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Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease. Int J Mol Sci 2022; 23:ijms23158749. [PMID: 35955885 PMCID: PMC9368757 DOI: 10.3390/ijms23158749] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/21/2022] [Accepted: 08/03/2022] [Indexed: 11/21/2022] Open
Abstract
Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD.
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Abstract
The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.
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3
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Chen L, Zhu Y, Hou X, Yang L, Chu H. The Role of Gut Bacteria and Fungi in Alcohol-Associated Liver Disease. Front Med (Lausanne) 2022; 9:840752. [PMID: 35308525 PMCID: PMC8927088 DOI: 10.3389/fmed.2022.840752] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Cirrhosis and liver cancer caused by alcohol-associated liver disease (ALD) are serious threats to people's health. In addition to hepatic cell apoptosis and liver inflammation caused by oxidative stress during alcohol metabolism, intestinal microbiota disorders are also involved in the onset and development of ALD. Ethanol and its' oxidative and non-oxidative metabolites, together with dysbiosis-caused-inflammation, destroys the intestinal barrier. Changes of several microbial metabolites, such as bile acids, short-chain fatty acids, and amino acid, are closely associated with gut dysbiosis in ALD. The alcohol-caused dysbiosis can further influence intestinal barrier-related proteins, such as mucin2, bile acid-related receptors, and aryl hydrocarbon receptor (AhR), and these abnormal changes also participate in the injury of the intestinal barrier and hepatic steatosis. Gut-derived bacteria, fungi, and their toxins, such as lipopolysaccharide (LPS) and β-glucan translocate into the liver through the damaged intestinal barrier and promote the progression of inflammation and fibrosis of ALD. Thus, the prevention of alcohol-induced disruption of intestinal permeability has a beneficial effect on ALD. Currently, multiple therapeutic treatments have been applied to restore the gut microbiota of patients with ALD. Fecal microbial transplantation, probiotics, antibiotics, and many other elements has already shown their ability of restoring the gut microbiota. Targeted approaches, such as using bacteriophages to remove cytolytic Enterococcus faecalis, and supplement with Lactobacillus, Bifidobacterium, or boulardii are also powerful therapeutic options for ALD.
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Affiliation(s)
- Liuying Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yixin Zhu
- Department of Medicine, University of California, San Diego, San Diego, CA, United States
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Xiaohua Hou
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Ling Yang
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Huikuan Chu
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Nawroth JC, Petropolis DB, Manatakis DV, Maulana TI, Burchett G, Schlünder K, Witt A, Shukla A, Kodella K, Ronxhi J, Kulkarni G, Hamilton G, Seki E, Lu S, Karalis KC. Modeling alcohol-associated liver disease in a human Liver-Chip. Cell Rep 2021; 36:109393. [PMID: 34289365 PMCID: PMC8342038 DOI: 10.1016/j.celrep.2021.109393] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 04/03/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is a global health issue and leads to progressive liver injury, comorbidities, and increased mortality. Human-relevant preclinical models of ALD are urgently needed. Here, we leverage a triculture human Liver-Chip with biomimetic hepatic sinusoids and bile canaliculi to model ALD employing human-relevant blood alcohol concentrations (BACs) and multimodal profiling of clinically relevant endpoints. Our Liver-Chip recapitulates established ALD markers in response to 48 h of exposure to ethanol, including lipid accumulation and oxidative stress, in a concentration-dependent manner and supports the study of secondary insults, such as high blood endotoxin levels. We show that remodeling of the bile canalicular network can provide an in vitro quantitative readout of alcoholic liver toxicity. In summary, we report the development of a human ALD Liver-Chip as a powerful platform for modeling alcohol-induced liver injury with the potential for direct translation to clinical research and evaluation of patient-specific responses.
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Affiliation(s)
| | | | | | | | | | | | - Anke Witt
- Emulate, Inc., 27 Drydock Avenue, Boston, MA 02210, USA
| | | | | | - Janey Ronxhi
- Emulate, Inc., 27 Drydock Avenue, Boston, MA 02210, USA
| | | | | | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Shelly Lu
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Leskelä J, Pietiäinen M, Safer A, Lehto M, Metso J, Malle E, Buggle F, Becher H, Sundvall J, Grau AJ, Pussinen PJ, Palm F. Serum lipopolysaccharide neutralizing capacity in ischemic stroke. PLoS One 2020; 15:e0228806. [PMID: 32084157 PMCID: PMC7034831 DOI: 10.1371/journal.pone.0228806] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 01/21/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction Periodontitis is associated with increased serum lipopolysaccharide (LPS) activity, which may be one mechanism linking periodontitis with the risk of cardiovascular diseases. As LPS-carrying proteins including lipoproteins modify LPS-activity, we investigated the determinants of serum LPS-neutralizing capacity (LPS-NC) in ischemic stroke. The association of LPS-NC and Aggregatibacter actinomycetemcomitans, a major microbial biomarker in periodontitis, was also investigated. Materials and methods The assay to measure LPS-NC was set up by spiking serum samples with E. coli LPS. The LPS-NC, LPS-binding protein (LBP), soluble CD14 (sCD14), lipoprotein profiles, apo(lipoprotein) A-I, apoB, and phospholipid transfer protein (PLTP) activity, were determined in 98 ischemic stroke patients and 100 age- and sex-matched controls. Serum and saliva immune response to A. actinomycetemcomitans, its concentration in saliva, and serotype-distribution were examined. Results LPS-NC values ranged between 51–83% in the whole population. Although several of the LPS-NC determinants differed significantly between cases and controls (PLTP, sCD14, apoA-I, HDL-cholesterol), the levels did not (p = 0.056). The main determinants of LPS-NC were i) triglycerides (β = -0.68, p<0.001), and ii) HDL cholesterol (0.260, <0.001), LDL cholesterol (-0.265, <0.001), PLTP (-0.196, 0.011), and IgG against A. actinomycetemcomitans (0.174, 0.011). Saliva A. actinomycetemcomitans concentration was higher [log mean (95% CI), 4.39 (2.35–8.19) vs. 10.7 (5.45–21) genomes/ml, p = 0.023) and serotype D more frequent (4 vs. 0%, p = 0.043) in cases than controls. Serotypeablity or serotypes did not, however, relate to the LPS-NC. Conclusion Serum LPS-NC comprised low PLTP-activity, triglyceride and LDL cholesterol concentrations, as well as high HDL cholesterol and IgG against A. actinomycetemcomitans. The present findings let us to conclude that LPS-NC did not associate with stroke.
