Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice.
Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice.
复制标题
DOI：
10.1371/journal.pone.0174544
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Lowe PP;Gyongyosi B;Satishchandran A;Iracheta-Vellve A;Ambade A;Kodys K;Catalano D;Ward DV;Szabo G
酒精引起的肠道菌群失调会破坏肠道-肝轴的稳态功能，并且对于酒精性肝病的发展至关重要。在这里，我们研究了早期酒精性脂肪性肝炎模型中肠道微生物组成的变化，并剖析了肠道微生物在酒精诱导的肝脏病理中的致病作用。野生型小鼠接受为期 10 天的含 5% 酒精的饮食或等热量对照饮食加单次暴饮暴食。 16S rDNA 测序确定了酒精喂养和配对喂养动物盲肠中的细菌群落。在饮酒之前和整个过程中，一些小鼠接受了抗生素混合物的治疗。评估肝脏中性粒细胞、细胞因子和脂肪变性。慢性酒精急性给药引起盲肠中各种细菌门的变化，包括放线菌增加和疣微菌减少，这完全是由阿克曼氏菌属减少所致。抗生素治疗减少了肠道细菌负荷和循环细菌壁成分脂多糖（LPS）。我们发现，细菌负荷抑制可防止肝脏中与酒精相关的髓过氧化物酶（MPO）阳性浸润中性粒细胞数量的增加。在抗生素治疗的酒精喂养小鼠中，肝脏 mRNA 肿瘤坏死因子 α (Tnfα)、C-X-C 基序趋化因子配体 1 (Cxcl1) 和循环蛋白单核细胞趋化蛋白 1 (MCP-1) 的表达也有所减少。通过油红 O 染色测量，在抗生素治疗的小鼠中，酒精诱导的肝脂肪变性显着减少。酒精和抗生素治疗也改变了调节脂质产生和储存的基因。有趣的是，抗生素治疗并不能防止酒精引起的血清转氨酶（ALT/AST）升高。我们的数据表明，慢性酒精喂养会在多个分类水平上改变微生物群落，并将阿克曼氏菌的丧失确定为酒精引起的肠道菌群失调的早期标志。我们得出的结论是，肠道微生物影响饮酒后的肝脏炎症、中性粒细胞浸润和肝脏脂肪变性，这些数据进一步强调了肠-肝轴在早期酒精性肝病中的作用。
Alcohol-induced intestinal dysbiosis disrupts homeostatic gut-liver axis function and is essential in the development of alcoholic liver disease. Here, we investigate changes in enteric microbiome composition in a model of early alcoholic steatohepatitis and dissect the pathogenic role of intestinal microbes in alcohol-induced liver pathology. Wild type mice received a 10-day diet that was either 5% alcohol-containing or an isocaloric control diet plus a single binge. 16S rDNA sequencing defined the bacterial communities in the cecum of alcohol- and pair-fed animals. Some mice were treated with an antibiotic cocktail prior to and throughout alcohol feeding. Liver neutrophils, cytokines and steatosis were evaluated. Acute-on-chronic alcohol administration induced shifts in various bacterial phyla in the cecum, including increased Actinobacteria and a reduction in Verrucomicrobia driven entirely by a reduction in the genus Akkermansia. Antibiotic treatment reduced the gut bacterial load and circulating bacterial wall component lipopolysaccharide (LPS). We found that bacterial load suppression prevented alcohol-related increases in the number of myeloperoxidase- (MPO) positive infiltrating neutrophils in the liver. Expression of liver mRNA tumor necrosis factor alpha (Tnfα), C-X-C motif chemokine ligand 1 (Cxcl1) and circulating protein monocyte chemoattractant protein-1 (MCP-1) were also reduced in antibiotic-treated alcohol-fed mice. Alcohol-induced hepatic steatosis measured by Oil-Red O staining was significantly reduced in antibiotic treated mice. Genes regulating lipid production and storage were also altered by alcohol and antibiotic treatment. Interestingly, antibiotic treatment did not protect from alcohol-induced increases in serum aminotransferases (ALT/AST). Our data indicate that acute-on-chronic alcohol feeding alters the microflora at multiple taxonomic levels and identifies loss of Akkermansia as an early marker of alcohol-induced gut dysbiosis. We conclude that gut microbes influence liver inflammation, neutrophil infiltration and liver steatosis following alcohol consumption and these data further emphasize the role of the gut-liver axis in early alcoholic liver disease.