Definition and Overview
The enteric nervous system (ENS) is a unique nerve network embedded in the wall of the gastrointestinal tract and contains approximately 200 to 600 million nerve cells (average approximately 500 million). This is equivalent to the number of nerve cells in the spinal cord, and allows the digestive function to be autonomously controlled without direct commands from the central nervous system. Because of this independence, Gershon named the enteric nervous system the 'second brain' in 1999.
The enteric nervous system is distributed throughout the gastrointestinal tract from the esophagus to the anus and uses more than 20 types of neurotransmitters. These include serotonin, acetylcholine, nitric oxide, dopamine, and substance P. The fact that approximately 95% of the body's serotonin is produced in the intestines shows the neurochemical importance of the enteric nervous system.
The autonomic nervous system has traditionally been divided into the sympathetic and parasympathetic nervous systems, but the enteric nervous system is separately classified as a third division of the autonomic nervous system due to its complexity and independence. The enteric nervous system has a complete reflex circuit of sensory neurons, interneurons, and motor neurons, capable of processing sensory input and generating motor output on its own.
anatomy
The enteric nervous system is arranged into two major plexuses within the wall of the gastrointestinal tract. Each nerve plexus consists of a ganglion where nerve cell bodies are gathered and a bundle of nerve fibers that connect them.
Auerbach's plexus
The Auerbach plexus, also called the myenteric plexus, is located between the longitudinal and circular muscle layers of the gastrointestinal tract. It is continuously distributed throughout the gastrointestinal tract from the esophagus to the anus, and mainly regulates the motor function of the gastrointestinal tract.
Motor neurons in the Auerbach plexus are divided into excitatory neurons and inhibitory neurons. Excitatory neurons secrete acetylcholine and substance P to contract muscles, and inhibitory neurons secrete nitric oxide and vasoactive intestinal peptide (VIP) to relax muscles. These two types of nerve cells work cooperatively to produce the contraction-relaxation pattern of peristalsis.
Meissner plexus
The Meissner plexus, also called the submucosal plexus, is located in the submucosa. It is well developed in the small and large intestines and mainly regulates the secretory function and blood flow of the mucous membrane.
Sensory neurons in the Meissner plexus sense chemical components and mechanical stimulation of the intestinal lumen. Based on this information, it regulates the secretion of digestive enzymes, mucus, and electrolytes and changes mucosal blood flow. It is responsible for creating the microenvironment necessary for nutrient absorption.
enteric glial cells
In the enteric nervous system, in addition to neurons, enteric glial cells exist in numbers 4 to 7 times greater than neurons. Enteric glial cells perform similar functions to astrocytes in the central nervous system and are involved in supplying nutrients to neurons, regulating neurotransmitter metabolism, and maintaining the intestinal mucosal barrier. Recent studies have accumulated reports that dysfunction of enteric glial cells is associated with intestinal inflammation and functional gastrointestinal diseases.
function
Control of peristalsis
The most core function of the enteric nervous system is the control of peristalsis. When food irritates the intestinal lining, sensory neurons detect this and transmit signals to motor neurons via interneurons. As the cricoid muscle on top of the food contracts and the cricoid muscle on the lower part relaxes, the contents move toward the anus, which is called the peristaltic reflex.
This process is completed only by local reflex circuits within the enteric nervous system and occurs autonomously without intervention of the central nervous system. In animal experiments, it was confirmed that peristalsis was maintained normally even in intestinal segments where external nerve connections were completely blocked. In addition to peristalsis, the enteric nervous system programs various motor patterns such as segmentation and the migrating motor complex of the small intestine.
secretion regulation
The enteric nervous system, centered on the Meissner plexus, regulates the secretion of digestive juices. Secretion of gastric acid, bile, pancreatic juice, intestinal juice, mucus, etc. is precisely adjusted according to the nutrient composition and acidity of the intestinal lumen. When the glucose concentration in the intestinal lumen increases, the sensory neurons of the enteric nervous system detect this and there is a reflex that induces the secretion of incretin, a hormone that promotes insulin secretion.
The enteric nervous system also regulates the secretion and absorption of water and electrolytes in the intestinal mucosa. Hyperactivation of the enteric nervous system's secretory reflex is also involved in the mechanism by which cholera toxin causes severe diarrhea.
