copi普雷沃菌产生的5-氨基戊酸促进儿童代谢功能障碍相关的脂肪变性肝病。

IF 4.4 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY
Qing-Yang Xu , Tian-Yi Ren , Yong-Chang Zhou , Juan Xu , Lan-Duoduo Du , Dong-Yang Hong , Qian-Ren Zhang , Hui-Kuan Chu , Zhong Peng , Jian-Gao Fan , Lu Jiang
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引用次数: 0

摘要

背景:最近的研究表明,copri普雷沃菌的扩张与代谢功能障碍相关脂肪变性肝病(MASLD)儿童的疾病严重程度之间存在关联。我们旨在探讨copri在儿童MASLD中的致病作用和分子机制。方法:3周龄C57BL/ 6j小鼠饲喂高脂饲料(HFD),并口服copri 5周。我们评估了MASLD的主要特征和肠道微生物群概况。通过对小鼠粪便样本和copri培养的上清进行非靶向代谢组学分析,我们鉴定了copri衍生的代谢物并测试了其在体外的作用。结果:在饲喂hfd的小鼠中,copri可显著促进肝脏脂肪变性。与HFD组相比,HFD + copri组肝脏中与炎症和纤维化相关的基因显著上调。此外,copri降低了肠道微生物多样性,增加了厚壁菌门的比例,减少了拟杆菌门的比例。重要的是,5-氨基戊酸(5-AVA)在HFD + copri组小鼠粪便和copri培养上清液中均显著富集。在体外,5-AVA加重了棕榈酸诱导的HepG2细胞和小鼠原代肝细胞的脂质积累。从机制上讲,p.c copi产生的5-AVA通过促进脂肪生成和脂肪酸摄取而加剧了肝脏脂肪变性,同时也减少了肝脏极低密度脂蛋白的输出。结论:我们的研究结果表明,copri通过其代谢物5-AVA促进hfd喂养的幼年小鼠的肝脏脂肪变性,这表明它有可能成为治疗小儿MASLD的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Prevotella copri-produced 5-aminopentanoic acid promotes pediatric metabolic dysfunction-associated steatotic liver disease

Background

Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the causative role and molecular mechanisms of P. copri in pediatric MASLD.

Methods

C57BL/6 J mice aged 3 weeks were fed a high-fat diet (HFD) and orally administered with P. copri for 5 weeks. We assessed the key features of MASLD and the gut microbiota profile. By untargeted metabolomics on mouse fecal samples and the supernatant from P. copri culture, we identified P. copri-derived metabolite and tested its effects in vitro.

Results

In HFD-fed mice, administration of P. copri significantly promoted liver steatosis. Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD + P. copri group compared with those in the livers from the HFD group. In addition, P. copri reduced gut microbial diversity, increased the proportion of Firmicutes and decreased Bacteroidota. Importantly, 5-aminopentanoic acid (5-AVA) was significantly enriched in both mouse feces from the HFD + P. copri group and the culture supernatant of P. copri. In vitro, 5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes. Mechanistically, P. copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake, while also reducing hepatic very-low-density lipoprotein export.

Conclusions

Our findings demonstrated that P. copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA, suggesting its potential as a therapeutic target for the management of pediatric MASLD.
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来源期刊
CiteScore
5.40
自引率
6.10%
发文量
152
审稿时长
3.0 months
期刊介绍: Hepatobiliary & Pancreatic Diseases International (HBPD INT) (ISSN 1499-3872 / CN 33-1391/R) a bimonthly journal published by First Affiliated Hospital, Zhejiang University School of Medicine, China. It publishes peer-reviewed original papers, reviews and editorials concerned with clinical practice and research in the fields of hepatobiliary and pancreatic diseases. Papers cover the medical, surgical, radiological, pathological, biochemical, physiological and historical aspects of the subject areas under the headings Liver, Biliary, Pancreas, Transplantation, Research, Special Reports, Editorials, Review Articles, Brief Communications, Clinical Summary, Clinical Images and Case Reports. It also deals with the basic sciences and experimental work. The journal is abstracted and indexed in SCI-E, IM/MEDLINE, EMBASE/EM, CA, Scopus, ScienceDirect, etc.
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