非酒精性脂肪性肝病对肠道菌群多样性影响的初步研究

目的通过高脂饮食建立非酒精性脂肪性肝病(NAFLD)大鼠模型,观察NAFLD对肠道菌群多样性及群落组成的影响。方法建立NAFLD大鼠模型,通过大鼠肝脏病理切片HE染色验证NAFLD模型的成立,利用16sRNA测序技术对粪便肠道微生物进行检测分析,探讨NAFLD对肠道菌群多样性及群落组成的影响。结果肝脏组织学检查显示NAFLD组大鼠肝脏脂肪变明显,提示NAFLD动物模型建立成功。对照组Shannon多样性指数显著高于NAFLD组(P0.05)。提示对照组的肠道微生物多样性显著丰富于NAFLD组。在门水平的变化情况提示,与对照组相比,NAFLD组中厚壁菌门和变形菌门的相对丰度较高(均P0.05),而拟杆菌门的相对丰度则较低(P0.05)。在科水平的变化情况提示,正常对照组以毛螺菌科、瘤胃球菌科、拟杆菌科_S24-7为优势菌科,而NAFLD组则以毛螺菌科、瘤胃球菌科为优势菌科。与对照组相比,NAFLD组中的毛螺菌科、拟杆菌科、脱硫弧菌科、氨基酸球菌科、Christensenellaceae菌科等相对含量较高(均P0.05),而拟杆菌科_S24-7、普雷沃氏菌科、乳杆菌科等相对含量较低(均P0.05)。结论 NAFLD可降低肠道菌群的多样性,并且显著改变肠道菌群的组成和含量。     

饮食干预对非酒精性脂肪性肝病肠道菌群的影响

非酒精性脂肪性肝病(NAFLD)的发生与遗传和环境密切相关,肠道菌群在其发生和发展中发挥了重要作用,调节肠道菌群已成为干预NAFLD的重要靶点之一.无论是饮食总量还是结构都会对肠道菌群产生直接且长期的影响.通过低脂饮食、增加饮食中不饱和脂肪酸或者增加难以吸收的多糖等方式调整饮食结构,可以有效调节肠道菌群并治疗NAFLD,但高蛋白饮食的作用还存在争议.     

肠道菌群改变对非酒精性脂肪性肝病的影响

目的研究非酒精性脂肪性肝病（NAFLD）患者的肠道菌群变化,以及微生态制剂对其影响。方法60例N A FLD患者,以60例健康体检者作对照,采集粪便标本,测定肠道菌群。N A FLD患者给予枯草杆菌二联活菌肠溶胶囊口服（500 mg/次,3次/d）,疗程3个月,观察治疗前后肝功能（ALT、AST、GGT ）及血脂（TC、TG）水平的变化,肝脏脂肪定量及粪便中肠道菌群变化。结果 NAFLD组治疗前肠道葡萄球菌较健康对照组显著增多,双歧杆菌、乳杆菌、肠球菌数量明显降低（P＜0．05）;NAFLD患者治疗后与治疗前相比,肝功能（ALT、AST ）、血脂（TC）水平明显下降、肝脏脂肪定量明显减少,肠球菌、双歧杆菌及乳杆菌数量明显上升,葡萄球菌数量明显下降（P＜0．05）。结论 NAFLD患者存在肠道菌群改变,微生态制剂在N A FLD治疗中有重要的临床意义。     

肠道菌群与非酒精性脂肪性肝病

非酒精性脂肪性肝病（NAFLD）是一种常见慢性肝病,发病率呈逐年升高趋势,已逐渐引起人们的重视。1998年马歇尔正式提出了“肠-肝轴”的概念,肠道内环境与肝脏关系密切,越来越多的证据表明肠道菌群失调在NAFLD发病机制中起到了重要的作用。本文介绍了肠道菌群与NAFLD发病机制的关系。     

非酒精性脂肪性肝病与肠道菌群的关系

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是一种多病因导致的临床病理综合征,已成为最常见的慢性肝病之一,目前NAFLD完整的生理机制尚不完全清楚,近年来提出肠道菌群通过调控能量代谢、增加内源性乙醇、调节胆汁酸及胆碱代谢,破坏免疫平衡引发机体低度炎症等途径促进NAFLD的发生、发展,本文就肠道菌群与NAFLD的相关机制做一概述。     

