Dysfunctional Sympathetic-Immune Interface in Disease States of the Gastrointestinal Tract

Sympathetic-immune interface in gastrointestinal tract

The sympathetic nervous system (SNS) is an integrative interface between the central nervous system and viscera that contributes to the maintenance of homeostasis. It is comprised of cholinergic preganglionic sympathetic neurons which innervate postganglionic sympathetic neurons (PGSNs) and adrenal chromaffin cells (ACCs). Catecholamines and sympathetic co-transmitters, including adenosine triphosphate (ATP), or a related purine, and neuropeptide Y (NPY), are locally released by PGSNs and systemically secreted by ACCs [1,2]. Sympathetic activation underlies important fight-or-flight responses during stressful situations by increasing cardiac output, enhancing the blood supply to skeletal and cardiac muscle cells, elevating blood glucose levels, dilating the pupils and bronchioles, and decreasing gastrointestinal (GI) motility. In addition to these well-recognized functions, mounting evidence indicates that the SNS also provides dynamic regulation of the immune system [3-5].

The SNS provides complex modulation of immune function through the interaction of locally and systemically secreted catecholamines with adrenoceptors expressed by immune cells and accessory lymphoid structures. PGSNs innervate parenchymal immune cells within lymphoid tissues located throughout the body, including the gut-associated lymphoid tissues (GALT) [6]. In addition, ACCs provide systemic catecholamines that can interact with both circulating and parenchymal immune cells. Depending upon the source of catecholamines, the type of adrenoceptor activated and the specific class of immune cell involved, the SNS can either enhance or inhibit inflammatory processes. In general, activation of beta-adrenoceptors limits inflammation by promoting humoral immunity and the secretion of anti-inflammatory cytokines, while inhibiting cellular immunity and proinflammatory cytokine release [3]. In contrast, alpha-adrenoceptors exert proinflammatory effects through immune cell activation.

During pathological GI inflammation, including inflammatory bowel disease (IBD), there is an inhibition of catecholamine secretion from PGSNs [7-10], a decreased availability of beta-adrenoceptors and an upregulation of alpha-adrenoceptor expression [11-13]. These alterations may promote the preferential activation of alpha-adrenoceptors expressed by immune cells located within the GI tract, thereby enhancing the severity of inflammation. In the present review, the role of sympathetic neuro-immune interactions during normal and pathological inflammatory processes in the GI tract is described.

Gut-associated lymphoid tissues

The GI tract is a tubular organ system extending from the oral cavity to the anus that functions to digest food, absorb nutrients and protect against infection. With respect to the latter, the GI tract gives rise to the largest mucosal surface in the body and is home to a diverse population of commensal bacteria that limit colonization by pathogens, generate important nutrients and contribute to immune system development [14-19]. However, if the composition of the GI microbiota is altered, commensal bacteria can become pathogenic and damage host tissues [20]. In addition to antigens derived from commensal bacteria, the GI tract is also exposed to an array of non-self antigens associated with food. The unique environment associated with the GI tract therefore requires a highly specialized immune system that can protect the body from pathogenic microbes and regulate bacterial colonization, while maintaining a state of tolerance toward innocuous food antigens and symbiotic bacteria.

A continuous sheet of epithelial cells connected by tight junctions and covered by an apical layer of mucous lines the GI lumen, forming a physical barrier against invading micro-organisms. A group of lymphoid structures, known as the GALT, responds to microbes and antigens that have breached the mucosal barrier. The GALT consists of organized lymphoid structures, including the mesenteric lymph nodes, isolated lymphoid follicles, cryptopatches and Peyer’s patches, as well as immune cells scattered throughout the GI mucosa. These immune structures generate tolerance toward innocuous antigens and orchestrate innate and adaptive immune responses against perceived pathogens [21]. GI immune cells exhibit unique characteristics that are thought to promote tolerance of commensal bacteria and food antigens. For example, lamina propria macrophages display decreased proinflammatory cytokine secretion and reduced expression of innate immune receptors that detect microbial antigens and stimulate immune responses [22,23]. Evidence also suggests that GI immune cells favour the secretion of tolerogenic type 2 T helper cell (Th2) cytokines, including interleukin (IL)-10 and IL-4, which suppress type 1 T helper cell (Th1) responses [3,21,24-26]. However, during pathological inflammatory conditions, proinflammatory cytokine secretion from GI macrophages is enhanced, and the balance of Th1 cytokines, including IL-2 and interferon (IFN)-gamma, to Th2 cytokines may become altered to promote an overall state of inflammation [27,28].