Regulation of mucosal blood flow
Vasomotor neurons of the enteric nervous system regulate blood flow in the arterioles and arterioles of the submucosa. During the digestion process, it selectively increases blood flow in areas where nutrient absorption is active. Nitric oxide and VIP act as major vasodilating neurotransmitters and optimize the supply of oxygen and nutrients to the mucous membrane by regulating local blood flow.
immune regulation
The enteric nervous system closely interacts with gut-associated lymphoid tissue (GALT). Approximately 70% of the body's immune cells are distributed in the intestinal mucosa, and two-way communication occurs between nerve cells of the enteric nervous system and immune cells mediated by neurotransmitters. The enteric nervous system protects against pathogen invasion by regulating the permeability of the mucosal barrier and also plays a role in regulating the inflammatory response of the intestinal mucosa.
gut-brain axis
two-way communication path
The gut-brain axis is a two-way communication system between the enteric nervous system and the central nervous system. The vagus nerve is the key pathway for this communication, and many of the sensory signals of the enteric nervous system are transmitted to the nucleus tractus solitarius of the brain stem via vagal afferent fibers.
Downstream signals from the brain to the gut reach the enteric nervous system via vagal efferent fibers. In stressful situations, when the brain's hypothalamic-pituitary-adrenal (HPA) axis is activated, cortisol is secreted, which causes increased intestinal permeability, changes in intestinal motility, and changes in the composition of intestinal flora. This mechanism explains the phenomenon of stress during exam periods causing stomach pain and diarrhea, and the phenomenon of feeling sick when nervous.
Intestinal microorganisms and enteric nervous system
The gut microbiota is a key component of the gut-brain axis. Intestinal bacteria produce neuroactive substances such as short-chain fatty acids, tryptophan metabolites, and gamma-aminobutyric acid (GABA), which directly stimulate sensory neurons of the enteric nervous system.
In a germ-free animal study, it was confirmed that mice without intestinal bacteria have incomplete development of the enteric nervous system and reduced gastrointestinal motility. There are also reports that administration of certain probiotics (e.g. Lactobacillus rhamnosus) changed the expression of GABA receptors in the brain via the vagal pathway and reduced anxiety behavior. This effect did not appear in animals with the vagus nerve cut, confirming that the vagus nerve is an essential communication route between intestinal bacteria and the brain.
Serotonin and gut-brain communication
Approximately 95% of serotonin in the body is synthesized in enterochromaffin cells of the intestinal mucosa. Serotonin secreted by enterochromaffin cells acts on the sensory nerve endings of the enteric nervous system, causing peristalsis, secretion, and gag reflex. At the same time, it transmits visceral sensory information such as satiety and nausea to the brain through vagus nerve afferent fibers.
Abnormalities in the serotonin signaling system of the intestinal mucosa have been confirmed in patients with irritable bowel syndrome (IBS), and drugs targeting serotonin receptors (5-HT₃ receptor antagonists, 5-HT₄ receptor agonists) are used to treat IBS.
Enteric nervous system abnormalities and related diseases
irritable bowel syndrome
Irritable bowel syndrome (IBS) is a functional gastrointestinal disease that causes chronic abdominal pain and changes in bowel habits without organic lesions. Approximately 11% of the world's population is affected. Visceral hypersensitivity of the enteric nervous system is one of the key pathophysiological mechanisms. IBS patients complain of pain at lower doses than normal subjects during rectal balloon dilation, which reflects a lowered threshold of enteric nervous system sensory neurons.
Abnormal communication of the gut-brain axis is also involved in the onset and maintenance of IBS. In IBS patients, the HPA axis response to stress is excessive, and brain imaging studies confirm changes in activity in visceral sensory processing areas. Based on this, IBS is currently being redefined as 'disorder of gut-brain interaction'.
functional dyspepsia
Functional dyspepsia is a disease in which epigastric pain, early satiety, and postprandial bloating recur without any organic cause. The global prevalence is approximately 10-30%. Abnormalities in the sensory and motor functions of the gastric enteric nervous system are involved, and the main mechanisms are reduced gastric accommodation and delayed gastric emptying. Gastric compliance is a reflex in which the proximal part of the stomach relaxes to accept food after a meal, and is handled by inhibitory motor neurons of the enteric nervous system.
Parkinson's disease and enteric nervous system
Alpha-synuclein aggregates, a pathological characteristic of Parkinson disease, are also found in the enteric nervous system. According to Braak's hypothesis, alpha-synuclein pathology may originate in the enteric nervous system and propagate ascending to the brain stem via the vagus nerve. In an epidemiological study supporting this, patients who underwent vagus nerve transection had an approximately 40% reduced risk of developing Parkinson's disease.
