Morgane Florens

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.

245 Evidence for a New Mechanism Underlying Persistent Visceral Hypersensitivity and Increased Permeability in a Model of Post-Infectious IBS

and cortisol responses to stimulation with CRH and ACTH: 1) differ between IBS patients and healthy controls (HCs), 2) are affected by sex and EALs, 3) are associated with GR mRNA expression. Methods: Male and female Rome III+ IBS patients and HCs underwent CRH (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured. GR mRNA levels were measured from peripheral blood mononuclear cells using real-time PCR. Presence of EALs <18 yrs of age was measured with the Trauma History questionnaire. Linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups with a knot at the peak of the curve to model the rates of change from baseline to peak (rise) and from peak to the last time point (decline). Area under the curve (AUC) was also measured. Results: 60 IBS patients (65%F, mean age 33yrs) and 56 HCs (52%F, mean age 31yrs) underwent hormone stimulation studies. 74 IBS (65%F, mean age 33yrs) and 69 HCs (52%F, mean age 33yrs) had GR mRNA expression levels. A subset (37 IBS, 28 HCs) had both hormone stimulation and GR mRNA studies. 34 (60%) IBS patients and 27 (48%) HCs had +EAL. CRH stimulation test: IBS patients showed a slower rate of decline from peak ACTH levels than HCs (p<0.05). Women with IBS had a slower rate of decline of ACTH (p=0.01) and cortisol (p=0.001) than men with IBS. ACTH stimulation test: Cortisol responses were similar in IBS and HCs, likely due to a significant interaction between IBS and sex (p<0.001). Within women, IBS had a lower cortisol response (AUC) than HCs. In contrast, in men, IBS had a greater cortisol response than HCs. GR mRNA expression: Levels were lower in IBS vs HCs (p= 0.03), which was mainly seen within men. Lower GR mRNA levels were associated with faster rise in ACTH and cortisol responses (p=0.01-0.03). EAL did not have a significant effect on hormone responses. Conclusion: HPA axis response was dysregulated in IBS. The enhanced HPA axis response was associated with downregulation of the GR mediated negative feedback system. Sex differences in the stress response may play a role in the female predominance of IBS.

Effect of genetic background and postinfectious stress on visceral sensitivity in Citrobacter rodentium-infected mice

Infectious gastroenteritis is a major risk factor to develop postinfectious irritable bowel syndrome (PI‐IBS). It remains unknown why only a subgroup of infected individuals develops PI‐IBS. We hypothesize that immunogenetic predisposition is an important risk factor. Hence, we studied the effect of Citrobacter rodentium infection on visceral sensitivity in Th1‐predominant C57BL/6 and Th2‐predominant Balb/c mice.

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.