Summary Background The pathogenesis of irritable bowel syndrome (IBS) is founded on interactive mechanisms. Disentangling these processes is a prerequisite for the development of effective drug therapy. Aim To identify the interaction between the various factors implicated in IBS. Methods Articles pertaining to IBS pathogenesis focusing on psychoneuroimmunology were identified using following search terms: IBS, animal models, microbiota, probiotics, immunology, visceral hypersensitivity, imaging, psychology and visceral pain. Results Cerebral imaging using MRI and proton emission tomography scanning has revealed differential regional cerebral activation, whereas stimuli induced activation has been captured by both MRI and cortical evoked potentials. At the peripheral neurological level, the concept of visceral hypersensitivity has been challenged as perhaps representing psychological traits with symptom over‐reporting or hyper‐vigilance. Gut mucosal immunology is thought to be relevant with immunological changes reflected as peripheral blood cytokine level changes. Molecular technology advances suggest a role for microbiota by activating the gut immunological system. These interactions have been examined in IBS animal models. Conclusions Translation of animal model findings to humans is needed to link the various psychological, neurological and immunological changes noted in IBS. This analysis may identify patient sub‐groups, which will ultimately be critical for drug testing to be focused accordingly.
The objective of this study was to determine whether cortical evoked potentials (CEPs) can define neurophysiological patterns in irritable bowel syndrome (IBS). In this prospective study of consecutive patients attending secondary and tertiary centers, patients with Rome II-defined IBS underwent rectal sensory and pain threshold (RST and RPT, respectively) testing with electrical stimulation on three separate visits. CEPs were collated for 75% pain thresholds, and anxiety [Spielberger State-Trait Anxiety Inventory (SSTAI)] questionnaires were completed. Subjects were 33 IBS patients (27 female, mean age 40.1 yr) and 21 healthy controls (14 female, mean age 31.4 yr). At visit 3, RPT was significantly lower [mean (95% CI)] in IBS patients than in control subjects: 58.2 mA (48.0-68.5) vs. 79.5 mA (69.3-89.6) (P < 0.01). No significant differences were observed in CEP latencies and amplitudes between visits 1, 2, and 3 within each group, except P2 latency for controls (P = 0.04) and N2 latency (P = 0.04) and N2 amplitude (P = 0.02) for IBS patients. Group comparisons showed significant differences in 3-day mean RPT, CEP amplitudes, and CEP latencies between IBS patients and controls. RPT <50 mA and P1 latency >106 ms were identified four IBS subgroups: 24% were hypersensitive, 12% were hypervigilant, 15% were hyposensitive, and 49% exhibited normal P1 latency and pain threshold. CEPs are reliable and reproducible measures of early sensory processing. Identification of four IBS neurophysiological patterns highlights its heterogeneous nature. These findings mark the first step toward personalized medicine in IBS, whereby therapy may be directed at the underlying physiological process.
IntroductionStress 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.Methods24-IBS patients and 9-matched controls subjects were studied. Comprehensive clinical, psychological (eg, somatisation) and symptomatic (eg, Visceral Sensitivity Index (VSI)) evaluations were performed. Peripheral blood mononuclear 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).ResultsLevels of IL2 (−44.5 (−66 to −22) p<0.001), IL4 (−32.5 (−54 to −11) p=0.0004), IL5 (−15.3 (−21 to 8.9) p<0.001), IL10 (−1088 (685 to 1491) p<0.001), IL13 (−60.3 (−85 to −36) p<0.001), TNFα (−5452 (−3577 to −7327) p<0.001), and IFNγ (−1353 (−471 to −2235) p=0.002) were lower in IBS compared to controls and negatively correlated with measures of symptom severity (eg, IL-5 and Verbal Descriptor Visual Analogue Scale for symptom intensity (VDVAS-I) r=−0.65, p<0.001) and psychological comorbidity (eg, IL-5 and somatisation, r=−0.41, p=0.02). In contrast, IL6 (8431 (13 160 to 3703) p<0.001) and IL8 (14 186 (17 934 to 10 437) p<0.001) levels were higher in IBS and positively correlated with measures of symptom severity (eg, IL-8 and VDVAS-I, r=0.61, p<0.001) and psychological comorbidity (eg, 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 to 999) p=0.05).ConclusionAs 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 comorbidity. 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.
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