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Fundamentals of Neurogastroenterology: Basic Science

2016; Elsevier BV; Volume: 150; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2016.02.018

1528-0012

Stephen J. Vanner, Beverley Greenwood‐Van Meerveld, Gary M. Mawe, Terez Shea‐Donohue, Elena F. Verdú, Jackie D. Wood, David Grundy,

Intestinal and Peritoneal Adhesions

This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled Rome IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs, and new areas for future research into their pathophysiology. This review examines the fundamentals of neurogastroenterology that may underlie the pathophysiology of functional GI disorders (FGIDs). It was prepared by an invited committee of international experts and represents an abbreviated version of their consensus document that will be published in its entirety in the forthcoming book and online version entitled Rome IV. It emphasizes recent advances in our understanding of the enteric nervous system, sensory physiology underlying pain, and stress signaling pathways. There is also a focus on neuroimmmune signaling and intestinal barrier function, given the recent evidence implicating the microbiome, diet, and mucosal immune activation in FGIDs. Together, these advances provide a host of exciting new targets to identify and treat FGIDs, and new areas for future research into their pathophysiology. In the 8 years since the publication of Rome III there has been rapid expansion in our understanding of the fundamentals of neurogastroenterology. What has fueled this advance is the desire to integrate basic science research with clinical gastroenterology to better diagnose and treat functional gastrointestinal disorders (FGIDs). This research continues to shed light on the complex hierarchy of neural, molecular, and cellular interactions that control gut function. However, what recent research also has shown is the complex interaction between the host gut wall and the luminal microbial environment that is responsible for balancing immune tolerance with protection against pathogenic and antigenic material. Neuroimmune function and the mechanisms that regulate mucosal barrier function, immune surveillance, innate and adaptive immunity, sensory signaling, and central nervous system (CNS) adaptation consequently are the major themes for this review. The GI tract has important barrier and immune functions that interface with the luminal microbiota and protect against potential pathogenic and antigenic material. Integral to these ostensibly conflicting functions is the ability to monitor events in the gut wall and within the gut lumen to orchestrate reflexes that bring about appropriate patterns of motility, secretion, and blood flow to digest and absorb or to dilute and expel. GI sensory mechanisms play a pivotal role in triggering these reflexes by conveying sensory information to the enteric reflex circuits that provide local control and through afferent pathways to the CNS. Sensory information is conveyed from the GI tract to the brainstem and spinal cord via vagal and spinal (splanchnic and pelvic) afferents, respectively. Most dorsal root ganglion neurons innervate somatic structures. It is estimated that the proportion of dorsal root ganglion neurons innervating the GI tract range between 3% and -7%. The dominance of somatic afferent input to the spinal cord and the convergence of visceral and somatic afferents on ascending spinal pathways accounts for the phenomenon of referred pain. In addition, afferent fibers from the colon and rectum may converge with fibers from other pelvic organs, contributing to cross-organ sensitization between gut, bladder, and reproductive organs that often complicates the clinical diagnosis of pelvic pain.1Brumovsky P.R. Gebhart G.F. Visceral organ cross-sensitization–an integrated perspective.Auton Neurosci. 2010; 153: 106-115Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The low density of innervation, convergence with somatic inputs, and viscerovisceral convergence in the spinal cord can explain why gut pain generally is localized poorly. GI afferent fibers terminate within the gut wall mainly as bare nerve endings and are classified according to their terminal distribution as mesenteric, serosal, muscular, ganglionic (intraganglionic laminar endings), or mucosal endings.2Grundy D. Brookes S.J. Neural control of gastrointestinal function. Morgan & Claypool, San Rafael, CA2011: 134Google Scholar The location of these endings plays an important role in determining the functional properties of the afferent. Mucosal afferents respond to distortion of the mucosal epithelium and to luminal chemicals. Stretch or distension is effective for stimulating endings in the muscle layers, ganglia, and serosa. These endings express an array of membrane receptors and ion channels that determine neuronal