T2067 Mechanosensitivity of Na V1.5, a Voltage-Gated Sodium Selective Ion Channel Found in the Human Gastrointestinal Tract

Abstract

Stress induced immunomodulation has evolved to confer maximum biological advantage to an organism exposed to varying environmental stressors. Stress is also implicated in the aetiology of Irritable Bowel Syndrome (IBS). Herein, we examined the immunophenotype of IBS patients for evidence of stress related immunomodulation. Methods: 24-IBS patients and 9-matched controls subjects were studied. Comprehensive clinical, psychological (e.g. somatisation) and symptomatic (e.g. Visceral Sensitivity Index (VSI)) evaluations were performed. Peripheral bloodmononuclear cells (PBMC's) were stimulated using lipopolysacharide (5-concentrations) in the presence or absence of exogenous corticotrophin releasing hormone (CRH). A broad panel of inflammatory markers were measured in the supernatant. A one-way ANOVA was performed and data reported as point estimates of difference, ±95%CI (IBS-Controls). Results: Levels of IL2 (-44.5 (-66,-22) p<0.001), IL4 (-32.5 (-54,11) p=0.0004), IL5 (-15.3 (-21, 8.9) p<0.001), IL10 (-1088 (685, 1491) p<0.001), IL13 (60.3 (-85, -36) p<0.001), TNFα (-5452 (-3577, -7327) p<0.001), and IFNγ (-1353 (-471, -2235) p=0.002) were lower in IBS compared to controls and negatively correlated with measures of symptom severity (e.g. IL-5 and Verbal Descriptor Visual Analogue Scale for symptom intensity (VDVAS-I) r=-0.65, p<0.001) and psychological co-morbidity (e.g. IL-5 and somatisation, r=-0.41, p=0.02). In contrast, IL6 (8431 (13160, 3703) p<0.001) and IL8 (14186 (17934, 10437) p<0.001) levels were higher in IBS and positively correlated with measures of symptom severity (e.g. IL-8 and VDVAS-I, r= 0.61, p<0.001) and psychological co-morbidity (e.g. IL-8 and somatisation, r=0.37, p=0.03). Co-incubation with CRH suppressed IFNγ levels in control subjects to the same level as IBS patients (254.1 (-491, 999) p=0.05). Conclusion: As seen in chronic stress, IBS patients suppress Th1 and Th2 cytokine release from stimulated PBMC's and this suppression is negatively correlated with increasing symptom severity and psychological co-morbidity. Elevation of IL-6, and suppression of IFN-γ, IL-2 and IL-4 may indicate a shift towards a TH17 immune profile. This immunophenotype would convey a biological advantage in terms of enhanced mucosal host defence but may also establish a pro-inflammatory mucosal cytokine profile which would promote gastrointestinal symptoms. The potential interaction between stress and TH17 immune function in IBS could represent a new insight in IBS pathophysiology.