Zinc transporter dynamics in the pathogenesis of 2,4,6-trinitrobenzenesulfonic acid/ethanol-induced ileitis in mice

Patients with Crohn's disease (CD) often exhibit low serum zinc levels. Experimentally, colitis models induced by intrarectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) have shown exacerbated pathogenesis with zinc deficiency. Zinc, which is regulated by transporters (zip and znt), plays a crucial role in maintaining intestinal integrity. Zip transports zinc into the cytoplasm from the extracellular spaces or organelles, while znt moves it out of the cytoplasm into the extracellular space or into organelles. Although CD is an intractable gastrointestinal inflammatory condition that is developed predominantly in the terminal ileum, few studies have focused on the ileitis. Therefore, we aimed to identify zinc transporters related to ileitis using the TNBS/ethanol-induced ileitis model. Ileitis was induced in mice by ileal luminal injection of TNBS (1.5 mg/0.8 mL/mouse) in 50% ethanol. The mice were euthanized 6, 24, or 48 h after the injection for histological and physiological analyses. Serum zinc levels and the expression of zinc transporters in duodenal and ileal tissues were also evaluated. Ileal luminal injection of TNBS/ethanol significantly increased tumor necrosis factor alpha (TNF-α) and interleukin 1beta (IL-1β) mRNA expression at 24 h, then caused ileal epithelium detachment at 48 h. Serum zinc levels were significantly decreased, accompanied by reduced expression of zip4 and znt1 in the ileum, 6 and 24 h after the injection. The expression of zip4 and znt1 in the duodenum was significantly increased at 24 and 48 h, respectively, and serum zinc levels recovered to around normal levels. Furthermore, zip7 expression in the ileum significantly decreased at 24 h but recovered slightly at 48 h, coinciding with re-epithelialization. Overall, the pathogenesis of TNBS/ethanol-induced ileitis involves dynamic changes in zinc transporters.