Activating Transcription Factor 6 Is a Therapeutic Target for Colitis Induced By Citrobacter rodentium Infection in Mice

Background: Inflammatory bowel disease (IBD)is a chronic gastrointestinal disorder characterized by over-activated immune responses of the enterocytes and impairment of the intestinal barrier function. However, nutritional strategies to ameliorate IBD-related colitis are not available. Methods: Female C57BL/6 mice were orally administered with glycine (3.5 or 5.2 mg/g BW) for 14 continuous days. On day 8 post glycine supplementation, mice were orally inoculated with 2 × 109 CFU Citrobacter rodentium (C. rodentium)to induce colitis or equal volume of vehicle. Findings: Glycine supplementation alleviated C. rodentium infection-induced body weight loss, disease activity index, colon length shortness, transmissible murine colonic hyperplasia, apoptosis, immune cell infiltration, and secretion of cytokines in the colon tissues of mice. This beneficial effect was associated with inactivation of activating transcription factor 6α (ATF6α)/CHOP (C/EBP homologous protein) signaling in the endoplasmic reticulum (ER), increased intestinal microbial diversity, and increased abundance of Lactobacillus johnsonii (L. johnsonii) in the colon. Interestingly, all these beneficial effects of glycine were phenocopied by orally administration of L. johnsonii in our animal model, indicating a critical role of glycine-modulated L. johnsonii in protecting mice from C. rodentium infection-induced colitis. Interpretation: All these data indicated that glycine supplementation might be a nutritional strategy to ameliorate C. rodentium -induced colitis by regulating Lactobacillus in mice. Funding: This work was supported by the National Natural Science Foundation of China (No. 31572412, 31572410, 31625025, 31272450, and 31272451). Declaration of Interests: The authors report no conflict of interest. Ethics Approval Statement: All experiments were approved by the Animal Care and Use Committee of China Agricultural University, and conformed to the Guide for the Care and Use of Laboratory Animals.