excitability, mechanosensitivity, and modulation by a host of chemical mediators within the GI milieu. Different populations of afferents respond over a range of distension volumes from innocuous (physiological) to noxious levels that cause pain. Powerful contractions, especially against an obstruction, cause traction on the mesentery and is especially painful. There is a continuous barrage of information projecting from the gut to the CNS. Many afferent endings respond to levels of distension that occur as part of normal digestion and these usually go unperceived. Instead, this information is used in reflexes that control motility, secretion, blood flow, and other aspects of GI function. In contrast, there are other afferents that respond only at high levels of stimulus intensity and function as nociceptors that mediate pain. Some afferents (so-called silent or “sleeping” nociceptors) are mechanically insensitive under normal circumstances but can be awakened in response to inflammation or injury. In patients this process of sensitization can give rise to altered pain perception. In some cases, stimuli that normally are innocuous can cause pain (allodynia), whereas responses that are painful can become exaggerated (hyperalgesia). Mechanotransduction refers to the process by which stimulus energy is interpreted by sensory nerve endings, leading to the generation of action potentials. There are specific molecular mechanisms that underlie mechanotransduction. Moreover, the excitability of the afferent ending is determined by various voltage-gated and calcium-dependent ion channels3Beyak M.J. Visceral afferents–determinants and modulation of excitability.Auton Neurosci. 2010; 153: 69-78Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar that set gain in the system, and that can change according to external influences leading to hypersensitivity. Sensory endings contain a variety of mechanosensitive ion channels that can convert the stimulus energy into action potentials. They respond to membrane deformation, causing channels to open or close, carrying ionic currents into or out of the nerve terminal to cause depolarization. Three main ion channel families have been identified as mechanosensitive: (1) the DEG/ENaC family that includes the acid-sensing ion channels 1, 2, and 3; (2) the transient-receptor potential (TRP) channel family; and (3) the 2-pore potassium channel family that includes TREK-1 and TRAAK. Different combinations of these channels exist in different populations of vagal, pelvic, and splanchnic afferents, suggesting a complex heterogeneity in sensory signaling.4La J.H. Schwartz E.S. Gebhart G.F. Differences in the expression of transient receptor potential channel V1, transient receptor potential channel A1 and mechanosensitive two pore-domain K+ channels between the lumbar splanchnic and pelvic nerve innervations of mouse urinary bladder and colon.Neuroscience. 2011; 186: 179-187Crossref PubMed Scopus (43) Google Scholar Another mechanism of mechanotransduction occurs when a secondary sense cell releases mediators that act on ionotropic or metabotropic receptors to stimulate sensory endings. This indirect mechanism relies on close association between afferent endings in the gut wall and various other cell types that are a source of these chemical ligands. These include mast cells, epithelial cells, enteroendocrine cells, macrophages, interstitial cells of Cajal (ICC), and enteric neurons. Considerable attention has been paid to the role of 5-hydroxytryptamine (5-HT) and adenosine triphosphate in sensory signaling, especially in the context of postinflammatory hypersensitivity.5Brierley S.M. Linden D.R. Neuroplasticity and dysfunction after gastrointestinal inflammation.Nat Rev Gastroenterol Hepatol. 2014; 11: 611-627Crossref PubMed Scopus (187) Google Scholar Some vagal and pelvic afferent endings come into close proximity to the mucosal epithelium, but never penetrate through to the lumen. However, their proximity to the mucosa exposes them to chemicals absorbed across the mucosal epithelium or released from enteroendocrine cells whose apical membrane is exposed to luminal content. This is similar to the relationship seen between taste buds in the mouth and gustatory afferents and as such provides a mechanism by which mucosal afferents can taste luminal contents. This is important for controlling digestive function via reflex effects on motility and secretion. However, nutrient detection also influences metabolic activity and energy intake. The molecular basis for each modality of gustatory taste has been identified. Strikingly, many of these same G-protein–coupled receptors and ion channels are expressed within the GI tract. The cells expressing taste-receptor molecules in the GI mucosa have a characteristic morphology, which is typified by the enterochromaffin (EC) cell.6Young R.L. Sutherland K. Pezos N. et al.Expression