The Enteric Nervous System


Introduction



The enteric nervous system (ENS), often referred to as “the second brain”, is a part of the peripheral nervous system and a division of the autonomic nervous system which controls the gastrointestinal tract. This system is not only complex, integrated, afferent and efferent connections with the central nervous system (CNS), but is also capable of autonomous function, controlling the digestive system in the context of the physiological state locally and the body as a whole.


Structure and Organization



The ENS is embedded within the wall of the digestive tract and extends to the esophagus and anus. Thousands of ganglia reside within the walls of these areas and the number of neurons contained in the ENS is approximately 400 million, more than any other peripheral organ and about the same number of neurons as the spinal cord. The nerve fibers within the walls of the ENS consist of enteric axons, extrinsic axons projecting to the gut wall, and glial cells.

These major ganglia can be of two plexuses: the myenteric plexus and the submucosal plexus, also refered to as Auerbach’s and Meissner’s plexuses, respectively. The myenteric ganglia are located deep between the external muscle layers and form a continous network around the stomach, which extends upward to the upper esophagus and downward to the internal anal sphincter. Myenteric ganglia exert control primarily over digestive tract motility. Their stimulation causes increased tone of the gut wall, increased intensity of the rhythmical contractions in the gut and their rate, and increased rapid movements of peristaltic waves, as well as inhibiting muscles that can impede movement of food between segments of the gastrointestinal tract. The submucosal ganglia are located in the submucosa, which is below the mucosal membrane in the small and large intestine. The submucosal plexus helps to control local intestinal secretion, absorption, and conrraction of the submucosal muscle.

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Layer of the ENS in the Small Intestine



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ENS Layers and Ganglia

The neurons in the ENS can be categorized into approximately twenty types based on their functions. These twenty types of neurons can be identified as three main classes of neurons: intrinsic primary afferent neurons (IPANs) or sensory neurons, motor neurons, and interneurons. The IPANs receive information from the sensory receptors in the mucosa and muscle. These receptors in the mucosa detect stimuli such as thermal, chemical, osmotic, and mechanical. Receptors in the muscle detect tension and stretch. Generally, IPANs function to detect the physical state of the gastrointestinal organs and chemical features of their contents. The motor neurons of the ENS control gastrointestinal motility, secretion and absorption, and come in three main types: muscle motor neurons, secretomotor neurons, and vasodilator neurons. To perform their functions, the ENS motor neurons act directly on cells in the smooth muscle and endocrine cells in the ENS. The function of the interneurons is primarily to convey signals from the IPANs to the motor neurons and also synapse with other interneurons.



Input and Output



Afferent fibers from sensory nerve endings in the epithelium are reiceved by both plexuses, which cause local reflexes within the gut and other reflexes that are relarded back to the gut from either the prevertebral ganglia or the basal regions of the brain. Both plexuses receive CNS output from the parasympathetic and smpathic system, which can further change the activation and inhibition of gastrointestinal functions. The sympathetic fibers originate in the spinal segments between T5 and L2. Upon leaving the spinal cord, these fibers enter the sympathetic chains lying lateral to the spinal colum and pass through to the celiac gnagliona nd various mesenteric ganglia, where most of the postganglionic sympathetic neuron bodies are located. Fibers spread from these ganglia nad terminate on the neurons in all portions of the ENS. The parasympathetic innervation is divided into cranial and sacral divisions. The cranial parasympathetics are transmitted in the vagus nerves and innervate the esophagus, stomach, pancreas, and the first half of the large intestine. The sacral parasympathetics orginate in the second third and forth scral segments of the spinal cord and pass through the pelvic nerves to the distal half of the large intestine, innervating the sigmoidal, rectal and anal regions of the intestine. Sympathetic stimulation causes inhibition of gastrointestinal secretion, motor activity, and sphintcer and blood vessel contraction, while parasympathetic stimuli excites these functions. There are two types of output from the ENS to the CNS. The first has its cell bodies in the ENS and sends axons thorugh the autonomic nerves to terminate in the celiac, mesenteric, and hpogastric ganglia. The second type has cell bodies in the dorsal root gnagliaor in the crnial nerve ganglia and its fibers send their signals from all areas of the gut to areas in the spinal cord and brain stem. Eighty percent of the nerve fibers in the vagus nerves are these fibers and they transmit their sensory signals to the medual, which initiates vagal reflex signals that return to the gastrointestinal tract.

