Bernd Schnabl

University of California, San Diego, San Diego, California, United States

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Publications (75)616.62 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has spawned hundreds of pathophysiogical studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multi-organ dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 07/2015; DOI:10.1016/j.jhep.2015.07.004 · 10.40 Impact Factor
  • Katharina Brandl, Bernd Schnabl
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    ABSTRACT: Changes in the intestinal microbiota composition contribute to the pathogenesis of many disorders including gastrointestinal and liver diseases. Recent studies have broadened our understanding of the "gut-liver" axis. Dietary changes, other environmental and genetic factors can lead to alterations in the microbiota. Dysbiosis can further disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In this article, the authors dissect the different steps involved in disease pathogenesis to further refine approaches for the medical management of liver diseases. The authors will specifically discuss the role of dysbiosis in inducing intestinal inflammation and increasing intestinal permeability.
    Expert review of gastroenterology & hepatology 06/2015; DOI:10.1586/17474124.2015.1057122 · 2.55 Impact Factor
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    ABSTRACT: Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. Alcoholic fatty liver disease can progress to steatohepatitis, alcoholic hepatitis, fibrosis, and cirrhosis. Patients with alcohol abuse show quantitative and qualitative changes in the composition of the intestinal microbiome. Furthermore, patients with ALD have increased intestinal permeability and elevated systemic levels of gut-derived microbial products. Maintaining eubiosis, stabilizing the mucosal gut barrier, or preventing cellular responses to microbial products protect from experimental ALD. Therefore, intestinal dysbiosis and pathological bacterial translocation appear fundamental for the pathogenesis of ALD. This review highlights causes for intestinal dysbiosis and pathological bacterial translocation, their relationship, and consequences for ALD. We also discuss how the liver affects the intestinal microbiota. Copyright © 2015 by the Research Society on Alcoholism.
    Alcoholism Clinical and Experimental Research 05/2015; 39(5). DOI:10.1111/acer.12704 · 3.31 Impact Factor
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    Cristina Llorente, Bernd Schnabl
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    ABSTRACT: The leaky gut hypothesis links translocating microbial products with the onset and progression of liver disease, and for a long time was considered one of its major contributors. However, a more detailed picture of the intestinal microbiota contributing to liver disease started to evolve. The gut is colonized by trillions of microbes that aid in digestion, modulate immune response, and generate a variety of products that result from microbial metabolic activities. These products together with host-bacteria interactions influence both normal physiology and disease susceptibility. A disruption of the symbiosis between microbiota and host is known as dysbiosis and can have profound effects on health. Qualitative changes such as increased proportions of harmful bacteria and reduced levels of beneficial bacteria, and also quantitative changes in the total amount of bacteria (overgrowth) have been associated with liver disease. Understanding the link between the pathophysiology of liver diseases and compositional and functional changes of the microbiota will help in the design of innovative therapies. In this review, we focus on factors resulting in dysbiosis, and discuss how dysbiosis can disrupt intestinal homeostasis and contribute to liver disease.
    04/2015; 1(3). DOI:10.1016/j.jcmgh.2015.04.003
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    ABSTRACT: The association between quantity of liver fat and the presence of metabolic syndrome has not been systematically assessed. We aimed to determine the association between quantity of liver fat and presence of metabolic syndrome in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), independent of nonalcoholic steatohepatitis (NASH). We recruited 146 patients with well-characterized biopsy-proven NAFLD and 50 individuals without NAFLD (controls) to participate in a case-control study the NAFLD Translational Research Unit at University of California San Diego. Liver fat was quantified in patients with NAFLD and controls using an advanced magnetic resonance imaging-based biomarker, the proton-density-fat-fraction (MRI-PDFF). Patients with NAFLD were divided into groups based on whether they were above or below the median MRI-PDFF value (15.4% in patients with NAFLD); the MRI-PDFF value for controls was <5%. The primary outcome was presence of metabolic syndrome using Adult Treatment Panel III criteria without and with adjustment for presence of NASH. Compared to NAFLD patients with MRI-PDFF values below the median, and compared with controls, NAFLD patients with MRI-PDFF values above the median were more likely to have abdominal obesity (P<.0001), lower levels of high-density cholesterol (P<.0001), higher levels of triglycerides (P<.0001), and higher fasting levels of glucose (P<.001). Compared to NAFLD patients with MRI-PDFF values below the median, NAFLD patients with MRI-PDFF above the median were more likely to have metabolic syndrome (60.3% vs 44.4%; P<.04), independent of biopsy-detected NASH. Increased liver fat content in patients with NAFLD is associated with increased rates of metabolic syndrome, independent of NASH. There appears to be an association between quantity of liver fat and risk for cardiovascular disease in patients with NAFLD. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Clinical Gastroenterology and Hepatology 02/2015; DOI:10.1016/j.cgh.2015.01.027 · 6.53 Impact Factor
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    ABSTRACT: Liver disease is often times associated with increased intestinal permeability. A disruption of the gut barrier allows microbial products and viable bacteria to translocate from the intestinal lumen to extraintestinal organs. The majority of the venous blood from the intestinal tract is drained into the portal circulation, which is part of the dual hepatic blood supply. The liver is therefore the first organ in the body to encounter not only absorbed nutrients, but also gut-derived bacteria and pathogen associated molecular patterns (PAMPs). Chronic exposure to increased levels of PAMPs has been linked to disease progression during early stages and to infectious complications during late stages of liver disease (cirrhosis). It is therefore important to assess and monitor gut barrier dysfunction during hepatic disease. We review methods to assess intestinal barrier disruption and discuss advantages and disadvantages. We will in particular focus on methods that we have used to measure increased intestinal permeability and bacterial translocation during experimental liver disease models. Copyright © 2015. Published by Elsevier B.V.
