Introduction

The gastrointestinal (GI) tract is the body’s organ system responsible for digestion, absorption, and excretion of matter vital for energy expenditure and compatibility with life. It utilizes a multitude of organs to achieve this including the mouth, esophagus, stomach, small and large intestines, rectum, liver, biliary tract, pancreas, and glands that work together via complex mechanisms. It can do this using three distinct centers of control[1]:

• Myogenic control: The intrinsic rhythm of the GI musculature. This rhythm primarily occurs via slow waves, a natural property of GI smooth muscle, the rate of which gets set via pacemaker activity of the interstitial cells of Cajal (ICC).
• Hormonal control: Utilizes various hormones including cholecystokinin, gastrin, and secretin, among multiple others for a myriad of functions.
• Neural control: including the GI's intrinsic enteric nervous system and the autonomic nervous system.[2]

These processes all work together to achieve four major actions required for a proper functioning GI tract: motility, secretion, digestion, and absorption. This activity will primarily focus on neural control, specifically the physiologic function of the enteric nervous system and autonomic nervous system, and their associated pathology.

Cellular Level

The GI tract is organized in distinct cellular layers, each containing unique properties integral to the physiological activity of the system as a whole. The layers include:

• Mucosa: Facing the lumen, the mucosa contains an epithelial cell layer, a lamina propria, and muscularis mucosae. These three components primarily provide protection from luminal matter and offer the first barrier of support.
• Submucosa: Found beneath the mucosa, this layer contains the submucosal, or Meissner plexus. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not the stomach and esophagus. This arrangement of nerves receives data from mechanoreceptors and chemoreceptors and manipulates secretion as well as blood flow.[3]
• Muscularis Externa: found beneath the submucosa, it includes the Myenteric plexus (Auerbach plexus) wedged between the proximal circular layer and the outer longitudinal muscular layer. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter, and primarily influences motor control through its effects on smooth muscle, thereby regulating GI motility. It accomplishes this by increasing intestinal length and decreasing intestinal radius. These nerves communicate with one another, primarily via gap junctions and are innervated by excitatory and inhibitory motor neurons[4]. Smooth muscle cells in this layer run from the distal esophagus to the internal anal sphincter and coordinate contractions to produce the motor patterns of GI motility.[5] The longitudinal muscle cells are innervated and undergo activation by excitatory motor neurons, and act to contract and shorten the intestinal length while increasing the intestinal radius. 
• Serosa: Facing the blood, this layer is formed by an epithelial layer and connective tissue, and primarily offers support, providing a barrier between blood and the GI tract.

Lastly, one specialized group of cells instrumental to GI function include Intramuscular interstitial cells of Cajal (ICC).  These cells are interposed between nerve terminals and smooth muscle cells, coupling with the smooth muscle cells to produce the pacemaker activity of the GI tract. 

Function

The GI tract consists mainly of the esophagus, stomach, small intestine, and large intestine, with each containing all of, or a combination of four functions mentioned previously.

• After swallowing, a food bolus must travel from the pharynx to the stomach. The esophagus acts as a conduit between these two points and has a unique system of propelling food from its proximal to its distal end and through the lower esophageal sphincter.
• Separated from the esophagus proximally by the LES, and the duodenum distally by the pyloric sphincter, the stomach uses a complex system of neural and hormonal signals to accomplish three main tasks: Acting as a reservoir, breaking food down into smaller particles and mixing them with gastric juices, and emptying gastric content at a controlled rate.
• The principal function of the small intestine is the absorption of food. The small intestines display an unsynchronized pattern of contractions ideal for the movement of food back and forth to allow both the mixing with digestive enzymes as well as to allow time for absorption. However, there is an overall albeit slow push forward which takes approximately 90 to 120 minutes to allow the first part of a meal to reach the large intestines, whereas the final portions of a meal may not arrive for five hours.
• The function of the large intestine is primarily to store fecal material, extract water and ions while secreting mucus, and move fecal material toward the rectum. In this process, there are no digestive enzymes secreted by the colon, and absorption of nutrients does not occur.
• The primary purpose of the rectum and anus are to propagate feces forward and to allow for the act of defecation.
• Salivary, gastric, intestinal, biliary, and pancreatic secretions are paramount for the digestion of food. These processes not only break food down, but they react with them chemically, altering the structures to allow for either excretion or absorption, the latter of which the body can then utilize for energy expenditure among a myriad of functions. 