of taste molecules in the upper gastrointestinal tract in humans with and without type 2 diabetes.Gut. 2009; 58: 337-346Crossref PubMed Scopus (147) Google Scholar However, EC cells are just one of a diverse family of enteroendocrine cells that are scattered diffusely in the GI mucosa and whose mediators can act in a paracrine fashion on afferent fibers or diffuse into the blood stream for more distant endocrine actions. Each type of enteroendocrine cell has a characteristic distribution along the GI tract. Among the mediators released, cholecystokinin and glucagon-like peptide-1 play important roles in reflex control of GI function and in regulating food intake. Sensory neurons express a large array of receptors that are activated by mediators released from various cellular sources within the gut wall. Neurotrophins, for example, play a role in axon guidance and remodeling of the sensory innervation after inflammation and injury. Their receptors are expressed on different populations of GI sensory neurons. Both nerve growth factor and glial-derived neurotrophic factor are important in the adaptive response to nerve injury and inflammation. Both also are possible mediators underlying chronic pain. Increasing neurotrophin signaling causes increased TRP channel expression (eg, TRPV1 and TRPA1), an increase in sodium channel expression (NaV1.87Fang X. Djouhri L. McMullan S. et al.trkA is expressed in nociceptive neurons and influences electrophysiological properties via Nav1.8 expression in rapidly conducting nociceptors.J Neurosci. 2005; 25: 4868-4878Crossref PubMed Scopus (114) Google Scholar), and a decrease in potassium channels. Any, or all of these, could contribute to the development of hypersensitivity.8Vergnolle N. Postinflammatory visceral sensitivity and pain mechanisms.Neurogastroenterol Motil. 2008; 20: 73-80Crossref PubMed Scopus (52) Google Scholar Many other mediators are released during inflammation, injury, and ischemia, from platelets, leukocytes, lymphocytes, macrophages, mast cells, glia, fibroblasts, blood vessels, muscle, and neurons. Some mediators act directly on sensory nerve terminals and others act indirectly, causing release of yet other agents from nearby cells. This “inflammatory soup” (Figure 1) contains amines, purines, prostanoids, proteases, cytokines, and so forth, which act on sensory nerve terminals to increase sensitivity to both mechanical and chemical stimuli (referred to as “plasticity”). Recent data have suggested that bacterial products also may drive afferent signaling.9Chiu I.M. Heesters B.A. Ghasemlou N. et al.Bacteria activate sensory neurons that modulate pain and inflammation.Nature. 2013; 501: 52-57Crossref PubMed Scopus (533) Google Scholar Hypersensitivity is a feature of chronic pain states and is considered to be a hallmark of FGIDs including irritable bowel syndrome (IBS). Moreover, because these afferents also trigger reflexes that coordinate gut function, sensitization also can cause hyper-reflexia or dysreflexia, leading to altered transit, resulting in diarrhea and constipation. Peripheral sensitization normally develops rapidly and is relatively short-lived. However, in the presence of maintained injury or inflammation, the sensitization can be prolonged by changes in gene expression. These genes may alter the expression of channels, receptors, or mediators in the sensory neuron.8Vergnolle N. Postinflammatory visceral sensitivity and pain mechanisms.Neurogastroenterol Motil. 2008; 20: 73-80Crossref PubMed Scopus (52) Google Scholar They also may modify the amount and pattern of neurotransmitters released by central nerve terminals in the brain and spinal cord. This alters the way that sensory signals are processed within the CNS and contributes to “central sensitization,”10Woolf C.J. Central sensitization: implications for the diagnosis and treatment of pain.Pain. 2011; 152: S2-S15Abstract Full Text Full Text PDF PubMed Scopus (2636) Google Scholar and may prolong hypersensitivity beyond the acute period of injury or inflammation. These mechanisms can undergo plasticity in response to injury and inflammation, leading to hypersensitivity and chronic pain states. These neurons transmit visceral signals to ascending spinal pathways via glutamate and neuropeptides. These transmitter mechanisms are up-regulated in response to inflammation and injury and contribute to hypersensitivity. In the brain and spinal cord there are central neuroplastic changes, termed central sensitization, that contribute to chronic pain. Within the dorsal horn of the spinal cord, there are 2 mechanisms that increase pain signals reaching the brain: (1) increased synaptic transmission via glutamate, calcitonin gene-related peptide, and substance P onto ascending excitatory pathways, and/or (2) decreased descending inhibitory modulation. In the brain, sensitization can occur in the second-order spinal neurons, such as the thalamus, periaqueductal gray (PAG), parabrachial nucleus, and locus coeruleus. Increased signaling from those nuclei then can promote neuroplasticity, similar to long-term potentiation mechanisms, that strengthen and/or add synaptic connectivity. The enhanced signaling then promotes abnormal processing of pain within the extended pain matrix (prefrontal cortex [PFC], anterior cingulate cortex, amygdala, insula), which can amplify the discomfort and negative emotions associated with chronic visceral pain,11Staud R. Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.Exp Rev Neurother. 2012; 12: 577-585Crossref PubMed Scopus (178) Google Scholar and/or a decrease in the descending pain inhibitory system through the PAG and rostroventral medulla.12Heinricher M.M. Tavares I. Leith J.L. et al.Descending control of nociception: specificity, recruitment and plasticity.Brain Res Rev. 2009; 60: 214-225Crossref PubMed Scopus (627) Google Scholar In particular, the amygdala is a key nucleus that integrates noxious visceral signals with anxiety/fear behaviors and hyperactivation could influence not only multiple nuclei in the central pain matrix, but also descending brainstem nuclei that modulate GI function.13Myers B. Greenwood-Van Meerveld B. Role of anxiety in the pathophysiology of irritable bowel syndrome: importance of the amygdala.Front Neurosci. 2009; 3: 47Crossref PubMed Scopus (50) Google Scholar Multiple clinical imaging studies also have shown differences in function, connectivity, and structure between IBS and healthy controls. Thus, central sensitization can promote chronic abdominal pain in IBS through remodeling of connections within both the brain and spinal cord. A universal perception of the enteric nervous system (ENS) as a brain-in-the-gut implies that, similar to the brain and spinal cord, the ENS is assembled in a hierarchy of neural organization.14Wood J.D. Enteric nervous system (the brain-in-the-gut). Morgan & Claypool Life Sciences, San Rafael, CA2011Google Scholar, 15Wood J.D. Integrative functions of the enteric nervous system.in: Johnson L.R. Kaunitz J.D. Ghishan F.K. Physiology of the gastrointestinal tract. Elsevier, San Diego2012: 671-689Crossref Scopus (12) Google Scholar Output from the ENS determines moment-to-moment behavior of the gastrointestinal musculature, secretory glands, and blood vasculature. Integration of output to the muscles and secretory glands is reflected by coordinated patterns of motility and secretion, recognizable during clearly defined digestive states. Five different behavioral states are recognizable in the small intestine: (1) physiological absence of motility; (2) postprandial state with segmenting (mixing) motility integrated with set-point feedback control of luminal pH and osmolarity; (3) migrating motor complex in the interdigestive state also integrated with set-point feedback control of luminal pH and osmolarity; (4) a defensive state with copious neurogenic hypersecretion and orthograde or retrograde power propulsion associated with urgency, diarrhea, and cramping abdominal pain; and (5) emetic program, which includes reversal of peristaltic propulsion in the upper jejunum and duodenum to rapidly propel luminal contents toward the open pylorus and relaxed antrum and corpus. Coordinated neurogenic patterns of behavior in the large intestine are recognized as haustral formation, physiological absence of motility, defecatory power propulsion and defense that also is associated with urgency, diarrhea, and cramping lower abdominal pain. Similar to the CNS, the ENS functions with chemical synaptic connections between sensory neurons, interneurons, and motor neurons. Interneurons are interconnected synaptically into neural networks, which process information on the state of the gut, contain a library of programs for different patterns of behavior, and control the activity of motor neurons. Motor neurons innervate the musculature, secretory glands, and blood vessels. Musculomotor neurons initiate or inhibit the contractile activity of the musculature when they fire.15Wood J.D. Integrative functions of the enteric nervous system.in: Johnson L.R. Kaunitz J.D. Ghishan F.K. Physiology of the gastrointestinal tract. Elsevier, San Diego2012: 671-689Crossref Scopus (12) Google Scholar Modulation of their firing frequency, by input from interneuronal microcircuitry, determines minute-to-minute contractile strength. Secretomotor neurons stimulate secretory glands to secrete chloride, bicarbonate, and mucus,16Fang X. Hu H.Z. Gao N. et al.Neurogenic secretion mediated by the purinergic P2Y1 receptor in guinea-pig small intestine.Eur J Pharmacol. 2006; 536: 113-122Crossref PubMed Scopus (35) Google Scholar, 17Fei G. Fang X. Wang G.D. et al.Neurogenic mucosal bicarbonate secretion in guinea pig duodenum.Br J Pharmacol. 