Light/Dark Shifting Promotes Alcohol-Induced Colon Carcinogenesis: Possible Role of Intestinal Inflammatory Milieu and Microbiota

Abstract

Background: Colorectal cancer (CRC) is associated with the modern lifestyle. Chronic alcohol consumption—a frequent habit of majority of modern societies—increases the risk of CRC. Our group showed that chronic alcohol consumption increases polyposis in a mouse mode of CRC. Here we assess the effect of circadian disruption—another modern life style habit—in promoting alcohol-associated CRC. Method: TS4Cre × adenomatous polyposis coli (APC)lox468 mice underwent (a) an alcohol-containing diet while maintained on a normal 12 h light:12 h dark cycle; or (b) an alcohol-containing diet in conjunction with circadian disruption by once-weekly 12 h phase reversals of the light:dark (LD) cycle. Mice were sacrificed after eight weeks of full alcohol and/or LD shift to collect intestine samples. Tumor number, size, and histologic grades were compared between animal groups. Mast cell protease 2 (MCP2) and 6 (MCP6) histology score were analyzed and compared. Stool collected at baseline and after four weeks of experimental manipulations was used for microbiota analysis. Results: The combination of alcohol and LD shifting accelerated intestinal polyposis, with a significant increase in polyp size, and caused advanced neoplasia. Consistent with a pathogenic role of stromal tryptase-positive mast cells in colon carcinogenesis, the ratio of mMCP6 (stromal)/mMCP2 (intraepithelial) mast cells increased upon LD shifting. Baseline microbiota was similar between groups, and experimental manipulations resulted in a significant difference in the microbiota composition between groups. Conclusions: Circadian disruption by Light:dark shifting exacerbates alcohol-induced polyposis and CRC. Effect of circadian disruption could, at least partly, be mediated by promoting a pro-tumorigenic inflammatory milieu via changes in microbiota.

Alcohol Effects on Colon Epithelium are Time‐Dependent

“…Epidemiological studies have shown that chronic disruption of the circadian clock (i.e., light/dark shifting) could increase CRC risk (Schernhammer et al., ; Wang et al., ). More recently, we observed that LD shift could promote CRC in mice fed alcohol (Bishehsari et al., ). However, the mechanism of how circadian disruption promotes colon carcinogenesis remains unclear.…”

“…Alcohol intake during the light (i.e., rest) period compared to the dark (i.e., active) period resulted in greater cell proliferation which coincided with decreased DNA repair and increased DNA damage. This is clinically relevant given the observed interaction of alcohol and circadian disruption in intestinal pathologies including barrier dysfunction and colon cancer (Bishehsari et al., ,, ).…”

“…Our data suggest that colonic XPA gene expression is circadian‐coupled. This could partly explain interaction of circadian disruption with alcohol in intestinal pathologies (Bishehsari et al., 2016a,b; Summa et al., ), particularly in promoting colon cancer (Bishehsari et al., ).…”

The effect of a multispecies probiotic on microbiota composition in a clinical trial of patients with diarrhea‐predominant irritable bowel syndrome

“…Sequencing was performed using an Illumina MiSeq, with a V2 kit and paired‐end 250 base reads at the University of Illinois at Chicago, as previously described . Primers (341F‐806R) targeting the V3‐V4 variable region of microbial 16S ribosomal RNA (rRNA) genes were used for PCR and prepared for next‐generation sequencing using a modified two‐step targeted amplicon sequencing approach, as described previously .…”

Depressionen und Lebererkrankungen: Die Rolle von Mikrobiom und Inflammation

“…Aber auch bei nur leicht ausgeprägten Hepatitiden kann es zur Aktivierung von Astrozyten, Gliazellen und Neuronen kommen [67]. Die Entzündungsparameter im Blut sowie die Expression entzündungsrelevanter Rezeptoren im Gehirn sind ebenfalls bei Leberzirrhose und Leberkrebs deutlich erhöht [68][69][70][71][72][73][74][75][76][77][78][79][80][81]. Eine mögliche Erklärung hierfür könnte die bei Patienten mit Lebererkrankungen erhöhte Durchlässigkeit des Darmepithels ("leaky gut") sein, die bei übermäßigen Alkoholkonsum [82], bei nichtalkoholischer Fettleber [83][84][85], bei zu hohem Nahrungs-Fettanteil [86], erhöhtem Stress [87,88], Major Depression [87,89] und mit zunehmendem Alter beobachtet wird [90].…”