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Deficiency of SLC26A3 promotes jejunal barrier damage in metabolic disease-susceptible transgenic pigs

文献类型： 外文期刊

作者： Yu Yang;Jiakun Miao;Juan Du;Shuang Xu;Kaiyi Zhang;Tianwen Wu;Cong Tao;Yanfang Wang;Meiying Fang;Shulin Yang

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关键词： CDX2;Intestinal disorders;Jejunal barrier function;SLC26A3;TG pig

期刊名称： International Journal of Biological Macromolecules

ISSN： 0141-8130

年卷期： 2024 年 281 卷

页码：

收录情况： SCIE（2024版） ; ; EI（2024版）

摘要： Intestinal disorders are common in metabolic syndrome. However, their pathogenesis is still not fully understood. Pig and human intestines are highly similar in terms of associated metabolic processes. Here, we successfully constructed a metabolic disease-susceptible transgenic (TG) Bama pig model by knocking in three humanized disease risk genes with the CRISPR/Cas9 technique to assess its potential as a model for human intestinal diseases and explore the possible pathological mechanisms involved. We found that jejunal barrier integrity was disrupted and that the infiltration of inflammatory cells increased in TG pigs after high-fat and high-sucrose diet (HFHSD) treatment. We revealed significant differences in the transcriptome, associated microbiome profiles and microbial metabolite short-chain fatty acid (SCFA) content of the jejunum of TG pigs. Notably, we found that SLC26A3 was significantly downregulated in TG pigs. Knockdown or overexpression of the SLC26A3 gene in IPEC-J2 cells significantly affected the expression of MUC2, MUC13 and occludin. Furthermore, in vitro experiments further verified that CDX2 directly regulated the expression of SLC26A3. Mechanistically, CDX2 mediated intestinal barrier function by enhancing the expression of SLC26A3 by binding to its promoter region between −1120 and − 1070 bp. TG pigs represent a promising model that provides new insights into preclinical research on human intestinal metabolic diseases associated with metabolic disorders and revealed that SLC26A3 may be a potential therapeutic target for intestinal metabolic diseases.

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