    Journal of Immunological Methods 01/2015; 421. DOI:10.1016/j.jim.2014.12.015 · 2.01 Impact Factor
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    ABSTRACT: The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.
    Nature Medicine 01/2015; 21(2). DOI:10.1038/nm.3760 · 28.05 Impact Factor
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    ABSTRACT: Translocation of bacteria and their products across the intestinal barrier is common in patients with liver disease, and there is evidence that experimental liver fibrosis depends on bacterial translocation. The purpose of our study was to investigate liver fibrosis in conventional and germ-free (GF) C57BL/6 mice. Chronic liver injury was induced by administration of thioacetamide (TAA) in the drinking water for 21 wk or by repeated intraperitoneal injections of carbon tetrachloride (CCl4). Increased liver fibrosis was observed in GF mice compared with conventional mice. Hepatocytes showed more toxin-induced oxidative stress and cell death. This was accompanied by increased activation of hepatic stellate cells, but hepatic mediators of inflammation were not significantly different. Similarly, a genetic model using Myd88/Trif-deficient mice, which lack downstream innate immunity signaling, had more severe fibrosis than wild-type mice. Isolated Myd88/Trif-deficient hepatocytes were more susceptible to toxin-induced cell death in culture. In conclusion, the commensal microbiota prevents fibrosis upon chronic liver injury in mice. This is the first study describing a beneficial role of the commensal microbiota in maintaining liver homeostasis and preventing liver fibrosis.-Mazagova, M., Wang, L., Anfora, A. T., Wissmueller, M., Lesley, S. A., Miyamoto, Y., Eckmann, L., Dhungana, S., Pathmasiri, W., Sumner, S., Westwater, C., Brenner, D. A., Schnabl, B. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. © FASEB.
    The FASEB Journal 12/2014; 29(3). DOI:10.1096/fj.14-259515 · 5.48 Impact Factor
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    ABSTRACT: Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease.
    Gastroenterology 09/2014; 148(1). DOI:10.1053/j.gastro.2014.09.014 · 13.93 Impact Factor
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    ABSTRACT: Little is known about how weight loss affects magnetic resonance imaging (MRI) of liver fat and volume or liver histology in patients with non-alcoholic steatohepatitis (NASH). We measured changes in liver fat and liver volume associated with weight loss using an advanced MRI method.
