1271
LONG-TERM DIETARY EXPOSURE TO THE FOOD ADDITIVE TITANIUM DIOXIDE TRIGGERS AND PROMOTES INTESTINAL AND METABOLIC DISORDERS IN A SEX- AND MICROBIOTA-DEPENDENT MANNER
Date
May 21, 2024
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.
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.
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