O-014 Unraveling the interplay of gut microbiota, metabolic alterations, and endometrial senescence in polycystic ovary syndrome and its implications for adverse pregnancy outcomes

IF 6 1区 医学 Q1 OBSTETRICS & GYNECOLOGY
M Jing, A Liu
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引用次数: 0

Abstract

Study question What gut microbiota and metabolic alterations are associated with Polycystic ovary syndrome (PCOS) and linked to adverse pregnancy outcomes (APOs)? Summary answer In PCOS, P. merdae decreases, BCAAs increase, raising the risk of APOs. Meanwhile, endometrial senescence and decidualization impairment are found, worsening with higher Ile concentration. What is known already PCOS, a prevalent and complex endocrine disorder, stands as the primary cause of anovulatory infertility. The rising prevalence of PCOS in China over the past decade has led to a substantial increase in disease burden. Our previous ten-year retrospective analysis revealed that PCOS patients undergoing their first fresh embryo transfer faced a heightened risk of APOs, such as miscarriage. However, the factors influencing disease progression and future obstetric outcomes in PCOS remain elusive. Study design, size, duration This prospective cohort study encompassed a diverse cohort of 220 women (110 with PCOS and 110 controls) from 44 cities across China, with a median follow-up duration of 16.6 months. Participants/materials, setting, methods Women aged < 35 years with PCOS (Rotterdam criteria) and age-/BMI-matched controls were recruited. Fecal microbiomes were analyzed using 16S rRNA sequencing and metagenomics, while serum metabolites were assessed through both untargeted and targeted metabolomics. Endometrial stromal cell senescence was evaluated based on a constellation of markers, including cell proliferation, senescence-associated secretory phenotype factors, cell cycle, ROS levels, and SA-β-Gal activity. Endometrial decidualization was gauged by measuring prolactin and IGFBP-1 levels using ELISA. Main results and the role of chance Our study revealed significant gut microbiota alterations, including reduced α-diversity and a notable decline in Parabacteroides merdae (P. merdae), a key species differentiating PCOS from controls. Serum metabolomics identified 45 differential metabolites, with branched-chain amino acids (BCAAs), especially isoleucine (Ile), exhibiting strong diagnostic potential. Targeted metabolomics further validated BCAAs’ (Valine, Leucine, and Ile) upregulation and short-chain fatty acids’ downregulation in PCOS. During follow - up, PCOS patients had a higher cumulative incidence of APOs despite similar pregnancy rates. And the adjustment for potential confounders did not substantially change the estimates. Intriguingly, individuals who experienced APOs showed a reduction in gut P. merdae levels and an elevation in serum BCAAs, suggesting their potential association with APOs occurrence. Further analysis revealed increased Ile levels in the endometrial tissue of PCOS (P < 0.05) and higher proportions of cells positive for senescence markers (P21, P16, IL6, and IL1β), indicating aggravated cellular