{"title":"Soluble Siglec-9 Improves Intestinal Barrier Function in a Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis.","authors":"Hisanori Muto, Fumitaka Mizuno, Takashi Honda, Shinya Yokoyama, Taku Tanaka, Kenta Yamamoto, Takanori Ito, Norihiro Imai, Yoji Ishizu, Kiyoshi Sakai, Hideharu Hibi, Masatoshi Ishigami, Hiroki Kawashima","doi":"10.3390/metabo15060366","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background/Objectives:</b> Metabolic dysfunction-associated steatohepatitis (MASH), characterized by liver inflammation, fibrosis, and fat accumulation, can develop into cirrhosis and liver cancer. Despite its increasing prevalence worldwide, there are few established therapies for advanced MASH. We previously demonstrated that stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM) exerted therapeutic effects in a MASH mouse model. The gut-liver axis is thought to be associated with liver disease progression, and soluble Siglec-9 (sSiglec-9), an immunoinhibitory receptor, is a key protein in SHED-CM that induces anti-inflammatory macrophages and has intestinal epithelial protective effects. Therefore, we evaluated sSiglec-9's role in intestinal barrier protection in MASH mice. <b>Methods</b>: We evaluated sSiglec-9 effects on intestinal barrier function using in vitro Caco-2 cell monolayers injured by TNF-α and IFN-γ. For the MASH mouse model, male C57BL/6J mice were given a Western diet and high-sugar solution orally; to induce liver injury, CCl4 was intraperitoneally administered for 12 weeks. Mice were treated weekly with 10 ng/g sSiglec-9 or vehicle. Intestinal permeability was assessed by blood 4 kDa FITC-dextran concentration, and intestinal transcriptomes and liver histology were analyzed. <b>Results</b>: sSiglec-9 decreased intestinal permeability and liver inflammation in MASH mice. sSiglec-9 and SHED-CM reduced 4 kDa FITC-dextran permeability in injured Caco-2 cells, and sSiglec-9 significantly reduced intestinal permeability and modulated expression of 34 intestinal genes. The NAFLD Activity Score indicated significantly reduced inflammation following sSiglec-9 treatment. <b>Conclusions</b>: sSiglec-9 may protect intestinal barrier function by mitigating mucosal inflammation. sSiglec-9 treatment may represent a novel therapeutic approach for MASH via gut-liver axis modulation.</p>","PeriodicalId":18496,"journal":{"name":"Metabolites","volume":"15 6","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195191/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Metabolites","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/metabo15060366","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH), characterized by liver inflammation, fibrosis, and fat accumulation, can develop into cirrhosis and liver cancer. Despite its increasing prevalence worldwide, there are few established therapies for advanced MASH. We previously demonstrated that stem cells from human exfoliated deciduous teeth-conditioned media (SHED-CM) exerted therapeutic effects in a MASH mouse model. The gut-liver axis is thought to be associated with liver disease progression, and soluble Siglec-9 (sSiglec-9), an immunoinhibitory receptor, is a key protein in SHED-CM that induces anti-inflammatory macrophages and has intestinal epithelial protective effects. Therefore, we evaluated sSiglec-9's role in intestinal barrier protection in MASH mice. Methods: We evaluated sSiglec-9 effects on intestinal barrier function using in vitro Caco-2 cell monolayers injured by TNF-α and IFN-γ. For the MASH mouse model, male C57BL/6J mice were given a Western diet and high-sugar solution orally; to induce liver injury, CCl4 was intraperitoneally administered for 12 weeks. Mice were treated weekly with 10 ng/g sSiglec-9 or vehicle. Intestinal permeability was assessed by blood 4 kDa FITC-dextran concentration, and intestinal transcriptomes and liver histology were analyzed. Results: sSiglec-9 decreased intestinal permeability and liver inflammation in MASH mice. sSiglec-9 and SHED-CM reduced 4 kDa FITC-dextran permeability in injured Caco-2 cells, and sSiglec-9 significantly reduced intestinal permeability and modulated expression of 34 intestinal genes. The NAFLD Activity Score indicated significantly reduced inflammation following sSiglec-9 treatment. Conclusions: sSiglec-9 may protect intestinal barrier function by mitigating mucosal inflammation. sSiglec-9 treatment may represent a novel therapeutic approach for MASH via gut-liver axis modulation.
MetabolitesBiochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
5.70
自引率
7.30%
发文量
1070
审稿时长
17.17 days
期刊介绍:
Metabolites (ISSN 2218-1989) is an international, peer-reviewed open access journal of metabolism and metabolomics. Metabolites publishes original research articles and review articles in all molecular aspects of metabolism relevant to the fields of metabolomics, metabolic biochemistry, computational and systems biology, biotechnology and medicine, with a particular focus on the biological roles of metabolites and small molecule biomarkers. Metabolites encourages scientists to publish their experimental and theoretical results in as much detail as possible. Therefore, there is no restriction on article length. Sufficient experimental details must be provided to enable the results to be accurately reproduced. Electronic material representing additional figures, materials and methods explanation, or supporting results and evidence can be submitted with the main manuscript as supplementary material.