Neuroimmune mechanisms in functional bowel disorders

The enteric nervous system regulates diverse functions including gastrointestinal motility and nociception. The sensory neurons detect mechanical and chemical stimuli while motor neurons control peristalsis and secretion. In addition to this extensive neuronal network, the gut also houses a highly specialised immune system which plays an important role in the induction and maintenance of tolerance to food and other luminal antigens and in the protection of the epithelial barrier against pathogenic invasion. It is now increasingly recognised that the gastrointestinal immune system and the enteric nervous system closely interact. This review will focus on two common functional gastrointestinal disorders in which neuroimmune interaction is involved in the pathophysiology: i.e. postoperative ileus and irritable bowel syndrome. Postoperative ileus arises after almost every abdominal surgical procedure. Handling of the bowel results in local inflammation and activation of inhibitory neuronal pathways resulting in a generalised impairment of gastrointestinal motor function or ileus. On the other hand, postinfectious irritable bowel syndrome (PI-IBS) occurs in 10 to 30% of patients who suffer from infectious gastroenteritis. PI -IBS patients develop abnormal gastrointestinal sensitivity, motility and secretion which contribute to abdominal pain and discomfort, bloating and abnormal bowel function (diarrhoea and/or constipation). Biopsy studies revealed persistent low-grade inflammation and altered immunological function which may lead to abnormal pain perception and motor activity within the gastrointestinal tract.     

Neural stimulations regulate the infiltration of immune cells into the CNS

The systemic regulation of immune reactions by the nervous system is well studied and depends on the release of hormones. Some regional regulations of immune reactions, on the other hand, depend on specific neural pathways. Better understanding of these regulations will expand therapeutic applications for neuroimmune and organ‐to‐organ functional interactions. Here, we discuss one regional neuroimmune interaction, the gateway reflex, which converts specific neural inputs into local inflammatory outputs in the CNS. Neurotransmitters released by the inputs stimulate specific blood vessels to express chemokines, which serve as a gateway for immune cells to extravasate into the target organ such as the brain or spinal cord. Several types of gateway reflexes have been reported, and each controls distinct CNS blood vessels to form gateways that elicit local inflammation, particularly in the presence of autoreactive immune cells. For example, neural stimulation by gravity creates the initial entry point to the CNS by CNS‐reactive pathogenic CD4+ T cells at the dorsal vessels of fifth lumbar spinal cord, while pain opens the gateway at the ventral side of blood vessels in the spinal cord. In addition, it was recently found that local inflammation by the gateway reflex in the brain triggers the activation of otherwise resting neural circuits to dysregulate organ functions in the periphery including the upper gastrointestinal tract and heart. Therefore, the gateway reflex represents a novel bidirectional neuroimmune interaction that regulates organ functions and could be a promising target for bioelectric medicine.     

Therapeutic action of ghrelin in a mouse model of colitis

BACKGROUND & AIMS: Ghrelin is a novel growth hormone-releasing peptide with potential endogenous anti-inflammatory activities ameliorating some pathologic inflammatory conditions. Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon. The aim of this study was to investigate the therapeutic effect of ghrelin in a murine model of colitis. METHODS: We examined the anti-inflammatory action of ghrelin in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid. Diverse clinical signs of the disease were evaluated, including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of ghrelin, such as inflammatory cytokines and chemokines, Th1-type response, and regulatory factors. RESULTS: Ghrelin ameliorated significantly the clinical and histopathologic severity of the trinitrobenzene sulfonic acid-induced colitis; abrogating body weight loss, diarrhea, and inflammation; and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response through the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of interluekin-10/transforming growth factor-beta1-secreting regulatory T cells in this therapeutic effect was demonstrated. Importantly, the ghrelin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. CONCLUSIONS: Our data demonstrate novel anti-inflammatory actions for ghrelin in the gastrointestinal tract, ie, the capacity to deactivate the intestinal inflammatory response and to restore mucosal immune tolerance at multiple levels. Consequently, ghrelin administration represents a novel possible therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.     

Characteristic features of ghrelin cells in the gastrointestinal tract and the regulation of stomach ghrelin expression and production

