BACKGROUND 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. METHOD 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

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酒精与进食时间对昼夜节律不同步和结肠组织损伤标志物的相互作用。


背景酒精会增加患结肠癌（CRC）的风险，部分原因是组织炎症和屏障完整性受损。昼夜节律失调 (CD) 是一种尚未得到充分研究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和包括结直肠癌在内的恶性肿瘤的数量。我们之前的研究表明，在酒精治疗的情况下，明暗循环的转变会加剧屏障功能障碍和结肠炎症，并增加结直肠癌的风险。在这里，我们研究了酒精与异常饮食模式对 CD 和结肠屏障完整性标记物的相互作用。方法 小鼠在白天（休息期 = 错误时间 WT）或夜间（活动期 = 正确时间 RT）进食并结合水或 15% 酒精，总持续时间为 10 周。测量食物和液体摄入量。在整个研究过程中，使用断束系统记录运动活动数据。在两个时间点（ZT2 和 ZT14）对小鼠实施安乐死。测量中枢（下丘脑）和肠道（结肠）组织中生物钟分子标记（per2 基因）表达的时间变化。研究了屏障标记（Occludin 和 Claudin-1）的结肠蛋白表达。结果 研究期间各组的体重增加和酒精摄入量没有显着差异。我们观察到 WT 饮食与酒精对昼夜节律行为标记的相互作用。与 RT + 水处理的动物（“参考组”）相比，WT 饮食和饮酒的组合（WT + 酒精）显着改变了 per2 振荡模式，这在结肠和下丘脑之间是不同的，表明昼夜节律不同步恶化。 这与结肠中屏障完整性标记物的表达总体受损有关。结论 酒精会引起昼夜节律不同步，进食时间异常会加剧这种不同步，这与结肠屏障完整性受损有关。未来关于酒精和进食时间相互作用的研究可以为酒精相关的结直肠癌病理生理学提供进一步的见解。