Long-term exposure to food-grade silicon dioxide from in utero life until adulthood led to sex-specific alterations of the microbiota-gut-immunesystem axis with development of metabolic disorders

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إنجليزي. Background and Purpose: The food-grade (fg) SiO2 is used as anticaking and antifoaming agent in powdered food (e.g., sugar, salt, milk, instant soup, infantformulae), with chronic dietary exposure in Humans (0.8-74 mg/kg bw/day). This food additive is composed of aggregated nanoparticles (NPs) that crossbiological barriers, like the intestine and placenta, and accumulate in systemic organs raising public health issues. Following ingestion, SiO2-NPs could also alterthe intricate dialogue linking the intestinal microbiota to various functions under its control, including the intestinal barrier, immune functions, and hostmetabolism, with health consequences. Through a longitudinal study from in utero life to adulthood in mice, the aim of this study is to explore the consequencesof chronic oral exposure to fg-SiO2 on the microbiota-intestine-immune system axis, and on metabolic functions of the descendants.Methods: Female mice were exposed to a control or fg-SiO2-enriched diet at a human relevant level (10 mg/kg bw/day) during pregnancy and lactation untilweaning of pups, then the descendants (F1) were fed the same diet as their mother until postnatal day (PND) 150. Intestinal permeability to macromolecules (oralFITC-Dextran 4kD) was determined in vivo at PND136 while oral glucose tolerance was assessed at PND143. At PND150, intestinal and systemic production ofpro- and anti-inflammatory cytokines was measured by ELISA, and gut microbiota composition was assessed by 16S gene sequencing. All animal experimentswere approved by the Local Animal Care and Use Committee.Results: Chronic fg-SiO2 exposure starting in utero increased the intestinal permeability and the production of the pro-inflammatory cytokines TNF-α and IL-6and of the anti-inflammatory cytokine IL-10 in the colon of adult F1 males. In F1 females exposed to fg-SiO2 a decrease in TGF-β and an increase in IFN-γsecretion were observed in gut mucosa without intestinal permeability alteration. The systemic immune response following exposure to the food additive alsodiffered between the sexes, with a decreased production of TNF-α, IL-6, IFN-γ, IL-17, IL-10 and TGF-β in males, while an increase in the secretion of IL-17 andTGF-β was found in females only. Changes in gut microbiota composition occurred in fg-SiO2-exposed males only, exhibiting increased β-diversity and decreasedproportion of the Actinobacteria and of the species Akkermansia muciniphila and Bifidobacterium pseudolongum, both known to alleviate metabolic disorders.Accordingly, an increased glucose intolerance was observed in F1 males exposed to fg-SiO2, while no alteration of glucose metabolism was reported in fg-SiO2-exposed F1 females.Conclusions: These results showed that long-term exposure to fg-SiO2 from in utero life until adulthood initiate the development of metabolic disorders in a sexdependent manner via an alteration of the gut microbiota and of systemic immune response associated with gut inflammation and permeability in males only.This study provides new data relevant for risk assessment in pregnant women exposed to fg-SiO2 through their diet, and supports the establishment of toxicreference values for the safe use of SiO2 as food additive.