肠道菌群对非酒精性脂肪性肝病铁代谢的影响

<正>非酒精性脂肪性肝病(NAFLD)是与胰岛素抵抗(IR)及遗传易感性密切相关的一组以肝脏脂质过度蓄积为主要病理表现的慢性代谢性肝脏疾病^[1]。其主要包括：单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)、NASH相关性肝硬化。预计到2030年中国的NAFLD总人数将增加到3.145 8亿例,是全球NAFLD患病率增长最快的国家^[2]。然而,关于NAFLD的发病机制目前尚未完全阐明。“多重打击学说”是当前研究最多的NAFLD的发病机制,     

肠道微生态变化与非酒精性脂肪性肝病研究进展

由定植于肠道的大量固有菌群、肠道上皮细胞及肠道局部粘膜免疫系统组成了肠道微生态系统。"肝-肠轴"概念的提出为从肠道微生态角度寻找非酒精性脂肪性肝病(NAFLD)的诊疗措施提供了依据。肠道微生态失衡所致的肠道菌群过度生长、肠黏膜通透性改变、免疫功能紊乱、肠源性内毒素血症、效应细胞激活及炎症因子生成等在NAFLD发生发展中发挥了不容忽视的作用。深入研究肠道菌群与NAFLD之间的关系将为NAFLD的预防和治疗提供新靶点。     

应用454测序技术评价非酒精性脂肪性肝病患者肠道菌群结构差异

目的阐明非酒精性脂肪性肝病(NAFLD)患者肠道菌群结构特征。方法采用454焦磷酸测序技术,对47例经"肝活检"确诊的NAFLD患者和34例健康人新鲜粪便样品16S DNA V3~V5可变区进行测序,通过序列比较及操作分类单元(OTU)划分评价肠道菌群结构差异。结果 NAFLD患者OTUs为(88.32±28.27),显著低于健康人[(109.65±30.65),P0.01];在"门"水平,NAFLD患者厚壁菌门所占比例为(51.2±17.8)%,显著高于健康人的[(46.4±12.8)%,P=0.048],而拟杆菌门为(31.6±18.9)%,显著低于健康人的[(43.3±14.4)%,P0.001];在"纲"水平上,NAFLD组Erysipelotrichi纲占(3.2±5.1)%,显著高于健康人的[(1.0±1.2)%,P=0.009],而Bacteroidia纲占(31.0±18.8)%,显著低于对照组的[(42.3±14.0)%,P=0.004];在"属"水平上,NAFLD组乳球菌占(0.0038±0.0001)%,低于健康组的[(0.0145±0.001)%,P=0.003],普氏菌属也同样显著减少(P=0.022),而链球菌(Streptococcus)在NAFLD占(1.50±0.03)%,显著高于对照组的[(0.21±0.24)%,P=0.004]。结论 NAFLD患者肠道菌群多样性减少,存在构成显著异常,是致病因素抑或其后果仍有待于进一步研究。     

肠道菌群及其代谢物与非酒精性脂肪性肝病

总结相关的实验研究发现,人体肠道菌群是非酒精性脂肪性肝病(NAFLD)发生发展的关键因素,除了人体肠道菌群组成的变化外,肠道菌群的代谢物也成为调节NAFLD病理过程的关键因素;有研究发现,肠道菌群的代谢物如短链脂肪酸、胆汁酸、三甲胺和乙醇等通过肠-肝轴途径影响肝脏代谢功能,从而导致疾病发生。现从NAFLD患者肠道菌群和代谢物的变化及发病机制,总结并探讨通过调节肠道菌群及其代谢物来治疗NAFLD,期望这些治疗策略会成为未来优化治疗NAFLD等代谢性肝病的有效方法。     

Significance of gut microbiota in alcoholic and non-alcoholic fatty liver diseases

Liver-gut communication is vital in fatty liver diseases, and gut microbes are the key regulators in maintaining liver homeostasis. Chronic alcohol abuse and persistent overnutrition create dysbiosis in gut ecology, which can contribute to fatty liver disease. In this review, we discuss the gut microbial compositional changes that occur in alcoholic and nonalcoholic fatty liver diseases and how this gut microbial dysbiosis and its metabolic products are involved in fatty liver disease pathophysiology. We also summarize the new approaches related to gut microbes that might help in the diagnosis and treatment of fatty liver disease.     

