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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.

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.

[Purpose] While the anti-obesity effects of exercise and capsiate are well-observed individually, the effect of exercise with capsiate intake has not been system atically explored yet. Therefore, the purpose of this study is to investigate whether the anti-obesity effects of exercise training can be further enhanced by capsi ate intake. [Methods] 8-week-old male mice were divided into 3 groups (n = 8 per group): sedentary group (SED; non-trained), exercise-trained group (EXE) and exercise-trained group with 10 mg/kg of capsiate intake (EXE+CAP). All mice were offered high-fat diet and water ad libitum. The mild-intensity treadmill training was conducted 5 times a week for 8 weeks. After 8 weeks, metabolism during exercise and abdominal fat weight were measured. [Results] Body weight and the rate of total abdominal fat were significantly less in EXE+CAP than in SED but not between EXE and SED. The average of respiratory exchange rate during exercise was significantly much lower in EXE+SED (p = 0.003) compared to the differ ence between EXE and SED (p = 0.025). Likewise, the fat oxidation during exercise was significantly much higher in EXE+SED (p = 0.016) compared to the dif ference between EXE and SED (p = 0.045). Then, the carbohydrate oxidation during exercise was signifi cantly much lower in EXE+SED (p = 0.003) compared to the difference between EXE and SED (p = 0.028). [Conclusion] In conclusion, the anti-obesity functions of exercise training can be further enhanced by capsi ate intake by increasing fat oxidation during exercise. Therefore, we suggest that capsiate could be a can didate supplement which can additively ameliorate obesity when combined with exercise.