Characteristics of intestinal bacteria with fatty liver diseases and cirrhosis

Non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) are significant health burdens worldwide with a substantial rise in prevalence. Both can progress to liver cirrhosis. Recent studies have shown that the gut microbiome was associated with NAFLD/AFLD development and progression. The present review focuses on the characteristics of bacteria in NAFLD, AFLD and liver cirrhosis. The similarities and differences of intestinal bacteria are discussed.This study reviews the existing literatures on the microbiota, fatty liver disease, and liver cirrhosis based on Pubmed database.The study showed NAFLD was characterized by increased amounts of Lachnospiraceae from the phylum Firmicutes and Roseburia from the Lachnospiraceae family, and the proportion of Enterobacteria and Proteobacteria was increased after alcohol intake. Reduced Bacteroidetes was observed in cirrhosis. Microbiota can improve or aggravate the above liver diseases through several mechanisms, like increasing liver lipid metabolism, increasing alcohol production, increasing intestinal permeability, bacterial translocation, intestinal bacterial overgrowth, enteric dysbiosis, and impairing bile secretion.Different hepatic diseases owned different intestinal bacterial characters. Microbiota can improve or aggravate three kinds of liver diseases through several mechanisms. However, the depletion of these bacteria is needed to verify their role in liver disease.     

Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update

Non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide. NAFLD progresses in some cases to non-alcoholic steatohepatitis (NASH), which is characterized, in addition to liver fat deposition, by hepatocyte ballooning, inflammation and liver fibrosis, and in some cases may lead to hepatocellular carcinoma. NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus (T2DM). Currently, lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in the management of T2DM and do not have major side effects like hypoglycemia. In patients with NAFLD, the GLP-1 receptor production is down-regulated. Recently, several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation, alleviating the inflammatory environment and preventing NAFLD progression to NASH. In this review, we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH. Finally, as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD, we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.     

Tamarix chinensis Lour inhibits chronic ethanol-induced liver injury in mice

BACKGROUND Tamarix chinensis Lour(TCL) is a shrub that usually grows in arid or semiarid desert areas and saline-alkali fields. It is a traditional Chinese herbal medicine with hepatoprotective, antioxidant, antibacterial, and antitumor activities.AIM To investigate the possible protective effects of TCL against liver injury induced by chronic ethanol intake.METHODS C57 BL/6 J male mice were fed a Lieber-DeCarli lipid diet containing alcohol and received(by gavage) a water-alcohol extract(80%) of TCL(100 and 200 mg/kg BW) or distilled water for 4 wk. After euthanasia, liver tissues were observed histologically with hematoxylin and eosin staining and Oil red O staining, and the levels of alanine aminotransferase, aspartate transaminase, hepatic lipids,reactive oxygen species, malondialdehyde, and superoxide dismutase were measured. In addition, expression of the NOD-like receptor family, pyrin domain-containing 3(NLRP3) inflammasome and downstream proinflammatory cytokines were determined.RESULTS Compared with the ethanol group, mice in the TCL-treated group(200 mg/kg)had significantly lower serum levels of alanine aminotransferase(mean, 34.1 IU/L vs 45.3 IU/L, P 0.01) and aspartate transaminase(mean, 89.6 IU/L vs115.7 IU/L, P 0.01), as well as marked reduction of hepatic tissue reactive oxygen species(decreased by 27.5%, P 0.01) and malondialdehyde(decreased by 76.6%, P 0.01) levels, with a significant increase of superoxide dismutase (Increased by 73.2%, P 0.01). Expression of the NLRP3 inflammasome and its downstream cytokines [interleukin(IL)-1β, tumor necrosis factor-α, and IL-6],and recruitment of natural killer T cells to the liver, were reduced in the TCLtreated incubation with a Lieber-DeCaril ethanol lipid diet group.CONCLUSION These findings suggest that a TCL extract(200 mg/kg) protects against chronic ethanol-induced liver injury, probably by inhibiting the NLRP3-caspase-1-IL-1βsignaling pathway and suppressing oxidative stress.     

