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

Cell Mol Gastroenterol Hepatol. 2020;9(2):219-237. doi: 10.1016/j.jcmgh.2019.10.011. Epub 2019 Nov 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / adverse effects*
  • Animals
  • Butyrates / metabolism
  • Carcinogenesis / immunology
  • Carcinogenesis / pathology
  • Circadian Rhythm / physiology*
  • Colitis / chemically induced
  • Colitis / immunology
  • Colitis / pathology
  • Colitis-Associated Neoplasms / etiology
  • Colitis-Associated Neoplasms / pathology*
  • Colon / immunology
  • Colon / pathology
  • Colonic Polyps / etiology*
  • Colonic Polyps / pathology
  • Disease Models, Animal
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology
  • Ethanol / administration & dosage
  • Ethanol / toxicity
  • Feeding Behavior / physiology*
  • Gastrointestinal Microbiome / immunology
  • Humans
  • Immunity, Mucosal / physiology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Period Circadian Proteins / genetics
  • Photoperiod
  • Receptors, G-Protein-Coupled / metabolism
  • Time Factors


  • Butyrates
  • Hcar2 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Receptors, G-Protein-Coupled
  • Ethanol