The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis

• Published in: Gut microbes 2021-01, Vol.13 (1), p.1-21
• Main Authors: Deng, Fan, Zhao, Bing-Cheng, Yang, Xiao, Lin, Ze-Bin, Sun, Qi-Shun, Wang, Yi-Fan, Yan, Zheng-Zheng, Liu, Wei-Feng, Li, Cai, Hu, Jing-Juan, Liu, Ke-Xuan
• Format: Article
• Language: English
• Subjects: Aminopyridines - pharmacology; Animals; Capsaicin - analogs & derivatives; Capsaicin - metabolism; capsiate; Carbolines - pharmacology; Cecum - microbiology; Disease Models, Animal; DNA, Bacterial; Feces - chemistry; Ferroptosis; Gastrointestinal Microbiome; Gene Expression Regulation; Gpx4; Host Microbial Interactions; Humans; Intestinal ischemia/reperfusion injury; Male; metabolites; Mice; Mice, Inbred C57BL; Phospholipid Hydroperoxide Glutathione Peroxidase - antagonists & inhibitors; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Piperazines - pharmacology; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Research Paper; RNA, Ribosomal, 16S; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism; TRPV1
• ISSN: 1949-0976; 1949-0984
• DOI: 10.1080/19490976.2021.1902719

Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury. However, little is known about the changes of gut microbiota and metabolites in intestinal I/R and the role of gut microbiota metabolites on ferroptosis-induced intestinal I/R injury. This study aimed to establish a mouse intestinal I/R model and ileum organoid hypoxia/reoxygenation (H/R) model to explore the changes of the gut microbiota and metabolites during intestinal I/R and protective ability of capsiate (CAT) against ferroptosis-dependent intestinal I/R injury. Intestinal I/R induced disturbance of gut microbiota and significant changes in metabolites. We found that CAT is a metabolite of the gut microbiota and that CAT levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with intestinal I/R injury. Furthermore, CAT reduced ferroptosis-dependent intestinal I/R injury in vivo and in vitro. However, the protective effects of CAT against ferroptosis-dependent intestinal I/R injury were abolished by RSL3, an inhibitor of glutathione peroxidase 4 (Gpx4), which is a negative regulator of ferroptosis. We also found that the ability of CAT to promote Gpx4 expression and inhibit ferroptosis-dependent intestinal I/R injury was abrogated by JNJ-17203212, an antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). This study suggests that the gut microbiota metabolite CAT enhances Gpx4 expression and inhibits ferroptosis by activating TRPV1 in intestinal I/R injury, providing a potential avenue for the management of intestinal I/R injury.