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Input and Output ENS Pathways




Functions


The ENS has several functions which include: control of motility, regulation of fluid exchange and local blood flow, regulation of gastric and pancreatic secreation, regulation of gastrointestinal endocrine cells, defense reactions, and entero-enteric reflexes. For example, the ENS controls the external muscle coat of the gastrointestinal tract, which mixes food so it is digested by enzymes, asborbed by the intestin lining, and moved down the digestive tube. The muscle coat also can relax so it can expand to allow room for large masses. The colon, controlled by the ENS and muscle coat as well, retains fecal matter until defecation. The enteric reflex circuits regulate movement by either inhibiting or exciting the motor neurons which innervate the muscle. The neurons are excited by acetylcholine and tachykinins, and inhibited by nitric oxide, vasoactive intestinal peptide (VIP), and ATP. The reflexes of the ENS are fundamental to the generation of the patterns of motility of the small and large intestines, which it is programmed to produce different variations in. The relaxation (which accommodates incoming food) and peristalsis of the stomach is due to electrical events generated in the muscle, which result from actions of the vagus nerves synapsing with enteric neurons in the myenteric ganglia. The ENS also allows for the movement of food from the mouth to the anus, which is a result of sympathetic, which has an inhibitory effect on gastrointestinal motor activity, nerve activity levels. When the activity levels are high the enteric excitatory reflexes are inhibited and the sphincters contract.

The movement of water between the gut lumen and tissue fluid compartments is regulated by the ENS which directs the activity of secretomotor neurons, with cell bodies in the submucosal ganglia, which innervate the mucosa in the intestines. The ENS controls of fluid fluxes which cross the epithelial surfaces of the gastrointestinal tract to maintain the electrolyte and fluid balance of the body. These fluxes occur in the epithelium of the small intestine, the large intestine, stomach, pancreas, and gal bladder. The ENS balances secretion periods with ones of absorption through enteric motor reflex circuits, which respond to changes in sympathetic nerve activity due to changes blood pressure and blood volume. The ENS vasodilator neurons regulate local blood flow to the mucosa so that it receives enough nutrients and the fluid exchange between the vasculature, interstitial fluid and gut lumen is balanced. Gastric acid secretion in the stomach, such as HCL, is regulated through cholinergic neurons in the stomach wall which receive excitatory input from both the ENS and vagus nerves.

The ENS also regulates the production and secretion of enteric endocrine cells, the 3 most common of which are: gastrin, which is important in gastric acid secretion the stomach; cholecystokinin, which stimulates the secretion of pancreatic enzymes and bile; and secretin, which stimulates secretion of bicarbonate rich fluids in the pancreas and liver. Hormones in the ENS are secreted in responses to very specific stimuli and cease secretion when those stimuli are no longer present. The endocrine cells are located in the epithelium, which also them to continuously sense and respond to changes in the gastrointestinal environment.

Disorders


The ENS is susceptible to disorders such as Chron's disease, infectious diarrhea, food poisoning, and irritable bowel syndrome. Chron's may result from damage to the enteric glial cells. Furthermore, any disease with an autonomic component or one that may affect the CNS. For example, Parkinson's and Alzheimer's can affect the ENS. The bowels of individuals with Parkinson's disease contain Lewy bodies, which are found in the brain of those who have Parkinson's and Alzheimer's. Parkinson's patients also suffer from digestive problems such as severe constipation which has been shown to be caused by depletion of dopaminergic neurons in the ENS.

Another disease which effects the ENS is Chaga's Disease, which damages both excitatory and inhibitory enteric motor neurons. This can result in the delayed emptying of solid meals by the digestive tract, and fast emptying of liquid meals, respectively. Since the motor neurons are damaged, the ENS cannot innervate the stomach to relax or tense, so it is not able to accommodate for food properly. Enteric motor neuron damage also alters the motility of the intestines, and can result in severe constipation due to altered motor function in the colon. Chaga's disease results from the virus T. cruzi, which is most commonly transmitted by an insect of the subfamily Triatominae.



