Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Transl Res ; 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32553670

RESUMO

Alcohol-associated liver disease is accompanied by dysregulation of bile acid metabolism and gut barrier dysfunction. Peroxisome proliferator-activated receptor-delta (PPARδ) agonists are key metabolic regulators and have anti-inflammatory properties. Here, we evaluated the effect of the selective PPAR-delta agonist seladelpar (MBX-8025) on gut barrier function and bile acid metabolism in a mouse model of ethanol-induced liver disease. Wild type C57BL/6 mice were fed LieberDeCarli diet containing 0%-36% ethanol (caloric) for 8 weeks followed by a single binge of ethanol (5 g/kg). Pair fed mice received an isocaloric liquid diet as control. MBX-8025 (10 mg/kg/d) or vehicle were added to the liquid diet during the entire feeding period (prevention), or during the last 4 weeks of Lieber DeCarli diet feeding (intervention). In both prevention and intervention trials, MBX-8025 protected mice from ethanol-induced liver disease, characterized by lower serum alanine aminotransferase (ALT) levels, hepatic triglycerides, and inflammation. Chronic ethanol intake disrupted bile acid metabolism by increasing the total bile acid pool and serum bile acids. MBX-8025 reduced serum total and secondary bile acids, and the total bile acid pool as compared with vehicle treatment in both prevention and intervention trials. MBX-8025 restored ethanol-induced gut dysbiosis and gut barrier dysfunction. Data from this study demonstrates that seladelpar prevents and treats ethanol-induced liver damage in mice by direct PPARδ agonism in both the liver and the intestine.

2.
J Hepatol ; 72(3): 391-400, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31606552

RESUMO

BACKGROUND & AIMS: Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease. METHODS: C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin. RESULTS: The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the ß-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis. CONCLUSIONS: Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis. LAY SUMMARY: Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the ß-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.

3.
Nature ; 575(7783): 505-511, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723265

RESUMO

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.


Assuntos
Bacteriófagos/fisiologia , Enterococcus faecalis/patogenicidade , Enterococcus faecalis/virologia , Microbioma Gastrointestinal , Hepatite Alcoólica/microbiologia , Hepatite Alcoólica/terapia , Terapia por Fagos , Alcoolismo/complicações , Alcoolismo/microbiologia , Animais , Enterococcus faecalis/isolamento & purificação , Etanol/efeitos adversos , Fígado Gorduroso/complicações , Fígado Gorduroso/microbiologia , Fezes/microbiologia , Feminino , Vida Livre de Germes , Hepatite Alcoólica/complicações , Hepatite Alcoólica/mortalidade , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Perforina/metabolismo
4.
Am J Physiol Gastrointest Liver Physiol ; 316(5): G563-G573, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767680

RESUMO

The intestinal microbiome plays a major role in the pathogenesis of liver disease, with a hallmark event being dysbiosis, or an imbalance of pathobionts and beneficial bacteria with the associated deleterious effects on their host. Reducing the number of intestinal bacteria with antibiotic treatment is generally advantageous in experimental liver diseases. Complete absence of intestinal microbiota as in germ-free rodents can be protective in autoimmune hepatitis and hepatic tumors induced by chemicals, or it can exacerbate disease as in acute toxic liver injury and liver fibrosis/cirrhosis. In alcoholic liver disease, nonalcoholic fatty liver disease, and autoimmune cholangiopathies, germ-free status can be associated with worsened or improved hepatic phenotype depending on the experimental model and type of rodent. Some of the unexpected outcomes can be explained by the limitations of rodents raised in a germ-free environment including a deficient immune system and an altered metabolism of lipids, cholesterol, xenobiotics/toxins, and bile acids. Given these limitations and to advance understanding of the interactions between host and intestinal microbiota, simplified model systems such as humanized gnotobiotic mice, or gnotobiotic mice monoassociated with a single bacterial strain or colonized with a defined set of microbes, are unique and useful models for investigation of liver disease in a complex ecosystem.


Assuntos
Disbiose , Microbioma Gastrointestinal , Hepatopatias , Animais , Disbiose/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Hepatopatias/classificação , Hepatopatias/microbiologia , Modelos Animais , Medição de Risco
5.
Gut ; 68(2): 359-370, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30171065

RESUMO

The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis, commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD pathophysiology involves environmental, genetic and metabolic factors, as well as changes in the intestinal microbiota and their products. Dysfunction of the intestinal barrier can contribute to NAFLD development and progression. Although there are technical limitations in assessing intestinal permeability in humans and the number of patients in these studies is rather small, fewer than half of the patients have increased intestinal permeability and translocation of bacterial products. Microbe-derived metabolites and the signalling pathways they affect might play more important roles in development of NAFLD. We review the microbial metabolites that contribute to the development of NAFLD, such as trimethylamine, bile acids, short-chain fatty acids and ethanol. We discuss the mechanisms by which metabolites produced by microbes might affect disease progression and/or serve as therapeutic targets or biomarkers for NAFLD.


Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Ácidos e Sais Biliares/metabolismo , Progressão da Doença , Disbiose/complicações , Etanol/metabolismo , Ácidos Graxos Voláteis/metabolismo , Humanos , Metilaminas/metabolismo , Fatores de Risco , Transdução de Sinais
6.
Liver Res ; 2(1): 43-51, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30416839

RESUMO

Intestinal bacteria contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Recently developed microbial profiling techniques are beginning to shed light on the nature of the changes in the gut microbiota that accompany NAFLD and non-alcoholic steatohepatitis (NASH). In this review, we summarize the role of gut microbiota in the development of NAFLD, NASH, and hepatocellular carcinoma (HCC). We highlight the mechanisms by which gut microbiota contribute to NAFLD/NASH, including through alterations in gut epithelial permeability, choline metabolism, endogenous alcohol production, release of inflammatory cytokines, regulation of hepatic Toll-like receptor (TLR), and bile acid metabolism. In addition, we analyze possible mechanisms for enhanced hepatic carcinogenesis, including alterations in bile acid metabolism, release of inflammatory cytokines, and expression of TLR-4. Finally, we describe therapeutic approaches for NAFLD/NASH and preventive strategies for HCC involving modulation of the intestinal microbiota or affected host pathways. Although recent studies have provided useful information, large-scale prospective studies are required to better characterize the intestinal microbiota and metabolome, in order to demonstrate a causative role for changes in the gut microbiota in the etiology of NAFLD/NASH, to identify new therapeutic strategies for NAFLD/NASH, and to develop more effective methods of preventing HCC.

7.
Br J Pharmacol ; 175(3): 469-484, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29139555

RESUMO

BACKGROUND AND PURPOSE: The gut-liver axis is associated with the progression of non-alcoholic fatty liver disease (NAFLD). Targeting the gut-liver axis and bile acid-based pharmaceuticals are potential therapies for NAFLD. The effect of tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD, on intestinal barrier function, intestinal inflammation, gut lipid transport and microbiota composition was analysed in a murine model of NAFLD. EXPERIMENTAL APPROACH: The NAFLD mouse model was established by feeding mice a high-fat diet (HFD) for 16 weeks. TUDCA was administered p.o. during the last 4 weeks. The expression levels of intestinal tight junction genes, lipid metabolic and inflammatory genes were determined by quantitative PCR. Tissue inflammation was evaluated by haematoxylin and eosin staining. The gut microbiota was analysed by 16S rRNA gene sequencing. KEY RESULTS: TUDCA administration attenuated HFD-induced hepatic steatosis, inflammatory responses, obesity and insulin resistance in mice. Moreover, TUDCA attenuated gut inflammatory responses as manifested by decreased intestinal histopathology scores and inflammatory cytokine levels. In addition, TUDCA improved intestinal barrier function by increasing levels of tight junction molecules and the solid chemical barrier. The components involved in ileum lipid transport were also reduced by TUDCA administration in HFD-fed mice. Finally, the TUDCA-treated mice showed a different gut microbiota composition compared with that in HFD-fed mice but similar to that in normal chow diet-fed mice. CONCLUSIONS AND IMPLICATIONS: TUDCA attenuates the progression of HFD-induced NAFLD in mice by ameliorating gut inflammation, improving intestinal barrier function, decreasing intestinal fat transport and modulating intestinal microbiota composition.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácido Tauroquenodesoxicólico/uso terapêutico , Animais , Células CACO-2 , Microbioma Gastrointestinal/fisiologia , Humanos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Distribuição Aleatória , Ácido Tauroquenodesoxicólico/farmacologia
8.
PLoS One ; 11(3): e0152801, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27031865

RESUMO

BACKGROUND AND AIMS: Although a range of guidelines for the diagnosis and treatment of chronic constipation has been carried out, there was very little information about the understanding on constipation. The aim of the present study was to estimate the understanding of constipation symptoms and the diagnosis and management of constipation by clinical physicians in China. METHODS: Participants were physicians and researchers in the field of gastroenterology in China who were scheduled to attend the National Conference on gastrointestinal motility (Constipation). Based on the recommendation of the Rome Foundation Board, the self-reported questionnaire was constructed. FINDINGS: Although most of the opinions on symptoms of constipation were consistent, there were still some differences. Opinions on the Bristol stool form during constipation were discordant, 34% of the doctors thought that it was type 1 and type 2, while 46%of the doctors suggested that type 3 should also be considered constipation. There was no significant difference between them (P = 0.05); We investigated the interpretation on the duration of defecation prolonged, 27% of the doctors suggested it should be longer than 10 minutes, 22% of the doctors suggested it should be longer than 20 minutes, and other 22% of the doctors suggested it should be time of defecation became longer compared to previously bowel habits, there was no significant difference among them (P = 0.38).Only 36% of the doctors thought that psychotherapy was most important in the treatment of severe constipation, while 37% of the doctors thought that medication treatment was most important in the treatment of severe constipation, there was no significant difference between them (P = 0.895). CONCLUSION: We were able to obtain valuable information about current views on symptoms of constipation and the diagnosis and treatment of constipation among Chinese doctors. Although most of the opinions were consistent there were still some differences. This study indicated that in practice in China there was a need for further study on the role of constipation symptoms and there may also be a need for better establishment of consensus guidelines for constipation.


