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

ABSTRACT: 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.

SUBMITTER: Deng F

PROVIDER: S-EPMC8009132 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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The gut microbiota metabolite capsiate promotes Gpx4 expression by activating <i>TRPV1</i> to inhibit intestinal ischemia reperfusion-induced ferroptosis.

Deng Fan F Zhao Bing-Cheng BC Yang Xiao X Lin Ze-Bin ZB Sun Qi-Shun QS Wang Yi-Fan YF Yan Zheng-Zheng ZZ Liu Wei-Feng WF Li Cai C Hu Jing-Juan JJ Liu Ke-Xuan KX

Gut microbes 20210101 1

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 prote ...[more]

PMID: 33779497

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Project description:Ferroptosis is an iron-dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota- OA axis refers to the bidirectional information network between the gut microbiota and OA, which may provide a new way to protect the OA. However, the role of gut microbiota-derived metabolites in ferroptosis-relative osteoarthritis remains unclear. The objective of this study was to analyze the protective effect of gut microbiota and its metabolite capsiate (CAT) on ferroptosis-relative osteoarthritis in vivo and in vitro experiments. From June 2021 to February 2022, 78 patients were evaluated retrospectively and divided into two groups: The health group (n = 39) and the OA group (n = 40). Iron and oxidative stress indicators were determined in peripheral blood samples. And then in vivo and in vitro experiments, a surgically destabilized medial meniscus (DMM) mice model was established and treated with CAT or Ferric Inhibitor-1 (Fer-1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) was utilized to inhibit SLC2A1 expression. Serum iron was increased significantly but total iron binding capacity was decreased significantly in OA patients than healthy people (p < 0.0001). The least absolute shrinkage and selection operator clinical prediction model suggested that serum iron, total iron binding capacity, transferrin, and superoxide dismutase were all independent predictors of OA (p < 0.001). Bioinformatics results suggested that SLC2A1, Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1), and HIF-1α (Hypoxia Inducible Factor 1 Alpha)-related oxidative stress signaling pathways play an important role in iron homeostasis and OA. In addition, gut microbiota 16s RNA sequencing and untargeted metabolomics were used to find that gut microbiota metabolites CAT in mice with osteoarthritis were negatively correlated with Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration (p = 0.0017). Moreover, CAT reduced ferroptosis-dependent osteoarthritis in vivo and in vitro. However, the protective effect of CAT against ferroptosis-dependent osteoarthritis could be eliminated by silencing SLC2A1. SLC2A1 was upregulated but reduced the SLC2A1 and HIF-1α levels in the DMM group. HIF-1α, MALAT1, and apoptosis levels were increased after SLC2A1 knockout in chondrocyte cells (p = 0.0017). Finally, downregulation of SLC2A1 expression by Adeno-associated Virus (AAV) -SLC2A1 shRNA improves osteoarthritis in vivo. Our findings indicated that CAT inhibited HIF-1a expression and reduced ferroptosis-relative osteoarthritis progression by activating SLC2A1.

Project description:BackgroundMyocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy.MethodsA rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot.ResultsThe ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury.ConclusionsIncreased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation.

Dataset Information

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

Publications

The gut microbiota metabolite capsiate promotes Gpx4 expression by activating <i>TRPV1</i> to inhibit intestinal ischemia reperfusion-induced ferroptosis.

Similar Datasets

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