Neuro Immuno Regulation Of Inflammation In The Colonic Mucosa

Intestinal homeostasis is key to control uptake across the mucosa and protect from harmful substances. Disturbances in the bidirectional communication between the gut and the brain are implicated in irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD), being Crohn’s disease (CD) and ulcerative colitis (UC) the two most common IBD subtypes. Although these chronic bowel-relapsing inflammatory disorders present different histopathology, they share similar pathological features. Both IBS and IBD are characterized by a disrupted intestinal barrier function, a pro-inflammatory chronic condition, and an altered gut-brain axis. Despite all the scientific effort, the sequence or exact combination of events that drive these diseases are still unknown, and so is the exact role of every single component. Growing evidence suggests altered neuro-immune interactions as a pathogenic factor. The general aim of this thesis was to elucidate the potential involvement of mast cells and eosinophils in IBS and IBD, and the neuro-immune intercellular circuit via vasoactive intestinal polypeptide (VIP) that might exacerbate mucosal inflammation and intestinal barrier disruption. Intestinal tissues from IBS, inactive IBD, healthy controls (HC), and murine colitis were collected. Electrophysiological and permeability studies were performed using the ex vivo Ussing chamber technique. Tissues were processed with immunohistological procedures to study cell numbers, activation, location, and interactions in relation to VIP. We demonstrated for the very first time an increased transcellular passage of live commensal and pathogenic bacteria through the colonic mucosa of IBS, identifying VIP as a key regulatory molecule together with mast cells activation. In vitro experiments revealed the ability of VIP to activate mast cells. Image analysis identified VIP-mast cells in closer proximity in IBD patients and murine colitis compared to controls. Communication between mast cells and VIP was shown upregulated in IBD and mice colitis via VIP receptor (VPAC)1. Similarities and differences between HC, IBS, and IBD were further studied. Results indicated a pronounced increased intestinal permeability in UC, even during remission, followed by IBS, compared to healthy controls. Surprisingly, permeability results did not correlate with mast cells, but with eosinophil number and activation. A further image analysis suggested an inhibitory effect of eosinophils and VIP on mast cells and an altered interaction between them under inflammatory conditions. Lastly, intestinal VIP levels were shown to increase in IBD patients after the treatment with biological agents and were suggested as a possible biomarker for biological treatment outcome. This thesis presents novel insights into the regulation of intestinal permeability, as well as into the pathophysiology of IBD and IBS by demonstrating the importance of neuro-immune interactions between mast cells, VIP, and eosinophils. Altogether, our findings have broadened the knowledge of neuro-immune interactions in IBS and IBD and might have the potential to onsight lead to new therapeutic approaches thereby improving the outcomes for patients suffering from these diseases.

Scientists from various disciplines integrate the neuro-biological and immunological aspects of mucosal function in the context of traditional mucosal physiological processes. Coverage includes epithelium-barrier function to antigens, lamina propria-immune and other effector cells, epithelial response to inflammation, epithelial secretory responses to inflammation, interactions of immune cells/mediators with the nervous system, neuro/immune modulation of epithelial function and pathophysiology of inflammation.

The enteric nervous system (ENS) is a complex neural network embedded in the gut wall that orchestrates the reflex behaviors of the intestine. The ENS is often referred to as the “little brain” in the gut because the ENS is more similar in size, complexity and autonomy to the central nervous system (CNS) than other components of the autonomic nervous system. Like the brain, the ENS is composed of neurons that are surrounded by glial cells. Enteric glia are a unique type of peripheral glia that are similar to astrocytes of the CNS. Yet enteric glial cells also differ from astrocytes in many important ways. The roles of enteric glial cell populations in the gut are beginning to come to light and recent evidence implicates enteric glia in almost every aspect of gastrointestinal physiology and pathophysiology. However, elucidating the exact mechanisms by which enteric glia influence gastrointestinal physiology and identifying how those roles are altered during gastrointestinal pathophysiology remain areas of intense research. The purpose of this e-book is to provide an introduction to enteric glial cells and to act as a resource for ongoing studies on this fascinating population of glia. Table of Contents: Introduction / A Historical Perspective on Enteric Glia / Enteric Glia: The Astroglia of the Gut / Molecular Composition of Enteric Glia / Development of Enteric Glia / Functional Roles of Enteric Glia / Enteric Glia and Disease Processes in the Gut / Concluding Remarks / References / Author Biography

Proceedings of the Third Hans Selye Symposium on Neuroendocrinology and Stress held in Budapest, Hungary, August 17-21, 1992.

This book addresses important issues regarding the interaction between the nervous system, the immune system, and the digestive system. Gut flora has a profound influence on the shaping of the immune response, not only in the gastrointestinal system but also in the nervous system. Fascinatingly, manipulation of intestinal immune responses can be used to modulate neurological disease. Conversely, the nervous system and the psyche have significant effects on the functioning of the gut and liver. After introductory chapters on the neurology, the immunology and microbiology of the gut, the effects of the gut immune system and gut flora and its manipulation on neurological disease are discussed, followed by molecular mimicry and immune tolerance in neuroimmune diseases. Additionally, several chapters deal with gastrointestinal manifestations of neurological diseases. Neuro-Immuno-Gastroenterology is aimed at neurologists, gastroenterologists, and immunologists.

Few human illnesses today are so challenging, medically, scientifically, and socio-economically, as the "nonspecific" inflammatory bowel diseases (IBD): ulcerative colitis and Crohn's disease. Originating several centuries ago but essentially diseases of the 20th century, often attacking children and young adults, involving all bodily systems as well as the gastrointestinal tract, ulcerative colitis and Crohn's disease have emerged in recent decades as among the more "glamorous" unsolved diseases, presenting unusual opportunities for insightful clinical and investigative study. Many of the prevailing concepts originated during the early and mid 20th century. The purpose of Origins and Directions of Inflammatory Bowel Disease is to review these earlier studies and their evolution "from the mystical to the molecular," and guide investigators and physicians through the challenging clinical and scientific maze of IBD.

Diseases of the digestive system have a higher morbidity rate than any other group of disorder. There is a growing body of evidence that the immune system participates in the pathogenesis of a wide range of these diseases, including peptic ulcer disease and the gastropathy induced by nonsteroidal anti-inflammatory drugs (NSAIDS). For these reasons, efforts to develop novel therapies for digestive diseases are increasingly focused on the immune system. This volume reviews the immunopharmacology of the gastrointestinal tract at four distinct levels: Immunomodulation at a cellular level Cellular targers for immunomodulating drugs Specific classes of inflammatory mediators Utility and mechanisms of action of glucocorticoids in the treatment of diseases of the gastrointestinal tract.