Circadian rhythms, alcohol and gut interactions
Circadian rhythms, alcohol and gut interactions
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DOI：
10.1016/j.alcohol.2014.07.021
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发表时间：
2015-06-01
期刊：
影响因子：
2.3
通讯作者：
Keshavarzian, Ali
中科院分区：
文献类型：
--
作者：
Forsyth, Christopher B.;Voigt, Robin M.;Keshavarzian, Ali
生物钟以大约24小时的周期在整个身体内建立节律，影响数百个基因的表达。流行病学数据显示，在我们的社会中常见的慢性昼夜节律失调，大大增加了无数疾病的风险，包括心血管疾病，糖尿病，癌症，不孕症和胃肠道疾病。肠屏障功能的破坏，也称为肠漏，在酒精性肝病（ALD）中尤其重要。一些研究表明，酒精导致ALD的只有20-30%的酗酒者。因此，需要更好地了解为什么只有一部分酗酒者会患上酒精性痴呆症。令人信服的证据表明，肠道对微生物产物，特别是LPS的渗漏增加在ALD的发病机制中起着关键作用。生物钟和其他生物钟基因已被证明可以调节脂质转运，运动和其他肠道功能。我们假设酒精诱导的肠通透性增高的一个可能机制是通过中枢或外周（肠道）昼夜节律调节的破坏。为了支持这一假设，我们最近的数据表明，昼夜节律的破坏使肠道更容易受到伤害。我们的体外数据表明，酒精刺激增加的时钟和Per 2生物钟蛋白，这些蛋白质的siRNA敲低防止酒精诱导的渗透性。我们还表明，肠Cyp 2 e1介导的氧化应激是所需的酒精诱导的上调时钟和Per 2和肠道通透性过高。我们的慢性酒精喂养小鼠模型表明，通过遗传学（在Clock 19小鼠中）的昼夜节律破坏或每周12小时相移的环境破坏仅导致肠道渗漏，并加剧酒精诱导的肠道渗漏和肝脏病理学。我们在人类酗酒者中的数据显示，他们表现出昼夜节律紊乱的异常褪黑激素特征。总之，我们的数据支持酒精诱导的肠道渗漏的昼夜机制，可以为ALD提供新的治疗靶点。(C)2015 Elsevier Inc. All rights reserved.
The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20-30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyperpermeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1 -mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in Clock 19 mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our data support circadian mechanisms for alcohol-induced gut leakiness that could provide new therapeutic targets for ALD. (C) 2015 Elsevier Inc. All rights reserved.