McMahan Rachel H, Najarro Kevin M, Mullen Juliet E, Paul Madison T, Orlicky David J, Hulsebus Holly J, Kovacs Elizabeth J
Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, 12700 East 19th Ave, RC2, Mail Stop #8620, CO, 80045, Aurora, USA.
GI and Liver Innate Immune Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, 80045, USA.
Immun Ageing. 2021 Sep 23;18(1):37. doi: 10.1186/s12979-021-00247-8.
There are currently > 600 million people over the age of 65 globally and this number is expected to double by the year 2050. Alcohol use among this population is on the rise, which is concerning as aging is associated with increased risk for a number of chronic illnesses. As most studies investigating the effects of alcohol have focused on young/middle-aged populations, there is a dearth of information regarding the consequences of alcohol use in older consumers. In addition, most murine ethanol models have concentrated on exposure to very high levels of ethanol, while the vast majority of elderly drinkers do not consume alcohol in excess; instead, they drink on average 2 alcoholic beverages a day, 3-4 days a week.
We designed a murine model of aging and moderate ethanol consumption to determine if the deleterious effects of alcohol on the gut-liver axis are exacerbated in aged, relative to younger, animals. Aged and young mice were exposed to a multi-day moderate exposure ethanol regimen for 4 weeks and changes in gut permeability along with intestinal tight junction protein and antimicrobial peptide gene expression were measured. In addition, hepatic inflammation was assessed by histological analysis, inflammatory gene expression and flow cytometric analysis of inflammatory infiltrate.
Our results reveal that in aged, but not young mice, moderate ethanol exposure yielded significantly worsened intestinal permeability, including increased bacterial translocation from the gut, elevated serum iFABP and leakage of FITC-dextran from the gut. Interestingly, moderate ethanol exposure in young animals led to gut protective transcriptional changes in the ileum while this protective response was blunted in aged mice. Finally, moderate ethanol exposure in aged mice also resulted in marked inflammatory changes in the liver.
These results demonstrate that aged mice are more susceptible to ethanol-induced gut barrier dysfunction and liver inflammation, even at moderate doses of ethanol. This increased vulnerability to ethanol's gastrointestinal effects has important implications for alcohol use in the aging population. Future studies will explore whether improving intestinal barrier function can reverse these age-related changes.
目前全球65岁以上人口超过6亿，预计到2050年这一数字将翻番。该人群中的酒精使用呈上升趋势，鉴于衰老与多种慢性疾病风险增加相关，这令人担忧。由于大多数研究酒精影响的研究都集中在年轻/中年人群，关于老年饮酒者酒精使用后果的信息匮乏。此外，大多数小鼠乙醇模型都集中在暴露于非常高剂量的乙醇，而绝大多数老年饮酒者并非过量饮酒；相反，他们平均每天饮用2杯酒精饮料，每周饮用3 - 4天。
我们设计了一种衰老和适度乙醇摄入的小鼠模型，以确定相对于年轻动物，衰老动物中酒精对肠 - 肝轴的有害影响是否会加剧。将老年和年轻小鼠暴露于为期4周的多日适度乙醇摄入方案，测量肠道通透性以及肠道紧密连接蛋白和抗菌肽基因表达的变化。此外，通过组织学分析、炎症基因表达和炎症浸润的流式细胞术分析评估肝脏炎症。
我们的结果显示，在老年小鼠而非年轻小鼠中，适度乙醇暴露导致肠道通透性显著恶化，包括肠道细菌易位增加、血清iFABP升高以及FITC - 葡聚糖从肠道渗漏。有趣的是，年轻动物中的适度乙醇暴露导致回肠中肠道保护性转录变化，而这种保护反应在老年小鼠中减弱。最后，老年小鼠中的适度乙醇暴露也导致肝脏出现明显的炎症变化。
这些结果表明，即使在适度剂量的乙醇情况下，老年小鼠对乙醇诱导的肠道屏障功能障碍和肝脏炎症更敏感。对乙醇胃肠道作用的这种易感性增加对老年人群中的酒精使用具有重要意义。未来的研究将探索改善肠道屏障功能是否可以逆转这些与年龄相关的变化。