Assuntos
Constipação Intestinal/diagnóstico , Constipação Intestinal/terapia , China/epidemiologia , Constipação Intestinal/epidemiologia , Defecação , Gerenciamento Clínico , Motilidade Gastrointestinal , Humanos , Médicos
9.
Gastroenterol Res Pract ; 2014: 532734, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25386187

RESUMO

Objective. To acquire more data about the epidemiologic characteristics of constipation in different kinds of populations in China. Methods. Using "constipation" and "China" as search terms; relevant papers were searched from January 1995 to April 2014. Data on prevalence, gender, diagnostic criteria, geographical area, educational class, age, race, and physician visit results were extracted and analyzed. Results. 36 trials were included. Prevalence rates of constipation in elderly population (18.1%) and pediatric population (18.8%) were significantly higher than that in general population (8.2%). Prevalence of constipation defined by non-Rome criteria was higher than that by Rome criteria in general population. Prevalence rates of constipation were different for different geographical area. People with less education were predisposed to constipation. In pediatric population, prevalence of constipation was the lowest in children aged 2-6 years. Prevalence of constipation in ethnic minorities was higher than that in Han people. People with constipation were predisposed to FD, haemorrhoid, and GERD. Only 22.2% patients seek medical advice in general population. Conclusions. In China, prevalence of constipation was lower compared with most of other countries. The factors including female gender, diagnostic criteria, geographical area, age, educational class, and race seemed to have major effects on prevalence of constipation.

10.
J Gastroenterol Hepatol ; 27(6): 1017-26, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22128901

RESUMO

BACKGROUND AND AIMS: The aim of this study was to assess the effects of gastric electrical stimulation (GES) on symptoms and gastric emptying in patients with gastroparesis, and the effects of GES on the three subgroups of gastroparesis. METHODS: A literature search of clinical trials using high-frequency GES to treat patients with gastroparesis from January 1995 to January 2011 was performed. Data on the total symptom severity score (TSS), nausea severity score, vomiting severity score, and gastric emptying were extracted and analyzed. The statistic effect index was weighted mean differences. RESULTS: Ten studies (n = 601) were included in this study. In the comparison to baseline, there was significant improvement of symptoms and gastric emptying (P < 0.00001). It was noted that GES significantly improved both TSS (P < 0.00001) and gastric retention at 2 h (P = 0.003) and 4 h (P < 0.0001) in patients with diabetic gastroparesis (DG), while gastric retention at 2 h (P = 0.18) in idiopathic gastroparesis (IG) patients, and gastric retention at 4 h (P = 0.23) in postsurgical gastroparesis (PSG) patients, did not reach significance. CONCLUSIONS: Based on this meta-analysis, the substantial and significant improvement of symptoms and gastric emptying, and the good safety we observed, indicate that high-frequency GES is an effective and safe method for treating refractory gastroparesis. DG patients seem the most responsive to GES, both subjectively and objectively, while the IG and PSG subgroups are less responsive and need further research.


Assuntos
Terapia por Estimulação Elétrica/métodos , Gastroparesia/terapia , Terapia por Estimulação Elétrica/efeitos adversos , Humanos , Índice de Gravidade de Doença , Resultado do Tratamento
11.
J Huazhong Univ Sci Technolog Med Sci ; 29(4): 409-12, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19662352

RESUMO

This study investigated the ability of millimeter-wave (MMW) to promote the differentiation of bone marrow stromal cells (BMSCs) into cells with a neural phenotype. The BMSCs were primarily cultured. At passage 3, the cells were induced by beta-mercaptoethanol (BME) in combination with MMW or BME alone. The expressions of nucleostemin (NS) and neuron-specific enolase (NSE) were detected by immunofluorescent staining and Western blotting respectively to identify the differentiation. The untreated BMSCs predominately expressed NS. After induced by BME and MMW, the BMSCs exhibited a dramatic decrease in NS expression and increase in NSE expression. The differentiation rate of the cells treated with BME and MMW in combination was significantly higher than that of the cells treated with BME alone (P<0.05). It was concluded that MMW exposure enhanced the inducing effect of BME on the differentiation of BMSCs into cells with a neural phenotype.


Assuntos
Células da Medula Óssea/efeitos da radiação , Diferenciação Celular/efeitos da radiação , Micro-Ondas , Neurônios/citologia , Células Estromais/efeitos da radiação , Animais , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Mercaptoetanol/farmacologia , Fenótipo , Ratos , Células Estromais/citologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA