Supporting immunotherapy efficacy using novel nutrition-based approaches to treat food allergy: "Teaming up with the enemy"

Abstract

Food allergies impact the quality of life of both patients and their families and cause limitations in dietary and social habits. Moreover, food allergies can lead to life-threatening situations in case of food-induced systemic anaphylaxis. The world-wide prevalence of IgE-mediated food allergies has been estimated to be 4% in children and 1-3% in the adult population. To date, no curative treatments exist and food allergy management relies primarily on avoidance of the offending food(s). Novel therapeutic strategies aiming for induction of specific oral tolerance to food proteins are under study. In particular, oral immunotherapy (OIT) has shown promising results in relation to effective desensitization and sustained unresponsiveness after discontinuation of the treatment. Nevertheless, safety concerns and a lack of (long-term) efficacy have hampered translation to the clinic thus far. Non-digestible oligosaccharides (prebiotics) are fermented into bacterial metabolites, e.g. short-chain fatty acids (SCFA), by bacteria residing in the gut. SCFA can exert anti-inflammatory functions, both locally and at distinct sites in the body after uptake in the systemic circulation. SCFA can directly communicate with immune cells and intestinal epithelial cells via specific surface-bound receptors. In addition to stimulation of the growth of beneficial microbes, non-digestible oligosaccharides were shown to induce tolerance-associated immune cells and support homeostasis in the gut. In this PhD thesis, it was investigated whether a diet supplemented with non-digestible oligosaccharides can support the efficacy of OIT to treat cow’s milk allergy in a murine model. The data indicated that the combination of OIT and a non-digestible oligosaccharide supplemented diet effectively reduced acute allergic symptoms upon allergen challenge in cow’s milk allergic mice. The Th2-dominated allergic immune response was suppressed and Th1 and regulatory T cell responses were increased. Lower levels of allergen-specific IgE were detected in mice after the combination therapy and mast cell and basophil responses toward the allergen were decreased. Moreover, bone marrow-derived mast cell development was altered after in vivo exposure to non-digestible oligosaccharides. In addition to immunological parameters, higher levels of the SCFA butyrate were detected in mice treated with the combination therapy. Oral supplementation with butyrate during OIT was as effective as supplementation with non-digestible oligosaccharides in terms of desensitization. Specific alterations in bacterial species were observed in cow’s milk allergic mice treated with the combination of OIT and the prebiotic diet. Interestingly, higher levels of the dysbiosis-associated bacterial phylum Proteobacteria were observed in mice only treated with OIT. It was therefore hypothesized that providing the diet supplemented with non-digestible oligosaccharides during OIT improves bacterial composition and metabolism, leading to improved immune function and control of allergies. In conclusion, the research conducted in this PhD thesis supports the use of food components with immunomodulatory capacities to improve the efficacy of immunotherapy strategies. Future (pre-clinical) studies are needed to investigate the potential of non-digestible oligosaccharide supplementation to enhance safety of immunotherapy and to retain long-term allergy protection.