Mechanism

As mentioned previously, mediation of the innervation of the GI system is via the enteric nervous system and the autonomic nervous system. Enteric nervous system- is the intrinsic nervous system of the GI tract, containing a mesh-like system of neurons. This system coordinates digestion, secretion, and motility to achieve adequate nutrient absorption. It does this through information stimulating the CNS such as sight and smell, and by local mechanical and chemical receptors found within the GI tract. Included in the enteric nervous system is the ICC. These cells positioned between the two muscular layers create the intrinsic pacemaker activity and are primarily responsible for slow-wave propagation found throughout the GI tract. Included in the enteric nervous system is the myenteric plexus, which exhibits control over the longitudinal and circular muscle layers. Additionally, it is estimated that 30% of the neurons in this plexus are sensory neurons.

The second aspect included in the neural control of the GI tract is the autonomic system. This system is comprised of the sympathetic and parasympathetic systems. In the case of the GI tract, the parasympathetic tract is typically excitatory. The parasympathetic system exerts its effects primarily via the vagus (innervates the esophagus, stomach, pancreas, upper large intestine) and pelvic nerves (innervates the lower large intestine, rectum, and anus.) The vagus nerve regulates tone and volume by activating the enteric motor neurons. They do this by synapsing on the myenteric motor neurons and either exhibiting inhibitory action via nitric oxide, or excitatory action via acetylcholine and neurokinins. The enteric motor neurons, including the myenteric plexus, then synapse on the ICC’s found within muscle bundles. These cells then communicate via gap junctions to the smooth muscles cells.

Sympathetic activity in the GI tract is fundamentally inhibitory. These fibers originate from spinal cord levels T-8 through L-2. These fibers then synapse on the pre-vertebral ganglia and continue onward to finally synapse on the myenteric and submucosal plexuses, which respond to manipulate smooth muscle cells, secretory cells, and endocrine cells.

• Before a food bolus can reach the esophagus, it must be swallowed. It is that action of swallowing that then begins the sequence of peristalsis in the esophagus. Initially, swallowing induces a stimulus that begins the sequence of peristalsis within the esophagus. This stimulus activates the lower motor neurons in the nucleus ambiguous in the brainstem. When the peripheral end of these neurons is stimulated via the vagus nerve, different segments of the esophagus contract. Initially, the caudal end of the dorsal nucleus of the vagus (DMN) is activated via an inhibitory pathway. This inhibition is exerted on all the parts of the esophagus. However, the inhibition lingers for a longer time in the distal areas of the esophagus. Once the inhibition ceases, there is excitatory input leading to sequential activation of the neurons in the rostral zone of the DMN leading a contraction wave that is considered peristaltic. This action allows the area proximal to the food bolus to contract while the area distal remains relaxed, propelling the food down the esophagus. The nerves that allow for this peristaltic motion within the esophagus consists of the myenteric plexus and its association with the circular and longitudinal muscular layers. To continue from the esophagus to the stomach, the food bolus must propel through the lower esophageal sphincter. While this sphincter typically contracted via the effects of acetylcholine on its intrinsic muscle activity, the neurological sequelae of swallowing inhibit this normally remains contracted sphincter, allowing it to relax before the peristaltic wave reaches down the esophagus.[6]