2013; 168: 880-890Crossref Scopus (9) Google Scholar and determine the osmolarity and liquidity in the lumen. Neurogenic control of bicarbonate secretion maintains a physiological pH set-point in the lumen and accounts for some of the mucosal protection against acid delivery from the stomach. A subset of secretomotor neurons simultaneously innervates both secretory glands and periglandular arterioles, and thereby enhance blood flow with secretion. Interaction of the ENS with ICC18Sanders K.M. Ward S.M. Koh S.D. Interstitial cells: regulators of smooth muscle function.Physiol Rev. 2014; 94: 859-907Crossref PubMed Scopus (301) Google Scholar is a major determinant of each of the motility programs stored in its library. Electrically conducting junctions (gap junctions) connect smooth muscle fibers one to another to form a functional electrical syncytium. Action potentials propagate from muscle fiber to muscle fiber in 3 dimensions and trigger a contraction as they enter each neighboring muscle fiber. ICC are non-neuronal pacemaker cells that also connect one to another to form electrical syncytial networks that extend around the circumference and throughout the longitudinal axis of the small and large intestine. The ICC networks generate electrical pacemaker potentials (also called electrical slow waves) that spread via gap junctions into the intestinal circular muscle, where they depolarize the muscle to action potential threshold and thereby trigger contractions. The functional characteristics of the circular muscle as a self-excitable electrical syncytium implies that ICC networks should continuously evoke contractions that spread in 3 dimensions throughout the entire syncytium, which is in effect the entire length of the intestine. Nonetheless, in the normal bowel, long stretches of intestine are found in a state of physiological ileus. Attention to the functional electrical syncytial properties of the musculature suggests that inhibitory musculomotor neurons and control of their activity by the integrative microcircuits in the ENS have evolved as a mechanism that determines when ongoing slow waves initiate a contraction, as well as the distance and direction of propagation after the contraction starts. Overall, a normal ENS is essential for a healthy bowel and absence of irritating symptoms, such as those associated with Rome-based diagnostic criteria for FGIDs. Any neuropathic change in the ENS most likely will result in a symptomatic bowel. Functional propulsive motility and its integration with specialized secretory functions cannot work in the absence of the ENS, as underscored in the aganglionic terminal segment of Hirschsprung’s disease and autoimmune ENS denervation of the lower esophageal sphincter in achalasia. Gut functions are altered under various pathophysiological conditions, and it has become increasingly clear that alterations in the intrinsic reflex circuits of the gut are involved. Over the past decade, much progress has been made toward determining what elements of the circuits are altered, the mechanisms of these alterations, which changes persist after recovery from inflammation, and the effects of neuroplasticity on propulsive motility. One mechanism of activating enteric neural reflex circuits is the release of 5-HT from EC cells in the intestinal mucosa.19Mawe G.M. Hoffman J.M. Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets.Nat Rev. 2013; 10: 473-486Google Scholar Serotonin released from EC cells activates intrinsic enteric reflexes and also sends signals related to digestive reflexes, satiety, and pain to the CNS via vagal and spinal afferents. Serotonin signaling is terminated by reuptake into epithelial cells, all of which express the serotonin selective reuptake transporter (SERT) on their basal surface. A consistent feature of mucosal 5-HT signaling in the inflamed bowels of human beings and experimental animals is a decrease in SERT expression.19Mawe G.M. Hoffman J.M. Serotonin signalling in the gut–functions, dysfunctions and therapeutic targets.Nat Rev. 2013; 10: 473-486Google Scholar This has been shown in ulcerative colitis and diverticulitis in human beings, and also in diarrhea-predominant and constipation-predominant IBS. The effects of decreased SERT expression are likely to be comparable with those related to serotonin-selective–receptor inhibitor use, with increased mucosal 5-HT availability resulting in alterations in gut reflexes. Decreased SERT expression in the inflamed bowel is likely to involve the actions of the proinflammatory cytokines, tumor necrosis factor α, and interferon γ.20Foley K.F. Pantano C. Ciolino A. et al.IFN-gamma and TNF-alpha decrease serotonin transporter function and expression in Caco2 cells.