Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA.
Department of Biological Sciences, University of Wisconsin Parkside, Kenosha, WI, USA.
Chem Biol Interact. 2020 Jul 1;325:109132. doi: 10.1016/j.cbi.2020.109132. Epub 2020 May 11.
Alcohol increases the risk of developing colon cancer (CRC), in part via tissue inflammation and impaired barrier integrity. Circadian dyssynchrony (CD) is an understudied but common lifestyle associated factor that increases the risk of multi-organ tissue injury and number of malignancies including CRC. Our prior studies showed that the shift in light-dark cycle exacerbates barrier dysfunction and colonic inflammation in the setting of alcohol treatment, and increases the risk of CRC. Here we studied the interaction of alcohol with an abnormal eating pattern on markers of CD and colonic barrier integrity.
Mice were subjected to day (rest-phase = wrong-time WT) or night-time (active-phase = right-time RT) access to food in combination with access to water or 15% alcohol for total duration of 10 weeks. The food and liquid intake was measured. The locomotor activity data was recorded throughout the study, using a beam-break system. Mice were euthanized at two time points (ZT2 and ZT14). Time variation in the expression of the molecular marker of circadian clock (per2 gene) was measured in the central (hypothalamus) and intestinal (colon) tissue. Colonic protein expression of barrier markers (Occludin and Claudin-1) was studied.
No significant differences were present in the weight gain and alcohol intake among the groups over the study period. We observed an interaction of WT eating with alcohol on behavioral markers of circadian rhythm. Compared to the RT + Water treated animals ("reference group"), combination of WT eating and alcohol consumption (WT + Alcohol) significantly changed the per2 oscillatory pattern, that was different between the colon and hypothalamus, indicative of worsening circadian dyssynchrony. This was associated with an overall impaired expression of barrier integrity markers in the colon.
Alcohol induces circadian dyssynchrony which is worsened by abnormal food timing, associated with impaired barrier integrity in the colon. Future studies on the interaction of alcohol and food timing could provide further insights into alcohol associated CRC pathophysiology.
酒精会增加结肠癌（CRC）的发病风险，部分原因是其会导致组织炎症和屏障完整性受损。昼夜节律失调（CD）是一种研究较少但常见的生活方式相关因素，它会增加多器官组织损伤的风险，并增加包括 CRC 在内的多种恶性肿瘤的发生风险。我们之前的研究表明，在酒精治疗的情况下，明暗周期的改变会加剧屏障功能障碍和结肠炎症，并增加 CRC 的风险。在这里，我们研究了酒精与异常进食模式对 CD 和结肠屏障完整性标志物的相互作用。
将小鼠置于白天（休息期=错误时间 WT）或夜间（活动期=正确时间 RT）进食，并同时提供水或 15%酒精，总时长为 10 周。测量食物和液体摄入量。使用光束中断系统记录整个研究期间的运动活动数据。在两个时间点（ZT2 和 ZT14）处死小鼠。测量中央（下丘脑）和肠道（结肠）组织中生物钟分子标志物（per2 基因）的时间变化。研究了结肠屏障标志物（Occludin 和 Claudin-1）的蛋白表达。
在整个研究期间，各组的体重增加和酒精摄入量没有显著差异。我们观察到 WT 进食与酒精对昼夜节律行为标志物的相互作用。与 RT+水治疗的动物（“参考组”）相比，WT 进食和酒精摄入的组合（WT+酒精）显著改变了 per2 振荡模式，该模式在结肠和下丘脑之间不同，表明昼夜节律失调恶化。这与结肠中整体屏障完整性标志物表达受损有关。
酒精会引起昼夜节律失调，异常的进食时间会使其恶化，导致结肠屏障完整性受损。关于酒精和进食时间相互作用的进一步研究可能会为酒精相关性 CRC 发病机制提供更多的见解。
