PPARγ/NF-κB axis contributes to cold-induced resolution of experimental colitis and preservation of intestinal barrier

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-10, Vol.1870 (7), p.167326, Article 167326
• Main Authors: Di, Yuzhu, Li, Hui, Yang, Jia, Feng, Minghao, Wang, Shuang, Li, Wanying, Wang, Xiuqing, Zhu, Yuxin, Shi, Yan, Feng, Rennan, Qu, Bo
• Format: Article
• Language: English
• Subjects: Animals; Cold exposure; Cold Temperature; Colitis - chemically induced; Colitis - metabolism; Colitis - pathology; Colon - metabolism; Colon - pathology; Dextran Sulfate - toxicity; Disease Models, Animal; IBD; Inflammation; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Male; Mice; Mice, Inbred C57BL; Multi-omics; NF-kappa B - metabolism; PPAR gamma - metabolism; PPARγ signaling; Signal Transduction
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167326

Environmental stress is a significant contributor to the development of inflammatory bowel disease (IBD). The involvement of temperature stimulation in the development of IBD remains uncertain. Our preliminary statistical data suggest that the prevalence of IBD is slightly lower in colder regions compared to non-cold regions. The observation indicates that temperature changes may play a key role in the occurrence and progression of IBD. Here, we hypothesized that cold stress has a protective effect on IBD. The cold exposure model for mice was placed in a constant temperature and humidity chamber, maintained at a temperature of 4 °C. Colitis models were induced in the mice using TNBS or DSS. To promote the detection methods more clinically, fluorescence confocal endoscopy was used to observe the mucosal microcirculation status of the colon in the live model. Changes in the colonic wall of the mice were detected using 9.4 T Magnetic Resonance Imaging (MRI) imaging and in vivo fluorescence imaging. Hematoxylin and eosin (H&E) and Immunofluorescence (IF) staining confirmed the pathological alterations in the colons of sacrificed mice. Molecular changes at the protein level were assessed through Western blotting and Enzyme-Linked Immunosorbent Assay (ELISA) assays. RNA sequencing (RNA-seq) and metabolomics (n = 18) were jointly analyzed to investigate the biological changes in the colon of mice treated by cold exposure. Cold exposure decreased the pathologic and disease activity index scores in a mouse model. Endomicroscopy revealed that cold exposure preserved colonic mucosal microcirculation, and 9.4 T MRI imaging revealed alleviation of intestinal wall thickness. In addition, the expression of the TLR4 and PP65 proteins was downregulated and epithelial cell junctions were strengthened after cold exposure. Intriguingly, we found that cold exposure reversed the decrease in ZO-1 and occludin protein levels in dextran sulfate sodium (DSS)- and trinitrobenzenesulfonic acid-induced colitis mouse models. Multi-omics analysis revealed the biological landscape of DSS-induced colitis under cold exposure and identified that the peroxisome proliferator-activated receptor (PPAR) signaling pathway mediates the effects of cold on colitis. Subsequent administration of rosiglitazone (PPAR agonist) enhanced the protective effect of cold exposure on colitis, whereas GW9662 (PPAR antagonist) administration mitigated these protective effects. Overall, cold exposure ameliorated t