靶向肠道菌群代谢产物防治非酒精性脂肪性肝病*

<正>非酒精性脂肪性肝病(NAFLD)是以肝脏脂质沉积为特点的慢性疾病,疾病谱包括单纯性脂肪肝、非酒精性脂肪性肝炎(NASH)及其相关肝硬化和肝细胞癌。NASH是NAFLD的严重类型,NASH相关的肝脏炎症很难自行缓解,目前尚缺乏有效的治疗手段~([1])。肠道菌群与宿主的代谢状况密切相关~([2]),肠道菌群紊乱在NAFLD的发生发展中起着重要作用~([3,4])。除了肠道菌群本身,基于肠道菌群分泌、修饰和降解的代     

胰高血糖素样肽1受体激动剂对代谢相关脂肪性肝病作用机制的研究进展

非酒精性脂肪性肝病(NAFLD)(现已更名为代谢相关脂肪性肝病)是一种以肝实质内脂质过度沉积为特征,常与中心性肥胖、2型糖尿病、胰岛素抵抗、代谢综合征等疾病合并存在,被认为是代谢综合征的肝脏表现.非酒精性脂肪性肝炎(NASH)是一种可能导致肝硬化、肝细胞癌的进行性肝病.目前尚无批准用于治疗NAFLD/NASH的药物.近...     

Novel insights into the mechanisms whereby isoflavones protect against fatty liver disease

Fatty liver disease(FLD) is a growing public health problem worldwide. There is an urgent requirement for alternative and natural medicine to treat this disease. As phytochemicals, isoflavones have attracted considerable attention for the prevention of FLD. Numerous studies have revealed that isoflavones protect against FLD through various pathways which modulate fatty acid β-oxidation, lipid synthesis, and oxidative stress. Recently, the aldose reductase(AR)/polyol pathwayhas been reported to be involved in the development of FLD by modulating hepatic fructose production, peroxisome proliferator-activated receptor(PPAR)α activity, cytochrome P450(CYP)2E1 expression, and gut bacterial endotoxin-induced cytokine release. It has been reported that some isoflavones are potent AR inhibitors. Here, we review the anti-FLD actions of isoflavones and the proposed mechanism whereby isoflavones protect against FLD, with regard to the AR/polyol pathway. We propose that isoflavones block the AR/polyol pathway and in turn reduce fructose production and subsequent fat accumulation in the liver in diabetic or high-glucose-diet mice. In addition, in rodents with alcoholic liver disease or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, inhibition of AR by isoflavones may improve PPARα-mediated fatty acid oxidation, reduce hepatic steatosis, and attenuate CYP2E1-mediated oxidative stress or AR/gut bacterial endotoxin-mediated cytokine overproduction, to alleviate progression of FLD.     

Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Fatty infiltration and fibrosis are major issues in chronic liver disease. Recent reports suggest a role for the endocannabinoid system in these processes. AIM: To characterize localization and expression of CB2 in normal liver and nonalcoholic fatty liver. METHODS: We studied 64 liver biopsies: eight were considered normal; 56 had a diagnosis of nonalcoholic fatty liver disease (NAFLD); 32 with nonalcoholic steatosis and 24 nonalcoholic steatohepatitis (NASH). CB2 immunolocalization was studied in 38 samples in paraffin blocks using immunohistochemistry, and a computerized semiquantitative analysis was carried out. CB2 mRNA expression was assessed through RT-PCR in 26 frozen liver samples and the ratio CB2/beta-actin was used to evaluate differences between groups. Statistical analysis was performed with central tendency measures and the Mann-Whitney U-test. We considered as significant differences those with a P-value <0.05. RESULTS: Neither parenchymal nor nonparenchymal cells in normal liver tissue react towards anti-CB2 antibodies. All the samples from patients with steatosis and nonalcoholic steatohepatitis showed hepatocellular immunoreactivity. Cholangiocytes were positive only in the NAFLD group. Normal liver tissue showed a normalized CB2/beta-actin ratio of 0.001+/-0.01, steatosis 6.52+/-17.3 (P=0.05 vs normal) and NASH 6.49+/-12.2 (P=0.06 vs normal and P=0.6 vs steatosis). CONCLUSION: CB2 receptors are expressed by hepatocytes in nonalcoholic fatty liver disease but not in normal liver.     

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。     

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP-1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials.     

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.     

Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease

BACKGROUND: Gut microbiota plays a significant role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study aimed to assess the contribution of gut microbiota dysbiosis to the pathogenesis of NAFLD. METHODS: Forty-seven human feces samples (25 NAFLD patients and 22 healthy subjects) were collected and 16S rDNA amplicon sequencing was conducted on Hiseq 2000 platform. Discrepancy of species composition between controls and NAFLD group was defined by Metastats analysis under P value<0.01. RESULTS: NAFLD patients harbored lower gut microbiota diversity than healthy subjects did. In comparison to the control group, the Proteobacteria (13.50%) and Fusobacteria (2.76%) phyla were more abundant in NAFLD patients. Ad-ditionally, the Lachnospiraceae (21.90%), Enterobacteriaceae (12.02%), Erysipelotrichaceae (3.83%), and Streptococcaceae (1.39%) families, as well as the Escherichia_Shigella (10.84%), Lachnospiraceae_Incertae_Sedis (7.79%), and Blautia (4.95%) genera were enriched in the NAFLD group. However, there was a lower abundance of Prevotella in the NAFLD group than that in the control group (5.83% vs 27.56%, P<0.01). The phylum Bacteroidetes (44.63%) also tended to be more abundant in healthy subjects, and the families Prevotellaceae (28.66%) and Ruminococcaceae (26.44%) followed the same trend. Compared to those without non-alcoholic steatohepa-titis (NASH), patients with NASH had higher abundance of genus Blautia (5.82% vs 2.25%; P=0.01) and the correspond-ing Lachnospiraceae family (24.33% vs 14.21%; P<0.01). Patients with significant fibrosis had a higher abundance of genus Escherichia_Shigella (12.53% vs 1.97%; P<0.01) and the corresponding Enterobacteriaceae family (13.92% vs 2.07%;P<0.01) compared to those with F0/F1 fibrosis. CONCLUSIONS: NAFLD patients and healthy subjects harbor varying gut microbiota. In contrast to the results of previous research on children, decreased levels of Prevotella might be detrimental for adults with NAFLD. The increased level of the genus Blautia, the family Lachnospiraceae, the genus Escherichia_Shigella, and the family Enterobacteriaceae may be a primary contributor to NAFLD progression.     

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.     

Beneficial effects of LRP6-CRISPR on prevention of alcohol-related liver injury surpassed fecal microbiota transplant in a rat model

ABSTRACT

Alcohol intake can modify gut microbiota composition, increase gut permeability, and promote liver fibrogenesis. LRP6 is a signal transmembrane protein and a co-receptor for the canonical Wnt signaling pathway. This study compared the curative effect of LRP6-CRISPR on alcohol-related liver injury with that of traditional fecal microbiota transplant (FMT) and investigated the alteration of the gut microbiome following the treatment. A rat model of alcohol-related liver injury was established and injected with lentiviral vectors expressing LRP6-CRISPR or administered with fecal filtrate from healthy rats, with healthy rat served as the control. Liver tissues of rats were examined by HE staining, Sirius staining, and Oil red O staining, respectively. The expression of LRP6 and fibrosis biomarkers were tested by PCR. The fecal sample of rats was collected and examined by 16S rRNA sequencing. Our data indicated that LRP6-CRISPR was more efficient in the prevention of alcohol-related liver injury than FMT. Microbiome analysis showed that alcohol-related liver injury related to gut microbiota dysbiosis, while treatment with LRP6-CRISPR or FMT increased gut microflora diversity and improved gut symbiosis. Further, bacteria specific to the disease stages were identified. Genera Romboutsia, Escherichia-Shigella, Pseudomonas, Turicibacter, and Helicobacter were prevalent in the intestine of rats with alcohol-related liver injury, while the domination of Lactobacillus was found in rats treated with LRP6-CRISPR or FMT. Besides, Lactobacillus and genera belonging to family Lachnospiraceae, Bacteroidales S24-7 group, and Ruminococcaceae were enriched in healthy rats. LRP6-CRISPR and FMT have beneficial effects on the prevention of alcohol-related liver injury, and correspondently, both treatments altered the disrupted gut microflora to a healthy one.     

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.     

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.     

Intestinal and hepatic microbiota changes associated with chronic ethanol administration in mice

ABSTRACT

Alcohol-induced liver disease is closely related to translocation of bacterial products and bacteria from the intestine to the liver. However, it is not known whether bacterial translocation to the liver depends on certain intestinal microbiota changes that would predispose bacteria to translocate to the liver. In this study, we investigated the microbiota in the jejunum, ileum, cecum, feces and liver of mice subjected to chronic ethanol feeding using a Lieber DeCarli diet model of chronic ethanol feeding for 8 weeks. We demonstrate that chronic ethanol administration changes alpha diversity in the ileum and the liver and leads to compositional changes especially in the ileum. This is largely driven by an increase in gram-negative phyla – the source of endotoxins. Moreover, gram-negative Prevotella not only increased in the mucus layer of the ileum but also in liver samples. These results suggest that bacterial translocation to the liver might be associated with microbiota changes in the distal gastrointestinal tract.