• The stomach has two main centers of control consisting of nervous control and hormonal control, including hormones such as gastrin and cholecystokinin, which relax the proximal stomach, and contracts the distal stomach. The pacemaker cells in the fundus of the stomach establish a basal electrical rhythm continuously that spread down to the pyloric sphincter, creating a rate of approximately three to eight contractions per minute. Relaxation of the stomach is pivotal for its acceptance of the incoming food bolus and is mediated predominately by inhibitory vagal fibers. These fibers are stimulated first by the action of swallowing, and second by stretch receptors that are activated when the bolus reaches the stomach. The stomach then acts as a sieve, mixing food particles with gastric fluids, and breaking those particles down into smaller parts. This occurs through three main mechanisms: First is the non-adrenergic, non-cholinergic (NANC) control. This mechanism utilizes substances such as nitric oxide, vasoactive intestinal peptide, and others. The second is sympathetic fiber activation utilizing norepinephrine. Third, is excitatory vagal stimulation. These three processes serve to give the stomach a unique mixing motion, dubbed segmentation. In this process, mechanoreceptors in the gastric wall activate, leading to a unique parasympathetic sequence. Once the bolus reaches the pylorus, long vago-vagal activity, as well as short reflexes through the enteric nervous system, activate the pyloric pump and contract the pyloric sphincter leading to both the mixing of particles and inhibition of the forward movement of the bolus through the pylorus respectively. The antral pump stimulated by mechanoreceptors as well as the enteric system then propels food back to the fundus, which creates a circuit. Throughout this process, the smallest particles, as well as some fluids are released into the duodenum, until finally, most of the bolus has made its way out of the stomach[7].

• The small intestine utilizes two different mechanisms regarding motility. First is the pacemaker activity which propagates slow waves. Second is the migrating motility complex (MMC). This process is dependent on the enteric nervous system and has three phases. The first is the quiet phase in which there is minimal propulsion, which lasts approximately 70 minutes. The second phase includes intermittent motor activity, in which there are one to five contractions with each slow wave. This entire phase lasts between 10 and 20 minutes. Last, there is the regular, propagating contractile activity phase in which there are regular contractions, and the bulk of the food gets moved through the small intestine in a peristaltic pattern, which lasts a total of five minutes. This peristaltic pattern is under the mediated of the “law of the intestine” in which distension of one area is sensed by mechanoreceptors, leading to contraction above the area of distension, and relaxation below the area. This phase is mediated predominately by the autonomic and enteric nervous systems, and repeat every 90 to 120 minutes[8].  

• The large intestine is mainly involved in the storage and propulsion of feces, and take approximately 8-15 hours to accomplish this task. They accomplish this task in three ways: The first is the mixing movement, in which there is no net movement of its contents. The second mode of motility is through Haustral migration in which there are slow waves as well as long bursts of spike activity. Haustrations form from the concomitant constricted and relaxed portions of the intestines. The large intestines accomplish Haustral migration in a similar pattern as the stomach and proximal small intestine, through the process of segmentation, with the distinction of stronger contractions due to the ring-like contractions of the circular muscle as it encircles the large intestine in its entirety. The purpose of this movement type is to mix chyme and fecal material while providing slow forward movement. Lastly is the “mass movement,” which consists of frequent, powerful propulsions. Mediation of this process is via the enteric nervous system of the transverse and descending colon. This mechanism is similar to the peristaltic contractions seen previously.[9]

• Rectum and Anus: As stool reaches the distal large intestine, rectum, and anal sphincter, the myenteric plexus is stimulated to initiate peristalsis as well as relax the internal anal sphincter. This reflex, called the rectosphincteric reflex, also stimulates the external anal sphincter to contract, leading to the urge to defecate. At the same time, there is parasympathetic activation leading to relaxation of the internal anal sphincter to allow the passage of stool. The external sphincter, as well as the puborectalis muscle, is then voluntary controlled to either avoid the leakage of contents via voluntary constriction or to allow defecation, via voluntary relaxation. The striated muscle of the puborectalis muscle, as well as the external anal sphincter, are both innervated by somatic fibers of the pudendal nerves.[10] While hormonal control exerts signficant influence on salivary and gastric secretions, there are numerous effects of nervous control as well.

