Long‐term exposure from perinatal life to food‐grade TiO2 alters intestinal homeostasis and predisposes to food allergy in young mice

Background Food allergy (FA) is an inappropriate immunological response to food proteins resulting from an impaired induction of oral tolerance. Various early environmental factors can affect the establishment of intestinal homeostasis, predisposing to FA in early life. In this context, we aimed to assess the effect of chronic perinatal exposure to food‐grade titanium dioxide (fg‐TiO2), a common food additive. Methods Dams were fed a control versus fg‐TiO2‐enriched diet from preconception to weaning, and their progeny received the same diet at weaning. A comprehensive analysis of baseline intestinal and systemic homeostasis was performed in offspring 1 week after weaning by assessing gut barrier maturation and microbiota composition, and local and systemic immune system and metabolome. The effect of fg‐TiO2 on the susceptibility of progeny to develop oral tolerance versus FA to cow's milk proteins (CMP) was performed starting at the same baseline time‐point, using established models. Sensitization to CMP was investigated by measuring β‐lactoglobulin and casein‐specific IgG1 and IgE antibodies, and elicitation of the allergic reaction by measuring mouse mast cell protease (mMCP1) in plasma collected after an oral food challenge. Results Perinatal exposure to fg‐TiO2 at realistic human doses led to an increased propensity to develop FA and an impaired induction of oral tolerance only in young males, which could be related to global baseline alterations in intestinal barrier, gut microbiota composition, local and systemic immunity, and metabolism. Conclusions Long‐term perinatal exposure to fg‐TiO2 alters intestinal homeostasis establishment and predisposes to food allergy, with a clear gender effect. This study investigates the effect of chronic perinatal exposure to food‐grade titanium dioxide (fg‐TiO 2), a common food additive. Chronic perinatal exposure to food‐grade TiO2 (E171) at realistic human doses led to an increased propensity to develop food allergy and an altered induction of oral tolerance in male progeny. Chronic perinatal exposure to E171 alters the establishment of the different components of intestinal homeostasis in early life in male progeny, that is, epithelial barrier function, immune system maturation, and microbiota composition, associated with the alteration of systemic immunity and metabolism.Abbreviations: Actb, actin beta; Actc1, actin alpha cardiac muscle 1; Actn2, actin alpha 2; cDC, conventional dendritic cells; Ctnna1, catenin