Microbes that have breached the epithelial barrier are rapidly eliminated by resident GI macrophages [23]. Penetrating antigens can also be taken up, processed and presented on major histocompatibility complex (MHC) class II molecules by immature dendritic cells [24]. Dendritic cells presenting novel antigen enter local lymphatic vessels and access the mesenteric lymph nodes where they interact with naïve T cells expressing T cell receptors specific for the antigen that is being presented [29,30]. Depending upon the type of antigen and the inflammatory mediators present within the dendritic cell’s microenvironment, the dendritic cell can either promote tolerance of the antigen through T cell anergy or deletion, or it can initiate an immune response [24].

During an active immune response, dendritic cells promote clonal expansion of naïve T cells specific for the presented antigen, regulate T cell differentiation and help determine whether a predominantly Th1 or Th2 type response occurs [24]. Activated T cells then enter the systemic circulation and return to the GI tract, where they initiate an immune response specific to the invading antigen. Homing of activated T cells to the GI mucosa is achieved by localized chemokine production, and an upregulation of adhesion molecules expressed by primed T cells and endothelial cells in the GI microvasculature [21]. Given the complexity of GI immune responses to invading micro-organisms, it is likely that the inflammatory process is regulated at multiple levels by modulatory inputs, including the SNS.

Distribution of sympathetic axons in the gut and GALT

Neural regulation of GI function relies on a delicate balance of inputs from intrinsic and extrinsic neuronal populations. The enteric nervous system (ENS) provides intrinsic innervation of the GI tract and is composed of sensory, inter- and motor neurons located within the myenteric and submucosal plexuses [31]. Extrinsic innervation includes preganglionic parasympathetic neurons, extrinsic afferent neurons and PGSNs [31]. The majority of PGSNs that supply the GI tract have cell bodies in abdominal prevertebral ganglia, including the celiac, superior mesenteric, and inferior mesenteric ganglia [32,33]. These ganglia integrate central and peripheral inputs from preganglionic sympathetic neurons, PGSNs from neighbouring sympathetic ganglia, collaterals from spinal afferent neurons, and intestinofugal neurons of the ENS to regulate a variety of GI functions [32,33].

The axons of PGSNs enter the GI tract alongside the mesenteric arteries, ramify within the serosal surface and then penetrate through the intestinal wall, extending to the mucosa [34-37]. Many of these axons terminate within myenteric and submucosal ganglia where they exert inhibitory influence over the ENS to decrease GI motility and secretion [31]. PGSNs also innervate blood vessels and lymphatic vessels of the GI tract where they evoke vasoconstriction and regulate lymphatic drainage, respectively [38-42].

Postganglionic sympathetic varicosities can be found in close proximity to parenchymal immune cells located within every primary and secondary lymphoid structure of the body [5,43-45]. Ultrastructural studies on sympathetic fibres in lymphoid tissues suggest that sympathetic varicosities do not make traditional synaptic contacts with immune cells [3,5,46]. Instead, PGSNs release norepinephrine non-synaptically to diffuse upwards of 1 µm before interacting with local immune cells [46,47]. Sympathetic varicosities predominantly innervate areas rich in T cells, macrophages and plasma cells, though mast cells and eosinophils can also be found in proximity to noradrenergic fibres [6]. Developing or maturing B cells do not appear to receive significant sympathetic innervation [34,48].

Peyer’s patches are diffuse lymphoid structures located within the small intestine that consist of follicles of B cells covered by an apical dome region. A layer of specialized epithelium scattered with M cells and intraepithelial immune cells lines the luminal surface above each follicle [21]. Neighbouring follicles are separated by T cell-enriched interfollicular areas that extend from the base of the follicles to an apical interdomal region. Perivascular plexuses associated with the muscularis mucosae can be found along the basal surfaces of the Peyer’s patches and often extend radially through the interfollicular regions [6,34,49].

Sympathetic axons have been shown to project from these perivascular plexuses to innervate populations of T cells within the interfollicular areas, and T cells and plasma cells within the interdomal regions [6,34,49]. The GI tract also contains isolated immune cells that are scattered throughout the mucosa. Noradrenergic fibres that are not associated with blood vessels terminate in the colonic lamina propria among macrophages and T cells [6,50]. Postganglionic sympathetic axons also form dense plexuses within the GI crypts and adjacent to the basement membrane in close proximity to intraepithelial lymphocytes [4].

