Alteration of oxidative-stress and related marker levels in mouse colonic tissues and fecal microbiota structures with chronic ethanol administration: Implications for the pathogenesis of ethanol-related colorectal cancer.

Hideo Ohira,Rie Mamoto,Seiji Takahashi,Toshiyuki Waki,Daiki Oikawa,Yoshio Fujioka,Masahira Hattori,Wao Nakagawa,Atsuki Tsuruya,Toru Nakayama,Hiroyasu Nakano

doi:10.1371/journal.pone.0246580

Abstract

Chronic ethanol consumption is a risk factor for colorectal cancer, and ethanol-induced reactive oxygen species have been suggested to play important roles in the pathogenesis of ethanol-related colorectal cancer (ER-CRC). In this study, the effects of 10-week chronic administration of ethanol on the colonic levels of oxidative stress and advance glycation end product (AGE) levels, as well as fecal microbiota structures, were examined in a mouse model. Chronic oral administration of ethanol in mice (1.0 mL of 1.5% or 5.0% ethanol (v/v) per day per mouse, up to 10 weeks) resulted in the elevation of colonic levels of oxidative stress markers (such as 8-hydroxy-2’-deoxyguanosine and 4-hydroxynonenal) compared to control mice, and this was consistently accompanied by elevated levels of inflammation-associated cytokines and immune cells (Th17 and macrophages) and a decreased level of regulatory T (Treg) cells to produce colonic lesions. It also resulted in an alteration of mouse fecal microbiota structures, reminiscent of the alterations observed in human inflammatory bowel disease, and this appeared to be consistent with the proposed sustained generation of oxidative stress in the colonic environment during chronic ethanol consumption. Moreover, the first experimental evidence that chronic ethanol administration results in elevated levels of advanced glycation end products (AGEs) and their receptors (RAGE) in the colonic tissues in mice is also shown, implying enhanced RAGE-mediated signaling with chronic ethanol administration. The RAGE-mediated signaling pathway has thus far been implicated as a link between the accumulation of AGEs and the development of many types of chronic colitis and cancers. Thus, enhancement of this pathway likely exacerbates the ethanol-induced inflammatory states of colonic tissues and might at least partly contribute to the pathogenesis of ER-CRC.

Highlights

Chronic ethanol consumption has been shown to be one of the major risk factors for colorectal cancer (CRC) [1, 2]
The results showed that the gut microbiotas of alcoholics were in a dysbiosis state, in which obligate anaerobes decreased, and facultative anaerobes were enriched
The mRNA levels of colonic inflammatory cytokines (TNF-α, IL-6, and IL-17A) and the chemokine monocyte chemotactic protein-1 (MCP-1) were all elevated from the control level with chronic oral administration of ethanol (Fig 4A–4D), and the relative abundances of Th17 cells and macrophages in the colonic tissues were greater in the ethanol groups than in the control (Fig 5D and 5F)

Summary

Introduction

Chronic ethanol consumption has been shown to be one of the major risk factors for colorectal cancer (CRC) [1, 2]. Previous colonoscopic screening results of Japanese alcoholic men, who are chronic ethanol consumers, showed colorectal adenoma in 54.5% of these subjects and intramucosal and invasive CRCs in 5.9% [3]. The mechanism by which chronic ethanol consumption increases CRC risk has been under examination. In the colorectal epithelial cells, ethanol oxidation, coupled with the mitochondrial electron transport system, coincidentally gives rise to the formation of reactive oxygen species (ROS) [7, 8]. There are few studies using animal models that have examined the effect of long-term chronic administration of ethanol on the pathophysiological processes in the gut [10], there are numerous animal studies about its effect on hepatic disorders (see [11] for example)

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Discussion

Conclusion