Goele Bosmans

The Neuromodulation of the Intestinal Immune System and Its Relevance in Inflammatory Bowel Disease

One of the main tasks of the immune system is to discriminate and appropriately react to “danger” or “non-danger” signals. This is crucial in the gastrointestinal tract, where the immune system is confronted with a myriad of food antigens and symbiotic microflora that are in constant contact with the mucosa, in addition to any potential pathogens. This large number of antigens and commensal microflora, which are essential for providing vital nutrients, must be tolerated by the intestinal immune system to prevent aberrant inflammation. Hence, the balance between immune activation versus tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent immune activation indiscriminately against all luminal antigens. Loss of this delicate equilibrium can lead to chronic activation of the intestinal immune response resulting in intestinal disorders, such as inflammatory bowel diseases (IBD). In order to maintain homeostasis, the immune system has evolved diverse regulatory strategies including additional non-immunological actors able to control the immune response. Accumulating evidence strongly indicates a bidirectional link between the two systems in which the brain modulates the immune response via the detection of circulating cytokines and via direct afferent input from sensory fibers and from enteric neurons. In the current review, we will highlight the most recent findings regarding the cross-talk between the nervous system and the mucosal immune system and will discuss the potential use of these neuronal circuits and neuromediators as novel therapeutic tools to reestablish immune tolerance and treat intestinal chronic inflammation.

Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus

Electrical stimulation of the cervical vagus nerve (VNS) prevents postoperative ileus (POI) in mice. As this approach requires an additional cervical procedure, we explored the possibility of peroperative abdominal VNS in mice and human.

Vagotomy affects the development of oral tolerance and increases susceptibility to develop colitis independently of the alpha-7 nicotinic receptor

Vagotomy (VGX) increases the susceptibility to develop colitis suggesting a crucial role for the cholinergic anti-inflammatory pathway in the regulation of the immune responses. Since oral tolerance and the generation of regulatory T cells (Tregs) are crucial to preserve mucosal immune homeostasis, we studied the effect of vagotomy and the involvement of α7 nicotinic receptors (α7nAChR) at the steady state and during colitis. Therefore, the development of both oral tolerance and colitis (induced by dextran sulfate sodium (DSS) or via T cell transfer) was studied in vagotomized mice and in α7nAChR−/− mice. VGX, but not α7nAChR deficiency, prevented oral tolerance establishment. This effect was associated with reduced Treg conversion in the lamina propria and mesenteric lymphnodes. To the same extent, vagotomized mice, but not α7nAChR−/− mice, developed a more severe DSS colitis compared with control mice treated with DSS, associated with a decreased number of colonic Tregs. However, neither VGX nor absence of α7nAChR in recipient mice affected colitis development in the T cell transfer model. In line, deficiency of α7nAChR exclusively in T cells did not influence the development of colitis induced by T cell transfer. Our results indicate a key role for the vagal intestinal innervation in the development of oral tolerance and colitis, most likely by modulating induction of Tregs independently of α7nAChR.

Absence of intestinal inflammation and postoperative ileus in a mouse model of laparoscopic surgery

Postoperative ileus (POI) is characterized by impaired gastrointestinal motility resulting from intestinal handling‐associated inflammation. The introduction of laparoscopic surgery has dramatically reduced the duration of POI. However, it remains unclear to what extent this results in a reduction of intestinal inflammation. The aim of the present study is to compare the degree of intestinal inflammation and gastrointestinal transit following laparoscopic surgery and open abdominal surgery.

Ghrelin receptor modulates T helper cells during intestinal inflammation

The orexigenic peptide ghrelin has anti‐inflammatory properties in colitis, however, the mechanism of action and the immune cells targeted remain still to be elucidated. Here, we assessed the possible effect of ghrelin on T helper (Th) cells in a T cell transfer model of chronic colitis.

Cholinergic Modulation of Type 2 Immune Responses

In recent years, the bidirectional relationship between the nervous and immune system has become increasingly clear, and its role in both homeostasis and inflammation has been well documented over the years. Since the introduction of the cholinergic anti-inflammatory pathway, there has been an increased interest in parasympathetic regulation of both innate and adaptive immune responses, including T helper 2 responses. Increasing evidence has been emerging suggesting a role for the parasympathetic nervous system in the pathophysiology of allergic diseases, including allergic rhinitis, asthma, food allergy, and atopic dermatitis. In this review, we will highlight the role of cholinergic modulation by both nicotinic and muscarinic receptors in several key aspects of the allergic inflammatory response, including barrier function, innate and adaptive immune responses, and effector cells responses. A better understanding of these cholinergic processes mediating key aspects of type 2 immune disorders might lead to novel therapeutic approaches to treat allergic diseases.

Tu1730 Novel Transgenic Mast Cell-Deficient Mouse Model Reveals No Role for Mast Cells in the Pathogenesis of Postoperative Ileus

Background & Aims: The neuropeptide NT and its receptor NTR1 mediate intestinal inflammation and their expression is increased in IBD. Colitis and associated hypoxia through the activation of the transcription factor hypoxia-inducible factor HIF-1modulates the expression of miR-210. NT promotes the transcriptional activity of HIF-1α, an event associated with increased intestinal angiogenesis (DDW2013: #1738), and induces the expression of miR210 (Gastroenterology, 2011; 141:1749). Here we examined the implication of HIF-1α in miR-210 regulation by NT, and assessed the role of miR-210 in the development of colitis and intestinal angiogenesis. Methods: NCM460 cells overexpressing NTR1 (NCM460-NTR1) were exposed to NT (0.1 μM, 6 h), +/the HIF-1α inhibitor PX-478 (40 μM, 18 h); miR-210 expression was evaluated by qPCR. Acute colonic inflammation was induced by intracolonic administration of TNBS (5 mg/kg, 48 h) in wild type (WT) and NTR1 knockout (KO) mice. Colonic miR-210 was inhibited by intracolonic administration of locked nucleic acid anti-miR-210 (LNA-anti-miR-210). The degree of inflammation was evaluated on distal colon segments stained with H&E and angiogenesis was evaluated by von-Willebrand (vWB) staining. Results: NT treatment of NCM460-NTR1 cells induced miR-210 expression (p<0.006) that was attenuated (by ~65%, p<0.005) by treatment with the HIF-1α inhibitor, PX-478. TNBS treatment increased colonic miR-210 expression in WT mice, an effect suppressed in NTR1 KO mice (p=0.02, n=6/group). Moreover, miR-210 levels were elevated in tissue samples from patients with Ulcerative Colitis (UC) compared to controls (p=0.003, n=11/group). Intracolonic administration of LNA-anti-miR-210 in mice reduced endogenous colonic miR-210 levels by ~55% (p=0.01), without affecting expression of other miRs. LNAanti-miR-210 pre-treated colons (n=8/group) exhibited reduced levels of IL-6, Cxcl1, and TNFα (p<0.05 for all), diminished mucosal integrity score (p=0.0001), neutrophil infiltration (p=0.0004), total colitis score (p=0.0001), and vWB staining (p=0.008) compared to colons treated with TNBS alone. Conclusions: Our results demonstrate the importance of NT/miR210 axis in the pathophysiology of colitis and IBD. The successful intracolonic microRNA silencing indicates the utility of microRNA inhibitors as a novel therapeutic approach towards IBD. Supported by NIH grant DK60729 (CP), the Crohns and Colitis Foundation of America (KB) and the Blinder Research Foundation for Crohns Disease (IKML).