Mesenteric lymph nodes are encapsulated lymphoid structures that survey interstitial fluid collected from the GI tract for invading micro-organisms, antigen presenting dendritic cells and inflammatory mediators. Each mesenteric lymph node can be anatomically and functionally divided into an outer cortex, a paracortical region and an inner medulla [51]. Postganglionic sympathetic axons enter the lymph node through the hilus in association with blood vessels [48,52].  Perivascular plexuses containing noradrenergic fibres can be found throughout lymph nodes and a prominent network of sympathetic fibres exists beneath the capsule [6,48,53]. Postganglionic sympathetic varicosities are also observed outside the perivascular plexuses adjacent to T cells within the outer cortex and paracortical region [6,48,52].

Sympathetic regulation of GI immune cell function

Sympathetic varicosities innervating lymphoid tissues provide rapid, local release of norepinephrine to regulate parenchymal leukocyte function. Epinephrine and norepinephrine can also be secreted by ACCs into the systemic circulation to interact with circulating and resident immune cells. Catecholamines provide complex regulation of diverse immune cell functions, including cell trafficking, proliferation, differentiation and activation [3,4]. Catecholamines exert their immunomodulatory effects through the activation of adrenoceptors expressed by immune cells and accessory lymphoid structures. Functional adrenoceptor expression has been observed in several immune cell types. Beta-adrenoceptor expression has been described in macrophages, dendritic cells, naïve T cells, cytotoxic T cells, Th1 T helper cells, natural killer (NK) cells, B cells, neutrophils and eosinophils [54-65]. Beta-adrenoceptor activation enhances anti-inflammatory cytokine secretion, inhibits cellular immunity and reduces the release of proinflammatory cytokines [3]. Alpha-adrenoceptors are also expressed by certain classes of immune cells, including macrophages which express alpha2-adrenoceptors [66], and NK cells and dendritic cells which express both alpha1- and alpha2-adrenoceptors [55,56,61,67].

Although catecholamines can either enhance or inhibit inflammatory processes, the SNS is generally thought to provide anti-inflammatory effects through the predominant activation of beta-adrenoceptors [3,68]. The anti-inflammatory nature of sympathetic neurotransmitters is particularly true for systemic catecholamines secreted by ACCs. For example, co-incubation of human whole blood samples with epinephrine and lipopolysaccharide (LPS) enhances anti-inflammatory IL-10 secretion and inhibits proinflammatory tumour necrosis factor (TNF)-alpha secretion [69,70]. Whole blood samples taken from individuals with high epinephrine secretion at rest exhibit increased IL-10, and decreased TNF-alpha and IL-12 secretion following LPS treatment ex vivo compared to blood samples taken from individuals with lower circulating epinephrine levels [71]. Circulating catecholamines can also enhance IL-10 secretion and reduce serum TNF-alpha concentrations during aberrant systemic inflammatory conditions, such as sepsis [69,72].

The sympathetic regulation of GI immunity has not been extensively studied to date. As a result, the effects of catecholamines on GI immune cells are often inferred from studies on similar populations of immune cells located within other regions of the body. It is important to note however that certain classes of immune cells found within the GI tract exhibit unique characteristics [22,25,26]. Consequently, the sympathetic regulation of immune cell function may be slightly modified within the GI tract.

Circulating monocytes can enter the GI tract through local blood vessels and subsequently differentiate into macrophages [23,73,74]. Macrophages are professional antigen presenting cells that protect the GI tract from invading micro-organisms, remove cellular debris and promote tissue repair [23]. Norepinephrine enhances monocyte and macrophage migration in vitro through the activation of beta-adrenoceptors [75]. As a result, it has been suggested that norepinephrine may act as a chemoattractant to recruit monocytes into the tissue and bring macrophages in close proximity with sympathetic varicosities [75]. Locally released norepinephrine can also modulate macrophage activation and cytokine secretion within the GI tract.

