多囊卵巢综合征（PCOS）患者肠道菌群谱及药物治疗对肠道菌群结构的影响

Polycystic ovary syndrome (PCOS) is the most common endocrine disorders in women in childbearing age. As an important cause of infertility, it has always been the focus of female reproductive disorders researches. But its etiology is complex, and its pathogenesis is also unclear, and there is still no specific effective treatment by now. Since PCOS has close correlation with chronic inflammation, insulin resistance, and metabolic syndrome. And these metabolic diseases have important relationship with the profiles of gut microbiota, while in return, gut microbiota also affects the development of multiple endocrine and metabolic disorders. We try to use microbial sequencing technology, to analysis the changes of gut microbiota in PCOS patients with/without accompanied by hyperandrogenism and/or impaired glucose tolerance, and to draw the gut microbiota profiles of PCOS patients. We will also study whether diane-35 or metformin would help regulate the gut microbiota after the three month’s treatment. We will study its correlation with chronic inflammation, insulin resistance and hyperandrogenism, to clarify the mechanism of drugs during the treatment of hyperandrogenism and impaired glucose tolerance, and further acquire specific bacterial spectrum related to the development of PCOS. It will help providing theoretical basis for the development of target drugs on the gut microbiota and probiotics, which can guide the clinical diagnosis and treatment of PCOS more effectively, and help to guide the clinical diagnosis and medication of PCOS patients. So it can promote women’s reproductive health.

多囊卵巢综合征（PCOS）是育龄期妇女中最常见的内分泌紊乱疾病，是女性生殖障碍疾病研究的重点，其病因复杂，发病机制不明确。PCOS与慢性炎症、胰岛素抵抗、代谢综合征等密切相关，这些代谢性疾病与肠道菌群谱的变化有着重要的关系。我们试图通过微生物测序技术，解析PCOS患者伴/不伴高雄激素血症和/或糖耐量异常情况下肠道菌群各自特点，绘制PCOS肠道菌群谱；研究对PCOS患者应用达英-35或二甲双胍治疗后，是否有助于调节患者肠道菌群结构，通过菌群移植明确肠道菌群与慢性炎症反应、胰岛素抵抗、高雄激素血症等的关联，从肠道菌群的角度阐明药物在改善高雄激素血症或糖耐量异常中的具体机制，明确PCOS发病及治疗有关的特异菌谱；随访妊娠结局，分析肠道菌群与妊娠结局是否关联，为PCOS患者肠道微生态平衡的重建提供数据，为开发以肠道菌群为靶向的药物或者益生菌提供基础，以指导临床对PCOS的诊断和用药，促进生殖健康。

研究背景：多囊卵巢综合征（polycystic ovary syndrome，PCOS）是育龄期女性中常见的代谢性和内分泌障碍性疾病，发病率约为5%~20%。一些研究发现PCOS女性肠道菌谱丰度及组成结构的变化情况，但与PCOS相关的微生物的功能和作用机制仍尚未明确，针对肠道菌谱的PCOS诊治手段仍有待探索。.研究方法：本课题通过对上海交通大学医学院附属仁济医院生殖中心就诊的PCOS患者的肠道菌群进行宏基因组测序分析，同时利用测序手段探索PCOS动物模型中的肠道菌谱变化，及应用恢复光照节律、使用益生菌、褪黑素等不同手段探究PCOS的有效治疗手段。.重要结果：课题组研究发现，在PCOS女性肠道中富集的微生物之间呈正相关联系，这些微生物与对照组富集的微生物呈负相关关系；肠道菌谱所构建的多个MGS与PCOS相关指标，如总睾酮、AMH、LH呈明显相关性。在持续光照或黑暗诱导的类PCOS鼠中都发现了肠道菌谱改变，而口服乳酸杆菌可改善PCOS鼠糖耐量受损症状。针对肠道菌群的机制研究层面，发现向无菌鼠中移植DHEA诱导的PCOS鼠粪便会引起无菌鼠PCOS相关表型的发生。.科学意义：本项研究利用前沿的16SrRNA测序技术及宏基因组测序技术阐述了在PCOS动物及PCOS女性患者肠道菌谱的改变，提示肠道菌群在PCOS的高雄激素血症等不同表型中可能发挥其功能，为后续的肠道菌群研究及应用提供理论依据。菌群移植实验在无菌动物中部分重现了PCOS相关表型证明了肠道菌群在这一病理生理变化中存在作用，特别是内分泌紊乱及排卵障碍方面。持续黑暗诱导出大鼠PCOS代谢、生殖等表型发生，高雄激素血症、胰岛素抵抗继而引发卵巢局部颗粒细胞凋亡增多，加重PCOS病情。口服乳酸杆菌对改善糖代谢异常有所帮助，恢复节律及应用褪黑素对PCOS症状亦有改善，这为PCOS的临床诊治方案提供了理论基础，也为未来的治疗方案提供了更多可能。