Brain-mediated regulation of oral tolerance

Introduction: Immune cells in the gut are exposed daily to a range of foreign antigens that are mostly innocuous (e.g. dietary antigens). Accordingly, inflammatory immune reactions towards orally consumed antigens are prevented by an active process named oral tolerance. This process requires the generation of a local immunosuppressive environment in the gut, conditioned by cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10). Although the mechanisms of oral tolerance were extensively studied, the factors that regulate the formation of a tolerogenic state in the gut (e.g. TGF-β secretion) remain unknown. Here, we introduce the involvement of the gut-brain axis in the regulation of the intestinal environment and oral tolerance establishment. Our hypothesis is based on the fact that whenever we consume food, the brain receives sensory information (e.g. taste, odor) that can predict whether it is safe or harmful (e.g. sour taste can indicate fermented food). Thus, the brain can offer valuable information required for the formation of an adequate immune response. Materials & methods: In this study, we examined whether food-related sensory information encoded by the insular cortex in the brain can affect the intestinal immune response towards ingested antigens. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that allow us to control neural activity, we were able to manipulate neurons in the insular cortex and evaluate the impact on the ensuing immune response in the gut and the development of oral tolerance. Results & discussion: We show that neurons in the mid-posterior region of the insular cortex (mpIC), an area known to integrate sensory and visceral information, respond to oral consumption of a novel antigen. Inhibition of this neural activity affects the intestinal immune response towards the antigen and attenuates oral tolerance evaluated by the delayed-type hypersensitivity model. In contrast, activation of the mpIC promoted tolerogenic conditions in the gut by increasing the proportion of TGFβ-expressing immune cells. Conclusion: Collectively, our results suggest that although oral tolerance is generated in the gut, it can be regulated centrally, specifically by the insular cortex in the brain. This offers new mechanistic insight to understand pathologies in which oral tolerance is disrupted (e.g. food allergies) and novel potential therapeutic interventions by targeting the brain.