For example, treatment of isolated peritoneal macrophages with beta-adrenoceptor agonists in vitro results in decreased TNF-alpha secretion and increased IL-10 release in response to stimulation with LPS [76-80]. Activation of beta-adrenoceptors also inhibits phagocytosis and decreases nitric oxide production in peritoneal macrophages [58,76,81]. Conversely, activation of alpha2-adrenoceptors enhances LPS-induced TNF-alpha production and inhibits IL-10 release in peritoneal macrophages in vitro [66,78]. The balance between alpha- and beta-adrenoceptor activation on resident macrophages may therefore play an important role in shaping GI inflammation.

Immature dendritic cells take up antigen within the GI lamina propria, present the antigen to T cells and help coordinate the ensuing immune response [24]. Immature dendritic cells are also found in the epidermis of the skin where they provide similar responses to antigen challenge. Topical application of an alpha1-adrenoceptor antagonist to the surface of the skin has been shown to decrease the migration of dendritic cells to regional lymph nodes and reduce contact hypersensitivity responses [67]. In contrast, topical application of a beta2-adrenoceptor antagonist was found to have the opposite effect [56]. Stimulation of beta-adrenoceptors expressed by epidermal dendritic cells has also been shown to inhibit antigen presentation in vitro [55].

Adoptive transfer of bone marrow derived dendritic cells treated with norepinephrine promotes the induction of Th2 T helper cell-mediated responses, while ganglionic blockade with pentolinium enhances Th1 cytokine secretion [82]. Given that Th2 cytokines promote oral tolerance, it is not surprising that oral administration of a beta-adrenoceptor agonist was found to induce tolerance toward a previously immunized antigen [83]. Catecholamines have also been shown to regulate TNF-alpha, IL-23, IL-12 and IL-6 production in human cord-derived dendritic cells following LPS challenge [84].

T helper cells coordinate adaptive immune responses by modulating cytotoxic T cell, leukocyte and B cell activities. Evidence suggests that catecholamines acting on T helper cell populations provide anti-inflammatory effects by inhibiting Th1 T helper cell-mediated cellular immunity and promoting Th2 T helper cell-mediated humoral immunity [3]. For example, beta2-adrenoceptor activation inhibits T cell proliferation, decreases naïve T cell differentiation into Th1 T helper cells and reduces the secretion of proinflammatory Th1 cytokines, including IL-2 and IFN-gamma [59,63,85,86]. Given that Th1 cytokines inhibit Th2 type responses, catecholamines acting on beta2-adrenoceptors can indirectly enhance the secretion of anti-inflammatory Th2 cytokines, including IL-10, despite the fact that adrenoceptors are not expressed by Th2 T helper cells [59,63,87].

GI immune cells appear to favour Th2 cytokine profiles [25,26]. It is therefore possible that the SNS may help maintain the Th1:Th2 cytokine balance within the GI tract in conditions that would otherwise skew the balance toward Th1 T helper cell activation. Locally released norepinephrine may also regulate T lymphocyte trafficking within the GALT, as sympathetic nerve ablation with 6-hydroxydopamine (6-OHDA) was found to decrease the migration of adoptively transferred T lymphocytes to the mesenteric lymph nodes and Peyer’s patches, and reduce the mucosal response to luminal antigen challenge [88]. It is important to mention, however that chemical sympathectomy has been shown to enhance catecholamine secretion from the adrenal medulla [89,90]. Therefore, elevated systemic catecholamine concentrations may continue to provide anti-inflammatory effects to circulating and resident immune cells.

In addition to catecholamines, evidence also supports an important role for the sympathetic co-transmitters, NPY and ATP, or a related purine, in the modulation of immune cell function. Several classes of immune cells bear functional NPY receptors, primarily belonging to the Y1 and Y5 subtypes [91-93]. NPY signaling has largely been shown to suppress the immune response through inhibition of proinflammatory cytokine release and immune cell activity [75,94-97]. In addition, NPY co-released with norepinephrine in lymphoid tissues can potentiate catecholamine-mediated immunomodulatory effects. For example, NPY co-administered with norepinephrine significantly reduced IL-6 release from splenic macrophages compared to when either transmitter was given alone [98]. ATP also exerts potent immunomodulatory effects that can vary depending upon the type of receptor that is activated [99,100]. Stimulation of metabotropic P2Y11 purinoceptors on macrophages favours the release of anti-inflammatory IL-10, whereas ATP binding to ligand-gated P2X7 receptors enhances proinflammatory cytokine production but can also cause leukocyte apoptosis [101-104]. ATP secreted by postganglionic sympathetic varicosities is rapidly catabolized to the purine nucleoside adenosine, which has been shown to inhibit inflammatory responses by decreasing complement protein activation, leukocyte migration and superoxide anion production in neutrophils [105-109].

