Obesity,fatty liver disease and intestinal microbiota

Nonalcoholic fatty liver disease(NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota(dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations.     

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。     

非酒精性脂肪性肝病发生及进展的危险因素

非酒精性脂肪性肝病(NAFLD)的患病率逐年增加,目前成为我国成年人中最常见的慢性肝病之一。NAFLD可由非酒精性肝脂肪变性进展为非酒精性脂肪性肝炎、肝硬化、肝细胞癌及NAFLD相关性心血管事件、死亡等重大疾病。现对NAFLD发生的危险因素以及进展为肝纤维化、肝硬化、肝癌、相关心血管事件和死亡等重大疾病的相关危险因素进行综述,以便进一步探讨NAFLD发生发展的机制,降低NAFLD的患病率,减缓NAFLD的进展程度,降低相关疾病的病死率。     

粪菌移植治疗非酒精性脂肪性肝病研究进展

非酒精性脂肪肝病（non-alcoholic fatty liver disease, NAFLD）的发病率在世界范围内呈明显上升趋势,由于目前尚无确切的特效治疗方式,严重影响人类健康。近年来,越来越多的研究表明肠道菌群通过肝-肠轴影响肝功能,肠道菌群失调是NAFLD发病的重要原因。因此,纠正肠道菌群失调,可以预防和减轻NAFLD的发生、发展。粪菌移植（fecal microbiota transplantation, FMT）被认为是纠正肠道菌群失调最有效的方法,但其在NAFLD中的治疗作用还未明确。此外,FMT治疗NAFLD的潜在分子机制也尚未阐明。本文就FMT治疗NAFLD的研究现状进行总结,并发掘其潜在的分子机制,为FMT作为治疗NAFLD的有效手段提供理论支持。     

Final results of a long-term,clinical follow-up in fatty liver patients

Objective. There is increasing focus on non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to conduct a long-term clinical follow-up of patients with biopsy-confirmed fatty liver without inflammation or significant fibrosis (pure fatty liver), to analyse for potential risk factors at the time of index liver biopsy important for survival and the development of cirrhosis and to describe the causes of death. Material and methods. Patients were linked through their personal identification number to the Danish National Registry of Patients and the Register of Causes of Death. All admissions, discharge diagnoses and causes of death during follow-up were collected. All surviving patients were invited to a clinical follow-up. Results. The follow-up period was 20.4 and 21.0 years, respectively, for the NAFLD and alcoholic fatty liver disease (AFLD) groups. Two NAFLD patients (1.2%) developed cirrhosis during the follow-up period versus 54 (22%) AFLD patients. Sixty-four percent of 178 surviving patients out of an original cohort of 417 patients attended the clinical follow-up. In NAFLD patients, none of the risk factors studied was significant in relation to the risk of death. Patients with AFLD died primarily from cirrhosis and other alcohol-related disorders, whereas in patients with NAFLD the main causes of death were cardiovascular disease and cancer. Conclusions. For patients with pure non-alcoholic fatty liver, survival was good and independent of the histological, clinical and biochemical characteristics at the time of biopsy; the main causes of death were cardiovascular disease and cancer.     

Comparison of the natural history of alcoholic and nonalcoholic fatty liver disease

Fatty liver disease represents a common clinical entity. It is classically divided into alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD). Whereas AFLD occurs in as many as 10 million Americans, NAFLD represents the most common chronic liver disease and is the most common cause of liver enzyme abnormalities in the United States. Both diseases encompass the clinical spectrum of steatosis, steatohepatitis, and cirrhosis. Although they are histologically indistinct, AFLD and NAFLD follow different clinical courses. This article compares the natural history of these diseases.     

Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease

Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.     

omega-3多不饱和脂肪酸治疗非酒精性脂肪性肝病的研究进展

随着人们生活方式和饮食结构的改变,非酒精性脂肪性肝病(NAFLD)发病率逐年上升,严重威胁人类健康。NAFLD疗法一直是基础和临床肝病研究的热门领域。近年来,诸多研究揭示omega-3多不饱和脂肪酸(ω3-PUFA)可促进脂肪酸氧化并改善肠道稳态,从而改善脂代谢和肝脏炎症,因而越来越多的临床研究开始将ω3-PUFA运用于NAFLD的治疗中。然而,ω3-PUFA治疗NAFLD的机制尚不明确,相关临床研究也存在一定局限性。主要介绍了ω3-PUFA在NAFLD中发挥的作用以及相关的临床研究结果,并进一步讨论ω3-PUFA治疗NAFLD尚需解决的问题。     

