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.