Abnormal Eating Patterns Cause Circadian Disruption and Promote Alcohol-Associated Colon Carcinogenesis
Abnormal Eating Patterns Cause Circadian Disruption and Promote Alcohol-Associated Colon Carcinogenesis
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DOI：
10.1016/j.jcmgh.2019.10.011
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发表时间：
2020-01-01
影响因子：
7.2
通讯作者：
Khazaie, Khashayarsha
中科院分区：
文献类型：
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作者：
Bishehsari, Faraz;Engen, Phillip A.;Khazaie, Khashayarsha
背景与目的：昼夜节律紊乱（CRD）的酒精摄入会增加结肠癌的风险。我们假设，在生理休息时间内或前后进食，这是现代社会的一种常见习惯，会导致CRD，并研究了其促进酒精相关结肠癌发生的机制。方法：使用表达PERIOD 2和LUCIFERASE融合蛋白的B6小鼠评估进食时间对CRD的影响（PER 2：：LUC）用于模拟结肠息肉病并评估进食时间表、酒精消耗和益生元治疗对微生物群组成的影响，短链脂肪酸水平、结肠炎症和癌症风险。通过丁酸受体GPR 109 A的失活来评估丁酸信号传导与促炎性特征之间的关系。结果：静息进食（错误时间进食[WTE]）改变了PER 2：：LUC小鼠结肠节律的时相。在TS 4Cre x APC（lox 468）小鼠中，WTE和酒精暴露（WTE +酒精）的组合降低了短链脂肪酸产生菌和丁酸盐的水平，降低了结肠调节性T细胞的密度，诱导了以通透性过高和粘膜辅助性T细胞17/调节性T细胞比率增加为特征的促炎性特征，并促进了结直肠癌。益生元治疗改善了粘膜炎症状况，减轻了炎症和癌症。WTE +酒精诱导的息肉病与信号转导子和转录激活子3表达增加相关。丁酸信号的减少在体外激活了上皮细胞的信号转导和转录激活因子3。丁酸信号和proin-flammatory配置文件之间的关系被证实在人类结直肠癌使用癌症基因组Atlas.CONCLUSIONS：异常的食物摄入时间引起CRD和相互作用与酒精消费，以促进结肠癌的发生诱导protumorigenic炎症配置文件的变化，在结肠微生物群和丁酸信号。微生物群序列数据库的登录号：原始FASTQ数据在项目PRJNA 523141下保存在NCBI Sequence Read Archive中。
BACKGROUND & AIMS: Alcohol intake with circadian rhythm disruption (CRD) increases colon cancer risk. We hypothesized that eating during or around physiologic rest time, a common habit in modern society, causes CRD and investigated the mechanisms by which it promotes alcohol-associated colon carcinogenesis.METHODS: The effect of feeding time on CRD was assessed using B6 mice expressing a fusion protein of PERIOD2 and LUCIFERASE (PER2::LUC) were used to model colon polyposis and to assess the effects of feeding schedules, alcohol consumption, and prebiotic treatment on microbiota composition, short-chain fatty acid levels, colon inflammation, and cancer risk. The relationship between butyrate signaling and a proin-flammatory profile was assessed by inactivating the butyrate receptor GPR109A.RESULTS: Eating at rest (wrong-time eating [WTE]) shifted the phase of the colon rhythm in PER2::LUC mice. In TS4Cre x APC(lox468) mice, a combination of WTE and alcohol exposure (WTE + alcohol) decreased the levels of short-chain fatty acid-producing bacteria and of butyrate, reduced colonic densities of regulatory T cells, induced a proinflammatory profile characterized by hyperpermeability and an increased mucosal T-helper cell 17/regulatory T cell ratio, and promoted colorectal cancer. Prebiotic treatment improved the mucosal inflammatory profile and attenuated inflammation and cancer. WTE + alcohol-induced polyposis was associated with increased signal transducer and activator of transcription 3 expression. Decreased butyrate signaling activated the epithelial signal transducer and activator of transcription 3 in vitro. The relationship between butyrate signaling and a proin-flammatory profile was confirmed in human colorectal cancers using The Cancer Genome Atlas.CONCLUSIONS: Abnormal timing of food intake caused CRD and interacts with alcohol consumption to promote colon carcinogenesis by inducing a protumorigenic inflammatory profile driven by changes in the colon microbiota and butyrate signaling. Accession number of repository for microbiota sequence data: raw FASTQ data were deposited in the NCBI Sequence Read Archive under project PRJNA523141.