Background and Aim: Ingestion of food additives in ultra-processed food is viewed as possible co-factor contributing to metabolic disorders associated to Western diet (WD). Among them, the whitener and opacifying agent titanium dioxide (TiO₂) raises public health issues due to maternofetal passage and systemic accumulation through life. Immunotoxic and biocidal properties of TiO₂ could impact the microbiota-gut-immune system axis that play a key role in metabolic functions. Our aim is to evaluate in mice the impact of long-term dietary exposure to food-grade (fg) TiO₂ on intestinal and metabolic homeostasis, and to determine its microbiota-dependent effects, while assessing the relevance of these findings in a cohort of obese children.
Methods: Female mice were fed a control or fgTiO₂-enriched diet (10 mg/kg bw/d) during pregnancy and lactation. Until postnatal day 150, part of the F1 descendants were fed the same diet as their mother, while another group received a WD with or without fg-TiO₂. Gut inflammation and permeability as well as microbiota composition and fecal LPS and aryl hydrocarbon receptor ligand (AhR-L) levels were assessed. Metabolic status was evaluated using oral glucose tolerance test and fasting insulin. The role of microbiota in fgTiO₂-induced metabolic disorders was assessed using fecal microbiota transplantation (FMT). Twenty six obese and 34 normal weight children (age 7-12) were recruited and Ti, flagellin and AhR-L levels were determined in stools.
Results: Male F1 mice exposed to fgTiO₂ under normal diet (ND) compared to non-exposed controls exhibited higher intestinal IL1β production, together with a gut dysbiosis characterized by an increased β-diversity and Firmicutes/Bacteroidetes ratio, as well as a decreased AhR-L production by the microbiota, and increased fecal LPS levels. In this group of mice, a glucose intolerance and increased fasting insulin levels were also observed while the fgTiO₂-treatment exacerbated WD-induced gut permeability and inflammation as well as dysbiosis and glucose intolerance. The FMT showed that the fgTiO₂-induced metabolic disorders in F1 males fed ND were microbiota-dependent. In contrast, fgTiO₂ exposure in F1 female mice under ND reduced gut production of pro- and anti-inflammatory cytokines while under WD, intestinal and metabolic alterations were not aggravated by fgTiO₂ treatment. Higher fecal Ti and flagellin levels as well as lower microbiota production of AhR-L were observed in obese compared to normal weight children.
Conclusions: These data in mice show that fgTiO₂ exposure from in utero life until adulthood initiates and promotes the development of intestinal and metabolic disorders in a sex-dependent manner via a gut dysbiosis. Our data also suggest that the dysmetabolic status of obese children may partly relate to gut dysbiosis exacerbated by chronic fgTiO₂ dietary exposure.

Benoit Chassaing

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