Although ACCs and PGSNs can rapidly release catecholamines, NPY and ATP in response to stimulation, the SNS is not the only cellular source of these chemical mediators. For example, certain classes of immune cells, including macrophages, T cells and B cells have been shown to take up, synthesize, store and secrete catecholamines [80,110-114]. Immune cells, vascular endothelial cells and smooth muscle cells can also release NPY and ATP into the extracellular environment [115-117]. Within the GI tract, enteric secretomotor neurons have been shown to synthesize NPY and recent evidence suggests that the enteric microbiota is a prominent source of ATP [118-121].

The role of the SNS during inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic pathological condition characterized by relapsing and remitting inflammation of the GI tract. Patients with active Crohn’s disease exhibit transmural, discontinuous inflammatory lesions that can affect any region of the GI tract [122]. In contrast, patients with ulcerative colitis exhibit mucosal inflammation that is often localized to the colon [123]. Although it is generally well-accepted that IBD results from an exaggerated immune response in a genetically susceptible host, the precise etiology of IBD remains elusive [124-127].

Animal models that reflect aspects of IBD in human patients are routinely used to investigate the causes and consequences of pathological GI inflammation. Dextran sulfate sodium (DSS) is a water-soluble glucose polymer that can be administered to animals through their drinking water over acute or chronic regimens to induce mucosal inflammation of the colon [128,129]. DSS disrupts the structural integrity of the mucosal barrier, exposing components of the mucosal immune system to luminal antigens and triggering a mixed Th1/Th2 inflammatory response [128,130]. 2,4,6-Trinitrobenzene sulfonic acid (TNBS) and 2,4-dinitrobenzene sulfonic acid (DNBS) are hapten molecules that can be administered to the GI lumen to produce a predominantly Th1 T cell-mediated inflammatory response which affects the full thickness of the intestinal wall [128,130,131]. IL-10-/- mice, adoptive transfer of specific immune cell subsets to irradiated hosts, certain strains of bacteria and GI parasites can also be used to study GI inflammation.

IBD and animal models of GI inflammation are characterized by aberrant innate and adaptive immune responses [124]. During IBD, there is massive infiltration of immune cells into the intestinal wall, including neutrophils, macrophages, dendritic cells and lymphocytes [132,133]. Large amounts of proinflammatory cytokines, including TNF-alpha, are often released within inflamed regions of the GI tract and can spill over into the systemic circulation [12,134-137]. Antibodies that neutralize the activity of TNF-alpha have proven to be a promising treatment for patients with IBD, suggesting that TNF-alpha plays a central role in IBD pathogenesis [127]. In contrast, IL-10 is a potent anti-inflammatory cytokine that limits GI inflammation and protects against the development of IBD [138,139].

Sympathetic neurotransmitters have been shown to alter the functional properties of several classes of immune cells implicated in the pathogenesis of IBD, and they can also regulate TNF-alpha and IL-10 secretion. Furthermore, stress, which contains a large sympathetic component, can affect disease severity and has been associated with the reactivation of GI inflammation [140-144]. It is therefore likely that the SNS plays an important role during IBD. However, only a few studies have directly investigated the sympathetic regulation of IBD pathogenesis. In many of these studies, SNS function was altered using techniques such as chemical sympathectomy with 6-OHDA or the systemic administration of adrenergic agents, both of which can affect sympathetic neurons located throughout the body and not just those innervating the GI tract. As a result, our knowledge concerning the role of specific populations of sympathetic neurons or distinct sympathetically innervated target tissues during IBD is limited.

In human patients, studies assessing the sympathetic regulation of IBD pathogenesis are restricted to ulcerative colitis. In this patient population, intrarectal administration of lidocaine, a non-specific inhibitor of neuronal signaling, was found to enhance patient well-being, and improve endoscopic and histological measures of disease severity [145]. Although this study did not determine the specific population of neurons responsible for the improved outcome, it demonstrated that components of the peripheral nervous system could modulate pathological GI inflammation. Sympathetic varicosities express alpha2-adrenoceptors, which can be activated by secreted norepinephrine in an autocrine fashion to limit further catecholamine secretion.

