E2 dose on microbiome rat model

A decline in estradiol (E2) production during menopause has been associated with weight gain and memory changes. These comorbidities have been linked with disturbances in the gut microbiome. We hypothesized that E2 regulates the gut microbiome in a dose-dependent manner, and that E2-dependent changes in the gut microbiome are linked to menopausal comorbidities. We characterized gut microbiome composition using 16S rRNA gene sequencing, quantified host body weight and memory scores in middle-aged ovariectomized (OVX) rats that received Vehicle, Low-E2, or High-E2 treatments. E2 significantly altered gut microbiota composition in mucosal and luminal space of proximal and distal regions of the colon. Relative abundance of Turicibacter, Bifidobacterium, and Allobaculum, as well as predicted abundances of genes involved in E2 deconjugation, beta-glucuronidase and beta-glucosidase, increased with E2 dose. The Vehicle group had significant weight gain compared to E2-treated groups. Body-weight positively correlated with Lactobacillus and negatively with Turicibacter abundance. Although E2 treatment did not alter spatial working memory load performance, gut microbiome composition correlated with the memory errors independently from the E2 dose. In summary, E2 dose-dependently altered fecal and mucosal microbiota throughout the colon, suppressed weight gain, and was correlated with cognitive benefits through manipulation of complex gut microbiota-host physiology interactions.

更年期期间雌二醇（estradiol, E2）合成减少，与体重增加及记忆功能改变密切相关。上述共病状态与肠道菌群失调存在关联。本研究提出假设：雌二醇可通过剂量依赖性方式调控肠道菌群，且雌二醇依赖的肠道菌群变化与更年期共病相关。本研究采用16S rRNA基因测序技术对肠道菌群组成进行表征，并对接受赋形剂（Vehicle）、低剂量E2或高剂量E2处理的中年去卵巢（ovariectomized, OVX）大鼠的宿主体重及记忆评分进行量化。结果显示，雌二醇可显著改变结肠近端与远端区域黏膜及肠腔空间内的肠道菌群组成。Turicibacter、双歧杆菌（Bifidobacterium）及Allobaculum的相对丰度，以及参与雌二醇脱结合、β-葡萄糖醛酸苷酶与β-葡萄糖苷酶相关基因的预测丰度，均随雌二醇剂量升高而增加。与雌二醇处理组相比，赋形剂组大鼠出现显著体重增加。宿主体重与乳杆菌（Lactobacillus）的丰度呈正相关，与Turicibacter的丰度呈负相关。尽管雌二醇处理未改变空间工作记忆负荷任务的表现，但肠道菌群组成与记忆错误存在关联，且该关联不受雌二醇剂量的影响。综上，雌二醇以剂量依赖性方式改变整个结肠内的粪便及黏膜菌群组成，抑制体重增加，并通过调控复杂的肠道菌群-宿主生理相互作用，与认知获益相关。