Neural regulation of the digestive tract – understanding changes in enteric neural circuits that contribute to altered gut function in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)
Neurons 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. In states of inflammation, such as Crohn’s disease or ulcerative colitis, various features of gut function, including motility, secretion and sensitivity are altered. As nerve cells of the bowel regulate all of these functions, it is likely that changes in these neurons cause the symptoms that lead to so much suffering in these individuals. Discoveries in gut neurobiology 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 now examining what changes occur in various parts of the reflex circuits and the mechanisms responsible for these changes.
Determining how disruptions in gallbladder muscle function occur, and how they contribute to the development of gallstone disease
Gallbladder disease is one of the most common digestive disorders, and hallmark properties include decreased contractility, inflammation, and gallstone formation. Recent reports suggest that decreased gallbladder motility is caused by elevated cholesterol and hydrophobic salts in the bile, and that ensuing inflammation and impairments in gallbladder emptying lead to stone formation. Furthermore, mounting evidence suggests that hydrophilic bile salts may have therapeutic potential by restoring gallbladder smooth muscle contractility and reducing gallstone development and inflammation. Nevertheless, the interrelationships between decreased contractility, inflammation, and gallstone formation are not understood, and this reflects our lack of understanding of the cellular events that lead to gallbladder muscle dysfunction in gallstone disease. The objectives of our ongoing research are to: (1) elucidate the cellular and ionic mechanisms by which gallbladder smooth muscle contractility is disrupted in gallstone disease; (2) determine the role of inflammation in smooth muscle dysfunction and associated biliary stasis in gallstone disease; and (3) explore the utility and mechanisms of hydrophilic bile salts in the protection of gallbladder function by preventing or reversing these disruptions.
Serotonin signaling in the mucosa layer of the gastrointestinal tract
We typically think of serotonin as a neurotransmitter in the brain, but most of the body’s serotonin is actually located in the gastrointestinal tract, and this is where serotonin was initially discovered. Within the wall of the gut, serotonin is used as a transmitter by interneurons, but the real mother-load of serotonin is synthesized by specialized cells in the inner lining of the intestine, called enterochromaffin (EC) cells. Serotonin released by EC cells activates receptors on nearby nerve fibers to activate reflexes involved in fluid secretion into the lumen and coordinated muscle responses that propel ingested food and fluids along the intestines. Serotonin signaling in the intestine is stopped via reabsorption (reuptake) by a protein called the serotonin transporter (SERT). This is the same serotonin transporter that stops 5-HT signaling at synapses in the central nervous system. It also is the molecule whose 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 essentially all of the cells that line the intestines. Therefore, it is as though the gut has a huge sponge responsible for regulating levels of 5-HT, and this is further evidence of the importance of 5-HT signaling for gut function. Studies conducted in our laboratory and others have demonstrated that various aspects of mucosal serotonin signaling are altered in humans with inflammatory bowel disease or irritable bowel syndrome, as well as animal models of intestinal inflammation. Current studies in our laboratory are directed towards understanding how these changes occur and whether they contribute to altered gut function and sensation
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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.
B.D. 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.
Hons, I.M., M.A. Storr, K. Mackie, B. Lutz, Q.J. Pittman, G.M. Mawe and K.A. Sharkey. (2012) Plasticity of mouse enteric synapses mediated though retrograde endocannabinoid and purinergic signalling. Neurogastroenterology and Motility 24:e113-24.
J.M. Hoffman, N.D. McKnight, K.A. Sharkey, G.M. Mawe. (2011) The relationship between inflammation-induced neuronal excitability and disrupted motor activity in the guinea pig distal colon. Neurogastroenterology and Motility 23: 673-682.
Balemba, O.B., Y. Bhattarai, C. Stenkamp-Strahm, M.S.B. Lesakit and G.M. Mawe. (2010) The traditional anti-diarrheal remedy, Garcinia buchananii stem bark extract, inhibits propulsive motility and fast synaptic potentials in the guinea pig distal colon. Neurogastroenterology and Motility 22:1332-1339.
Costedio MM, Coates MD, Brooks EM, Glass LM, Ganguly EK, Blaszyk H, Ciolino AL, Wood MJ, Strader D, Hyman NH, Moses PL, Mawe GM. (2010) Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation. Am J Gastroenterol. 105(5):1173-80.
Faure C, Patey N, Gauthier C, Brooks EM, Mawe GM. (2010) Serotonin signaling is altered in irritable bowel syndrome with diarrhea but not in functional dyspepsia in pediatric age patients. Gastroenterology. 139(1):249-58.
Lavoie B, Balemba OB, Godfrey C, Watson CA, Vassileva G, Corvera CU, Nelson MT, Mawe GM. (2010) Hydrophobic bile salts inhibit gallbladder smooth muscle function via stimulation of GPBAR1 receptors and activation of KATP channels. J Physiol. 588(17):3295-3305.
Accompanied by a Perspectives piece by Simon J. Gibbons entitled A little humour relaxes the gallbladder.
Strong DS, Cornbrooks CF, Roberts JA, Hoffman JM, Sharkey KA, Mawe GM. (2010) Purinergic neuromuscular transmission is selectively attenuated in ulcerated regions of inflamed guinea pig distal colon. The Journal of Physiology, 588:847–859.
Accompanied by a Perspectives piece by Stuart M. Brierley entitled All ahead stop! How intestinal motility adapts to cope with inflammation induced ulceration.
Linden DR, White SL, Brooks EM, and Mawe GM. (2009) Novel Promoter and Alternate Transcription Start Site of the Human Serotonin Reuptake Transporter (SERT) in Intestinal Mucosa. Neurogastroenterol Motil. 21:534-543.
Balemba OB, Bartoo AC, Nelson MT and Mawe GM. (2008) The role of mitochondria in spontaneous rhythmic activity and intracellular calcium waves in guinea pig gallbladder smooth muscle. American Journal of Physiology 294: G467-G476.
Bartoo AC, Nelson MT and Mawe GM. (2008) ATP Induces Guinea Pig Gallbladder Smooth Muscle Excitability via the P2Y4 Receptor and COX-1 Activity.American Journal of Physiology 294:G1362-G1368.
Lavoie B, Balemba OB, Nelson MT, Ward SM and Mawe GM. (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.
Krauter EC, Linden DR, Sharkey KA and Mawe GM. (2007) Synaptic plasticity in guinea pig myenteric neurons: Presynaptic mechanisms of inflammation-induced synaptic facilitation. The Journal of Physiology 581: 787-800.
For more papers by Gary Mawe, click here.RECENT REVIEWS AND COMMENTARIES Sharkey, K. A. and G. M. Mawe (2012). “Neurogastroenterology in 2011: Emerging concepts in neurogastroenterology and motility.” Nature Reviews Gastroenterology & Hepatology 9(2): 74-76.
Mawe GM, Strong D, and Sharkey KA. (2009) Plasticity of enteric nerve functions in the inflamed and post-inflamed gut. Neurogastroenterology and Motility 21:481-491.
Mawe, GM. (2009) Intersititial Cells of Cajal in the gut: what makes them tick. The Journal of Physiology. 587: 4765.
Costedio MM, Hyman N, and Mawe GM. (2007) Serotonin and its role in colonic function and in gastrointestinal disorders. Diseases of the Colon and Rectum 50: 376-388.