Background: Episodic bouts of abdominal pain and altered bowel habit are characteristic of irritable bowel syndrome (IBS). Although a comprehensive understanding of IBS pathophysiology remains elusive, support is growing for a primary role for immune activation in disease severity as evidenced by altered cytokine profiles in IBS plasma. Additionally, aberrant stimulation of the stress axis is likely to result in altered plasma constituents. Methods: Whole-mount preparations of submucosal plexus from adult male Sprague Dawley rats were exposed to plasma from IBS patients and healthy controls. Ratiometric calcium imaging recordings were used to measure changes in intracellular calcium [Ca2+] as a marker of neuronal excitability. Key results: IBS plasma stimulated a robust increase in [Ca2+, (0.09 +/- 0.02) whereas plasma from healthy volunteers had little effect (-0.02 +/- 0.02. n = 24, p < 0.001). The neuromodulatory actions of IBS plasma were reduced by pre-neutralisation with anti-interleukin (IL)-6 (p <0.01) but not IL-8, immunoglobulin G or C-reactive protein. Moreover. IBS plasma-evoked responses (0.22 +/- 0.06) were inhibited by the corticotrophin releasing factor receptor (CRFR) 1 antagonist, antalarmin (1 mu M, 0.015 +/- 0.02, n = 14, p < 0.05). but not the CRFR2 antagonist, astressin 2B. Neuronal activation was mediated by ERK/MAPK signalling. Conclusions: These data provide evidence that factors present in IBS plasma modulate neuronal activity in the submucosal plexus and that this is likely to involve CRFR1 activation and IL-6 signalling. These neuromodulatoty actions of stress and immune factors indicate a potential mechanism by which immune activation during periods of stress may lead to symptom flares in IBS. (C) 2014 Elsevier Inc. All rights reserved.