Temporal profiles of germ-free and conventionally raised female and male mice (LIVER)

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) female and male under ad libitum feeding regime. Temporal mRNA profiles of liver 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) 均可调控机体代谢。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，肠道菌群反过来可在多大程度上调控宿主基因表达与生理活动的近日节律，目前仍尚不明确。本研究对雌雄无菌小鼠的转录组 (transcriptome) 进行了分析。尽管该分析发现，肝脏、肠道与白色脂肪组织中的生物钟基因表达仅出现细微变化，但无菌小鼠体内与节律性生理活动相关的基因表达却发生了显著改变。值得注意的是，菌群缺失会严重破坏转录组与代谢组 (metabolome) 层面的肝脏性别二态性 (sex-dimorphism)，其性别特异性节律性大幅减弱。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，可能源于性别与生长激素分泌的性别二态性改变，该改变与异生物素受体 (xenobiotic receptors) 的差异化激活相关。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 (Germ-free, GF) 雌雄小鼠在自由进食 (ad libitum feeding regime) 条件下开展总RNA测序 (Total RNA-Seq)。在昼夜周期 (diurnal cycle) 中，每隔4小时对肝脏的时序mRNA表达谱进行检测，检测时间点为Zeitgeber时间 (ZT) 2至22。