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ObjectiveResolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown.DesignThe effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca2+ imaging. Based on the results obtained in vitro, we further studied the effect of RvD2 in vivo using a murine model of post-infectious IBS and a rat model of post-inflammatory VHS. Finally, we also tested the effect of RvD2 on submucosal neurons in rectal biopsies of patients with IBS.ResultsRvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3–30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca2+ response of rectal submucosal neurons of patients with IBS. Finally, treatment with RvD2 normalised pain responses to colorectal distention in both preclinical models of VHS.ConclusionsOur data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS.

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal(1), 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 H-1-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. In mice, oral tolerance to food antigens can break down after enteric infection, and this leads to food-induced pain resembling irritable bowel syndrome in humans.

International audience; NeuroGUT is a EU-funded initial training network (ITN) of 14 research projects in neurogastroenterology that have employed an equal number of early-stage researchers. Neurogut trainees haveamong other activitiesattended an international conference on irritable bowel syndrome (IBS) in Bologna in 2016 and were asked to critically review and evaluate the current knowledge on IBS for their respective research activities, and to state what they were missing. Most appreciated were the topics brain imaging of gut activity, the role of the gut microbiota, the pharmacology of gut functions, the IBS-IBD interrelation, the new Rome IV criteria, the role of gas, and the placebo response in functional disorders. Missed were more detailed coverage of high-resolution manometry, functional brain imaging, advanced systems medicine approaches and bioinformatics technology, better sub-classification of IBS patients, and the development of disease biomarkers, extended at the molecular (genetic/epigenetic, proteonomic) level. They summarize that despite excellent specialized research, there is a gap open that should be filled with systems medicine. For this, it would be necessary that medical research learns even more from the data sciences and other basic disciplines, for example, information technology and system biology, and also welcomes a change in paradigm that enhances open sharing of data, information, and resources.

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

and cortisol responses to stimulation with CRH and ACTH: 1) differ between IBS patients and healthy controls (HCs), 2) are affected by sex and EALs, 3) are associated with GR mRNA expression. Methods: Male and female Rome III+ IBS patients and HCs underwent CRH (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured. GR mRNA levels were measured from peripheral blood mononuclear cells using real-time PCR. Presence of EALs