Gary M. Mawe, PhD
Professor, Department of Neurological Sciences
CONTRIBUTIONS TO SCIENCE
Intestinal Serotonin Signaling
The majority of the serotonin (5-HT) in the body is synthesized and released by enterochromaffin cells in the mucosa of the GI tract. There, it acts as an important signaling molecule to activate GI reflexes and to send physiological and pathophysiological signals to the CNS. During my postdoctoral studies under the direction of Dr. Michael Gershon, we made the novel discovery that enteric neurons express more than one type of 5-HT receptor. At the University of Vermont, my colleagues and I have investigated changes in serotonin signaling that occur in animal models of intestinal inflammation, and we have studied the distribution and functions of 5-HT receptors that are targeted in therapies for irritable bowel syndrome (IBS). For example, we have shown in a number of animal models that the serotonin selective reuptake transporter (SERT), which terminates serotonin signaling, is down-regulated in colitis. We subsequently found that, of many pro-inflammatory molecules tested, IFN-γ and TNF-α, decrease SERT expression and function in intestinal epithelial cells, and that SERT expression is differentially regulated in intestinal epithelial cells as compared to neurons. We have also demonstrated that 5-HT4 receptors are extensively expressed in the colonic mucosa, and that their activation promotes motility and suppresses visceral hypersensitivity. This could be of clinically applicable because 5-HT4 agonists have been shown to have benefit for IBS with constipation and chronic constipation. Mucosal 5-HT4 receptors could provide a safe and effective target for this class of drugs that has been plagued with cardiovascular side effects. Most recently, we have discovered that luminal administration of 5-HT4 agonists accelerates recovery from colitis, and that inhibition or deletion of this receptor leads to a low level inflammatory state in the colon. These results indicate that 5-HT4 receptors are important for epithelial homeostasis.
Linden, D.R., J.-X. Chen, M.D. Gershon, K.A. Sharkey and G.M. Mawe (2003) Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. American Journal of Physiology 285: G207-G216. PMID: 12646422
Foley, K.F., C. Pantano, A. Ciolino and G.M. Mawe (2007) IFN-γ and TNF-α decrease serotonin transporter function and expression in intestinal epithelial cells. American Journal of Physiology292:G779-G784. PMID: 17170025
Hoffman, J.M., K. Tyler, S.J. MacEachern, O.B. Balemba, A.C. Johnson, E.M. Brooks, H. Zhao, G.M. Swain, P.L. Moses, J.J. Galligan, K.A. Sharkey, B. Greenwood-Van Meerveld and G.M. Mawe (2012) Activation of colonic mucosal 5-HT4 receptors enhances propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142:844-854. PMID: 22226658
Spohn, S.N., F. Bianco, R.B. Scott, C.M. Keenan, C.H. O'Neill, E. Bonora, M. Dicay, B. Lavoie, R.L. Wilcox, W.K. MacNaughton, R. De Giorgio, K.A. Sharkey, G.M. Mawe (2016) Protective actions of epithelial 5-HT4 receptors in normal and inflamed colon. Gastroenterology 151:933-944
The existence of intrinsic reflex circuits in the intestines has been appreciated since the late 1890s when Bayliss and Starling established the Law of the Intestine, but it was not until a century later that we were able to identify the various neuronal elements of these circuits. Since then, my lab and the lab of Dr. Keith Sharkey, my colleague at the University of Calgary, have collaborated to systematically evaluate the reflex circuits in the intestines to determine what changes occur in response to inflammation, which of these changes persist beyond recovery of inflammation (which has implications for IBS), and what neuroplastic alterations contribute to inflammation-induced changes in gut function. We have shown that intrinsic sensory neurons are hyperexcitable, that interneuronal synaptic communication is augmented, and that purinergic neuromuscular communication is blunted in colitis. We have also shown that these changes contribute to disrupted propulsive motility, and that the changes in sensory neuron function and interneuronal synaptic strength persist well beyond recovery from inflammation, but that purinergic transmission is rapidly restored. This makes sense, because we recently demonstrated that purinergic neuromuscular transmission is decreased because oxidative stress disrupts purine synthesis in the mitochondria. An important discovery we made conducting these studies is that activation of enteric glia contributes to neuronal cell death in the colon.