    Clinical Gastroenterology and Hepatology 09/2014; 13(3). DOI:10.1016/j.cgh.2014.08.039 · 6.53 Impact Factor
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    ABSTRACT: Intestinal barrier dysfunction is an important contributor to alcoholic liver disease (ALD). Translocated microbial products trigger an inflammatory response in the liver and contribute to steatohepatitis. Our aim was to investigate mechanisms of barrier disruption after chronic alcohol feeding. A Lieber‐DeCarli model was used to induce intestinal dysbiosis, increased intestinal permeability, and liver disease in mice. Alcohol feeding for 8 weeks induced intestinal inflammation in the jejunum, which is characterized by an increased number of tumor necrosis factor alpha (TNF‐α)‐producing monocytes and macrophages. These findings were confirmed in duodenal biopsies from patients with chronic alcohol abuse. Intestinal decontamination with nonabsorbable antibiotics restored eubiosis, decreased intestinal inflammation and permeability, and reduced ALD in mice. TNF‐receptor I (TNFRI) mutant mice were protected from intestinal barrier dysfunction and ALD. To investigate whether TNFRI on intestinal epithelial cells mediates intestinal barrier dysfunction and ALD, we used TNFRI mutant mice carrying a conditional gain‐of‐function allele for this receptor. Reactivation of TNFRI on intestinal epithelial cells resulted in increased intestinal permeability and liver disease that is similar to wild‐type mice after alcohol feeding, suggesting that enteric TNFRI promotes intestinal barrier dysfunction. Myosin light‐chain kinase (MLCK) is a downstream target of TNF‐α and was phosphorylated in intestinal epithelial cells after alcohol administration. Using MLCK‐deficient mice, we further demonstrate a partial contribution of MLCK to intestinal barrier dysfunction and liver disease after chronic alcohol feeding. Conclusion: Dysbiosis‐induced intestinal inflammation and TNFRI signaling in intestinal epithelial cells mediate a disruption of the intestinal barrier. Therefore, intestinal TNFRI is a crucial mediator of ALD. (Hepatology 2015;61:883–894)
    Hepatology 09/2014; 61(3). DOI:10.1002/hep.27489 · 11.19 Impact Factor
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    ABSTRACT: Background & aims Chronic liver disease is characterized by fibrosis that may progress to cirrhosis. Nucleotide oligomerization domain 2 (Nod2), a member of the Nod-like receptor (NLR) family of intracellular immune receptors, plays an important role in the defense against bacterial infection through binding to the ligand muramyl dipeptide (MDP). Here, we investigated the role of Nod2 in the development of liver fibrosis. Methods We studied experimental cholestatic liver disease induced by bile duct ligation or toxic liver disease induced by carbon tetrachloride in wild type and Nod2-/- mice. Results Nod2 deficiency protected mice from cholestatic but not toxin-induced liver injury and fibrosis. Most notably, the hepatic bile acid concentration was lower in Nod2-/- mice than wild type mice following bile duct ligation for 3 weeks. In contrast to wild type mice, Nod2-/- mice had increased urinary excretion of bile acids, including sulfated bile acids, and an upregulation of the bile acid efflux transporters MRP2 and MRP4 in tubular epithelial cells of the kidney. MRP2 and MRP4 were downregulated by IL-1β in a Nod2 dependent fashion. Conclusions Our findings indicate that Nod2 deficiency protects mice from cholestatic liver injury and fibrosis through enhancing renal excretion of bile acids that in turn contributes to decreased concentration of bile acids in the hepatocyte.
    Journal of Hepatology 06/2014; 60(6). DOI:10.1016/j.jhep.2014.02.012 · 10.40 Impact Factor
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    Peng Chen, Bernd Schnabl
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    ABSTRACT: Alcoholic liver disease is a leading cause of morbidity and liver-related death worldwide. Intestinal bacterial overgrowth and dysbiosis induced by ethanol ingestion play an important role in the pathogenesis of alcoholic liver disease. After exposure to alcohol in the lumen, enteric bacteria alter their metabolism and thereby disturb intestinal homeostasis. Disruption of the mucosal barrier results in the translocation of microbial products that contribute to liver disease by inducing hepatic inflammation. In this review, we will discuss the effects of alcohol on the intestinal microbiome, and in particular, its effects on bacterial metabolism, bacterial translocation and ecological balance. A better understanding of the interactions among alcohol, the host and the microbiome will reveal new targets for therapy and lead to new treatments.
    Gut and Liver 05/2014; 8(3):237-241. DOI:10.5009/gnl.2014.8.3.237 · 1.49 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-911. DOI:10.1016/S0016-5085(14)63315-1 · 13.93 Impact Factor
  • Bernd Schnabl
    Hepatology 05/2014; 59(5). DOI:10.1002/hep.26785 · 11.19 Impact Factor
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    ABSTRACT: Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gramnegative bacteria from intestinal origin, yet grampositive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports and in-depth review and a position statement on bacterial infections in cirrhosis.
    Journal of Hepatology 02/2014; 60(6). DOI:10.1016/j.jhep.2014.01.024 · 10.40 Impact Factor
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    Bernd Schnabl, David A Brenner
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    ABSTRACT: The human intestine harbors a diverse community of microbes that promote metabolism and digestion in their symbiotic relationship with the host. Disturbance of its homeostasis can result in disease. We review factors that disrupt intestinal homeostasis and contribute to non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), alcoholic liver disease, and cirrhosis. Liver disease has long been associated with qualitative and quantitative (overgrowth) dysbiotic changes in the intestinal microbiota. Extrinsic factors, such as the Western diet and alcohol, contribute to these changes. Dysbiosis results in intestinal inflammation, a breakdown of the intestinal barrier, and translocation of microbial products in animal models. However, the contribution of the intestinal microbiome to liver disease goes beyond simple translocation of bacterial products that promote hepatic injury and inflammation. Microbial metabolites produced in a dysbiotic intestinal environment and host factors are equally important in the pathogenesis of liver disease. We review how the combination of liver insult and disruptions in intestinal homeostasis contribute to liver disease.