Ghrelin was isolated as an endogenous ligand for the GH secretagogue receptor from the rat stomach. Although physiological effects of ghrelin have been revealed by numerous studies, the regulation of stomach ghrelin remains obscure, and the factor that directly regulates ghrelin expression and production has not been identified. Here, we show some data regarding the characteristic features of ghrelin cells and the regulation of stomach ghrelin. In the gastrointestinal tract, ghrelin cells were identified as opened- and closed-type cells, and it was found that the number of ghrelin cells decreased from the stomach to the colon. The postnatal change in number of ghrelin cells in the stomach showed a sexually dimorphic pattern, indicating a role of estrogen in the regulation of stomach ghrelin. In vitro studies revealed that estrogen stimulated both ghrelin expression and production and that treatment with formestane, an aromatase （estrogen synthetase） inhibitor, decreased ghrelin expression level. On the other hand, leptin was found to inhibit both basal and estrogen-stimulated ghrelin expression. Moreover, both aromatase mRNA- expressing cells and leptin cells were found to be located close to ghrelin cells in the gastric mucosa. Furthermore, we found an inverse relationship between gastric ghrelin and leptin levels in a fasting state, and we revealed relative changes in expression of gastric ghrelin, estrogen and leptin in the postnatal rats. We propose that gastric estrogen and leptin directly regulate stomach ghrelin and that the balance control through gastric estrogen and leptin contributes to the altered ghrelin expression level in some physiological states.     

Halofuginone for fibrosis,regeneration and cancer in the gastrointestinal tract

Organ fibrosis and architectural remodeling can severely disrupt tissue function, often with fatal consequences. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli, and the key cellular mediator of fibrosis comprises the myofibroblasts which, when activated, serve as the primary collagen-producing cells. Complex links exist between fibrosis, regeneration and carcinogenesis, and the concept that all organs contain common tissue fibrosis pathways that could be potential therapeutic targets is an attractive one. Because of the major impact of fibrosis on human health there is an unmet need for safe and effective therapies that directly target fibrosis. Halofuginone inhibits tissue fibrosis and regeneration, and thereby affects the development of tumors in various tissues along the gastrointestinal tract. The high efficacy of halofuginone in reducing the fibrosis that affects tumor growth and tissue regeneration is probably due to its dual role in inhibiting the signaling pathway of transforming growth factor β, on the one hand, and inhibiting the development of Th17 cells, on the other hand. At present halofuginone is being evaluated in a clinical trial for other fibrotic indication, and any clinical success in that trial would allow the use of halofuginone, also for all other fibrotic indications, including those of the gastrointestinal tract.     

Nutritional stimulation of the autonomic nervous system

Disturbance of the inflammatory response in the gut is important in several clinical diseases ranging from inflmmatory bowel disease to postoperative ileus. Several feedback mechanisms exist that control the inflammatory cascade and avoid collateral damage. In the gast rointestinal tract, it is of particular importance tocontrol the immune response to maintain the balance that allows dietary up take and utilization of nutrientson one hand, while preventing invasion of bacteria and toxins on the other hand. ...     

Nitric oxide modulation as a therapeutic strategy in heart failure

Nitric oxide (NO) is recognized as one of the most important cardiovascular signaling molecules, with multiple regulatory effects on myocardial and vascular tissue as well as on other tissues and organ systems. With the growth in understanding of the range and mechanisms of NO effects on the cardiovascular system, it is now possible to consider pharmaceutical interventions that directly target NO or key steps in NO effector pathways. This article reviews aspects of the cardiovascular effects of NO, abnormalities in NO regulation in heart failure, and clinical trials of drugs that target specific aspects of NO signaling pathways.     

Therapeutic effects of rhubarb on gastrointestinal failure

AIM: To investigate the effects of rhubarb on gastrointestinal failure and the underlying pharmaceutical mechanism. METHODS: Ninety-seven patients in intensive care unit were divided into a treatment group (76 critically ill patients complicated with gastrointestinal failure) and a control group (21 recovered patients). The effects of rhubarb on stress ulcer and toxic paralytic ileus in the patients were observed. The rectal and gastric intramural pH values, cardiac index, oxygen delivery, and oxygen consumption were measured. RESULTS: Treatment with rhubarb achieved a significant curative effect in 30 of the 36 cases of stress ulcer complicated with gastrointestinal hemorrhage. Ha-2-receptor blocking agent had a poor effect on them (P < 0.05). Among the 49 cases of toxic paralytic ileus treated with rhubarb, peristalsis was recovered in 41, and gastrointestinal nutrition could be tolerated in 24, while other medicine had no effect on them. According to gastric and rectal intramural pH, rhubarb could improve gut mucosa perfusion. Among the 23 cases of multiple organ dysfunction syndrome who received treatment with rhubarb, 9 survived. CONCLUSION: This study suggests that rhubarb has a good curative effect on gastrointestinal failure.     

