Altered brain activation to colorectal distention in visceral hypersensitive maternal-separated rats

Background  Early life trauma can predispose to increased visceral pain perception. Human neuroimaging studies emphasize that altered brain processing may contribute to increased visceral sensitivity. The aim of our study was to evaluate brain responses to painful visceral stimuli in maternal-separated rats before and after acute stress exposure in vivo. Methods  H(2) (15) O microPET scanning was performed during colorectal distention in maternal-separated rats before and after water avoidance stress. Brain images were anatomically normalized to Paxinos space and analyzed by voxel-based statistical parametric mapping (SPM2). Colorectal induced visceral pain was assessed by recording of the visceromotor response using abdominal muscle electromyography. Key Results  Colorectal distention (1.0-2.0 mL) evoked a volume-dependent increase in visceromotor response in maternal-separated rats. Stress [water avoidance (WA)] induced an increased visceromotor response to colorectal distention in awake and anesthetized rats. In pre-WA rats, colorectal distention evoked significant increases in regional blood flow in the cerebellum and periaquaductal gray (PAG). Colorectal distention post-WA revealed activation clusters covering the PAG as well as somatosensory cortex and hippocampus. At maximal colorectal distention, the frontal cortex was significantly deactivated. Conclusions & Inferences  WA stress induced increased pain perception as well as activation of the somatosensory cortex, PAG, and hippocampus in maternal-separated rats. These findings are in line with human studies and provide indirect evidence that the maternal separation model mimics the cerebral response to visceral hypersensitivity in humans.status: publishe

Prospective study evaluating immune-mediated mechanisms and predisposing factors underlying persistent post-infectious abdominal complaints

BACKGROUND: The role of persistent immune activation in postinfectious irritable bowel syndrome (PI-IBS) remains controversial. Here, we prospectively studied healthy subjects traveling to destinations with a high-risk to develop infectious gastroenteritis (IGE) in order to identify immune-mediated mechanisms and risk factors of PI-IBS. METHODS: One hundred and one travelers were asked to complete questionnaires on psychological profile and gastrointestinal (GI) symptoms before travel, 2 weeks, 6 months and 1 year after travel. At each visit, blood was collected for PBMC isolation and rectal biopsies were taken. PI-IBS was diagnosed using the Rome III criteria and subjects with persistent postinfectious abdominal complaints (PI-AC) were identified using 3 GSRS symptoms (ie, loose stools, urgency and abdominal pain). RESULTS: Forty-seven of the 101 subjects reported IGE during travel. After 1 year, two subjects were diagnosed with PI-IBS and eight subjects were presented with PI-AC versus two subjects with IBS and two with abdominal complaints in the non-infected group. PBMC analysis showed no differences in T and B cell populations in subjects with PI-AC vs healthy. Additionally, no differences in gene expression were observed in the early postinfectious phase or after 1 year. Regression analysis identified looser stools, higher anxiety and somatization before infection and several postinfectious GI symptoms as risk factors for PI-AC. CONCLUSIONS: The incidence of PI-IBS is low following travelers' diarrhea and there is need for larger studies investigating the role of immune activation in PI-IBS. Psychological factors before infection and the severity of symptoms shortly after infection are risk factors for the persistence of PI-AC.status: publishe

Psychological comorbidity increases the risk for postinfectious IBS partly by enhanced susceptibility to develop infectious gastroenteritis

Psychological factors increase the risk to develop postinfectious IBS (PI-IBS), but the mechanisms involved are unclear. As stress affects the immune system, we investigated the potential interaction between psychological factors, the immune response against infectious gastroenteritis (IGE) and the development of IGE and PI-IBS in a large cohort exposed to contaminated drinking water.status: publishe

Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome

The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS.status: publishe

Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome

Objective The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS. Design 384 single nucleotide polymorphisms (SNPs) covering 270 genes were genotyped in an exploratory cohort (935 IBS patients, 639 controls). 33 SNPs with P-uncorrected<0.05 were validated in an independent set of 497 patients and 887 controls. Genotype distributions of single SNPs were assessed using an additive genetic model in IBS and clinical subtypes, IBS-C and IBS-D, both in individual and combined cohorts. Trait anxiety (N=614 patients, 533 controls), lifetime depression (N=654 patients, 533 controls) and mRNA expression in rectal biopsies (N=22 patients, 29 controls) were correlated with SNP genotypes. Results Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)). When combining both cohorts, the association of rs2349775 withstood post hoc correction for multiple testing in the IBS-D subgroup. Additionally, three SNPs in immune-related genes (rs1464510-LPP, rs1881457-IL13, rs2104286-IL2RA), one SNP in a neuronal gene (rs2349775-NXPH1) and two SNPs in epithelial genes (rs245051-SLC26A2, rs17837965-CDC42) were weakly associated with total-IBS (P-uncorrected<0.05). At the functional level, rs1881457 increased IL13 mRNA levels, whereas anxiety and depression scores did not correlate with rs2349775-NXPH1. Conclusions Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with IBS-D and IBS-C, respectively, in two independent cohorts. Further studies are warranted to validate our findings and to determine the mechanisms underlying IBS pathophysiology

Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome

Funded by a government grant (Odysseus program, G-0905-07) of the Research Foundation-Flanders and by a KU Leuven University Grant (Global Opportunities for Associations GOA 14.011) (G.E.B.); by a Research Foundation-Flanders postdoctoral fellowship (1248513N to M.M.W. and 12C2113N to C.C.); by a Research Foundation-Flanders PhD fellowship (1127415N to D.B.); by a KU Leuven postdoctoral fellowship (Y.A.A.); by Bowel and Cancer Research (UK charity number 1119105 to V.C.G.); and Séverine Vermeire is a senior clinical investigator of Research Foundation-Flanders . Also funded by a Research Foundation-Flanders research grant G-0699-10N (G.E.B. and M.M.W.), G-0501-10 (P.V.d.B.), and by a grant from Research Fund KU Leuven (GOA 14.011 to K.T.) and an European Research Counsil (ERC) Start Grant IMMUNO (A.L.). funded by the Canadian Institutes of Health Research (S.Va.); supported by a joint fellowship from the Canadian Association of Gastroenterology, the Canadian Institutes of Health Research, and Crohn’s and Colitis Canada (Y.N.); supported by a National Council of Science and Technology (CONACyT) grant: 203341 fellowship (E.E.V.M.); and funded by a KU Leuven University grant (PF-TRPLe to K.T.)