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

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.

Alcoholization and ethanol withdrawal leads to the activation of neuroimmune response in the prefrontal rat brain

The effects of acute (single) and chronic ethanol administration on the level of pro-inflammatory cytokines (IL-1β and TNF-α), as well as on the level of mRNA NF-κB, TLR4 and its endogenous agonist, HMGB1 protein, were investigated in rats. It was shown that the level of TLR4, HMGB1 and cytokines was significantly higher than in control group. The ethanol withdrawal after prolonged administration resulted in dysregulation of cytokine levels, TLR4 and HMGB1. Changes in the level of TLR4 and HMGB1 mRNA demonstrated a similar pattern. The obtained data confirm that prolonged alcoholization leads to the activation of TLR4-dependent signaling in the prefrontal cortex of rats, and this can lead to a prolonged neuro-inflammatory process in the brain.