Linden, D.R., K.A. Sharkey and G.M. Mawe (2003) Enhanced excitability of myenteric AH neurones in the inflamed guinea pig distal colon. TheJournal of Physiology 547: 589-601. PMID: 12562910
Krauter, E.C. D.R. Linden, K.A. Sharkey and G.M. Mawe (2007) Synaptic plasticity in guinea pig myenteric neurons: Presynaptic mechanisms of inflammation-induced synaptic facilitation. TheJournal of Physiology 581:787-800. PMID: 17363386
Strong, D.S., C.F. Cornbrooks, J.A. Roberts, J.M. Hoffman, K.A. Sharkey, G.M. Mawe (2010) Purinergic neuromuscular transmission is selectively attenuated in ulcerated regions of inflamed guinea pig distal colon. Journal of Physiology (London) 588: 847–859. PMID: 20064853
Gulbransen, M. Bashashati, S.A. Hirota, J.A. Roberts, P.L. Beck, J.A. MacDonald, D.A. Muruve, D.M. McKay, G.M. Mawe, R.J. Thompson, and K.A. Sharkey (2012) Activation of neuronal P2X7 receptor-Pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine 18: 600-604. PMID: 22426419Roberts, A.J, L. Durnan, K.A. Sharkey, V.N. Mutafova-Yambolieva, and G.M. Mawe (2013) Oxidative stress disrupts purinergic neuromuscular transmission in the inflamed colon. The Journal of Physiology 591: 3725–3737. PMID: 23732648
Translational Investigations of human GI motility and Inflammatory Disorders
As a basic scientist at The University of Vermont, I have been fortunate to enjoy a high level of cooperation from, and collaboration with, clinicians in Gastroenterology, Colorectal Surgery, and Pathology. These interactions have provided extensive access to human specimens and input from these clinicians has helped focus our studies on clinically relevant goals. In some cases, our animal model studies have led to hypotheses that we tested in human populations, and in other cases, our findings in human specimens have led to mechanistic studies involving animals and/or cell lines. We have determined the electrical, synaptic and neurochemical properties of human gallbladder neurons. We also demonstrated that the blood of achalasia patients contains anti-enteric neuron antibodies, supporting the concept that achalasia is an autoimmune disorder that involves inflammation of lower esophageal sphincter ganglia and associated neuronal loss. Our most extensive work involving human specimens has been related to mucosal serotonin signaling in various gastrointestinal disorders. We were the first to discover a molecular alteration in the intestines of individuals with IBS when we reported that SERT expression is decreased IBS, as well as ulcerative colitis. We have studied a number of other disorders, including chronic constipation and diverticulosis/itis, and we have shown that children with IBS also exhibit decreased mucosal SERT. The various changes in serotonin signaling that we have reported in these disorders likely contribute to altered colonic function and sensation.
