Irritable Bowel Syndrome, or IBS, is a multi-faceted disorder shrouded by decades of medical debate over its perplexing pathophysiology and stigmatized by unfounded beliefs that symptoms are entirely psychological in origin. IBS is the most common GI disorder seen by primary care doctors and affects an estimated 1 in 5 adults in North America. IBS patients are recognized by 3 subtypes based upon their predominant symptoms.
- IBS with diarrhea predominance (IBS-D)
- IBS with constipation predominance (IBS-C)
- IBS with mixed diarrhea/constipation (IBS-M)
IBS interferes with patients’ social life, family life, even their education and careers. It’s the second leading cause of worker absenteeism. Since the mid-1900s, evolving conceptual mechanisms have been suggested to explain the mysterious inner workings of IBS. Mounting evidence gives increasing support to a theory of a dysregulation between the brain-gut axis as well as the existence of a “second brain” in the intestines.
The altered bowel function, abdominal pain, and sensitivity symptoms indicative of IBS result from what appears to be a disturbance in the interaction among the gut, the brain, and the Autonomic Nervous System – which includes the Parasympathetic, Sympathetic, and the Enteric Nervous System – or ENS – now recognized as the “brain below.”
“The status of our knowledge of the enteric nervous system has been, until recently, positively medieval,” said Dr. Michael Gershon, Professor and Chairman, Department of Anatomy and Cell biology at Columbia University, “but in recent times, significant advances in the understanding of this brain in the gut have resulted in a greater appreciation of its importance in clinical medicine, and no more so than in IBS.”
The ENS consists of an extensive network of neurons supported by glia. Enteric glia are analogous to the astrocytes of the CNS. Enteric glial processes encircle large bundles of enteric axons. The small intestine contains about 100 million nerve cells, roughly equal to the number found in the spinal cord.
Two neural plexuses comprise the ENS: a larger, myenteric plexus, positioned between the muscle layers of the muscularis externa, which is home to the neurons responsible for motility. A smaller, submucosal plexus houses sensory cells that talk to the neurons of the myenteric plexus and contain motor nerves cells, which stimulate luminal secretion.
Signals from the brain to the gut play a critical role in maintaining optimal digestive function, reflex regulation of the GI tract, and modulation of mood states.
The ENS can regulate peristalsis and secretion – independently of the central nervous system.
If you cut the central nervous system connection to the gut, the bowel function persists. The ENS relies on a number of neuropeptides and small molecules to regulate both intestinal motility and secretion. Scientific evidence strongly suggests that serotonin – or 5HT – is one of the most important signalling molecules involved in the peristaltic reflex – and that alterations in serotonin signalling may be responsible for IBS symptoms. Ninety-five percent of the serotonin found in the body resides in the gut.
“I first proposed that serotonin was an enteric neurotransmitter in the 1960s,” explained Dr. Gershon, “and by the early 1980s, my suggestion had been confirmed, and teams of scientists determined that serotonin was not only a neurotransmitter but also a signalling molecule that ultimately triggers peristaltic and secretory reflexes. Today, the gut is known to have at least seven different serotonin receptors.”
In order for the gut to govern its own behaviour and trigger any reflexes, it has to sense what is going on in the lumen of the bowel. It does so using two detectors: the intrinsic primary afferent neurons of the intestine (IPANS) and enterochromaffin (EC) cells.
“IPANs are activated by luminal content, such as pressure, nutrients, or acidity and they are the detectors that mobilize the neurons that control mixing and propulsion in the small intestine,” said Dr. Gershon. The large concentration of serotonin in EC cells is located in the basal granules of these cells because the serotonin is secreted into the wall of the gut, not the lumen.
The ECs release serotonin into the underlying connective tissue space, which contains the nerve fibres that express serotonin receptors and thus respond to serotonin.
These receptors include the 5-HT3 receptors known to send signals encoding pain, nausea and other noxious sensations to the CNS. This serotonin release occurs as the result of mucosal stimulation.
The release of serotonin and activation of interneurons within the ENS triggers a cascade of other neurotransmitters, such as acetylcholine and Substance P, which excites peristaltic and secretary reflexes.
“We now have extensive data confirming that serotonin stimulates the peristaltic reflex when it is applied to the mucosal surface and that serotonin is released when peristalsis is initiated. We also know that this reflex disappears when the mucosal actions of serotonin are blocked,” said Dr. Gershon.