Administration of clonidine, an alpha2-adrenoceptor agonist, to decrease sympathetic activation and norepinephrine secretion was found to reduce clinical symptoms and improve the endoscopic appearance of the colon in patients with active ulcerative colitis [146,147]. The anti-inflammatory effects of clonidine may have also resulted from inhibition of alpha2-adrenoceptors expressed by GI macrophages. Given that Crohn’s disease is characterized by a predominantly Th1 T helper cell-mediated inflammatory response, it is possible that sympathetic neurotransmitters may improve disease outcomes by favouring Th2 cytokine secretion [27,28,148]. However, this theory remains to be directly tested.

The role of the SNS during experimental colitis varies depending upon the model of IBD used, the time at which SNS function is manipulated and the type of adrenoceptor that is primarily affected. For example, sympathetic nerve ablation with 6-OHDA prior to the induction of TNBS colitis was found to improve macroscopic damage scores [149]. Similarly, in the acute model of DSS-induced colitis, chemical sympathectomy improved histological scores and limited inflammatory reduction of colon length when performed prior to the initiation of inflammation [132]. In contrast, sympathetic nerve ablation performed during the chronic phase of colitis in IL-10-/- mice exacerbated colonic inflammation as exemplified by higher histological scores and enhanced colonic TNF-alpha mRNA expression [132].

In addition, using the chronic model of DSS-induced colitis, loss of sympathetic innervation 20 days after the last cycle of DSS administration resulted in elevated histological scores, enhanced inflammation-induced shortening of the colon, increased IL-6 and IFN-gamma secretion from mesenteric lymph nodes, and upregulation of colonic TNF-alpha and IFN-gamma mRNA expression [132]. These results suggest that during the initial stages of inflammation, the SNS exacerbates the inflammatory response, whereas at more chronic time points, sympathetic inputs improve disease severity.

Sympathetic neurotransmitters have been shown to regulate dendritic cell migration to regional lymph nodes during inflammatory responses and increase the number of circulating NK cells [56,67,150,151]. Catecholamines can also act as chemoattractants for monocytes, macrophages and dendritic cells, and may indirectly enhance neutrophil infiltration through elevated systemic IL-8 secretion [67,75,152,153]. During the early stages of experimental models of IBD, the SNS may therefore enhance inflammation by increasing immune cell infiltration into the inflamed intestine and promoting antigen presentation within the mesenteric lymph nodes. In contrast, during established GI inflammation, catecholamine-induced inhibition of TNF-alpha secretion and increased production of Th2 cytokines may limit the inflammatory response. The sympathetic regulation of GI blood flow and lymphatic drainage may also provide beneficial effects [38,40,154]. Furthermore, sympathetic neurotransmitters have been shown to promote epithelial cell proliferation, which may accelerate tissue repair during established inflammation [155]. A similar time dependent effect of the sympathetic modulation of inflammation has been described during joint inflammation [156].

Oral administration of a selective beta3-adrenoceptor agonist throughout the course of DNBS colitis in rats was found to improve macroscopic and histological scores, reduce myeloperoxidase activity and decrease proinflammatory cytokine production within the colon, including TNF-alpha, IL-1beta and IL-6 [12]. These results suggest that beta3-adrenoceptors may play a beneficial role in modulating the inflammatory response during colitis. However, within the GI tract, beta3-adrenoceptors are largely expressed by circular smooth muscle cells, myenteric neurons and vascular smooth muscle cells [12]. Consequently, the protection conferred by beta3-adrenoceptor activation may also be mediated by changes in GI motility and blood flow [157]. A similar protective effect of beta3-adrenoceptor agonists has been observed in models of gastric ulceration, where altered blood flow and motility were found to improve ulcer severity scores [158,159].

During both TNBS and acute DSS colitis, daily intraperitoneal injection of an alpha2-adrenoceptor antagonist was found to decrease histological severity, reduce myeloperoxidase activity, and inhibit TNF-alpha and IL-1beta production in the colon [160]. Macrophages have been shown to express functional alpha2-adrenoceptors, which promote the secretion of TNF-alpha and inhibit the release of IL-10 in response to LPS stimulation [66,78]. During this study, improved disease severity during acute DSS and TNBS colitis was largely attributed to inhibition of alpha2-adrenoceptors within these macrophage populations. However, it is important to note that alpha2-adrenoceptor antagonists would also act presynaptically on sympathetic varicosities to enhance catecholamine secretion and increase the amount of norepinephrine available to activate anti-inflammatory beta-adrenoceptors expressed by local immune cells. Enhanced norepinephrine secretion may also improve the blood supply, increase lymphatic drainage and promote mucosal repair.