In more than 80% of Parkinson's disease patients, constipation is observed 10 to 20 years before the onset of motor symptoms, suggesting early lesions of the enteric nervous system. In colonic mucosa biopsies, alpha-synuclein deposition has been confirmed even in patients before the onset of motor symptoms, and enteric nervous system pathology is being studied as an early diagnostic biomarker for Parkinson's disease.
congenital megacolon
Hirschsprung disease is a representative disease in which enteric nervous system neurons are congenitally lacking. During development, neural crest cells are unable to migrate to the distal part of the large intestine, so ganglia are not formed in that segment. The non-ganglionic segment cannot relax, resulting in functional intestinal obstruction, which occurs in approximately 1 in 5,000 newborns. The principle of treatment is surgical resection of the ganglionic segment.
Diabetic gastrointestinal disorders
Chronic hyperglycemia causes neurodegeneration in the enteric nervous system. Approximately 75% of diabetic patients report one or more gastrointestinal symptoms, gastroparesis being a representative example. Oxidative stress caused by high blood sugar damages enteric nervous system neurons and enteric glial cells, and loss of inhibitory motor neurons is especially noticeable.
Inspection and Evaluation
A single, standardized test that directly evaluates the enteric nervous system has not yet been established, but indirect evaluation is possible using the following methods.
- Autonomic nervous function test: Comprehensively evaluates the functional status of the autonomic nervous system, including the vagus nerve, through heart rate variability (HRV) analysis, cardiorespiratory testing, and Valsalva maneuver. Decreased high-frequency (HF) components of HRV reflect decreased vagal tone, which may be associated with gut-brain axis dysfunction.
- Gastrointestinal motility test: Gastric emptying scintigraphy diagnoses gastroparesis by quantitatively measuring the rate of stomach emptying. A colonic transit study evaluates colonic transit time using radiopaque markers.
- Anorectal manometry: Measures pressure in the rectum and anus to evaluate bowel function. Hirschsprung's disease shows a characteristic finding of loss of the rectoanal inhibitory reflex.
- Intestinal mucosa biopsy: Performed for research purposes, it can evaluate morphological changes in enteric nervous system neurons and alpha-synuclein deposition.
- Quantitative electroencephalography (QEEG): An auxiliary tool to evaluate the central nervous system aspect of the gut-brain axis, it can be used to identify changes in brain function accompanying autonomic dysfunction.
life management
Lifestyle rules for maintaining the health of the enteric nervous system and optimizing the balance of the gut-brain axis are as follows.
- Regular meals: Eating at regular times regularizes the rhythm of the migratory motor complexes of the enteric nervous system. Eating quickly or irregularly can cause intestinal motility disorders.
- Dietary fiber intake: Consuming 25 to 30 g of dietary fiber per day is essential for maintaining intestinal motility and preserving the diversity of intestinal flora. Dietary fiber is converted into short-chain fatty acids by intestinal bacteria and supplies energy to the nerve cells of the enteric nervous system.
- Consume fermented foods: Fermented foods such as kimchi, yogurt, and soybean paste contribute to the balance of intestinal flora by replenishing beneficial bacteria. Clinical studies have reported that probiotics alleviate anxiety and stress responses through the gut-brain axis.
- Slow abdominal breathing: Breathing 6 times per minute (4 seconds for inhalation, 6 seconds for exhalation) activates the vagus nerve and improves bowel function. There is a study that showed a significant reduction in abdominal pain and constipation symptoms in IBS patients after 4 weeks of breathing training.
- Regular aerobic exercise: 3-5 times a week, walking, swimming, or cycling for more than 30 minutes promotes intestinal motility and increases vagus nerve tone. Research has also shown that regular exercise increases the diversity of intestinal flora.
- Stress management: Chronic stress increases intestinal permeability and disrupts enteric nervous system function through HPA axis hyperactivity. Meditation, yoga, and relaxation training help restore gut-brain axis function.
- Sufficient sleep: Regular sleep of 7 to 8 hours is essential for restoring autonomic balance. Sleep deprivation increases intestinal permeability and changes the composition of intestinal flora.
If symptoms persist or worsen, or if you have chronic digestive symptoms whose cause cannot be identified through routine gastrointestinal testing, you should seek specialist treatment, including evaluation of autonomic function.