Role of Ghrelin in the Pathophysiology of Gastrointestinal Disease

Ghrelin is a 28-amino-acid peptide that plays multiple roles in humans and other mammals. The functions of ghrelin include food intake regulation, gastrointestinal (GI) motility, and acid secretion by the GI tract. Many GI disorders involving infection, inflammation, and malignancy are also correlated with altered ghrelin production and secretion. Although suppressed ghrelin responses have already been observed in various GI disorders, such as chronic gastritis, Helicobacter pylori infection, irritable bowel syndrome, functional dyspepsia, and cachexia, elevated ghrelin responses have also been reported in celiac disease and inflammatory bowel disease. Moreover, we recently reported that decreased fasting and postprandial ghrelin levels were observed in female patients with functional dyspepsia compared with healthy subjects. These alterations of ghrelin responses were significantly correlated with meal-related symptoms (bloating and early satiation) in female functional dyspepsia patients. We therefore support the notion that abnormal ghrelin responses may play important roles in various GI disorders. Furthermore, human clinical trials and animal studies involving the administration of ghrelin or its receptor agonists have shown promising improvements in gastroparesis, anorexia, and cancer. This review summarizes the impact of ghrelin, its family of peptides, and its receptors on GI diseases and proposes ghrelin modulation as a potential therapy.     

Role of intracellular zinc in molecular and cellular function in allergic inflammatory diseases

Zinc is an essential micronutrient in human body and a vital cofactor for the function of numerous proteins encoded by the human genome. Zinc has a critical role in maintaining many biochemical and physiological processes at the molecular, cellular, and multiple organ and systemic levels. The alteration of zinc homeostasis causes dysfunction of many organs and systems.In the immune system, zinc regulates the differentiation, proliferation and function of inflammatory cells, including T cells, eosinophils, and B cells, by modifying several signaling pathways such as NFκB signaling pathways and TCR signals. An adequate zinc level is essential for proper immune responses and decreased zinc levels were reported in many allergic inflammatory diseases, including atopic dermatitis, bronchial asthma, and chronic rhinosinusitis. Decreased zinc levels often enhance inflammatory activation. On the other hand, the inflammatory conditions alter the intracellular homeostasis of zinc, often decreasing zinc levels. These findings implied that there could be a vicious cycle between zinc deficiency and inflammatory conditions.In this review, we present recent evidence on the involvement of zinc in atopic dermatitis, bronchial asthma, and chronic rhinosinusitis, with insights into the involvement of zinc in the underlying molecular and cellular mechanisms related to these allergic inflammatory diseases.     

Severe gastrointestinal mucositis following high dose melphalan therapy for multiple myeloma

Mucositis is a known complication following use of chemotherapy,but fatal mucositis is unusual and management of such cases may be challenging.Pathologically there is denudation of mucosa of gastrointestinal tract. Severe cases can develop ileus and even perforation of bowel wall.We report here a case of multiple myeloma who developed World Health Organization grade 4 gut mucositis following the use of high dose melphalan with the expulsion of"intestine-like"material.     

Endoscopic and radiographic features of gastrointestinal involvement in vasculitis

Vasculitis is an inflammation of vessel walls,followed by alteration of the blood flow and damage to the dependent organ.Vasculitis can cause local or diffuse pathologic changes in the gastrointestinal (GI) tract.The variety of GI lesions includes ulcer,submucosal edema,hemorrhage,paralytic ileus,mesenteric ischemia,bowel obstruction,and life-threatening perforation.The endoscopic and radiographic features of GI involvement in vasculitisare reviewed with the emphasis on small-vessel vasculitis by presenting our typicalcases,including Churg-Strauss syndrome,HenochSch nlein purpura,systemic lupus erythematosus,and Beh et’s disease.Important endoscopic features are ischemic enterocolitis and ulcer.Characteristic computed tomographic findings include bowel wall thickening with the target sign and engorgement of mesenteric vessels with comb sign.Knowledge of endoscopic and radiographic GI manifestations can help make an early diagnosis and establish treatment strategy.     

Ghrelin and motilin are cosecreted from a prominent endocrine cell population in the small intestine

CONTEXT: Ghrelin is a novel hormone produced mainly in the gastric body. Hitherto, mapping studies of ghrelin cells covering the entire gastrointestinal (GI) tract in humans have been lacking. Furthermore, the phenotype of extragastric ghrelin cells is not known. OBJECTIVE: The objective of the study was to perform a detailed mapping with specimens from all parts of the GI tract, and colocalization studies to phenotype ghrelin cells along the tract. In addition, mapping of ghrelin cells was performed in porcine GI tract, and the plasma profiles of ghrelin and motilin in blood from the porcine intestine were measured. DESIGN: Biopsies from patients were obtained during gastroscopy or surgery. Ghrelin cell density and phenotyping was assessed with immunocytochemistry, in situ hybridization, and immunogold electron microscopy. Plasma ghrelin and motilin levels were measured in pigs, fitted with cannulas in the mesenteric vein. RESULTS: The upper small intestine is unexpectedly rich in ghrelin cells, and these cells contribute to circulating ghrelin. Ghrelin and motilin are coproduced in the same cells in the duodenum and jejunum of both species, and ghrelin and motilin are stored in all secretory granules of such cells in humans, indicating cosecretion. The plasma profiles of ghrelin and motilin in pig were parallel, and a correlation between ghrelin and motilin (r(2) = 0.22; P < 0.001) was evident in intestinal blood. CONCLUSIONS: The upper small intestine is an important source of ghrelin. The likely cosecretion of intestinal ghrelin and motilin suggests concerted actions of the two hormones. These data may have implications for understanding gut motility and clinical implications for dysmotility and bariatric surgery.     

