Gut Metabolites Are More Predictive of Disease and Cohoused States than Gut Bacterial Features in a Polycystic Ovary Syndrome-Like Mouse Model.
Gut Metabolites Are More Predictive of Disease and Cohoused States than Gut Bacterial Features in a Polycystic Ovary Syndrome-Like Mouse Model.
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DOI：
10.1128/msystems.01149-20
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发表时间：
2021-10-26
期刊：
影响因子：
6.4
通讯作者：
Kelley ST
中科院分区：
文献类型：
--
作者：
Ho B;Ryback D;Benson B;Mason CN;Torres PJ;Quinn RA;Thackray VG;Kelley ST
多囊卵巢综合症 (PCOS) 影响着全球约 10% 的育龄女性。除了不孕之外，患有 PCOS 的女性还患有代谢失调，这增加了她们患 2 型糖尿病、心血管疾病和非酒精性脂肪肝的风险。研究表明，与对照组相比，多囊卵巢综合症女性的肠道微生物组存在差异，这一模式在多囊卵巢综合症小鼠模型中也得到了复制。最近，我们使用来曲唑 (LET) 诱导的 PCOS 小鼠模型证明，同居可防止代谢和生殖表型的发展，并通过 16S 扩增子测序表明，这种保护与肠道细菌的时间依赖性变化相关。在这里，我们应用非靶向代谢组学和鸟枪宏基因组学方法来进一步分析共养实验的纵向样本。对β多样性的分析发现，非目标代谢物与疾病和共养状态具有最强的相关性，并且代谢物多样性的变化先于细菌多样性的变化被检测到。此外，log2 倍数分析发现许多代谢特征，特别是胆汁酸 (BA)，在安慰剂和 LET 之间以及 LET 与安慰剂共存与 LET 之间存在高度差异。我们的结果表明，肠道代谢物（尤其是 BA）的变化与 PCOS 样表型以及共同饲养的保护作用有关。我们的结果还表明，通过食粪进行代谢物的转移发生得很快，并可能导致细菌多样性的变化。这项研究加入了越来越多的研究，将初级和次级 BA 的变化与 PCOS 病理学相关的宿主代谢和肠道微生物联系起来。重要性 通过结合非靶向代谢组学和宏基因组学，我们对 PCOS 样小鼠模型的同居研究中收集的粪便进行了比较纵向分析。我们的结果表明，与微生物组成相比，疾病模型和共养小鼠的肠道代谢组成经历了更早、更明显的分化。值得注意的是，统计和机器学习方法发现了初级和次级 BA 相对丰度的变化，这被认为是肠道微生物生长和多样性的调节剂。网络相关分析显示特定 BA 与细菌种类（尤其是乳杆菌成员）之间存在很强的关联，并且这些相关性取决于时间和治疗。我们的研究结果为与女性高雄激素血症相关的宿主-微生物关系提供了新的见解，并表明对肠道微生物多样性和宿主生理学的小分子控制的集中研究可能为多囊卵巢综合征的治疗提供新的治疗选择。
Polycystic ovary syndrome (PCOS) impacts ∼10% of reproductive-aged women worldwide. In addition to infertility, women with PCOS suffer from metabolic dysregulation which increases their risk of developing type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Studies have shown differences in the gut microbiome of women with PCOS compared to controls, a pattern replicated in PCOS-like mouse models. Recently, using a letrozole (LET)-induced mouse model of PCOS, we demonstrated that cohousing was protective against development of metabolic and reproductive phenotypes and showed via 16S amplicon sequencing that this protection correlated with time-dependent shifts in gut bacteria. Here, we applied untargeted metabolomics and shotgun metagenomics approaches to further analyze the longitudinal samples from the cohousing experiment. Analysis of beta diversity found that untargeted metabolites had the strongest correlation to both disease and cohoused states and that shifts in metabolite diversity were detected prior to shifts in bacterial diversity. In addition, log2 fold analyses found numerous metabolite features, particularly bile acids (BAs), to be highly differentiated between placebo and LET, as well as LET cohoused with placebo versus LET. Our results indicate that changes in gut metabolites, particularly BAs, are associated with a PCOS-like phenotype as well as with the protective effect of cohousing. Our results also suggest that transfer of metabolites via coprophagy occurs rapidly and may precipitate changes in bacterial diversity. This study joins a growing body of research linking changes in primary and secondary BAs to host metabolism and gut microbes relevant to the pathology of PCOS. IMPORTANCE Using a combination of untargeted metabolomics and metagenomics, we performed a comparative longitudinal analysis of the feces collected in a cohousing study with a PCOS-like mouse model. Our results showed that gut metabolite composition experienced earlier and more pronounced differentiation in both the disease model and cohoused mice compared with the microbial composition. Notably, statistical and machine learning approaches identified shifts in the relative abundance of primary and secondary BAs, which have been implicated as modifiers of gut microbial growth and diversity. Network correlation analysis showed strong associations between particular BAs and bacterial species, particularly members of Lactobacillus, and that these correlations were time and treatment dependent. Our results provide novel insights into host-microbe relationships related to hyperandrogenism in females and indicate that focused research into small-molecule control of gut microbial diversity and host physiology may provide new therapeutic options for the treatment of PCOS.