Temporal profile of Liver of Cry1/2 double knockout (DKO) mice

Gut microbiota and the circadian clock both regulate metabolism. The circadian clock and associated feeding rhythms were shown to impact on the microbial community. However, to what extent gut microbiota reciprocally affect daily rhythms of gene expression and physiology in the host remains elusive. Here, we analyzed the transcriptomes of male and female germ-free mice. While this revealed subtle changes in circadian clock gene expression in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated to rhythmic physiology. Strikingly, absence of microbiome severely compromised liver sex-dimorphism at the transcriptome and metabolome level. Their sex-specific rhythmicity was strongly attenuated. The resulting feminization of male and masculinization of female hepatic gene expression in germ-free animals is likely caused by altered sex-dimorphism in sex and growth hormone secretion, linked to differential activation of xenobiotic receptors. This defines a novel mechanism by which the gut microbiome regulates host metabolism. Total RNA-Seq of night fed Cry1/2 DKO male mice. Temporal mRNA profiles of liver were assessed every 4 hours during a diurnal cycle (Zeitgerber time (ZT) 2-22). Night fed wild-type animals corresponding to the Cry1/2 DKO series are available under the accession numbers: GSM1897844-GSM1897855.肠道菌群（gut microbiota）与生物钟（circadian clock）均参与调控机体代谢。已有研究证实，生物钟及其关联的进食节律可影响微生物群落结构。然而，肠道菌群可在多大程度上反向调控宿主基因表达与生理活动的昼夜节律，目前仍有待阐明。本研究针对雌雄无菌小鼠（germ-free mice）的转录组开展了分析。尽管该分析揭示了肝脏、肠道及白色脂肪组织中生物钟相关基因表达的细微变化，但无菌小鼠体内与节律性生理活动相关的基因表达已出现显著改变。尤为值得关注的是，菌群缺失会在转录组（transcriptome）与代谢组（metabolome）层面严重破坏肝脏的性别二态性，其性别特异性节律已显著减弱。无菌动物中雄性肝脏基因表达的女性化与雌性肝脏基因表达的男性化，大概率由性别与生长激素分泌的性别二态性改变所介导，而该改变与异生物质受体（xenobiotic receptors）的差异化激活密切相关。这阐明了肠道菌群调控宿主代谢的全新机制。本研究对夜间进食的Cry1/2双敲除雄性小鼠进行了全转录组RNA测序（RNA-Seq）。在昼夜周期内（授时因子时间（Zeitgerber time, ZT）2至22），每4小时检测一次肝脏的时序性mRNA表达谱。与Cry1/2双敲除组对应的夜间进食野生型（wild-type）样本，其登录号为GSM1897844至GSM1897855。