• The salivary glands are mainly under sympathetic control, specifically with cranial nerves VII and IX. These stimulate the secretion of serous, low viscous saliva. This saliva secreted relative to to parasympathetic activation is copious in amount and contains large amounts of potassium and bicarbonate, and scant amounts of protein. These glands are under sympathetic control as well but to a lesser extent. Sympathetic fibers extend through the superior cervical ganglion and stimulate the secretion of a highly viscous, thick saliva. The saliva produced is minimal in amount, is rich in protein, and low in potassium and bicarbonate.[11]

• Gastric secretions are various and originate from parietal cells, chief cells, as well as mucous neck cells. Parietal cells secrete primarily hydrochloric acid (HCl), and intrinsic factor. There are three mechanisms for release of parietal cell contents, one of which is of neural influence. The first phase of gastric secretion is the cephalic phase. In this phase, a person sees, smells, or thinks about food, activating an area in the medulla oblongata. This then activates the Vagus nerve which secretes acetylcholine, which synapses at the muscarinic receptor allowing for the release of gastric contents. The gastric phase then begins as a bolus enters the stomach. Distension of the stomach activates stretch receptors in the wall of the stomach as well as chemoreceptors in the mucosa of the stomach, stimulating short reflexes which then stimulate the submucosal and myenteric plexuses, leading to parasympathetic activation and gastric secretion.[12]

• Intestinal secretions are similar to that of gastric secretions. Intestinal distenison activates mechanoreceptors, and intestinal contents activate chemoreceptors both leading to parasympathetic activation and intestinal secretions.

Clinical Significance

Ileus often presents in postoperative patients characteristically present with obstipation and the intolerance of oral consumption. Ileus primary results from an active slow wave but the absence of spike-wave activity. While slow waves get produced by the pacemaker cells of the GI tract, they don’t cause contractions by themselves. An action potential, as seen by a spike-wave on top of the slow-wave, is needed for the slow-wave to reach a threshold low enough for the propagation of a full action potential, and consequent stimulation of various GI tissue. In this condition, there is continuous inhibitory neural activity and potential peritoneal irritation from the stasis of food.[13]

Infectious diarrhea, which can be caused by many organisms, has a general theme of rapid, powerful peristalsis that results in a reduced transport time leading to an increased number of bowel movements, as well as a lack of time for absorption and water extraction to occur, leading to bulky and watery stools.

Achalasia, characterized by a perpetually contracted lower esophageal sphincter (LES), is due to the absence or disruption of the ganglionic cells in the myenteric plexus. As these nerves are responsible for esophageal sphincter relaxation and esophageal propulsion, the LES is unable to relax, and food cannot pass through to the stomach.[14]

Hirschsprung disease is a failure of neural crest cells, the precursors to the myenteric plexus, to migrate to the intestines; this leads to constriction of the affected segment, as well as the failure of the intestines to propel food forward. This failure causes a buildup of food in the affected area as well as intestinal distension, and the inability to produce a bowel movement, often seen as a failure to pass meconium.[15]

Diffuse esophageal spasm which can present as dysphagia, heartburn, and regurgitation, is primarily caused by an aberrant response to esophageal distension. Instead of relaxing in response to swallowing and consequent esophageal distension, the esophagus is unable to do so and remains in the contracted state, preventing proper peristaltic movement.

Gastroesophageal reflux disease (GERD), is a chronic problem resulting in the contents of the stomach to reflux back into the esophagus due to an incompetent LES that fails to stay in its contracted state leading to damage of the esophageal epithelium. This condition can have many complications, the most severe of which is disruption of the normal mucosa, and the development of esophageal adenocarcinoma. GERD is commonly exacerbated by specific foods and drinks such as certain proteins, alcohol, and caffeine, as they enhance gastric secretion significantly by stimulating chemoreceptors in the mucosa of the stomach, leading to increased release of HCl by the parietal cells, and an increase of the acidity of gastric contents.[16]