Temporal profile of germ-free and conventionally raised male mice (epididymal white adipose tissue (WAT))

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 conventional raised (convR) and Germ-free (GF) male under ad libitum feeding regime. Temporal mRNA profiles of WAT were assessed every 4 hours during the diurnal cycle (Zeitgerber time (ZT) 2-22).肠道菌群（gut microbiota）与生物钟（circadian clock）均参与代谢调控。已有研究表明，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的基因表达日节律与生理节律，目前仍不明确。本研究对雌雄无菌小鼠（germ-free mice）的转录组进行了分析。尽管仅在肝脏、肠道与白色脂肪组织（white adipose tissue, WAT）中发现了生物钟基因表达的细微变化，但无菌小鼠体内与节律性生理功能相关的基因表达已出现显著改变。值得注意的是，无菌状态下肝脏的性别二态性在转录组与代谢组层面均受到严重破坏，其性别特异性节律已大幅减弱。无菌动物中雄性肝脏基因表达的雌性化与雌性肝脏基因表达的雄性化，可能源于性激素与生长激素分泌的性别二态性改变，而该改变与异生物质受体（xenobiotic receptors）的差异化激活密切相关。本研究揭示了肠道菌群调控宿主代谢的全新机制。本研究对常规饲养（conventional raised, convR）与无菌（GF）雄性小鼠开展了总RNA测序实验，实验采用自由进食饲养方案；并在昼夜周期内以每4小时一次的频率采集白色脂肪组织的时序mRNA表达谱，采样区间为授时因子时间（Zeitgeber time, ZT）2至22。