Division of Clinical Nutrition, Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan.
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, Sendai, Japan.
PLoS One. 2021 Feb 12;16(2):e0246580. doi: 10.1371/journal.pone.0246580. eCollection 2021.
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.
慢性乙醇摄入是结直肠癌的一个风险因素，并且乙醇诱导的活性氧已被认为在乙醇相关结直肠癌（ER-CRC）的发病机制中发挥重要作用。在这项研究中，在小鼠模型中检查了 10 周慢性乙醇给药对结肠氧化应激和晚期糖基化终产物（AGE）水平以及粪便微生物组结构的影响。在小鼠中慢性口服给予乙醇（每天每只小鼠 1.0 毫升 1.5%或 5.0%乙醇（v/v），长达 10 周）导致结肠氧化应激标志物（如 8-羟基-2'-脱氧鸟苷和 4-羟壬烯醛）的水平升高与对照小鼠相比，这始终伴随着炎症相关细胞因子和免疫细胞（Th17 和巨噬细胞）水平升高以及调节性 T（Treg）细胞水平降低，以产生结肠病变。它还导致小鼠粪便微生物组结构的改变，类似于在人类炎症性肠病中观察到的改变，这似乎与在慢性乙醇摄入期间结肠环境中持续产生氧化应激一致。此外，还首次证明了慢性乙醇给药导致小鼠结肠组织中晚期糖基化终产物（AGEs）及其受体（RAGE）水平升高的实验证据，这表明 RAGE 介导的信号转导与慢性乙醇给药增强有关。迄今为止，RAGE 介导的信号通路已被认为是 AGEs 积累与多种类型的慢性结肠炎和癌症发展之间的联系。因此，该途径的增强可能会加剧乙醇诱导的结肠组织炎症状态，并可能至少部分有助于 ER-CRC 的发病机制。
