Local immune response as novel disease mechanism underlying abdominal pain in patients with irritable bowel syndrome.

OBJECTIVES: Irritable bowel syndrome (IBS) is the most frequently diagnosed functional gastrointestinal disorder, with a prevalence of up to 25% of the global population. IBS patients suffer from abnormal abdominal pain, or visceral hypersensitivity (VHS), associated with altered bowel habits in the absence of an organic detectable cause. The pathophysiology of the disease is incompletely understood, but the dysregulation of the brain-gut axis is well established in IBS. METHODS: IBS onset is mainly triggered by infectious gastroenteritis, psychological factors, and dietary factors, but genetic predispositions and intestinal dysbiosis might also play a role. Additionally, immune activation, and particularly chronic mast cell activation, have been shown to underlie the development of abdominal pain in IBS. RESULTS: By releasing increased levels of mediators, including histamine, mast cells sensitize enteric nociceptors and lead to VHS development. The mechanisms underlying aberrant mast cell activation in IBS are still under investigation, but we recently showed that a local break in oral tolerance to food antigens led to IgE-mediated mast cell activation and food-induced abdominal pain in preclinical models and in IBS patients. CONCLUSION: The concept of food-mediated VHS highlights the potential of therapies targeting upstream mechanisms of mast cell sensitization to treat IBS.

Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.

Evidence for long-term sensitization of the bowel in patients with post-infectious-IBS.

Post-infectious irritable bowel syndrome (PI-IBS) is a common gastrointestinal disorder characterized by persistent abdominal pain despite recovery from acute gastroenteritis. The underlying mechanisms are unclear, although long-term changes in neuronal function, and low grade inflammation of the bowel have been hypothesized. We investigated the presence and mechanism of neuronal sensitization in a unique cohort of individuals who developed PI-IBS following exposure to contaminated drinking water 7 years ago. We provide direct evidence of ongoing sensitization of neuronal signaling in the bowel of patients with PI-IBS. These changes occur in the absence of any detectable tissue inflammation, and instead appear to be driven by pro-nociceptive changes in the gut micro-environment. This is evidenced by the activation of murine colonic afferents, and sensitization responses to capsaicin in dorsal root ganglia (DRGs) following application of supernatants generated from tissue biopsy of patients with PI-IBS. We demonstrate that neuronal signaling within the bowel of PI-IBS patients is sensitized 2 years after the initial infection has resolved. This sensitization appears to be mediated by a persistent pro-nociceptive change in the gut micro-environment, that has the capacity to stimulate visceral afferents and facilitate neuronal TRPV1 signaling.

Effect of genetic background and postinfectious stress on visceral sensitivity in Citrobacter rodentium-infected mice.

BACKGROUND: Infectious gastroenteritis is a major risk factor to develop postinfectious irritable bowel syndrome (PI-IBS). It remains unknown why only a subgroup of infected individuals develops PI-IBS. We hypothesize that immunogenetic predisposition is an important risk factor. Hence, we studied the effect of Citrobacter rodentium infection on visceral sensitivity in Th1-predominant C57BL/6 and Th2-predominant Balb/c mice. METHODS: Eight-week-old mice were gavaged with C. rodentium, followed by 1 h of water avoidance stress (WAS) at 5 weeks PI. At 10, 14 days, and 5 weeks PI, samples were assessed for histology and inflammatory gene expression by RT-qPCR. Visceral sensitivity was evaluated by visceromotor response recordings (VMR) to colorectal distension. KEY RESULTS: Citrobacter rodentium evoked a comparable colonic inflammatory response at 14 days PI characterized by increased crypt length and upregulation of Th1/Th17 cytokine mRNA levels (puncorrected  < 0.05) in both C57BL/6 and Balb/c mice. At 5 weeks PI, inflammatory gene mRNA levels returned to baseline in both strains. The VMR was maximal at 14 days PI in C57BL/6 (150 ± 47%; p = 0.02) and Balb/c mice (243 ± 52%; p = 0.03). At 3 weeks PI, the VMR remained increased in Balb/c (176 ± 23%; p = 0.02), but returned to baseline in C57BL/6 mice. At 5 weeks PI, WAS could not re-introduce visceral hypersensitivity (VHS). CONCLUSIONS & INFERENCES: Citrobacter rodentium infection induces transient VHS in C57BL/6 and Balb/c mice, which persisted 1 week longer in Balb/c mice. Although other strain-related differences may contribute, a Th2 background may represent a risk factor for prolonged PI-VHS. As PI-VHS is transient, other factors are crucial for persistent VHS development as observed in PI-IBS.