*2.5.4. Biodistribution of TiO2*

Studies reported to date were mainly focused on the antibacterial activity of TiO2 nanoparticles in *in vitro* pure cultures using *Escherichia coli* as the bacterial representative [44–46]. Such an activ-

[50, 51]. Taylor et al. [47] investigated the *in vitro* exposure of a gut microbial community from a

colon. Such exposure-induced changes in the phenotypic traits of the gut community, including short-chain fatty acid production (particularly for butyric acid), cell hydrophobicity, sugar content of extracellular polymers, cell size and electrophoretic mobility. In a further study,

composition and phenotype of a human gut microbiota. An inhibition of the control-induced shift in microbial composition from Proteobacteria to Firmicutes phyla was observed. TiO<sup>2</sup> exposure also resulted in a lower value of the colonic pH (∼pH 4) as compared to the control (>5). Additionally, similar trends in microbial community hydrophobicity and electrophoretic mobility were obtained between control and food-grade exposures. Interestingly, different microbial responses were observed with the industrial-grade form, underlying the significance

Mucus is the viscoelastic gel that lines and protects the intestinal epithelium. It is secreted continuously along the whole intestine by specialized goblet cells in the epithelium (**Figure 4**), and is present in larger amounts in the colon than elsewhere. Mucus was long considered to act as a 'simple' physical barrier, but it is now known to have other key functions essential for the preservation of intestinal homeostasis [49–51], including (i) lubrication of the epithelium, facilitating the progress of material along the digestive tract, (ii) maintenance of a stable microenvironment at the epithelial surface, (iii) protection of the epithelium through the presence of immune sys-

depending on whether epithelial cells are cultured alone or in the presence of mucus-secreting goblet cells. In fact, Caco-2 cells in monoculture only displayed low levels of intracellular nano-

philicity/hydrophobicity, were able to permeate mucus and penetrate underlying tissues.

Epithelium is in charge of nutrients and water absorption while restricting the access for potentially noxious substances to the internal organs. Thus, it constitutes a selective—and dynamic—barrier, mediating transport of compounds through the transcellular pathway (i.e., across the cells) and/or the paracellular pathway (i.e., between the cells). It is polarized into an apical and basolateral surface with the apical surface covered with microvilli to increase

 accumulation after 24-h exposure, whereas the same treatment in Caco-2/HT29-MTX mucus-producing co-culture led to 50 times higher levels of accumulation [52]. In ex vivo stud-

tem molecules and (iv) provision of an ecological niche for the intestinal microbiota.

in intestinal homeostasis.

and intestinal mucus are far from being understood. Variable

nanoparticles have been described *in vitro* [52],

nanoparticles, regardless of their size and hydro-

healthy donor to three different types of metal oxide nanoparticles, including TiO<sup>2</sup>

, although increasing experi-

, in a model

) on the


(vs industrial-grade TiO2

ity is generally associated with the photocatalytic effects of TiO<sup>2</sup>

Waller et al. [48] evaluated the impact of food-grade TiO2

 *in interaction with the intestinal mucus*

mental evidence also demonstrated TiO2

14 Application of Titanium Dioxide

of physical and chemical properties of TiO2

capacities for absorption and transport of TiO2

ies on porcine buccal mucosa [36, 38], TiO2

 *in interaction with the intestinal epithelium*

*2.5.2. TiO2*

TiO2

*2.5.3. TiO2*

Interactions between TiO<sup>2</sup>

When TiO2 particles overcome the mucus/microbiota/epithelium-protective triad, they may enter systemic circulation [64, 65] but in an extremely limited amount [36] and infiltrate organs like liver and kidney which are the organs for exogenous chemicals metabolism and for the excretion of metabolic wastes, respectively. But they were also found in lung, spleen and brain [66, 67] and presented a poor clearance [67]. With a half-life of 12.7 days [66], TiO2 particles may be thus regularly renewed in the organism, suggesting a bioaccumulation [23] but there is an absence of toxicological effects in the conditions of the study [66]. In the terminal ileum of children suspected of having inflammatory bowel disease, the amount of pigment in Peyer's patches became denser with increasing age [68].
