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Cell Mol Gastroenterol Hepatol. 2019 Nov 2;9(2):219-237. doi: 10.1016/j.jcmgh.2019.10.011. [Epub ahead of print]

Abnormal Eating Patterns Cause Circadian Disruption and Promote Alcohol-Associated Colon Carcinogenesis.

Author information

1
Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois. Electronic address: Faraz_Bishehsari@rush.edu.
2
Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois.
3
Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois; Sequencing Core, Research Resources Center, University of Illinois at Chicago, Chicago, Illinois.
4
Sequencing Core, Research Resources Center, University of Illinois at Chicago, Chicago, Illinois; Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois.
5
Northwestern Medicine, Central DuPage Hospital, Winfield, Illinois.
6
Department of Immunology, Mayo Clinic, Rochester, Minnesota.
7
Whistler Center for Carbohydrate Research, Department of Food Science, Purdue University, West Lafayette, Indiana.
8
Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois; Department of Physiology, Rush University Medical Center, Chicago, Illinois; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
9
Department of Immunology, Mayo Clinic, Rochester, Minnesota. Electronic address: Khazaie@mayo.edu.

Abstract

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 proinflammatory 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 × APClox468 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 proinflammatory 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.

KEYWORDS:

Alcohol; Butyrate; Circadian; Colon Cancer; Food Time; Microbiota

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