丁酸在非酒精性脂肪性肝病发生发展中的作用

非酒精性脂肪性肝病(NAFLD)特征为非酒精性因素所致的肝脂肪变性,其发病机制、疾病演变过程以及治疗和预防都逐渐受到广泛重视。目前关于肠道微生态与肥胖、糖尿病、心血管疾病等代谢性疾病关系的研究越来越多。近来也有许多研究发现肠道菌群代谢产物丁酸与NAFLD有着密切的关系,通过多种机制影响NAFLD的发生发展,如减轻炎症反应、抑制胰岛素抵抗以及减弱肝线粒体氧化应激等,研究丁酸与NAFLD疾病发病的关系有望为NAFLD的防治开辟新的途径。     

G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment

Nonalcoholic fatty liver disease(NAFLD)is a broad-spectrum disease,ranging from simple hepatic steatosis to nonalcoholic steatohepatitis,which can progress to cirrhosis and liver cancer.Abnormal hepatic lipid accumulation is the major manifestation of this disease,and lipotoxicity promotes NAFLD progression.In addition,intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins,resulting in progression of NAFLD to fibrosis and even cirrhosis.G protein-coupled receptors(GPCRs)have been shown to play essential roles in metabolic disorders,such as NAFLD and obesity,through their function as receptors for bile acids and free fatty acids.In addition,GPCRs link gut microbiota-mediated connections in a variety of diseases,such as intestinal diseases,hepatic steatosis,diabetes,and cardiovascular diseases.The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids.GPCR agonists,including peptides and natural products like docosahexaenoic acid,have been applied to investigate their role in liver diseases.Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome.This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment.Overall,understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.     

Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is currently recognized as one of the most common causes of chronic liver disease. It involves a spectrum of conditionsthat include pure steatosis without inflammation, steatohepatitis, fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes and, thus, oxidative stress, which is followed by inflammatory response. However, NAFLD pathogenesis is still largely unknown and has been extensively investigated. Although life style modification with the aim of losing weight has been advocated to treat this disorder, its effectiveness is limited; additionally, there is no specific pharmacologic treatment until nowadays. Recent evidence suggests that the gut microbiota may play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. Differences in gut microbiota between NAFLD patients and lean individuals as well as presence of small intestinal bacterial overgrowth in NAFLD subjects have been demonstrated. Furthermore, some data indicate that the immunoregulatory effects of probiotics may be beneficial in NAFLD treatment as they modulate the intestinal microbiota; improve epithelial barrier function and strengthen the intestinal wall decreasing its permeability; reduce bacterial translocation and endotoxemia; improve intestinal inflammation; and reduce oxidative and inflammatory liver damage. In this article, we review the clinical trials on the use of probiotics in the treatment of NAFLD and discuss the effects of these agents and their efficacy as an emerging therapeutic resource to treat NAFLD patients.     

Potential mechanisms linking gut microbiota and portal hypertension

Gut microbiota is the largest collection of commensal micro‐organisms in the human body, engaged in reciprocal cellular and molecular interactions with the liver. This mutually beneficial relationship may break down and result in dysbiosis, associated with disease phenotypes. Altered composition and function of gut microbiota has been implicated in the pathobiology of nonalcoholic fatty liver disease (NAFLD), a prevalent condition linked to obesity, insulin resistance and endothelial dysfunction. NAFLD may progress to cirrhosis and portal hypertension, which is the result of increased intrahepatic vascular resistance and altered splanchnic circulation. Gut microbiota may contribute to rising portal pressure from the earliest stages of NAFLD, although the significance of these changes remains unclear. NAFLD has been linked to lower microbial diversity and weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defence and inflammation. Moreover, disrupted host‐microbial metabolic interplay alters bile acid signalling and the release of vasoregulatory gasotransmitters. These perturbations become prominent in cirrhosis, increasing the risk of clinically significant portal hypertension and leading to bacterial translocation, sepsis and acute‐on‐chronic liver failure. Better understanding of the gut‐liver axis and identification of novel microbial molecular targets may yield specific strategies in the prevention and management of portal hypertension.     

Fatty Liver: a Link to Cardiovascular Disease – Its Natural History,Pathogenesis, and Treatment

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in western society and is increasing in parallel with the worldwide epidemic of obesity. It exists in a simple form, steatosis, or a more complex and more dangerous form, steatohepatitis, and it is often but not always associated with the metabolic syndrome. NAFLD can progress to cirrhosis and hepatocellular carcinoma. It is responsible for the majority of cryptogenic cirrhosis cases. Increasingly, NAFLD and its more sinister form, steatohepatitis, have been linked to the increased incidence of cardiovascular disease (CVD) worldwide, independent of the metabolic syndrome. Death from CVD surpasses death from liver complications, but that is beginning to change as people are living longer with CVD. In this article, we will review nonalcoholic fatty liver disease and its epidemiology, prevalence, pathology, and link to CVD.     

