Understanding the immune drivers of food-induced abdominal pain

Abstract

Nature reviews | GastroenteroloGy & H e p a t o l o G y A new paper published in Nature explores the underlying mechanisms and links between infection, irritable bowel syndrome (IBS) symptoms and food intake. The research reveals that bacterial gastrointestinal infection can trigger a break in oral tolerance and localized immune responses that react to food antigens, leading to mealinduced abdominal pain. IBS can develop after gastrointestinal infection, and individuals with IBS often report symptoms (including abdominal pain) after food ingestion. Previous work had linked histamine release as a result of mast cell activation to hyperresponsiveness to TRP agonists and increased pain res ponses in patients with IBS. “We reasoned that during an infection, tolerance to food antigens could be broken by the infection, leading to activation of an immune response towards food antigens,” says author Guy Boeckxstaens. “This would generate food antigenspecific antibodies that then sensitize mast cells, which degranulate upon ingestion of the respective food antigen, explaining the link between an infection, IBS and food intake.” To explore their hypothesis, Boeckxstaens and colleagues used a model of mice infected with Citrobacter rodentium and then exposed to a food antigen (ovalbumin). After clearance of the infection, repeated exposure to ovalbumin resulted in diarrhoea and gut pain in the mice. This bacterial infection led to a local immune response that was limited to the intestine in the mice, with the production of dietary antigenspecific IgE antibodies. Moreover, reexposure to ovalbumin after infection induced increased visceral hypersensitivity (increased pain responses to colorectal distension). This visceral hypersensitivity was associated with increased mucosal permeability and was dependent on IgE production and mast cell activation (increased mast cell degranulation and histamine release). Notably, the development of increased dietaryantigenspecific visceral hypersensitivity was prevented in mice lacking IgE or those treated with antiIgE antibody, and in mice lacking mast cells or treated with a mast cell stabilizer. Interestingly, the researchers found that this increase in visceral pain signalling in their mouse model was mediated by the histamine receptor H1 and involved sensitization of visceral afferents (including sensitization of TRPV1 in sensory neurons). Finally, the investigators injected food antigens (solutions of soy, wheat, gluten and milk) directly into the rectosigmoid mucosa of 12 patients with IBS and 8 healthy individuals as controls. Importantly, none of the study participants were allergic to these antigens (as confirmed by allergy testing, including skin prick testing and checking IgE antibodies in serum). All 12 patients with IBS had mucosal reactions to at least one of the food antigens tested, compared with only two of the healthy individuals. Moreover, food antigens induced local mucosal oedema and mast cell activation in patients with IBS. Although there was no difference in total number of mast cells or IgE+ mast cells between patients with IBS and healthy individuals, those with IBS had more IgE+ mast cells in close proximity to nerve fibres. The distance between IgE+ mast cells and nerve fibres was smaller in those with IBS than in healthy individuals, and was inversely correlated with severity of abdominal pain. Further basic and clinical research are planned as the study findings provide potential new possibilities for the treatment of IBS and related abdominal pain disorders. “We previously demonstrated in a small clinical study that histamine receptor H1 blockade reduces symptoms,” notes Boeckxstaens, “we are currently performing a larger trial to confirm this”. “In addition, we are further unravelling the immune mechanisms involved and looking at the impact of stress.”