Altered sympathetic neurophysiology during inflammatory bowel disease

During IBD and experimental models of GI inflammation, elevated tissue and serum levels of inflammatory mediators may interact with extrinsic and intrinsic neuronal populations innervating the GI tract to alter their structure and function. Clinical manifestations of IBD include abdominal pain, diarrhea and microvascular dysfunction, supporting the possibility that aberrant neuronal function may contribute to symptom generation [38,125,161-164]. Indeed, GI inflammation has been shown to alter enteric, sensory and sympathetic neurophysiology. For example, the TNBS and Citrobacter rodentium models of colitis have been shown to enhance the intrinsic excitability of colonic projecting sensory neurons of the dorsal root ganglia (DRG) [165-168].

In addition, hyperexcitability and synaptic facilitation have been observed in myenteric and submucosal neurons during TNBS-induced colitis [169-171]. However, enteric neuronal cell death has also been described during animal models of IBD, which may limit the regulatory capabilities of the ENS within affected regions of the GI tract [172,173]. Many of the inflammation-induced alterations in enteric and sensory neuron function persist after microscopically or biochemically detectable inflammation has resolved [168,174,175]. As a result, neural mechanisms may contribute to the persistent dysfunction that is observed following the resolution of inflammation, particularly in patients with post-infectious irritable bowel syndrome [176].

Using non-invasive measurements of SNS function, including power spectral analysis of heart rate variability and muscle sympathetic nerve recordings, patients with active ulcerative colitis were shown to exhibit enhanced SNS activity at rest [146,177,178]. Increased sympathetic activity has also been described in IBD patients in clinical remission, suggesting that sympathetic nerve dysfunction persist in the absence of active disease [179]. Patients with ulcerative colitis also exhibit enhanced sympathetic innervation of the rectal mucosa and mesenteric arteries [145,180,181]. Early electron microscopic studies on ileal specimens from Crohn’s disease patients revealed both proliferation of autonomic axons as well as severe axonal necrosis [182,183]. Using more specific immunohistochemical techniques, investigators found that sympathetic innervation of the colon is decreased during Crohn’s disease [132]. In support of this finding, colonic mucosal norepinephrine concentrations were found to be reduced in Crohn’s disease patients compared to healthy controls [184]. However, Crohn’s disease patients exhibit an increased number of myenteric neurons expressing tyrosine hydroxylase, the rate limiting enzyme in catecholamine synthesis [185]. In addition, sympathetic innervation of the mesenteric arteries is enhanced during Crohn’s disease [181].

Alterations in SNS structure and function have also been observed during experimental models of IBD. For example, a significant loss of sympathetic fibres has been described within the colons of mice during chronic DSS colitis [186]. In contrast, TNBS colitis does not appear to affect the sympathetic innervation of colonic submucosal arterioles [38]. During TNBS-induced ileitis, PGSNs of the celiac ganglion exhibit enhanced excitability [187]. However, inhibition of norepinephrine secretion from PGSNs innervating the GI tract is a common feature of the TNBS, DNBS, Trichinella spiralis and acute DSS models of inflammation [7-11]. A reduction in N-type voltage-gated Ca2+ current has been described in PGSNs of the superior mesenteric ganglion during acute DSS colitis, suggesting that impaired Ca2+ signaling may contribute to the decreased norepinephrine secretion that is observed [7]. Upregulation of presynaptic alpha2-adrenoceptors may also play a role in inflammation-induced inhibition of norepinephrine secretion [11].

Decreased norepinephrine secretion occurs in PGSNs innervating both inflamed and uninflamed regions of the GI tract [7-9,11]. Given that local and systemic concentrations of inflammatory mediators are elevated during GI inflammation, it is possible that cytokines may promote aberrant SNS function. Overnight incubation of PGSNs of the superior mesenteric ganglion in TNF-alpha produced a similar inhibition of N-type voltage-gated Ca2+ current as acute DSS colitis [188]. In addition, TNF-alpha was found to reduce stimulus-induced norepinephrine secretion from postganglionic sympathetic varicosities innervating jejunal longitudinal smooth muscle-myenteric plexus preparations [189]. IL-1beta, IL-6 and prostaglandin E2 (PGE2) have also been shown to decrease norepinephrine release within the GI tract, further supporting a role for inflammatory mediators in the modulation of sympathetic activity during GI inflammation [190-193].