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G779-G784Crossref PubMed Scopus (86) Google Scholar The contributing factors for decreased SERT in IBS have not been identified, but it may involve a genetic predisposition, given that certain polymorphisms of the SERT gene are associated with decreased SERT expression. It also is possible that altered SERT expression in IBS develops as a compensatory response to altered gut function; however, SERT expression is not altered in opiate-induced constipation.21Costedio M.M. Coates M.D. Brooks E.M. et al.Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation.Am J Gastroenterol. 2010; 105: 1173-1180Crossref PubMed Scopus (44) Google Scholar Inflammation is associated with changes along the ENS reflex circuitry that include increased 5-HT availability, hyperexcitability of AH (sensory) neurons, interneuronal synaptic facilitation, and suppressed purinergic neuromuscular transmission22Mawe G.M. Colitis-induced neuroplasticity disrupts motility in the inflamed and post-inflamed colon.J Clin Invest. 2015; 125: 949-955Crossref PubMed Scopus (60) Google Scholar (Figure 2). It is highly likely that these alterations lead to changes in neurogenic secretory and motor functions in the bowel, but the nature of the changes probably differs between secretory and motor responses. Neurogenic secretion can be activated by 5-HT release from EC cells, and involves a 2-neuron reflex circuit consisting of an AH neuron and an S neuron. With increased 5-HT availability, AH neuron hyperexcitability, and a strengthening of synaptic signals to the secretomotor (S) neurons, it is likely that secretion is enhanced. One potential pitfall in this scheme is that 5-HT receptors on the processes of AH neurons could become desensitized by increased exposure to 5-HT. The effects of neuroplastic changes on motility are more convoluted than secretion because the reflex circuitry is more complicated, involving an excitatory signal passing upstream from a given site and an inhibitory signal passing downstream. For an unequivocal set of signals to be transmitted, there cannot be much noise in the system. This quiescent background state is disrupted in the inflamed colon by increased 5-HT availability in the lamina propria and by increased spontaneous activity of AH neurons throughout the inflamed regions. This results in an overlap of contradictory ascending and descending signals at a given site, and a decrease in the ability of the ENS to generate the pressure gradient that result in propulsive motility, resulting in a form of pseudo-obstruction. Experimentally, increasing AH neuron excitability in normal colons disrupts motility whereas suppressing hyperexcitability of AH neurons in inflamed preparations improves motility.23Hoffman J.M. McKnight N.D. Sharkey K.A. et al.The relationship between inflammation-induced neuronal excitability and disrupted motor activity in the guinea pig distal colon.Neurogastroenterol Motil. 2011; 23: 673-e279Crossref Scopus (34) Google Scholar Furthermore, when the inhibitory junction potential is protected and AH neuron activity is attenuated in trinitrobenzene sulfonic acid–inflamed colons, propulsive motility is restored to its control velocity.24Roberts J.A. Durnin L. Sharkey K.A. et al.Oxidative stress disrupts purinergic neuromuscular transmission in the inflamed colon.J Physiol. 2013; 591: 3725-3737Crossref PubMed Scopus (40) Google Scholar These findings underscore the delicate balance of enteric neural signaling, especially as it relates to motor functions. No perfect animal model exists for investigating the neurophysiological basis of altered motility in FGIDs, but one approach that has been used is to determine what inflammation-induced neuroplastic changes persist beyond the recovery of inflammation. This approach is obviously relevant to postinfectious IBS, but in the past decade a number of studies have shown that IBS is accompanied by a detectable increase in immune cells and inflammatory mediators in the mucosal layer. Furthermore, many inflammatory bowel disease patients show IBS-like symptoms after resolution of their macroscopic inflammation. Therefore, inflammation-induced changes in neuronal function could be a contributing factor in IBS and refractory inflammatory bowel disease, but these changes in neuronal excitability and synaptic strength would not be detectable with current diagnostic techniques. Several inflammation-induced changes in the ENS, including AH neuron hyperexcitability, do persist beyond recovery of inflammation,25Krauter E.M. Strong D.S. Brooks E.M. et al.Changes in colonic motility and the electrophysiological properties of myenteric neurons persist following recovery from trinitrobenzene sulfonic acid colitis in the guinea pig.Neurogastroenterol Motil. 2007; 19: 990-1000PubMed Google Scholar, 26Lomax A.E. O'Hara J.R. Hyland N.P. et al.Persistent alterations to enteric neural signaling in the guinea pig colon following the resolution of colitis.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G482-G491Crossref Scopus (68) Google Scholar supporting the possibility th