Transkingdom Control of Microbiota Diurnal Oscillations Promotes Metabolic Homeostasis
Cell Volume 159, Issue 3, 23 October 2014, Pages 514-529
Christoph A.Thaiss,DavidZeevi,MaayanLevy,GiliZilberman-Schapira,JothamSuez,Anouk C.Tengeler,LiorAbramson,Meirav N.Katz,TalKorem,NivZmora,YaelKuperman,InbalBiton,ShlomitGilad,AlonHarmelin,HagitShapiro,ZamirHalpern,EranSegal,EranElinav
Background:
Life on Earth is dictated by circadian fluctuations of light caused by the planet’s rotation around its own axis. Biological clocks are oscillators that enable the anticipation of diurnal variations in environmental conditions and thereby couple physiological processes to geophysical time (Mohawk et al., 2012). All three domains of life —archaea, bacteria, and eukarya—have evolved different methods of developing molecular machineries to coordinate this task (Edgar et al., 2012).
The mammalian circadian clock consists of several core transcriptional regulators, including CLOCK and BMAL1, which are most abundant during the light phase, as well as cryptochromes (CRYs) and period proteins (PERs), which are most highly expressed during the dark phase (Bass, 2012). The circadian clock is characterized by a hierarchical principle. The central clock in the suprachiasmatic nucleus is entrained by environmental light conditions. In turn, the central clock entrains the peripheral clocks through various hormonal and neuronal signals, which dictate the rhythmic gene expression of oscillating genes in most other organ systems (Dibner et al., 2010; Hogenesch and Ueda, 2011). In the periphery, the circadian clock controls many biological processes, ranging from metabolism and behavior to immunity, and helps to synchronize these processes to diurnal fluctuations in environmental conditions (Asher et al., 2010; Gerhart-Hines et al., 2013; Keller et al., 2009; Nguyen et al., 2013; Silver et al., 2012; Yu et al., 2013).
In humans, disruption of the circadian clock is a common hallmark of the modern alteration in lifestyle and is especially evident in individuals engaged in chronic shift work or frequently flying across time zones and experiencing the ‘‘jet lag’’ phenomenon. This new set of disruptive conditions to human physiology is associated with a propensity for a wide range of diseases, including obesity, diabetes, cancer, cardiovascular disease, and susceptibility to infection (Archer et al., 2014; Buxton et al., 2012; Fonken et al., 2010; Scheer et al., 2009; Suwazono et al., 2008). The mechanisms by which disruption of circadian rhythmicity contributes to these pathophysiological outcomes remain largely unknown.
The bacterial circadian clock has primarily been studied in light-responsive cyanobacterial communities (Johnson et al., 2011). In addition to transcriptional regulation, the bacterial clock is regulated at the posttranscriptional level. Rhythmic phosphorylation of proteins in a 24 hr rhythm functions as an oscillatory system, anticipating day-night variations in environmental conditions (Johnson et al., 2008; Rust et al., 2007). It remains unknown, however, whether rhythmic activity exists in complex microbial ecosystems, some of which are not directly exposed to light-dark cycles. The mammalian intestinal microbiota constitutes such an ecosystem, whose microbial members outnumber the amount of eukaryotic cells of the host by a factor of 10. The resultant human ‘‘metaorganism’’ comprises both a eukaryotic and a prokaryotic component (Gordon, 2012; Human Microbiome Project Consortium, 2012). The microbiota plays a pivotal role in the regulation of many physiological processes, including digestion of food components, host metabolism, the maturation and function of the immune system, and even host behavior and cognitive function (Clemente et al., 2012; Hooper et al., 2012; Hsiao et al., 2013; Sommer and Ba¨ ckhed, 2013), all of which show features of circadian control. Recently, rhythmic microbial sensing by intestinal epithelial cells was found to be essential for epithelial homeostasis (Mukherji et al., 2013).
Here, we demonstrate that the gut microbiota itself follows diurnal oscillations in composition and function whose regulation is governed by host feeding rhythms. Furthermore, we find evidence in both mice and humans that host circadian misalignment results in microbial dysbiosis, which drives metabolic imbalances, suggesting an involvement of transkingdom interactions between mammalian and prokaryotic diurnal rhythms in modern human disease.
Result:
•Intestinal microbiota exhibit diurnal oscillations in composition and function
•Feeding rhythms direct microbiota oscillations
•Chronic jet lag is associated with loss of microbiota rhythms and dysbiosis
•Jet-lag-associated dysbiosis in mice and humans promotes metabolic imbalances
Conclusion:
- A functional circadian clock of the host is required for diurnal microbiota oscillations
- Microbiota diurnal oscillations are controlled by feeding time
- Environmental disruption of normal sleep patterns induces loss of microbiota diurnal rhythmicity and dysbiosis
指導教授：徐堯煇、王敏盈 教授
報告序號：20191108-2
組員：生技碩二 林承義
生技碩一 劉兆慈
生技碩一 許育宇