    Gastroenterology 01/2014; 146. DOI:10.1053/j.gastro.2014.01.020 · 13.93 Impact Factor
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    ABSTRACT: Background. Ectopic fat deposition in the pancreas and its relationship with hepatic steatosis and insulin resistance have not been compared between patients with nonalcoholic fatty liver disease (NAFLD) and healthy controls. Aim. Using a novel magnetic resonance imaging (MRI) based biomarker, the proton-density-fat-fraction (MRI-PDFF), we compared pancreatic fat content in patients with biopsy-proven NAFLD to healthy controls and determined whether it is associated with insulin resistance and liver fat content. Methods. This nested case-control study was derived from two prospective studies including 43 patients with biopsy-proven NAFLD and 49 healthy controls who underwent biochemical testing and MRI. Results. Compared to healthy controls, patients with NAFLD had significantly higher pancreatic MRI-PDFF (3.6% versus 8.5%, P value <0.001), and these results remained consistent in multivariable-adjusted models including age, sex, body mass index, and diabetes (P value =0.03). We found a strong correlation between hepatic and pancreatic MRI-PDFF (Spearman correlation, P = 0.57, P value <0.001). Participants with increased insulin resistance determined by homeostatic-model-of-insulin-resistance (HOMA-IR) greater than 2.5 had higher pancreatic (7.3% versus 4.5%, P value =0.015) and liver (13.5% versus 4.0%, P value <0.001) MRI-PDFF. Conclusion. Patients with NAFLD have greater pancreatic fat than normal controls. Insulin resistance is associated with liver and pancreatic fat accumulation.
    Gastroenterology Research and Practice 11/2013; 2013:498296. DOI:10.1155/2013/498296 · 1.75 Impact Factor
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    ABSTRACT: The intestinal mucus layer protects the epithelium from noxious agents, viruses, and pathogenic bacteria present in the gastrointestinal tract. It is composed of mucins, predominantly mucin-2 (Muc2), secreted by goblet cells of the intestine. Experimental alcoholic liver disease requires translocation of bacterial products across the intestinal barrier into the systemic circulation, which induces an inflammatory response in the liver and contributes to steatohepatitis. We investigated the roles of the intestinal mucus layer, and in particular Muc2, in development of experimental alcohol-associated liver disease in mice. We studied experimental alcohol-induced liver disease, induced by the Tsukamoto-French method (which involves continuous intragastric feeding of an isocaloric diet or alcohol) in wild-type and Muc2(-/-) mice. Muc2(-/-) mice showed less alcohol-induced liver injury and steatosis that developed in wild-type mice. Most notably, Muc2(-/-) mice had significantly lower plasma levels of lipopolysaccharide than wild-type mice after alcohol feeding. In contrast to wild-type mice, Muc2(-/-) mice were protected from alcohol-associated microbiome changes that are dependent on intestinal mucins. The anti-microbial proteins Reg3b and Reg3g were expressed at significantly higher levels in the jejunum of Muc2(-/-) mice fed the isocaloric diet or alcohol, compared with wild-type mice. Consequently, Muc2(-/-) mice showed increased killing of commensal bacteria and prevented intestinal bacterial overgrowth. Conclusion: Muc2(-/-) mice are protected from intestinal bacterial overgrowth and dysbiosis in response to alcohol feeding. Subsequently, lower amounts of bacterial products such as endotoxin translocate into the systemic circulation, decreasing liver disease. (HEPATOLOGY 2013.).
    Hepatology 07/2013; 58(1). DOI:10.1002/hep.26321 · 11.19 Impact Factor

Publication Stats

2k Citations
616.62 Total Impact Points

Institutions

  • 2008–2015
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States
  • 2014
    • Genomics Institute of the Novartis Research Foundation
      San Diego, California, United States
  • 2007–2008
    • Universität Regensburg
      • Department of Internal Medicine I
      Ratisbon, Bavaria, Germany
  • 2004–2007
    • Columbia University
      • Department of Medicine
      New York City, NY, United States
  • 2006
    • University Hospital Regensburg
      • Klinik und Poliklinik für Innere Medizin II
      Ratisbon, Bavaria, Germany
  • 2001–2003
    • University of North Carolina at Chapel Hill
      • • Department of Medicine
      • • Department of Biochemistry and Biophysics
      Chapel Hill, NC, United States