Metabolomics reveals soluble epoxide hydrolase as a therapeutic target for high-sucrose diet-mediated gut barrier dysfunction.

Autor:	Lin AZ; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Fu X; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Jiang Q; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Zhou X; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Hwang SH; Department of Entomology and Nematology, University of California, Davis, CA 95616.; Comprehensive Cancer Center, University of California, Davis, CA 95616., Yin HH; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Ni KD; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Pan QJ; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., He X; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Zhang LT; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Meng YW; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Liu YN; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China., Hammock BD; Department of Entomology and Nematology, University of California, Davis, CA 95616.; Comprehensive Cancer Center, University of California, Davis, CA 95616., Liu JY; Department of Anesthesia of the Second Affiliated Hospital and CNTTI of College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing 400016, China.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Nov 26; Vol. 121 (48), pp. e2409841121. Date of Electronic Publication: 2024 Nov 18.
DOI:	10.1073/pnas.2409841121
Abstrakt:	Highsucrose diet (HSD) was reported as a causative factor for multiorgan injuries. The underlying mechanisms and therapeutic strategies remain largely uncharted. In the present study, by using a metabolomics approach, we identified the soluble epoxide hydrolase (sEH) as a therapeutic target for HSD-mediated gut barrier dysfunction. Specifically, 16-week feeding on an HSD caused gut barrier dysfunction, such as colon inflammation and tight junction impairment in a murine model. A metabolomics analysis of mouse colon tissue showed a decrease in the 5(6)-epoxyeicosatrienoic acid [5(6)-EET] level and an increase in soluble epoxide hydrolase, which is related to HSD-mediated injuries to the gut barrier. The mice treated with a chemical inhibitor of sEH and the mice with genetic intervention by intestinal-specific knockout of the sEH gene significantly attenuated HSD-caused intestinal injuries by reducing HSD-mediated colon inflammation and improving the impaired tight junction caused by an HSD. Further, in vitro studies showed that treatment with 5(6)-EET, but not its hydrolytic product 5,6-dihydroxyeicosatrienoic acid (5,6-DiHET), significantly ablated high sucrose-caused intestinal epithelial inflammation and impaired tight junction. Additionally, 5(6)-EET is anti-inflammatory and improves gut epithelial tight junction while 5,6-DiHET cannot do so. This study presents an underlying mechanism of and a therapeutic strategy for the gut barrier dysfunction caused by an HSD. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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