DataSheet_1_Antigen Presenting Cells Link the Female Genital Tract Microbiome to Mucosal Inflammation, With Hormonal Contraception as an Additional Modulator of Inflammatory Signatures.pdf

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa.

女性生殖道（female genital tract, FGT）的微生物组与生殖健康结局密切相关。以厌氧菌为主、乳酸杆菌（Lactobacillus）丰度偏低的多样化菌群，与早产、宫颈上皮内瘤变及包括人类免疫缺陷病毒（HIV）在内的性传播感染（sexually transmitted infections, STIs）等多种不良生殖结局显著相关。阴道微生态失调可引发局部黏膜炎症，而该炎症或为不良生殖结局的生物学介导因素。然而，女性生殖道炎症的确切机制目前仍不明确。针对人类的相关研究因混杂的人口学、行为学及临床变量而变得复杂。具体而言，激素避孕既可引起阴道微生物组改变，也可诱发黏膜炎症。本研究对一组阴道菌群类型各异的南非女性的宫颈细胞群体转录谱进行了分析，同时探讨了生殖激素对宫颈细胞转录谱的影响，重点关注注射用醋酸甲羟孕酮（depot medroxyprogesterone acetate, DMPA）——撒哈拉以南非洲最常用的避孕手段。研究发现，抗原呈递细胞（antigen presenting cells, APCs）是微生物组相关女性生殖道炎症的关键介导因子。此外，本研究还观察到，DMPA可引发多种细胞谱系的显著转录变化；与微生态失调相关的炎症特征相比，这些变化涉及部分共有通路与部分特异性通路。本研究结果凸显了采用整合性系统生物学方法解析宿主-微生物互作的重要性，同时也提示，在女性生殖道黏膜这一复杂系统中，需充分重视生殖激素等关键变量的影响。