Dietary titanium dioxide particles and intestinal health : a thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Manawatu, New Zealand

Abstract

The purpose of this dissertation was to investigate the relationship between food-grade titanium dioxide particles and intestinal health, in particular the development of Crohn’s disease after uptake of titanium dioxide particles in intestinal lymphoid tissues. Crohn’s disease is a common form of inflammatory bowel disease. It is characterised by chronic inflammation of the gastrointestinal tract and affects approximately 1 in 1,000 people. The aetiology of Crohn’s disease is unclear, but both genetic and environmental factors are involved in the development of the disease. The gene that is most commonly associated with Crohn’s disease is the nucleotide-binding oligomerisation domain (NOD) 2 gene. The diet is one of the most likely environmental factors that have been proposed to play a role in Crohn’s disease. It has been hypothesised that uptake of titanium dioxide particles, which are used as a whitening agent in processed foods, toothpaste, and pharmaceuticals, by macrophages in intestinal lymphoid tissues negatively affects intestinal health and contributes to the development of Crohn’s disease. To investigate this hypothesis, immune cell-stimulating properties of titanium dioxide were first assessed in vitro with macrophages derived from wild-type mice and mice with a Crohn’s disease-like Nod2 gene variant. These mouse models were also used to determine particle uptake in intestinal lymphoid tissues in vivo after exposure to titanium dioxide with the diet and effects of this dietary exposure on intestinal health and urine metabolites. The results from the in vitro studies showed that titanium dioxide induced the release of the pro-inflammatory cytokine interleukin-1β. For the first time, it has been shown that accumulation of particles in intestinal lymphoid tissues was a consequence of titanium dioxide intake with the diet. However, this had no negative effects on growth performance and intestinal health of both wild-type mice and mice with a Crohn’s disease-like Nod2 gene variant. Nevertheless, differences in urine metabolite profiles between wild-type mice exposed to titanium dioxide and unexposed wild-type mice indicated that consumption of a titanium dioxide-containing diet affected the metabolism. This dissertation forms the foundation for future studies with animal models about the relationship between titanium dioxide and intestinal health.