Della Gatta, Giusy (2021) "Diet, Microbiota and Epigenetics as target for innovative strategies against Food Allergy". [Tesi di dottorato]

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Food allergy (FA) is a growing health problem worldwide. Effective strategies are advocated to limit the disease burden. Human milk (HM) could be considered as a protective factor against FA, but its mechanisms remain unclear. Butyrate is a gut microbiota-derived metabolite able to exert several immunomodulatory functions. We aimed to define the butyrate concentration in HM and to see whether the butyrate concentration detected in HM is able to modulate the mechanisms of immune tolerance. HM butyrate concentration from 109 healthy women was assessed by GS-MS. The effect of HM butyrate on tolerogenic mechanisms was assessed in vivo and in vitro models. The median butyrate concentration in mature HM was 0.75 mM. This butyrate concentration was responsible for the maximum modulatory effects observed in all experimental models evaluated in this study. Data from mouse model show that in basal condition, butyrate up-regulated the expression of several biomarkers of gut barrier integrity, and of tolerogenic cytokines. Pretreatment with butyrate significantly reduced allergic response in three animal models of FA, with stimulation of tolerogenic cytokines, inhibition of Th2 cytokines production, and modulation of oxidative stress. Data from human cell models show that butyrate stimulated human beta defensin-3, mucus components, and tight junctions expression in human enterocytes, and IL-10, IFN-γ, and FoxP3 expression through epigenetic mechanisms in PBMCs from FA children. Furthermore, it promoted the precursors of M2 macrophages, DCs, and regulatory T cells. The study's findings suggest the importance of butyrate as a pivotal HM compound able to protect against FA. Increasing evidence indicated potential links between alterations of the gut microbiome (GM) and the development of allergy. Therefore, understanding the functional potential of GM is of primary importance for the design of innovative strategies for allergy treatment and prevention. With this aim, the MATFA project was designed to explore the influence of gut microbiome (GM) in pediatric allergy, we comparatively evaluated the GM of 90 children affected by immunoglobulin(Ig)-E mediated food (FA) or respiratory (RA) allergies and 30 age-matched healthy controls (CT). We identified specific microbial signatures in the GM of allergic children, such as a higher abundance of Ruminococcus gnavus and Faecalibacterium prausnitzii, and depletion of Bifidobacterium longum, Bacteroides dorei, B.vulgatus, and some fiber-degrading taxa. The metagenome of allergic children showed a pro-inflammatory potential, with an enrichment of genes involved in the production of bacterial lipo-polysaccharides and urease. On the contrary, genes related to complex fiber degradation were depleted, leading to a lower fecal concentration of beneficial short-chain fatty acids. We showed that specific GM signatures at baseline can be predictable of immune tolerance acquisition in FA children. Finally, we identified a strain-level selection occurring in the GM of allergic subjects. R.gnavus strains enriched in CT showed a higher ability to metabolize fibers, whereas R.gnavus strains observed in allergic children showed a higher ability to produce pro-inflammatory polysaccharides. We demonstrated that a GM dysbiosis occurs in allergic children, with selected R.gnavus strains emerging as main players in pediatric allergy. These findings support the pivotal role of the GM in the pathogenesis of allergic diseases and may open new preventive and therapeutic strategies for these conditions.

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