Soluble Siglec-9 Improves Intestinal Barrier Function in a Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis.

IF 3.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Metabolites Pub Date : 2025-05-30 DOI:10.3390/metabo15060366
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
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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.

可溶性siglece -9在代谢功能障碍相关脂肪性肝炎小鼠模型中改善肠道屏障功能
背景/目的:代谢功能障碍相关脂肪性肝炎(MASH)以肝脏炎症、纤维化和脂肪堆积为特征,可发展为肝硬化和肝癌。尽管其在世界范围内的发病率越来越高,但对于晚期MASH的治疗方法却很少。我们之前证明了来自人类脱落乳牙条件培养基(shedcm)的干细胞在MASH小鼠模型中发挥治疗作用。肠-肝轴被认为与肝脏疾病进展有关,可溶性Siglec-9 (Siglec-9)是一种免疫抑制受体,是SHED-CM中的关键蛋白,可诱导抗炎巨噬细胞并具有肠上皮保护作用。因此,我们评估了siglece -9在MASH小鼠肠道屏障保护中的作用。方法:利用体外经TNF-α和IFN-γ损伤的Caco-2细胞单层,评价siglec -9对肠屏障功能的影响。在MASH小鼠模型中,雄性C57BL/6J小鼠口服西式饮食和高糖溶液;腹腔注射CCl4诱导肝损伤12周。小鼠每周用10 ng/g siglec -9或对照剂治疗。采用血液4 kDa fitc -葡聚糖浓度评估肠道通透性,分析肠道转录组和肝脏组织学。结果:siglece -9可降低小鼠肠道通透性和肝脏炎症。ssiglece -9和shedc - cm降低了Caco-2损伤细胞4kda fitc -葡聚糖的通透性,ssiglece -9显著降低了肠道通透性并调节了34个肠道基因的表达。NAFLD活性评分显示siglece -9治疗后炎症明显减轻。结论:siglece -9可能通过减轻黏膜炎症来保护肠道屏障功能。siglece -9治疗可能是一种通过肠肝轴调节治疗MASH的新方法。
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来源期刊
Metabolites
Metabolites Biochemistry, 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.
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