Tran Laura, Shaikh Maliha, Engen Phillip A, Naqib Ankur, Frausto Dulce M, Ramirez Vivian, Gasteier Malia, Bogin Zlata, Lawrence Kristi, Zhang Lijuan, Song Shiwen, Green Stefan J, Bishehsari Faraz, Forsyth Christopher B, Keshavarzian Ali, Swanson Garth R
Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, USA.
Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, IL, USA.
Gut Microbes. 2025 Dec;17(1):2509281. doi: 10.1080/19490976.2025.2509281. Epub 2025 Jun 4.
Circadian organization is involved in many gastrointestinal tract (GIT) functions such as the maintenance of intestinal barrier integrity. There is compelling evidence that perturbation of the circadian clock decreases intestinal epithelial cells' resiliency to alcohol-induced injury. One of the most common causes of circadian misalignment is wrong-time eating (largest meal at dinner) in modern societies. Yet, few studies have examined the importance of peripheral circadian rhythms of the GIT to alcohol consumption. Eating patterns during physiologic rest time, defined as wrong-time eating (WTE), misalign the peripheral circadian clock of the GIT and the body's central clock. This study aims to fill this knowledge gap by testing the hypothesis that: (1) WTE worsens alcohol-induced disruption of intestinal barrier integrity and (2) decreased intestinal barrier resiliency to alcohol effects by WTE-disrupted circadian is, at least in part, due to microbiota dysbiosis. Alcohol (20% v/v) and a restricted timed-food paradigm were administered to PERIOD2 luciferase (PER2:LUC) reporter BL/6 mice for 10 weeks. Intestinal barrier integrity, intestinal (stool) microbiota, and microbial metabolites (cecal-derived) were examined. Peripheral circadian misalignment exacerbated alcohol-induced disruption of intestinal barrier integrity (tight junctional proteins) leading to increased intestinal permeability ( < 0.05). In addition, alcohol consumption changed the intestinal microbiota community, decreasing beneficial short-chain fatty acid-producing taxa. Further, we recapitulated the in vivo phenotype in a colonic organoid model and demonstrated that microbial metabolites from circadian-disrupted, alcohol-fed mice mediate decreased resiliency of intestinal epithelial barrier function. Peripheral circadian misalignment through food timing decreases the resiliency of the intestinal barrier to alcohol-induced injury and this effect is mediated through dysbiotic microbiota metabolites.
昼夜节律调控参与许多胃肠道（GIT）功能，如维持肠道屏障完整性。有确凿证据表明，生物钟紊乱会降低肠道上皮细胞对酒精诱导损伤的抵抗力。现代社会中，昼夜节律失调最常见的原因之一是进食时间不当（晚餐吃得最多）。然而，很少有研究探讨胃肠道外周昼夜节律对酒精摄入的重要性。在生理休息时间进食，即进食时间不当（WTE），会使胃肠道外周生物钟与身体的中央生物钟失调。本研究旨在通过检验以下假设来填补这一知识空白：（1）进食时间不当会加重酒精诱导的肠道屏障完整性破坏；（2）进食时间不当导致的昼夜节律紊乱降低肠道屏障对酒精作用的抵抗力，至少部分是由于微生物群失调。将酒精（20% v/v）和限时进食模式给予PERIOD2荧光素酶（PER2:LUC）报告基因BL/6小鼠，持续10周。检测肠道屏障完整性、肠道（粪便）微生物群和微生物代谢产物（盲肠来源）。外周昼夜节律失调加剧了酒精诱导的肠道屏障完整性破坏（紧密连接蛋白），导致肠道通透性增加（P<0.05）。此外，酒精摄入改变了肠道微生物群群落，减少了有益的产生短链脂肪酸的分类群。此外，我们在结肠类器官模型中重现了体内表型，并证明来自昼夜节律紊乱、喂食酒精的小鼠的微生物代谢产物介导了肠道上皮屏障功能抵抗力的降低。通过食物时间安排导致的外周昼夜节律失调会降低肠道屏障对酒精诱导损伤的抵抗力，这种作用是通过微生物群失调代谢产物介导的。
