The digestive tract is designed for the optimal processing of food that nourishes all organ systems. The esophagus, stomach, small bowel, and colon are sophisticated neuromuscular tubes with specialized sphincters that transport ingested food-stuffs from one region to another. Peristaltic contractions move ingested solids and liquids from the esophagus into the stomach[1
]; the stomach mixes the ingested nutrients into chyme and empties chyme from the stomach into the duodenum[2
]. The to-and-fro movement of the small bowel maximizes absorption of fat, protein, and carbohydrates[3
]. Peristaltic contractions are necessary for colon function and defecation[4
Sphincters of the digestive tract, on the other hand, have intrinsic muscle tone that produces sustained (tonic) pressure zones. The sphincteric pressures regulate movement of luminal content produced by the peristaltic contractions. Relaxation of the lower esophageal sphincter (LES), for example, allows the entry of esophageal content into the stomach[5
]; contraction and relaxation of the pyloric sphincter regulates movement of gastric content into the duodenum[6
]. The ileocecal valve regulates flow of content from the ileum into the cecum[7
]. The internal anal sphincter (IAS) regulates the elimination of rectal-sigmoid content[8
]. Sphincters not only provide resistance to flow in the areas distal to the sphincter but also limit the retrograde movement of intraluminal content into the areas proximal to the sphincter. Thus, normal neuromuscular function of the esophagus, stomach, small bowel, and colon requires the coordination of the tubular neuromuscular structures and the relevant sphincters. Symptoms such as dysphagia, nausea and vomiting, diarrhea, constipation, or incontinence may occur if neuromuscular function of the esophagus, stomach, intestine, and colon is disturbed, resulting in neuromuscular disorders such as achalasia, gastroesophageal reflux, gastroparesis, intestinal pseudo-obstruction, colonic inertia, and fecal incontinence, respectfully[1-4,9,10
The wall of gastrointestinal tract organs contains circular and longitudinal smooth muscle layers, the enteric nervous system including the myenteric plexus, and the interstitial cells of Cajal (ICCs) which control the rhythmicity of contractions[11,12
], all of which are targets for tissue bioengineering[13
]. The gastrointestinal tract wall is innervated by vagal afferent and efferent fibers and inputs from the sympathetic nervous system. Thus, neuromuscular disorders of the gastrointestinal tract may involve damage to the smooth muscle, enteric nerves, ICCs, extrinsic neurons, or all cell types. Neuromuscular diseases such as achalasia, gastroparesis, intestinal pseudo-obstruction, and colonic inertia represent the most severe forms of neuromuscular diseases of the gastrointestinal (GI) tract[14-17
]. These disorders are very difficult to treat, and very few drugs are designed to improve GI neuromuscular function. Table shows a summary of the human neuromuscular disorders from selected areas of the GI tract, the key neuromuscular abnormalities, the clinical neuromuscular diagnosis, and the medical and surgical treatments currently available for these diseases.
Neuromuscular disorders of the gastrointestinal tract, current treatments and future regenerative medicine approaches
In the most severe neuromuscular diseases, surgery is often required to improve symptoms. For example, a myotomy of the LES may be necessary to treat severe dysphagia due to achalasia. Partial resection of the colon and pull-through operations may also be necessary to treat drug-refractory, severe constipation or marked colonic dilation. Colectomy may be needed to correct aganglionic segments of colon as seen in Hirschsprung’s disease. While a surgical approach may relieve one set of symptoms, the consequence is often secondary neuromuscular disorders. After myotomy is performed for achalasia, for example, gastroesophageal reflux may occur and require drug treatment or fundoplication. Problems with fecal incontinence may also occur after colonic resection.
In this review, the normal neuromuscular function and disorders of neuromuscular function of the digestive organs in humans are discussed. We will focus on advances in regenerative medicine as an innovative and potential cure for GI neuromuscular diseases. The goal of this novel technology is restoration of the neuromuscular function of the bowel wall. A regenerative medicine approach aims to bioengineer “functional” circular and longitudinal smooth muscle, enteric neurons, ICCs, and mucosa in the correct anatomical configurations in order to produce normal physiologic gut functions. GI neuromuscular disorders are particularly suited to regenerative medicine approaches because drug and surgical therapies are extremely limited.