Evidence suggests that alterations in adrenoceptor expression and activation may favour a proinflammatory role for sympathetic neurotransmitters within the GI tract during experimental models of IBD. Alpha-adrenoceptors have a higher affinity for norepinephrine than beta-adrenoceptors. Therefore, decreased local norepinephrine concentrations may promote the preferential activation of proinflammatory alpha-adrenoceptors during GI inflammation. In addition, GI inflammation has been shown to increase alpha-adrenoceptor expression and downregulate beta-adrenoceptor expression. For example, TNBS jejunitis was found to upregulate alpha1- and alpha2-adrenoceptor expression and decrease beta-adrenoceptor availability in guinea pig smooth muscle-myenteric plexus preparations [13].

Similarly, during DNBS colitis in rats, alpha2-adrenoceptor expression is upregulated within the muscular layers of inflamed colon and un-inflamed ileum, while beta3-adrenoceptor expression is reduced within the inflamed colonic mucosa and submucosa [11,12]. In addition, beta3-adrenoceptor-mediated inhibition of colonic circular smooth muscle contraction is reduced during TNBS colitis in rats [163]. Although it is unclear whether similar alterations in adrenoceptor expression and function occur in GI immune cells, decreased beta- and enhanced alpha-adrenoceptor expression would be expected to promote inflammation by reducing IL-10 and enhancing TNF-alpha secretion from GI macrophages, and limiting the suppressive effects of catecholamines on Th1 type responses.


GI immune homeostasis is essential for appropriate GI function and requires complex interactions between immune cells, accessory lymphoid structures and modulatory inputs, including the SNS. PGSNs innervating the GALT may provide moment-to-moment regulation of GI immune cell function. Through alterations in immune cell trafficking, proliferation, differentiation and activation, the SNS can both enhance and inhibit protective and pathological inflammatory responses.

The outcome of sympathetic activation during inflammation likely depends on the type of adrenoceptor activated, the nature of the inflammatory stimulus and the classes of immune cells that are involved. Studies assessing sympathetic neuro-immune interactions during IBD and experimental models of GI inflammation are often confounded by adrenergic effects on non-immune structures, including vascular smooth muscle cells, epithelial cells, enteric neurons and GI smooth muscle cells. Future investigations focusing on the direct sympathetic modulation of immune cell function during IBD are warranted. Alterations in immune cell adrenoceptor expression and the sympathetic innervation of the GALT during IBD should also be examined.

Nonstandard Abbreviations: Adenosine triphosphate (ATP); adrenal chromaffin cell (ACC); dextran sulfate sodium (DSS); 2,4-dinitrobenzene sulfonic acid (DNBS); enteric nervous system (ENS); gastrointestinal (GI); gut-associated lymphoid tissues (GALT); 6-hydroxydopamine (6-OHDA); interferon (IFN); interleukin (IL); lipopolysaccharide (LPS); major histocompatibility complex (MHC); neuropeptide Y (NPY); postganglionic sympathetic neuron (PGSN); prostaglandin (PG); sympathetic nervous system (SNS); 2,4,6-trinitrobenzene sulfonic acid (TNBS); tumour necrosis factor (TNF)

Author(s) Affiliation

MK Lukewich & AL Cervi – Department of Physiology; Gastrointestinal Diseases Research Unit and Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada
AE Lomax – Department of Physiology and Department of Medicine; Gastrointestinal Diseases Research Unit and Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada

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Cover Image Credit

Bidirectional communication channels between the gut microbiome, the gut, and the brain. Endocrine-, neurocrine-, and inflammation-related signals generated by the gut microbiota and specialized cells within the gut can, in principal, affect the brain. In turn, the brain can influence microbial composition and function via endocrine and neural mechanisms. From: Gut Microbes and the Brain: Paradigm Shift in Neuroscience, Symposium Gut Microbes and the Brain: Paradigm Shift in Neuroscience, Emeran A. Mayer, Rob Knight, Sarkis K. Mazmanian, John F. Cryan, and Kirsten Tillisc; The Journal of Neuroscience, November 12, 2014, 34(46):15490 –15496 https://www.jneurosci.org/content/34/46/15490/tab-figures-data

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