Bioelectronics as a Possible Therapeutic Modality Targeting Sphincteric Dysfunction in Gastrointestinal Disorders
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Sphincters in the gastrointestinal tract control the movement of luminal contents in the forward direction and prevent their movement in the backward direction. Defective sphincters are responsible for many of the disorders in the gastrointestinal tract. The defects might be due to abnormally loose lower esophageal or anal sphincters, with the result being diseases such as gastroesophageal reflux disease and fecal incontinence, respectively. In some cases the lower esophageal or anal sphincter might be too tight and thus prevent the forward movement of gastrointestinal luminal contents, with the result being diseases such as achalasia or functional rectosigmoid obstruction, respectively. There are multiple causes that might lead to the disruption of the normal function of these sphincters. The probable causes include damage to the nerves supplying the sphincter or to the sphincter itself either owing to trauma or owing to infection or from congenital diseases. The majority of the causes responsible for sphincteric dysfunction are still unknown. Because the majority of the causes of sphincteric dysfunction are unknown, there are very few effective pharmacologic treatments for many of these conditions. For example, all the current treatments for gastroesophageal reflux disease are aimed at treating the symptoms by decreasing the stomach acid. These treatments do little to prevent the actual event of reflux. Bioelectronic medicine may play a major role in treating these conditions by directly manipulating either the sphincter or the nerves that supply the sphincters. Because this is a targeted approach, one can expect to have better efficiency and fewer side effects than traditional pharmacological treatments.
A sphincter in the gastrointestinal (GI) tract is a ring-like muscle that normally maintains constriction of a body passage or orifice and relaxes as required by normal physiological functioning. Sphincters in the gastrointestinal tract control forward passage and prevent or allow the backwards passage of solids, liquids and gases. Some of the examples of GI sphincters are upper esophageal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of oddi, Ileocecal sphincter and anal sphincter. Defective sphincters are responsible for many of the functional disorders in the GI tract. In general sphincter disorders in the GI tract are due to the sphincter muscle being too loose, as in gastroesophageal reflux disease (GERD) or fecal incontinence, or the sphincter muscles being too tight as in achalasia in the esophagus or functional rectosigmoid obstruction in the anal sphincter. Many of these sphincteric dysfunctions may be targeted for future therapy by using devices that deliver electrical current to the sphincteric muscle or to the nerves innervating the muscle to either relax or to contract the sphincter in an appropriate manner. The first attempts at electrical stimulation to affect gastrointestinal motility occurred in the 1960s and 1970s. Although most of these efforts were directed toward gastric electrical stimulation to treat gastroparesis, there have been more recent attempts at electrical stimulation of the sphincter directly or to the nerves innervating the sphincter.
The following are examples of sphincter dysfunction causing functional gastrointestinal disorders, which we have studied in our laboratory. These studies describe the normal physiology and the underlying pathophysiology of GERD and the role of the ileocecal valve in small bowel bacterial overgrowth. These identified sphincteric defects can be targeted by using bioelectronics to treat diseases.
The High-Pressure Zone of the Distal Esophagus and Proximal Stomach in Gerd
Thus the intrinsic sphincter is composed of two components, a proximal component (LEC) that overlaps and moves with the crural sphincter, and a distal component at the junction between the gastric cardia and esophagus, formed by the GC/GS complex. These two components along with the crural diaphragm combine to make up the high-pressure zone of the distal esophagus and proximal stomach which acts as an antireflux barrier (1).
The Muscularis Mucosa and its Role in Gerd
The Ileocecal Valve and its Role in Small Bowel Bacterial Overgrowth
Future Therapy for Functional Gastrointestinal Disorders
We are in the process of developing novel and innovative therapies to treat GI disorders targeting defective sphincteric mechanisms. GI functional disorders are some of the most common diseases worldwide. We have discovered that many of the underlying causes of functional GI disorders involve dysfunction of various sphincters. In a recent article by Rodriguez et al. (7) electrical stimulation therapy of the lower esophageal sphincter was successful in treating GERD. The final results of the trial demonstrated a significant and sustained improvement in GERD symptoms, esophageal pH, and a reduction in PPI usage without any side effects after electrical stimulation of the LES. In another article by Hofmann et al. (8), in a canine model they evaluated the motor activity and pressure in the ileum, ICV and the colon. They found that the resting pressure at the ICV was 12.7 ± 0.4 cmH2O. Electric stimulation of small mesenteric nerves to the ICV increased pressure in the ICV to 35.0 ± 4.1 cmH2O. We believe that electrical stimulation of gastrointestinal sphincters holds great promise in the future treatment of functional disorders of the gastrointestinal tract.
The authors declare that they have no competing interests as defined by Bioelectronic Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.
These studies were supported by a grant from National Institute of Health (RO1 DK079954).
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