Evaluating the Effects of Chronic Oral Exposure to the Food Additive Silicon Dioxide on Oral Tolerance Induction and Food Sensitivities in Mice

Background: The increasing prevalence of food sensitivities has been attributed to changes in gut microenvironment; however, ubiquitous environmental triggers such as inorganic nanoparticles (NPs) used as food additives have not been thoroughly investigated.

Objectives: We explored the impact of the NP-structured food-grade silicon dioxide ($fg\text{-}{\mathrm{SiO}}_2$) on intestinal immune response involved in oral tolerance (OT) induction and evaluated the consequences of oral chronic exposure to this food-additive using a mouse model of OT to ovalbumin (OVA) and on gluten immunopathology in mice expressing the celiac disease risk gene, HLA-DQ8.

Methods: Viability, proliferation, and cytokine production of mesenteric lymph node (MLN) cells were evaluated after exposure to $fg\text{-}{\mathrm{SiO}}_2$. C57BL/6J mice and a mouse model of OT to OVA were orally exposed to $fg\text{-}{\mathrm{SiO}}_2$ or vehicle for 60 d. Fecal lipocalin-2 (Lcn-2), anti-OVA IgG, cytokine production, and immune cell populations were analyzed. Nonobese diabetic (NOD) mice expressing HLA-DQ8 (NOD/DQ8), exposed to $fg\text{-}{\mathrm{SiO}}_2$ or vehicle, were immunized with gluten and immunopathology was investigated.

Results: MLN cells exposed to $fg\text{-}{\text{SiO}}_2$ presented less proliferative T cells and lower secretion of interleukin 10 (IL-10) and transforming growth factor beta ($\text{TGF-}\beta$) by T regulatory and $\text{CD}{45}^{+}$ $\text{CD}11b^{+}$ $\text{CD}{103}^{+}$ cells compared to control, two factors mediating OT. Mice given $fg\text{-}{\text{SiO}}_2$ exhibited intestinal Lcn-2 level and interferon gamma ($\text{IFN-}\gamma$) secretion, showing inflammation and less production of IL-10 and $\text{TGF-}\beta$. These effects were also observed in OVA-tolerized mice exposed to $fg\text{-}{\text{SiO}}_2$, in addition to a breakdown of OT and a lower intestinal frequency of T cells. In NOD/DQ8 mice immunized with gluten, the villus-to-crypt ratio was decreased while the $\text{CD}{3}^{+}$ intraepithelial lymphocyte counts and the Th1 inflammatory response were aggravated after $fg\text{-}{\text{SiO}}_2$ treatment.

Discussion: Our results suggest that chronic oral exposure to $fg\text{-}{\text{SiO}}_2$ blocked oral tolerance induction to OVA, and worsened gluten-induced immunopathology in NOD/DQ8 mice. The results should prompt investigation on the link between ${\text{SiO}}_2$ exposure and food sensitivities in humans. https://doi.org/10.1289/EHP12758.