Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome.

IF 5.7 2区 医学 Q1 Medicine
Kailu Liu, Xi He, Jingyu Huang, Simin Yu, Meiting Cui, Mengya Gao, Li Liu, Yu Qian, Ying Xie, Miao Hui, Yanli Hong, Xiaowei Nie
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引用次数: 2

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells' mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients' serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman's rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.

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短链脂肪酸-丁酸通过调节mettl3介导的FOSL2的n6 -甲基腺苷修饰改善多囊卵巢综合征颗粒细胞炎症。
多囊卵巢综合征(PCOS)是一种以慢性低度炎症为特征的内分泌代谢紊乱。先前的研究表明,肠道微生物组可以影响宿主组织细胞mRNA n6 -甲基腺苷(m6A)的修饰。本研究旨在了解肠道菌群在卵巢细胞炎症中的作用,通过调节mRNA m6A修饰,特别是PCOS的炎症状态。采用16S rRNA测序分析PCOS组和对照组的肠道微生物组组成,采用质谱法检测患者血清中的短链脂肪酸。与其他组相比,肥胖PCOS组(FAT)血清中丁酸水平降低,根据Spearman秩检验,这与链球菌科增加和里氏杆菌科减少相关。此外,我们使用RNA-seq和MeRIP-seq方法确定FOSL2是潜在的METTL3靶点。细胞实验表明,丁酸的加入通过抑制m6A甲基转移酶METTL3的表达,导致FOSL2 m6A甲基化水平和mRNA表达的降低。KGN细胞NLRP3蛋白表达下调,炎症因子IL-6、TNF-α表达下调。肥胖PCOS小鼠补充丁酸可改善卵巢功能,降低卵巢局部炎症因子的表达。综上所述,肠道微生物群与多囊卵巢综合征之间的相关性可能揭示特定肠道微生物群在多囊卵巢综合征发病机制中的重要作用。此外,丁酸可能是未来多囊卵巢综合征治疗的新前景。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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