Neuro-immuno-regulation of inflammation in the colonic mucosa : Focus on mast cells and eosinophils in bowel disorders

Sammanfattning: 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.

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