocrine or endocrine secretory cells, the microvasculature or cells involved in immunologic and inflammatory processes.
| Reflexes involving the ENS|| |
Reflex arcs may occur entirely within the ENS, between parts of the gut through the prevertebral ganglia, or between the gut and the CNS. Examples of intramural reflexes include the short reflexes in the stomach whereby distention leads to stimulation of acid secretion, and the coordinated reflexes within the ENS that are responsible for the travelling peristaltic movments. Examples of reflexes between parts of the gut include the enterogastric and gastrocolic reflexes. In the enterogastric reflex impulses probably relay in the coeliac ganglion. Longer reflexes occur between the gut and the spinal cord or brain stem. Two prominent examples are the defaecation reflexes between the terminal part of the gut and the sacral segments of spinal cord, and the vago-vagal reflexes (i.e. vagal afferents travel to the vagal nucleus in the medulla and efferent impulses go down the vagus nerve) that are involved in the control of gastric and pancreatic secretions.
| Role of the ENS in regulation of gastrointestinal motility|| |
Smooth muscle in the gastrointestinal tract can contract on its own, but such inherent rhythmic activity is regulated by the ENS and may be modulated by extrinsic neural and hormonal means. The electrical activity of gut smooth muscle can be explored by microelectrodes. Spontaneous waves of depolarization followed by repolarization, called slow waves or basal electric rhythm (BER), start at "pacemaker" areas in the stomach and small intestine, It is now believed that these spontaneous oscillations originate in specialized cells called interstitial cells of Cajal (ICC). ICC are confined to pacemaker areas; they are heavily innervated and form extensive cellular networks through gap junctions with smooth muscle cells,. During the interdigestive period bursts of depolarization accompanied by peristaltic contractions, called migrating motor complex (MMC), start in the stomach and travel along the small intestine to reach the ileocaecal junction after 11/2 to 2 hours. Such cycles continue as long as the stomach is empty and serve to propel remnants in the stomach or small bowel into the colon. The orderly propagation of the MMC along the gut is dependent on the ENS. The hormone motilin is involved in the regulation of MMC cycles since its fasting levels fluctuate with the same periodicity as MMC phases. Many types and subtypes of 5-HT receptors have been recognized several of which are found in gastric and intestinal myenteric neurons . Recently two receptor types (5-HT 3 and 5-HT 1p ) have been shown to be involved in regulation of MMC.
Peristalsis is the main propulsive movement in the gut. Intestinal peristalsis may be initiated by mucosal stimulation or luminal distention as by a bolus following which contraction of circular muscle above the bolus occurs while relaxation occurs at the bolus site and below it, and this contraction preceded by relaxation travels in an oral to caudal direction. Mucosal stimulation or luminal distention releases 5-HT. 5-HT triggers activitiy in an intrinsic afferent neuron which discharges to cholinergic ascending and descending interneurons. The ascending interneuron transmits the signal to excitatory motor neurons which release Ach and SP thus causing contraction above the bolus. The descending interneurons activate inhibitory motor neurons that release NO, VIP and ATP which cause relaxation at the bolus site and below it. As the bolus moves onwards, it elicits similar local peristaltic reflexes at successive sites along the intestine,,
| Role of the ENS in regulation of intestinal secretion|| |
The most important stimulus for stimulating intestinal secretion is the presence of chyme in the lumen. Distention as well as tactile and irritative stimuli produce secretion through local enteric reflexes. Secretion of electrolytes and water into the lumen is mainly due to active secretion of Clthrough a specific channel, followed passively by Na + and water. The Cl- channel is opened by an elevation of intracellular cAMP, and it is pertinent to mention that VIP opens this channel through elevation of cAMP and thus stimulates intestinal secretion of electrolytes and water. cAMP may also be elevated by bacterial enterotoxins e.g. cholera toxin, but in that pathological condition the ENS contributes to the causation of the resulting secretory diarrhoea (see below).
| Gut disorders related to ENS|| |
Absent or defective enteric neurons may result in lack of propulsion and consequently obstruction of function. A number of motility disorders belong to this category. The enteric nervous system may also be involved in secretory and inflammatory dysfunction of the gut.
Achalasia is due to loss of myenteric neurons in the esophagus. The loss may be nonselective or may selectively involve the inhibitory neurons that are responsible for relaxation of the lower esophageal sphincter (LES). Thus resting pressure of the LES becomes high and the sphincter fails to relax during swallowing. In addition peristalsis may be weak or abesent so that the esophagus dilates and food accumulates in it. It has recently been shown that the myenteric plexus at the gastroesophageal junction of patients with achalasia lacks the enzyme nitric oxide synthase (NOS) so that the impaired relaxant activity of the LES seems to be due to lack of NO. In most cases of achalasia the agent responsible for destruction of the myenteric neurons is unknown, except in South America where the condition may follow infection by Trypanosoma cruzi (Chagas' disease). A secondary form of achalasia may also occur in patients with Parkinson's disease.