The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients

Critically ill patients often have systemic activation of both inflammatory systems and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation leads to activation of coagulation and coagulation considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut off by proinflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa, and thrombin, can bind to protease-activated receptors on various cells, and the ensuing intracellular signaling leads to increased production of proinflammatory cytokines and chemokines. Activated protein C can bind to the protein C receptor on endothelial cells and mononuclear cells, thereby affecting NF-kappaB nuclear translocation and subsequently influencing inflammatory gene expression and inhibition of tissue factor expression on mononuclear cells. Observations in experimental models of targeted disruption of the protein C gene and restoration of the downregulated protein C pathway by administration of recombinant activated protein C support this notion.     

New insights into the molecular pathogenesis of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma is an aggressive malignancy and is one of the most devastating cancers of the gastrointestinal tract. The molecular mechanisms contributing to the pathogenesis of these cancers are not well understood. The recognition and distinction of these cancers from other tumors such as perihilar or extrahepatic distal cholangiocarcinoma and hepatocellular carcinoma are important in defining the pathogenesis. New insights into molecular mechanisms contributing to disease pathogenesis are emerging from recent epidemiological, genome-wide profiling and laboratory based studies. These have contributed to an improved understanding of risk factors, genetic mutations and pathophysiological mechanisms that are associated with these tumors. The contribution of well-established risk factors such as biliary tract inflammation and key signaling pathways involved in intrahepatic cholangiocarcinoma are being further defined. These new insights have several important implications for both molecular diagnosis and therapy of these cancers.     

Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract

Background Motilin and ghrelin have been recognized as important endogenous regulators of gastrointestinal motor function in mammals, mediated respectively by the motilin receptor and by the closely related ghrelin receptor. The aims of this study were to explore the distribution of motilin and ghrelin receptors along the human gastrointestinal tract and to establish the molecular nature of the human motilin receptor. Methods Post mortem and surgical human tissue specimens with no hemorrhage, necrosis, or tumor were obtained from various parts of the gastrointestinal tract. We analyzed levels of expression of mRNA for motilin and ghrelin receptors and examined their molecular identities. Portions of some specimens were also studied by immunohistochemistry for expression of the motilin and ghrelin receptor. Results The long form of the motilin receptor, but not the short form, was expressed in all parts of the gastrointestinal tract, and expressed at higher levels in muscle than in mucosa. Motilin receptor immunoreactivity was present in muscle cells and the myenteric plexus, but not in mucosal or submucosal cells. In contrast, ghrelin receptor mRNA was expressed equally in all parts of the gastrointestinal tract, with similar levels of expression in mucosal and muscle layers. Conclusions Both the motilin and ghrelin receptors are expressed along the human gastrointestinal tract, but they have clearly distinct distributions in regard to both level and layer. The diffuse muscle expression of the motilin receptor, at both the levels of the gene and the protein product, along the entire gastrointestinal tract makes it a useful potential target for motilide drugs for dysmotility.     

Immune modulation in gastrointestinal disorders: new opportunities for therapeutic peptides?

Inflammation is the response of vascularized tissues to injury, irritation and infection. Nearly always, the inflammatory response is successfully resolved and, when necessary, a process of wound healing is initiated. Nowhere in the body is this homeostatic process more challenging than in the gastrointestinal (GI) tract, where the microbial flora sits in very close proximity to the mucosal immune system, separated only by an epithelial cell barrier. Delicate regulatory systems of the mucosal immune system determine mucosal permeability and response to bacterial flora, and aberrations in this system result in acute or chronic inflammatory conditions. Examples of such are two commonly occurring inflammatory GI disorders: inflammatory bowel disease and postoperative ileus. Inflammatory bowel disease is the result of a chronic and excessive mucosal immune response, whereas postoperative ileus represents a transient condition of GI tract paralysis that is the result of an inflammatory response to abdominal surgery. The clinical management of both conditions is very challenging and depends heavily on the possibility of modulating the host immune response. In this brief report, we highlight the role of neuropeptides in GI physiology and immune regulation, discuss a recently discovered endogenous anti-inflammatory pathway mediated by the ChemR23 receptor and speculate on the therapeutic potential of peptides that bind G-protein-coupled receptors in the management of inflammation in the GI tract.