Objective: Up to 44% of particulates of food-grade titanium dioxide (TiO₂) are in nanoscale, while the effect and combined effect of which with other substances on intestinal barrier haven’t been fully understood yet. This study is aimed to study the effect of two kinds of TiO₂ nanoparticles (TiO₂ NPs and TiO₂ MPs) on intestinal barrier functions, to reveal the combined effect of TiO₂ NPs and Lipopolysaccharide (LPS) on intestinal barrier. Methods: Male ICR mice were randomly divided into 18 groups (3 feed types * 3 exposure length * 2 LPS dosage) and were fed with normal or TiO₂-mixed feed (containing 1% (mass fraction, w/w) TiO₂ NPs or TiO₂ MPs) for 1, 3, 6 months, followed by a single oral administration of 0 or 10 mg/(kg body weight) LPS. Four hours later, the transportation of TiO₂, the intestinal barrier functions and the inflammatory response were evaluated. Results: Both TiO₂ notably increased the intestinal villi height / crypt depth ratios after 1 and 3 months of exposure, and increased the expression of ileal tight junction proteins (ZO-1 and occludin) after 1 month of exposure. After 6 months of exposure, TiO₂ NPs led to reduced feed consumption, TiO₂ MPs caused spare microvilli in small intestine and elevated Ti content in the blood cells. The intestinal permeability didn’t change in both TiO₂ exposed groups. After LPS administration, we observed altered intestinal villi height / crypt depth ratios, lowered intestinal permeability (DAO) and upregulated expression of ileal ZO-1 in both (TiO₂ +LPS) exposed groups. There are no significant changes of ileal or serum cytokines except for a higher serum TNF-α level in LPS treated group. The antagonistic effect was found between TiO₂ NPs and LPS, but there are complicated interactions between TiO₂ MPs and LPS. Conclusion: Long-term intake of food additive TiO₂ could alter the intestinal epithelial structure without influencing intestinal barrier function. Co-exposure of TiO₂ and LPS would enhance intestinal barrier function without causing notable inflammatory responses, and there is antagonistic effect between TiO₂ NPs and LPS. All the minor effects observed might associate with the gentle exposure method where TiO₂ being ingested with feed.

Background: Titanium dioxide (TiO₂), no matter in nanoscale or micron sizes, has been widely used in food industry as additives for decades. Given the potential impact of TiO₂ on the gastrointestinal epithelial and parenchymal cells, including goblet cells, the public consumers may suffer the risk of diseases caused by its widespread dissemination in food products. We therefore set out to investigate the impact of TiO₂ NPs on the course and prognosis of ulcerative colitis by oral gavaging TiO₂ NPs at the doses levels of 0, 30, 100, and 300 mg/kg during the induction (7 days, from day 1 to day 7) and recovery (10 days, from day 8 to day 17) phases of colitis in mice. Results: The ulcerative colitis (UC) disease model was established by administrating of 2.5% dextran sulfate sodium (DSS) solution. Our results show that TiO₂ NPs significantly enhanced the severity of DSS-induced colitis, decreased the body weight, increased the disease activity index (DAI) and colonic mucosa damage index (CMDI) scores, shortened the colonic length, increased the inflammatory infiltration in the colon. The most significant changes occurred in the low dose (30 mg/kg) group of TiO₂ NPs exposure during the development phase of UC and the high dose (300 mg/kg) group of TiO₂ NPs during UC self-healing phase. Increased reactive oxygen species (ROS) level and upregulation of anti-oxidant enzymes including total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-PX) and catalase (CAT), demonstrate that the TiO₂ NP exposure has triggered oxidative stress in mice. Moreover, the upregulation of caspase-1 mRNA and increased expression of thioredoxin interacting protein (TXNIP) further demonstrate the involvement of the ROS-TXNIP-NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in aggravating the development of UC. Conclusion: Oral intake of TiO₂ NPs could affect the course of acute colitis in exacerbating the development of UC, prolonging the UC course and inhibiting UC recovery. Graphical