Infantile hypertrophic pyloric stenosis is a congenital condition in which there is obstruction at the gastric outlet. The disorder is due to lack of NO in the neurons innervating the circular muscle of the pyloric sphincter. In a recent study on patients with this condition it was found that there was reduced number of ganglion neurons in the myenteric plexus, coupled with almost complete absence of the interstitial cells of Cajal in the pyloric region.
Functional gastric outlet obstruction accompanied by gastric stasis and dilatation may follow surgical vagotomy, diabetic neuropathy, administration of anticholinergic drugs and opiates and overactivity of sympathetic nerves
Acute intestinal or paralytic ileus results from inhibition of excitatory motor reflexes in the intestine due to discharge in sympathetic nerves or sustained overactivity of intrinsic inhibitory neutral mechanisms The condition may also follow release of NO from non-neuronal sources
Chronic intestinal pseudo-obstruction may result from degeneration and chronic dysfunction of enteric neurons. Experimentally induced block of all neural transmission in the gut unmasks spontaneous myogenic activity, but such activity is uncoordinated and nonpropulsive resulting in functional obstruction, which is equivalent to intestinal pseudo-obstruction.
Hirschsprung's disease results from congenital absence of inhibitory enteric neurons containing NO and VIP in the distal colon and rectum; the aganglionic segment loses its tonic neural inhibition and therefore stays contracted, and obstructs passage of contents. It is now known that Hirschsprung's disease is a heterogenous genetic disorder. Some patients have an autosomal dominant defect due to a mutation in the RET gene which leads to the absence of the tyrosine kinase receptors normally essential for mediating the action of neurotrophins in promoting growth and differentiation of enteric neurons,. Other patients with an autosomal recessive defect have a mutation of the gene for the endothelin-B receptor which also has a role in the migration and development of the enteric nervous system
Idiopathic chronic constipation was believed to be due to reduced numbers of myenteric plexus neurons and VIP-positive nerve fibers in the circular muscle of the colon. A recent study on 5 patients with idiopathic chronic constipationhas confirmed that the total neuron density in the myenteric plexus is low, but whereas the density of VIP-positive neurons is low, that of NOS-positive neurons is increased in both plexuses. Thus the persistent inhibition of colonic contractions leading to idiopathic chronic constipation is due to excessive production of nitric oxide.
Secretory diarrhoea due to cholera It has been known for sometime that the cholera toxin acts on the enterocyte through activation of adenylyl cyclase which leads to increased intracellular cAMP concentration, opening of the Cl- channel and increased secretion of Cl-, Na + and water It is now clear that in addition to this mechanism the ENS is involved. Cholera toxin acts through enteric neurons to release 5-HT from mucosal enterochromaffin cells. 5-HT acts on intrinsic afferent neurons which then act through myenteric interneurons on the following: secretomotor neurons that release VIP which causes vasodilatation and secretion, motor neurons that cause giant peristaltic contractions, and a series of interneurons that transmit the secretory effect to the colon. The cholera toxin may in addition stimulate the secretomotor neurons directly.
Inflammatory bowel disease may be aggravated by psychological stress which illustrates the interactive links among the brain, the ENS and the gut. In Crohn's disease as well as ulcerative colitis substance P (SP) immunoreactivity in the colon is increased  and the binding sites for SP are expressed in high concentration by arterioles, venules and lymph nodules. Since in rats with colitis SP-receptor antagonists decreased granulocyte infiltration, SP may have proinflammatory actions in the gut. Nitric oxide may be involved in ulcerative colitis since NOS activity is increased in the colonic and rectal mucosae in patients with the disease,. NOS activity is also increased in the myenteric plexus, nerve fibres of the circular muscle layer and inflammatory cells in the ileal serosa of patients with Crohn's disease. NO is formed and released by macrophages and neutrophils,, and since it is involved in inflammatory reactions, it probably contributes to the pathogenesis of ulcerative colitis and Crohn's disease. Furthermore, the released NO may be a factor in the colonic distention of severe colitis through its relaxant effect on colonic circular smooth muscle.
| Conclusion|| |
The original perception of Bayliss and Starling about the function of the enteric nervous system and its independence from the central nervous system has been amply confirmed and extended. The gut indeed has a brain that plays a central role in the physiology and pathophysiology of the gastrointestinal tract. As more research is done on the ENS, more insight will emerge on understanding the pathogenesis and the rationale for treatment of a wide range of gut disorders.
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Hassan Ahmed El Munshid
Department of Physiology, College of Medicine & Medical Sciences, King Faisal University, P.O.Box 2114, Dammam 31451
Source of Support: None, Conflict of Interest: None
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