Award for Senior Investigator in Basic Science
Dr. Mawe is a Professor in the Department of Anatomy and Neurobiology at the University of Vermont in Burlington, Vermont with additional duties in the Department of Pharmacology and the GI Division of Medicine. He is also an Adjunct Professor of Physiology and Pharmacology at the University of Calgary.
Dr. Mawe has established an internationally renowned translational research program that focuses on how the nervous system regulates motor activity in the intestines and the biliary tract.
His research interests include the understanding of signaling by the neurotransmitter serotonin in the digestive tract; changes in the gut (enteric) nervous system in response to and following inflammation; and the mechanism by which smooth muscle function is disrupted in gallstone disease.
He and his colleagues have made discoveries that provide fundamental information about how the digestive organ systems work, and insight about changes that occur in inflammatory and functional/motility disorders.
Basic Science is the fundamental approach to understanding how systems work. Basic science research takes place in the laboratory and often involves the study of molecules and cells.
Translational Science is the conversion of basic science discoveries into the practical applications that benefit people.
While the big brain in our head is dealing with abstract thoughts and complicated equations, the “little brain” in our gut is dealing with the everyday, but complex, work of digestion and defecation. Known as the enteric nervous system, nerves in the wall of the intestines control how the gut reacts to an ingested meal, and they regulate the processes of digestion, nutrient absorption, and waste elimination.
The coordinated activities of this nervous system ensure that we efficiently extract the calories that are available from the food and drink that we ingest. When all is well, this process of intestinal motility and secretion occurs behind the scenes at a sub-conscious level. When all is not well, we are quickly reminded that we take our gastrointestinal (GI) tracts for granted. Diarrhea, constipation, vomiting, and abdominal pain can quickly shake us out of our status quo. All of these responses involve the actions of the nervous system of the gut.
My colleagues and I have been studying how nerve cells regulate muscle function in the gut and gallbladder under normal conditions and how the circuitry of the gut is altered under abnormal conditions. We have also been studying how the neurotransmitter serotonin acts as a critical signaling molecule to activate gut reflexes, and how key elements of serotonin signaling are altered by inflammatory bowel disease (IBD) and in irritable bowel syndrome (IBS).
Neural regulation of the digestive tract – understanding changes that contribute to IBD and IBS
Other organ systems in our body, such as the heart and bladder, are controlled by neural signals arising in the brain and spinal cord. In the GI tract, neural circuits that are housed entirely within the wall of the intestine are capable of regulating various features of gut function such as motility and secretion.
While these enteric neural circuits can be controlled by signals coming from the brain, they can also function independently. This means that the nervous system of the intestines, the enteric nervous system, has many special features.
These features include:
- The ability to sense changes within the gut, such as nutrients that would activate digestive responses, or invasive organisms that would activate protective responses such as vomiting and diarrhea
- The ability to process this information and activate the appropriate gut behaviors, such as moving contents to and fro for digestion, or propelling them along the gut for elimination
- The ability to excite or inhibit the muscle and glands in a given region of the gut
In states of inflammation, such as Crohn’s disease or ulcerative colitis, intestinal motility, secretion, and sensitivity are altered. As nerve cells of the intestines regulate all of these functions, it is likely that changes in how these neurons function contribute to the symptoms that lead to so much suffering in individuals with these conditions.
Discoveries in the biology of the gut nervous system over the past two decades have provided us with a solid understanding of the components that make up gut reflex circuits, and how these neurons function under normal physiological conditions. We are beginning to understand what changes occur in colitis at precise sites along the reflex circuits. We are also starting to determine the mechanisms responsible for these changes. We have discovered that inflammation leads to several changes in the response of nerves, which can disrupt colonic motility.
Interesting discoveries have been made in laboratory studies of inflammation-induced changes in nerves that could have implications for functional GI disorders. We have found that the changes in the physiological properties of neurons brought on by the inflammatory response persist long after inflammation has resolved. Also, inflammation-induced alterations in gut motility and sensitivity are observed weeks beyond the recovery from inflammation.
One of the puzzling and frustrating aspects of functional GI disorders like IBS is that there is no test for it, and the GI tracts of individuals with IBS appear completely normal. Our ability to study the electrical properties of single neurons allows us to detect the changes responsible for altered gut function and sensitivity. It is possible that in some forms of IBS, such as post-infectious IBS, a previous inflammatory condition has resulted in persistent changes in the properties of the neurons that supply the gut.
Serotonin signaling in the GI tract
We typically think of serotonin (5-HT) as a neurotransmitter – a signaling molecule – in the brain that influences our state of mind, but most of the body’s serotonin is actually located in the GI tract. The majority of serotonin is synthesized by specialized cells in the inner lining of the intestine called enterochromaffin (EC) cells.
Serotonin released by EC cells stimulates receptors on nearby nerve fibers to activate reflexes that are involved in secretion of fluid and coordinated muscle responses that propel ingested food and fluids along the intestines. The serotonin in the intestine is re-absorbed (in a process called reuptake) into cells lining the gut by a protein called the serotonin selective reuptake transporter (SERT). This molecule’s function is inhibited by serotonin selective reuptake inhibitors (SSRIs), which are commonly prescribed for the treatment of depression and anxiety disorders.
In the gut, SERT is located on cells throughout the inner lining of the intestines. Studies conducted in our laboratory and others have demonstrated that various aspects of serotonin signaling are reduced in people with IBD or IBS. We have pursued further studies to better understand how SERT activity is regulated.
Current studies in our laboratory are directed towards identifying serotonin related targets in the gut that could be useful for developing safe and effective treatments for functional GI disorders. Recently, we made an interesting discovery related to a type of serotonin receptor called the 5-HT4 receptor. Compounds that activate this receptor (5-HT4 agonists), such as cisapride, tegaserod, and prucalopride, have been developed for the treatment of constipation, and they also appear to relieve abdominal discomfort in constipation-predominant IBS. Unfortunately, previously approved 5-HT4 agonists are not available due to fear of cardiovascular side effects.
We discovered that essentially all of the cells in the inner lining of the colon have this receptor. We also found that the application of 5-HT4 agonists that target just the surface of the colon activates receptors that lead to mucus, serotonin, and fluid secretion. All of these actions could lead to the reduction of constipation and colonic pain. Formulating 5-HT4 agonists to prevent absorption outside the colon may improve treatment effects while avoiding potential side effects.
Each meal that we ingest triggers a highly choreographed series of physiological reflex responses along the GI tract that allow us to gain access to nutrients and to systematically eliminate waste byproducts. Ongoing basic science (lab) research is identifying the key elements of these reflex responses at the molecular, cellular, and tissue levels. Translational research studies aimed at converting these discoveries into practical applications are also being conducted to explain which of these key elements are changing in various GI disorders, and which of these changes have important implications for gut function and sensitivity. Collectively, these investigations are leading to discoveries that are revealing new targets for the treatment of inflammatory and functional GI disorders.
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