ASH and NASH

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) have a similar pathogenesis and histopathology but a different etiology and epidemiology. NASH and ASH are advanced stages of non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD). NAFLD is characterized by excessive fat accumulation in the liver (steatosis), without any other evident causes of chronic liver diseases (viral, autoimmune, genetic, etc.), and with an alcohol consumption ≤20-30 g/day. On the contrary, AFLD is defined as the presence of steatosis and alcohol consumption >20-30 g/day. The most common phenotypic manifestations of primary NAFLD/NASH are overweight/obesity, visceral adiposity, type 2 diabetes, hypertriglyceridemia and hypertension. The prevalence of NAFLD in the general population in Western countries is estimated to be 25-30%. The prevalence and incidence of NASH and ASH are not known because of the impossibility of performing liver biopsy in the general population. Up to 90% of alcoholics have fatty liver, and 5-15% of these subjects will develop cirrhosis over 20 years. The risk of cirrhosis increases to 30-40% in those who continue to drink alcohol. About 10-35% of alcoholics exhibit changes on liver biopsy consistent with alcoholic hepatitis. Natural histories of NASH and ASH are not completely defined, even if patients with NASH have a reduced life expectancy due to liver-related death and cardiovascular diseases. The best treatment of AFLD/ASH is to stop drinking, and the most effective first-line therapeutic option for NAFLD/NASH is non-pharmacologic lifestyle interventions through a multidisciplinary approach including weight loss, dietary changes, physical exercise, and cognitive-behavior therapy.     

Non‐alcoholic fatty liver disease and type 2 diabetes: An update

The global prevalence of non‐alcoholic fatty liver disease (NAFLD) is rising, along with the epidemic of diabesity. NAFLD is present in >70% of individuals with type 2 diabetes. Although the mutually detrimental relationship between NAFLD and type 2 diabetes has been well established, a multitude of recent studies have further shown that type 2 diabetes is closely linked to the development of cirrhosis, hepatocellular carcinoma, liver‐related morbidity and mortality. In contrast, NAFLD also negatively impacts type 2 diabetes both in terms of its incidence and related adverse clinical outcomes, including cardiovascular and chronic kidney diseases. In response to these global health threats, clinical care pathways for NAFLD and guidelines for metabolic dysfunction‐associated fatty liver disease have been developed. Several antidiabetic agents have been evaluated for their potential hepatic benefits with promising results. Furthermore, type 2 diabetes patients are increasingly represented in clinical trials of novel therapeutics for NAFLD. However, despite the wealth of knowledge in NAFLD and type 2 diabetes, lack of awareness of the disease and the potential weight of this problem remains a major challenge, especially among clinicians who are outside the field of hepatology and gastroenterology. This review therefore aimed to provide all diabetes care providers with a summary of the latest evidence that supports NAFLD as an emerging diabetic complication of increasing importance, and to present the current recommendations, focusing on the assessment and therapeutic strategies, on the management of NAFLD among type 2 diabetes patients.     

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis

A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.     

Endocrine causes of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship ofNAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.     

非酒精性脂肪性肝病的自然史和危险因素

非酒精性脂肪性肝病(NAFLD)是一种肝组织病理学改变,与酒精性肝病相类似,但无过量饮酒史的临床病理综合征.现有的研究提示大多数NAFLD是一个良性病变,但一些患者仍可导致肝硬化、肝癌和肝功能衰竭.肥胖、胰岛素抵抗、C-反应蛋白及糖尿病、高血脂、高血压、HCV等在NAFLD的发病过程中都是重要的危险因素,因此预防和治疗相关的危险因素对于NAFLD的发生和发展至关重要.     

Nonalcoholic fatty liver disease - A multisystem disease?

Non-alcoholic fatty liver disease(NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome(Met S). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of Met S. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease(CVD), diabetes mellitus type 2(T2DM) and chronic kidney disease(CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with Met S, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2 DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both(sub-) specialists and primary care physicians.     

Advanced hepatic fibrosis and cirrhosis due to nonalcoholic fatty liver disease in Sri Lankan children: a preliminary report

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and may progress to advanced hepatic fibrosis and cirrhosis in some patients. Cirrhosis due to NAFLD is considered extremely rare in children in the Asia–Pacific region. We report the characteristics of 5 children with advanced hepatic fibrosis and cirrhosis due to NAFLD. Four of them were obese, and all of them had high alanine transaminase levels and ultrasonographic evidence of fatty liver. None had diabetes mellitus or hyperlipidemia. The calculated HOMA-IR was more than two in all five cases. Liver biopsy showed stage III fibrosis in 2 patients and stage IV fibrosis (cirrhosis) in 3.