Moses, P.L., L.M. Ellis, M.R. Anees, R.I. Rothstein, K.M. Wood, M.C. Moses J.B. Meddings, W. Ho, K.A. Sharkey and G.M. Mawe (2003) Anti-Neuronal Antibodies in Idiopathic Achalasia and Gastroesophageal Reflux Disease. Gut 52:629-636. PMID: 12692044
Coates MD, CR Mahoney, DR Linden, JE Sampson, J Chen, H Blaszyk, MD Crowell, KA Sharkey, MD Gershon, GM Mawe*, PL Moses* (2004) Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and IBS. Gastroenterology 126:1657-1664. * indicates co-senior authors. PMID: 15188158
Faure, C., N. Patey, C. Gauthier, E.M. Brooks, G.M. Mawe (2010) Serotonin Signaling Is Altered in Irritable Bowel Syndrome With Diarrhea but Not in Functional Dyspepsia in Pediatric Age Patients. Gastroenterology 139:249-258. PMID: 20303355
Costedio, M.M., M.D. Coates, E.M. Brooks, Lisa M. Glass, Eric K. Ganguly, H.J. Blaszyk, A.L. Ciolino, M.J. Wood, D. Strader, N.H. Hyman, P.L. Moses, and G.M. Mawe (2010) Mucosal serotonin signaling is altered in chronic constipation, but not in opiate-induced constipation. American Journal of Gastroenterology 105: 1173-80. PMID: 20010921
I began working on the neural regulation of gallbladder function during my transition from my postdoc to my faculty position at the University of Vermont. At that time, little was known about the neurochemical, electrical or synaptic properties of gallbladder and sphincter of Oddi neurons or the ionic properties of gallbladder smooth muscle. Since then, our work has led to a thorough understanding of how gallbladder neurons and smooth muscle work, and it has contributed to a much better understanding of the mechanisms that lead to gallstone disease. For example, we have demonstrated that the physiological action of hormonal CCK involves a presynaptic facilitory effect on vagal efferent terminals, that phasic activity in gallbladder muscle is driven by interstitial cells of Cajal, and that cholesterol and hydrophobic bile salts disrupt gallbladder muscle through two different mechanisms, with cholesterol disrupting Ca2+ channel function, and hydrophobic bile salts activating an ATP-sensitive K+ conductance that is mediated by GPBAR1 receptors. We have also shown that, in contrast to conventional wisdom, gallbladder muscle dysfunction precedes, and likely contributes to, the onset of inflammation during the development of gallstone disease.
Mawe, G.M. (1991) The role of CCK in ganglionic transmission in the guinea-pig gall-bladder. The Journal of Physiology 439:89-102. PMID: 1654421
Lavoie, B., O.B. Balemba, M.T. Nelson, S.M. Ward, and G.M. Mawe (2007) Morphological and physiological evidence for interstitial cell of Cajal (ICC)-like cells in the guinea pig gallbladder. The Journal of Physiology 579:487-501. PMID: 17204499
Lavoie, B., O.B. Balemba, C. Godfrey, C. Watson, G. Vassileva, C. Corvera, M.T. Nelson, and G.M. Mawe. (2010) Bile acid receptor GPBAR1 stimulation decreases gallbladder smooth muscle activity by activating KATP channels. The Journal of Physiology 588: 3295-3305. PMID: 20624794
Lavoie, B., B. Nausch, E.A. Zane, M.R. Leonard, O.B. Balemba, A.C. Bartoo, R. Wilcox, M.T. Nelson, M.C. Carey and G.M. Mawe (2012) Disruption of Gallbladder Smooth Muscle Function is an Early Feature in the Development of Cholesterol Gallstone Disease. Neurogastroenterology and Motility 24: e313–e324. PMID: 22621672
Mawe, G.M. and J.M. Hoffman (2013) Serotonin Signaling in the gastrointestinal tract: functions, dysfunctions, and therapeutic targets. Nature Reviews Gastroenterology and Hepatology 10: 473–486. PMID: 23797870 PMCID: PMC4048923
Mawe, G.M. (2015) Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon. Journal of Clinical Investigation 125:949-955. PMID:25729851 PMCID: PMC4362261
Spohn, S.N. and G.M. Mawe (2017) Non-conventional features of peripheral serotonin signaling. Nature Reviews Gastroenterology and Hepatology 14:412-420. PMID:28487547 PMCID: PMC5672796
Coates, M.D., I Tekin, K.E. Vrana and G.M. Mawe (2017) The Many Potential Roles of Intestinal Serotonin Signaling in Inflammatory Bowel Disease. Alimentary Pharmacology and Therapeutics 46:569–580. PMID: 28737264
Complete List of Published Work in MyBibliography:
Mawe Lab August 2012
Jane Roberts, Cameron Hecht, Stephanie Spohn, Amanda Bolgioni, Dr. Gary Mawe, Brigitte Lavoie.
Mawe Lab Summer 2011
(L to R) Bernhard Nausch, André-Denis Wright, Stephanie Spohn, Gary Mawe, Jill Hoffman, Hannah Foote, and Brigitte Lavoie.
Mawe Lab Winter 2010
(L to R) Brigitte Lavoie, Jane Roberts, Gary Mawe, Jill Hoffman, Elice Brooks, and Bernhard Nausch.
Mawe Lab Summer 2010