Local immune response to food antigens drives meal-induced abdominal pain.

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.

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 Puncorrected<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 (Puncorrected<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.

Sensitivity testing in irritable bowel syndrome with rectal capsaicin stimulations: role of TRPV1 upregulation and sensitization in visceral hypersensitivity?

OBJECTIVES: Abnormal pain perception or visceral hypersensitivity (VH) is considered to be an important mechanism underlying symptoms in a subgroup of irritable bowel syndrome (IBS) patients. Increased TRPV1 (transient receptor potential cation channel subfamily V member 1) expression in rectal biopsies of IBS patients suggests a potentially important role for this nociceptor in the pathophysiology of IBS. However, evidence underscoring the involvement of TRPV1 in visceral perception in IBS is lacking. The objective of this study was to evaluate the role of TRPV1 in VH to rectal distension and clinical symptoms in patients with IBS. METHODS: A total of 48 IBS patients and 25 healthy volunteers (HVs) were invited to undergo subsequent assessment of sensitivity to rectal distensions and rectal capsaicin applications. Visceral sensitivity was evaluated by rectal distension at 3, 9, and 21 mm Hg above minimal distension pressure (MDP). Capsaicin was applied to the rectal mucosa (0.01%, 0.1%, or solvent only in random order). Visceral sensations (urge to defecate, pain, burning, and warmth sensation) were scored on a 100-mm visual analog scale (VAS). TRPV1 expression in rectal biopsies was determined by immunohistochemistry and real-time PCR. RESULTS: A total of 23 IBS patients (48%) were hypersensitive to rectal distensions (VH-IBS). A concentration-dependent increase of urge and pain perception was present in HVs and IBS patients during capsaicin 0.01 and 0.1% applications. VH-IBS patients experienced a significantly increased perception of pain, but not urge, during capsaicin applications compared with normosensitive patients (ns-IBS) and HVs. Increased pain perception was significantly associated with anxiety and VH, symptoms scores of abdominal pain, loose stools, and stool frequency. Anxiety experienced during the experimental procedure was enhanced in VH-IBS patients but not in ns-IBS or HVs. However, rectal TRPV1 expression was similar in VH-IBS, ns-IBS, and HVs on both mRNA and protein expression levels. TRPV1 expression levels did not correlate with pain perception to capsaicin or clinical symptoms in IBS patients or the subgroups. CONCLUSIONS: IBS patients with VH to rectal distension reveal increased pain perception to rectal application of capsaicin, as well as an increased anxiety response. No evidence for TRPV1 upregulation could be demonstrated. As both VH and anxiety are independently associated with increased pain perception to rectal capsaicin application, our data suggest that both peripheral and central factors are involved, with increased receptor sensitivity as a speculative possibility.