Gut inflammation promotes adverse food reactions by disrupting the microbial metabolism of food triggers

ABSTRACT Background & Aims Food-related adverse reactions are frequently reported by patients with inflammatory bowel disease (IBD), but the underlying mechanisms are poorly understood. We investigated how intestinal inflammation and the microbiota contribute to the development of adverse food reactions. Methods We sensitized mice to different foods (dairy and gluten) after intestinal inflammation (chemically- and hapten-induced models), and then re-exposure to the sensitized foods through diet enrichment. To study whether inflamed microbiota facilitates adverse food reactions, we employed gnotobiotic models and bacterial supplementation experiments. We assessed markers of intestinal inflammation and sensitization, clinical responses, RNA transcripts, and microbiota composition and function. In a translational approach, we recruited IBD patients in remission and healthy controls, recorded self-reported food intolerances and clinical responses to triggering foods, and feces for gut microbiota analyses were collected. Results Intestinal inflammation facilitates food sensitization by disrupting microbial antigen metabolism, recruiting mast cells to the colon, and promoting mucosal IgE production. In gnotobiotic models, inflammation-driven depletion of colonic bacteria involved in food digestion contributed to food sensitization. Upon re-exposure to triggering foods, sensitized mice experienced visceral pain and low-grade inflammation through mast-cell mediated mechanisms, which also worsened experimental colitis. Supplementation with depleted bacteria or treatment with mast cell stabilizers attenuated food-driven responses. In IBD patients, self-reported food intolerances were common and associated with microbial disruption and depletion of food-metabolizing bacteria. Conclusion Microbial metabolism of foods is disrupted after intestinal inflammation. This facilitates food sensitization, through colonic mast cell-mediated immune responses, which may explain the high number of adverse food reactions reported by IBD patients. WHAT YOU NEED TO KNOW Background and context Patients with inflammatory bowel disease (IBD) frequently report adverse food reactions, but the underlying mechanisms are not well understood. New findings Intestinal inflammation promotes food sensitization by depleting bacteria that degrade food triggers. IBD patients in remission with food intolerances show reduced microbial diversity and loss of bacteria involved in digesting food triggers. Limitations We used chemically- and hapten-induced mouse models in this study due to the importance of monitoring inflammation onset. Food-driven immune reactions in the mucosa of IBD patients were not performed. Clinical research relevance Impaired microbial food metabolism is linked to adverse food reactions in IBD. Microbiome-based therapies, such as probiotics capable of degrading dairy or gluten, should be considered for IBD patients with food intolerances. Basic research relevance We identified a novel mechanism in which microbial disruption caused by intestinal inflammation leads to adverse food reactions and worsened colitis in preclinical models. Restoring the microbial capacity to digest trigger foods reverses these effects. Lay Abstract Intestinal inflammation facilitates sensitization to gluten and dairy proteins by depleting microbes that digest them, contributing to the increase in adverse food reactions among IBD patients.