The more we know about serotonin’s role in the enteric nervous system, the closer we come toward creating effective therapeutic agents that can manipulate serotonin action and provide symptom relief.
“As the true abundance of neurotransmitters, such as serotonin, in the gut finally become apparent, it has become possible to use the actions of these substances to unlock the secrets of the second brain and to use the data to bring solace to a troubled gut,” explained Dr. Gershon.
Serotonin, or 5HT, is an integral neurotransmitter in the enteric nervous system that profoundly impacts bowel function. Of particular interest are the serotonin receptors 5HT3 and 5HT4 – key mediators of motility, secretion, and even pain sensation. After serotonin is released from enterochromaffin cells located in the lining of the gut, it flows to and binds to the receptors on nerve endings in the intestinal wall. A key to normal bowel function is how long free serotonin remains in the gut wall once it’s released. Serotonin transporter or SERT is an extremely important transporter protein that is responsible for the re-uptake of serotonin from the synaptic space. If re-uptake is blocked, the cells can’t inactivate serotonin.
“My colleagues and I have recently discovered that patients with IBS have a significant decrease in the serotonin transporter, or SERT, in the cells lining the bowel,” said Dr. Gershon. “That means some IBS patients have an inadequate SERT mechanism which causes serotonin to stay around longer, triggering troublesome bowel changes.”
In addition to the increased bowel reactions such as cramps and diarrhea, pain receptors seem to be more sensitive, so even the slightest intestinal distension after a meal can cause great pain.
“5HT3 receptors located in the enteric nervous system which resides within the intestinal wall are involved in the GI motor and secretory functions,” said Dr. Lin Chang, Associate Professor of Medicine at the Division of Digestive Diseases, David Geffen School of Medicine. “5HT3 receptors are also present on extrinsic sensory nerves that are critical for sending signals from the bowel back to the brain. So if the bowel is exposed to a painful stimulus such as excessive stretching or contractions in normal individuals, these extrinsic nerves are stimulated and the information is sent to certain areas of the brain that are involved in the pain response. Under normal conditions, these brain regions are activated and lead to the activation of other nerve pathways and release of chemicals that suppress and lower the pain.
“But this process does not seem to occur normally in people with IBS. That suggests that patients with IBS may fail to use central nervous system down-regulating mechanisms in response to incoming or anticipated visceral pain.”
In recent years, the discovery of new therapeutic targets capable of regulating serotonin levels and activity has made the pipeline for IBS very promising. By blocking or stimulating serotonin receptors in the gut, it is possible to treat abnormal bowel action in those afflicted with IBS.
Advances in understanding serotonin’s role in GI motility and sensitivity have led to the development of 5-HT4 agonists – which have a stimulatory action on gut motility and secretion and 5HT3 antagonists – which have an inhibitory action on gut motility and secretion.
“Selective 5-HT4 agonists have been shown to be beneficial in relieving symptoms of IBS with constipation in women. These types of drugs stimulate 5-HT4 receptors, promoting peristalsis and chloride secretion, and thereby improving stool frequency, consistency, even bloating,” said Dr. Chang.
The 5-HT3 antagonists, indicated for IBS are useful for patients whose chief complaint is diarrhea. 5-HT3 antagonists, block the action of serotonin at the corresponding receptor sites scattered throughout the enteric nervous system and extrinsic nervous system.
Research has shown that 5-HT3 antagonists not only decrease stool frequency and increase stool firmness in IBS-D, but also reduce abdominal pain and discomfort.
“Not only are you changing the patient’s pain perception,” explained Dr. Chang, “You are also changing the motility action of the gut as well. This may be partly due to the central effects of these agents in the brain, but it may also be due to the blockade of 5HT3 receptors within the enteric nervous system.”
It should be emphasized that these selective serotonin receptor drugs should be administered with an appropriate-use management plan and accompanied with patient education.
The 5HT3 antagonist, used for IBS, is designed specifically to treat IBS with diarrhea symptoms and not for patients with IBS with constipation. Therefore, prescribing it to a patient with IBS-constipation predominance would not be beneficial and could even be harmful.
Providing patients with more effective ways to treat IBS and the pain associated with it remains a priority. Based upon a US patient survey, about 39% of IBS suffers rate their pain as severe and over 50% of IBS patients are dissatisfied with their medications. Now, with the advent of novel therapies specifically designed to interact or interfere with serotonin activity in the gut, such as 5HT3 antagonists and 5HT4 agonists, modern medicine is making impressive strides towards changing those statistics.