Procyanidin B2 protects against diet-induced obesity and non-alcoholic fatty liver disease via the modulation of the gut microbiota in rabbits

BACKGROUND Procyanidins have beneficial effects on metabolic syndrome and antimicrobial activity,but the mechanisms underlying these effects are unclear.AIM To investigate the effects of procyanidin B2(PB2)on non-alcoholic fatty liver disease and to explore the possible mechanism.METHODS Thirty male New Zealand white rabbits were randomized into three groups.All of them were fed either a high-fat-cholesterol diet(HCD)or chow diet.HCD-fed rabbits were treated with vehicle or PB2 daily for 12 wk.Body weight and food intake were evaluated once a week.Serum biomarkers,such as total cholesterols,triglycerides,and aspartate transaminase,were detected.All rabbits were sacrificed and histological parameters of liver were assessed by hematoxylin and eosin-stained sections.Moreover,several lipogenic genes and gut microbiota(by 16S rRNA sequencing)were investigated to explore the possible mechanism.RESULTS The HCD group had higher body weight,liver index,serum lipid profile,insulin resistance,serum glucose,and hepatic steatosis compared to the CHOW group.PB2 treatment prevented HCD-induced increases in body weight and hypertriglyceridemia in association with triglyceride accumulation in the liver.PB2 also ameliorated low-grade inflammation,which was reflected by serum lipopolysaccharides and improved insulin resistance.In rabbit liver,PB2 prevented the upregulation of steroid response element binding protein 1c and fatty acid synthase and the downregulation of carnitine palmitoyltransferase,compared to the HCD group.Moreover,HCD led to a decrease of Bacteroidetes in gut microbiota.PB2 significantly improved the proportions of Bacteroidetes at the phylum level and Akkermansia at the genus level.CONCLUSION Our results indicate the possible mechanism of PB2 to improve HCD-induced features of metabolic syndrome and provide a new dietary supplement.     

Prolonged high-fat-diet feeding promotes non-alcoholic fatty liver disease and alters gut microbiota in mice

BACKGROUND Non-alcoholic fatty liver disease(NAFLD) has become an epidemic largely due to the worldwide increase in obesity. While lifestyle modifications and pharmacotherapies have been used to alleviate NAFLD, successful treatment options are limited. One of the main barriers to finding safe and effective drugs for long-term use in NAFLD is the fast initiation and progression of disease in the available preclinical models. Therefore, we are in need of preclinical models that(1) mimic the human manifestation of NAFLD and(2) have a longer progression time to allow for the design of superior treatments.AIM To characterize a model of prolonged high-fat diet(HFD) feeding for investigation of the long-term progression of NAFLD.METHODS In this study, we utilized prolonged HFD feeding to examine NAFLD features in C57 BL/6 male mice. We fed mice with a HFD(60% fat, 20% protein, and 20%carbohydrate) for 80 wk to promote obesity(Old-HFD group, n = 18). A low-fat diet(LFD)(14% fat, 32% protein, and 54% carbohydrate) was administered for the same duration to age-matched mice(Old-LFD group, n = 15). An additional group of mice was maintained on the LFD(Young-LFD, n = 20) for a shorter duration(6 wk) to distinguish between age-dependent and age-independent effects. Liver, colon, adipose tissue, and feces were collected for histological and molecular assessments.RESULTS Prolonged HFD feeding led to obesity and insulin resistance. Histological analysis in the liver of HFD mice demonstrated steatosis, cell injury, portal and lobular inflammation and fibrosis. In addition, molecular analysis for markers of endoplasmic reticulum stress established that the liver tissue of HFD mice have increased phosphorylated Jnk and CHOP. Lastly, we evaluated the gut microbial composition of Old-LFD and Old-HFD. We observed that prolonged HFD feeding in mice increased the relative abundance of the Firmicutes phylum. At the genus level, we observed a significant increase in the abundance of Adercreutzia,Coprococcus, Dorea, and Ruminococcus and decreased relative abundance of Turicibacter and Anaeroplasma in HFD mice.CONCLUSION Overall, these data suggest that chronic HFD consumption in mice can mimic pathophysiological and some microbial events observed in NAFLD patients.     

Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view

Non-alcoholic fatty liver disease(NAFLD) is a highly prevalent metabolic disorder with steadily increasing incidence rates worldwide, especially in the West. There are no drugs available at present to treat NAFLD, and the primary therapeutic options include weight loss and the combination of healthy diet and exercise. Therefore, novel interventions are required that can target the underlying risk factors. Gut microbiota is an "invisible organ" of the human body and vital for normal metabolism and immuno-modulation. The number and diversity of microbes differ across the gastrointestinal tract from the mouth to the anus, and is most abundant in the intestine. Since dysregulated gut microbiota is an underlying pathological factor of NAFLD, it is a viable therapeutic target that can be modulated by antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and microbial metabolites. In this review, we summarize the most recent advances in gut microbiota-targeted therapies against NAFLD in clinical and experimental studies, and critically evaluate novel targets and strategies for treating NAFLD.     

Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis

Recently, the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma (HCC), even in the absence of cirrhosis. Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC. The composition of the gut microbiota differs significantly in obese and lean individuals, especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla, and, after establishing steatohepatitis, it undergoes minor changes during the progression of the disease toward advanced fibrosis. Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice. On the contrary, the transplantation of healthy microbiota to obese mice relieves steatosis. However, further studies are needed to confirm these findings and the mechanisms involved. In this review, we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis (NASH). Furthermore, a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed, and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.     

Gut microbiota and liver diseases

Several studies revealed that gut microbiota are associated with various human diseases,e.g.,metabolic diseases,allergies,gastroenterological diseases,and liver diseases.The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein,and the liver-gut axis is important to understand the pathophysiology of several liver diseases,especially non-alcoholic fatty liver disease and hepatic encephalopathy.Moreover,gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis.Based on theseprevious findings,trials using probiotics have been performed for the prevention or treatment of liver diseases.In this review,we summarize the current understanding of the changes in gut microbiota associated with various liver diseases,and we describe the therapeutic trials of probiotics for those diseases.     

肠道微生物在非酒精性脂肪肝发生发展中的作用机制

非酒精性脂肪肝是代谢综合征的肝脏表现,可发展为肝硬化和肝癌。非酒精性脂肪肝的病因尚未明确,近年来宿主肠道微生物在非酒精性脂肪肝的发生、发展及治疗中的作用越来越受到重视。目前认为人类肠道是一个内在重要的代谢及免疫器官,肠道微生物的组成可影响宿主代谢,改变肠道通透性,引起炎症及一系列免疫反应。本文就肠道微生物在非酒精性脂肪肝的病理生理过程中的作用机制进行综述。     

降脂药物在NAFLD患者中的合理应用

精性脂肪性肝病（Non-alcoholic fatty liver disease, NAFLD）现已成为全球第一大肝病,而脂肪代谢异常是其发病机制中最关键的一环^[1]。NAFLD伴有的脂代谢紊乱不仅表现在肝脏脂质过载沉积引起的代谢应激损伤,而且常并发血脂水平异常,包括高胆固醇血症、高甘油三酯血症、低高密度脂蛋白血症和混合型高脂血症等,后者是导致NAFLD患者最终死于动脉粥样硬化性心血管疾病（ASCVD,包括冠心病、缺血性卒中以及外周动脉疾病）最重要的危险因素。控制血脂水平对于防治NAFLD相关的代谢综合征及其相关终末期器官病变,改善患者远期预后尤为重要。随着大量新研究成果的发表,针对血脂异常的治疗发生了重大观念上的改变。最近,欧美和我国均相继更新了血脂异常管理的权威指南,如2013年美国血脂控制指南、2014年美国脂质协会发布的血脂管理指南、2014 年中国胆固醇教育计划等。另一方面,应用最广泛的降脂药物如他汀类和贝特类均存在不同程度的肝损伤风险和其他不良反应,特别是NAFLD人群肝脏本身存在脂肪变及炎症多重打击,加上目前尚缺乏治疗NAFLD的特效药物,单纯依靠减肥、保肝抗炎药物、改善胰岛素抵抗药物治疗NAFLD的效果并不理想^[1]。因此,如何结合最新的研究成果,采取正确的降脂治疗方法,在有效改善NAFLD患者长期预后的同时不加重肝脏损伤,是当前临床治疗NAFLD的重点和难点。