Stool titanium dioxide is positively associated with stool alpha-1 antitrypsin and calprotectin in young healthy adults

Titanium dioxide (TiO2/E171) is used widely in foods, primarily as a food additive. Animal models have shown that chronic TiO₂ exposure may disturb homeostasis of the gastrointestinal tract by increasing gut permeability, inducing gut inflammation, and increasing the likelihood of microbial infection. Adults have a wide range of ingested TiO₂,which span two to three orders of magnitude, with a small portion of individuals consuming near gram quantities of TiO2/day. However, research on the health effects of chronic ingestion of TiO2/E171 in humans is limited. We hypothesized that regularly ingested TiO2/E171 is associated with increased gut inflammation and gut permeability in healthy adults. We tested this hypothesis in a cross-sectional design by measuring clinically established stool markers of gut inflammation (calprotectin, lactoferrin) and gut permeability (alpha-1 antitrypsin; A1AT) in 35 healthy adults, and comparing these markers between relatively high and low TiO2 exposure groups. Participants were stratified by TiO2 stool content (high dry stool TiO2 content: 0.95–9.92 μg/mg, n = 20; low content: 0.01–0.04 μg/mg; n = 15). Differences in gut health markers were tested between high and low exposure groups by independent samples t-test or Mann-Whitney U test. Multivariable linear regression was used to assess the association between TiO2 in dry stool and measured stool alpha-1 antitrypsin (A1AT). Participants in the high stool TiO2 group had greater stool A1AT (42.7 ± 21.6 mg/dL; median: 38.3; range: 1.0–49.2 mg/dL), compared to the low TiO2 group (22.8 ± 13.6 mg/dL; median: 20.9; range: 8.7–93.0 mg/dL), P = 0.003. There was also greater stool calprotectin in the high TiO₂ group (51.4 ± 48.6 μg/g; median 29.2 μg/g; range: 15.3–199.0 μg/g) than in the low group (47.5 ± 63.3 μg/g; median 18.8 μg/g; range: 1.6–198.1 μg/g), P = 0.04. No clear difference was observed for lactoferrin (high TiO2 group 1.6 ± 2.1 μg/g; median: 0.68 μg/g; range: 0.01–7.7 μg/g, low TiO2 group: 1.3 ± 2.6 μg/g; median: 0.2; range: 0.01–7.6 μg/g) (P = 0.15). A1AT concentration was positively associated with stool TiO2, after adjusting for confounders (β ± SE: 19.6 ± 7.2; P = 0.01) R² = 0.38). Community dwelling, healthy adults with the highest TiO2 stool content had higher stool A1AT and calprotectin, compared to those with the lowest TiO₂ stool content. Ongoing research is needed to validate these observations in larger groups, and to determine the long-term effects of ingested TiO₂ on human gut health, using these and additional health endpoints.