Insect Family that Carries Chaga's
Insect Family that Carries Chaga's




In Hirschsprung Disease, there is an absence of ganglion cells, or aganglionosis, in the distal colon, which results in a functional obstruction. Both the myenteric and submucosal layers are absent beginning at the anus. Since these ganglia are missing, there is a loss of smooth muscle contraction/relaxation. There is, however, an increase in extrinsic intestinal innervation, an increase of two to three times greater than normal, from the CNS. The excitatory innervation is higher than the inhibitory, resulting in an increase in smooth muscle tone. This leads to uncoordinated peristalsis and functional obstruction. Hirschsprung Disease is a developmental disorder, and is diagnosable within 24-48 hours from birth.



Depiction of Missing Myenteric and Submucosal Plexuses in Hirschsprung's
Depiction of Missing Myenteric and Submucosal Plexuses in Hirschsprung's

Glossary of Terms


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" (Furness, 2007)

Enteric neuron

"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" (Furness, 2007).

Myenteric plexus

"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" (Furness, 2007).

Submucosal plexus

"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" (Furness, 2007).

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" (Furness, 2007)

Chaga's disease

Disease of the ENS resulting from the virus T. cruzi, characterized by altered/damage excitatory and inhibitory enteric motor neurons.

Hirschsprung disease

Developmental disorder characterized by absence of ganglion cells in the colon, resulting in a functional obstruction and lack/uncoordinated peristalsis.

Further Reading

http://psychcentral.com/lib/2007/is-depression-all-in-the-stomach/
Discusses the role of the gut in clinical depression

http://www.scientificamerican.com/article.cfm?id=gut-second-brain
Looks at how the gut influences states of mind and bodily health

http://web.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=4&hid=122&sid=62c7c68b-f36d-4dc6-8692-1a3cac0b9dbe%40sessionmgr115
Article about the ENS and its pathologies

http://www.youtube.com/watch?v=bkeBjP_9ZR4
Video recording of a lecture about "The Brain in the Gut"

Quiz

Multiple Choice

1. Which of the following is not a type motor neuron in the enteric nervous system?
A. Muscle Motor Neuron
B. Secretomotor Neuron
C. Vasodilator Neuron
D. Omnipause Neuron

2. The two plexuses of the enteric nervous system are:
A. Premucosal and Myosin
B.Chaga's and Hirschsprung's
C. Myenteric and Submucosal
D. Enteric and Central

3. Which is a function of the enteric nervous system?
A. Control of Motility
B. Perception of Taste
C. Gastric Defense Reactions
D. A and C
E. All of the Above

4. Chaga's Disease is primarily spread by:
A. Sexual Intercourse
B. Eating Raw Meat
C. An Insect
D. None of the Above

True or False

5. The enteric nervous system is capable of operating without input from the central nervous system.

6. The enteric nervous system receives only parasympathetic input from the central nervous system, which produces an excitatory effect in the enteric motor neurons.

7. IPANs stands for InterPlexus Autonomic Neurons.

8. Hirschsprung Disease is only found in elderly males, age 65 and older.

Short Answer

9. Describe the neuronal connections between the enteric nervous system and the central nervous system, including efferent and afferent connections.

Essay

10. Explain the function of the the enteric nervous system as it pertains to the gastrointestinal system.


Answers:

1.D; 2. C; 3. D; 4. C; 5.T; 6.F; 7.F; 8.F

References


Bowen R. (2006). The Enteric Nervous System [Online]. http://www.vivo.colostate.edu/hbooks/pathphys/digestion/basics/gi_nervous.html

Burns AJ, Pachnis, V. Development of the enteric nervous system: bringing together cells, signals, and genes. Neurogastroenterol Motil 21:100-102, 2009

Furness JB. (2007). Enteric Nervous System [Online]. http://www.scholarpedia.org/article/Enteric_nervous_system

Guyton AC, Hall JE. Textbook of Medical Physiology 10th Edition. Elsevier, 2002.

Hopley L, van Schalkwyk J. (2006). The Enteric nervous system [Online]. http://www.anaesthetist.com/anaes/patient/ans/Findex.htm#ens.htm

Lee SL, Shekherdimian S, DuBois JJ. (2009). Hirschsprung Disease [Online]. http://emedicine.medscape.com/article/178493-overview

Matsuda NM, Miller SM, Evora PRB. The chronic gastrointestinal manifestations of chagas disease. Clinics 64: 1219-1224

Singaram C, Ashraf W, Gaumnitz EA, Torbey C, Sengupta A, Pfeiffer R, Quigley EM. Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic

constipation. Lancet 346: 861-864, 1995.

Enteric Nervous System [Online]. http://en.wikipedia.org/wiki/Enteric_nervous_system