senescence, particularly in endometrial stromal cells (ESCs). ESCs from PCOS patients displayed classical senescence features, including proliferation loss, increased SA-β-Gal activity, cell cycle arrest, and elevated ROS levels. The accumulation of senescent ESCs in PCOS endometrium ultimately resulted in a disrupted decidualization process, which was exacerbated by increasing concentrations of Ile supplementation. Limitations, reasons for caution However, we must acknowledge certain limitations of this study. While our study makes a significant contribution to existing scientific knowledge, it is crucial to validate these findings in diverse populations. In addition, clinical translatability of biomarkers needs further exploration. Wider implications of the findings This study highlights gut microbiota-metabolite crosstalk as a novel axis influencing reproductive health in PCOS. Moreover, the identification of P. merdae and BCAAs as potential biomarkers for PCOS patients and the associated APOs risk opens up new avenues for risk stratification and personalized interventions. Trial registration number No
揭示多囊卵巢综合征中肠道微生物群、代谢改变和子宫内膜衰老的相互作用及其对不良妊娠结局的影响
研究问题:哪些肠道微生物群和代谢改变与多囊卵巢综合征(PCOS)相关,并与不良妊娠结局(APOs)相关?在PCOS中,P. merdae减少,BCAAs增加,增加了apo的风险。同时,发现子宫内膜衰老和脱个体化损害,并随着il浓度的升高而加重。众所周知,多囊卵巢综合征是一种普遍而复杂的内分泌紊乱,是无排卵性不孕的主要原因。在过去十年中,中国多囊卵巢综合征的患病率不断上升,导致疾病负担大幅增加。我们之前的十年回顾性分析显示,接受首次新鲜胚胎移植的多囊卵巢综合征患者面临apo的高风险,如流产。然而,影响多囊卵巢综合征疾病进展和未来产科结局的因素仍然难以捉摸。这项前瞻性队列研究包括来自中国44个城市的220名女性(110名多囊卵巢综合征患者和110名对照组),中位随访时间为16.6个月。参与者/材料、环境、方法35岁的多囊卵巢综合征(鹿特丹标准)和年龄/ bmi匹配的对照组被招募。使用16S rRNA测序和宏基因组学分析粪便微生物组,通过非靶向和靶向代谢组学评估血清代谢物。子宫内膜间质细胞衰老的评估基于一系列标记,包括细胞增殖、衰老相关的分泌表型因子、细胞周期、ROS水平和SA-β-Gal活性。采用ELISA法测定催乳素和IGFBP-1水平,判断子宫内膜去个体化。我们的研究揭示了PCOS患者肠道微生物群的显著变化,包括α-多样性降低和merdae副芽孢杆菌(P. merdae)的显著减少,这是PCOS与对照组区分的关键物种。血清代谢组学鉴定出45种差异代谢物,其中支链氨基酸(BCAAs),特别是异亮氨酸(Ile),具有很强的诊断潜力。靶向代谢组学进一步证实了多囊卵巢综合征中BCAAs(缬氨酸、亮氨酸和Ile)的上调和短链脂肪酸的下调。在随访期间,尽管PCOS患者的妊娠率相似,但apo的累积发生率较高。对潜在混杂因素的调整并没有实质性地改变估计。有趣的是,经历过apo的个体表现出肠道merdae水平的降低和血清BCAAs的升高,这表明它们与apo的发生有潜在的关联。进一步分析显示多囊卵巢综合征(PCOS)患者子宫内膜中il水平升高(P <;0.05),衰老标志物(P21、P16、IL6和IL1β)呈阳性的细胞比例更高,表明细胞衰老加剧,尤其是在子宫内膜基质细胞(ESCs)中。PCOS患者的ESCs表现出典型的衰老特征,包括增殖丧失、SA-β-Gal活性增加、细胞周期停滞和ROS水平升高。PCOS子宫内膜中衰老ESCs的积累最终导致去体细胞化过程中断,并随着il补充浓度的增加而加剧。然而,我们必须承认本研究的某些局限性。虽然我们的研究对现有的科学知识做出了重大贡献,但在不同的人群中验证这些发现是至关重要的。此外,生物标志物的临床可译性有待进一步探索。本研究强调肠道微生物群-代谢物串扰是影响多囊卵巢综合征生殖健康的新轴。此外,鉴定P. merdae和BCAAs作为PCOS患者及其相关apo风险的潜在生物标志物,为风险分层和个性化干预开辟了新的途径。试验注册号
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来源期刊
Human reproduction
Human reproduction 医学-妇产科学
CiteScore
10.90
自引率
6.60%
发文量
1369
审稿时长
1 months
期刊介绍: Human Reproduction features full-length, peer-reviewed papers reporting original research, concise clinical case reports, as well as opinions and debates on topical issues. Papers published cover the clinical science and medical aspects of reproductive physiology, pathology and endocrinology; including andrology, gonad function, gametogenesis, fertilization, embryo development, implantation, early pregnancy, genetics, genetic diagnosis, oncology, infectious disease, surgery, contraception, infertility treatment, psychology, ethics and social issues.
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