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Affiliation(s)
- Jaakko Leskelä
- Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
| | - Milla Pietiäinen
- Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
| | - Anton Safer
- Institute of Global Health, University of Heidelberg, Heidelberg, Germany
| | - Markku Lehto
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
| | - Jari Metso
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Ernst Malle
- Division of Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Graz, Austria
| | - Florian Buggle
- Department of Neurology, Klinikum Ludwigshafen, Ludwigshafen, Germany
| | - Heiko Becher
- University Medical Center Hamburg-Eppendorf, Institute of Medical Biometry and Epidemiology, Hamburg, Germany
- University Hospital Heidelberg, Institute of Global Health, Heidelberg, Germany
| | - Jouko Sundvall
- National Institute for Health and Welfare, Helsinki, Finland
| | - Armin J. Grau
- Department of Neurology, Klinikum Ludwigshafen, Ludwigshafen, Germany
| | - Pirkko J. Pussinen
- Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
- * E-mail:
| | - Frederick Palm
- Department of Neurology, Helios Klinikum Schleswig, Schleswig, Germany
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García-Calvo X, Bolao F, Sanvisens A, Zuluaga P, Tor J, Muga R, Fuster D. Significance of Markers of Monocyte Activation (CD163 and sCD14) and Inflammation (IL-6) in Patients Admitted for Alcohol Use Disorder Treatment. Alcohol Clin Exp Res 2019; 44:152-158. [PMID: 31797394 DOI: 10.1111/acer.14228] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Monocyte activation and inflammation are prominent features of alcohol-related liver disease; however, they have not been thoroughly assessed in patients with alcohol use disorder (AUD) without overt liver disease. This study aimed to analyze associations among clinical and laboratory variables and markers of monocyte activation (CD163 and sCD14), and inflammation (interleukin [IL]-6) among AUD patients. METHODS We analyzed the aforementioned associations in the highest quartile in 289 patients (77.5% male; median age, 50 years) consecutively admitted for alcohol detoxification in 2 tertiary hospitals in the Barcelona metropolitan area, Spain. RESULTS Median alcohol intake was 142 g/d; median glucose, albumin, creatinine, and bilirubin levels (mg/dl), 92, 40, 0.78, and 0.69, respectively; median AST, 41 U/l; median hemoglobin, median corpuscular volume, and platelet count, 14.1 g/dl, 94.8 fL, and 189 × 109 /l, respectively; median cholesterol, triglyceride, fibrinogen, and ferritin levels, 187 mg/dl, 109.3 mg/dl, 341 mg/dl, and 177 ng/ml, respectively. In addition, 36.7% patients had an erythrocyte sedimentation rate >20 mm, 32.5% had a C-reactive protein (CRP) level of >5 mg/l, and 10.9% were hepatitis C virus (HCV)-positive. Median CD163, sCD14, and IL-6 levels were 759, 1.68 × 106 , and 4.37 pg/ml, respectively. On logistic regression analyses, glucose, AST, bilirubin, hemoglobin levels, and HCV infection (adjusted odds ratio [aORs]: 1.01, 1.02, 3.04, and 9.73, respectively) were associated with CD163. Glucose, AST, triglyceride, and CRP >5 mg/l (aORs: 1.02, 1.01, 1.00, and 3.49, respectively) were associated with sCD14. Alcohol consumption upon admission, MCV, total cholesterol levels, and CRP >5 mg/l (aORs: 0.99, 1.05, 0.99, and 2.56, respectively) were associated with IL-6. CONCLUSIONS Monocyte activation and systemic inflammation are associated with higher glucose, liver enzyme, and lipid levels, HCV infections, and CRP of >5 mg/l, thus potentially identifying patients with AUD at high risk of midterm poor outcomes.
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Affiliation(s)
- Xavier García-Calvo
- Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol. Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.,Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ferran Bolao
- Department of Internal Medicine, Hospital Universitari de Bellvitge-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Arantza Sanvisens
- Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol. Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.,Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Paola Zuluaga
- Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol. Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.,Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jordi Tor
- Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol. Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.,Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Robert Muga
- Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol. Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.,Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Daniel Fuster
- Department of Internal Medicine, Addiction Unit, Hospital Universitari Germans Trias i Pujol. Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain.,Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
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7
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Schwenger KJ, Clermont-Dejean N, Allard JP. The role of the gut microbiome in chronic liver disease: the clinical evidence revised. JHEP Rep 2019; 1:214-226. [PMID: 32039372 PMCID: PMC7001555 DOI: 10.1016/j.jhepr.2019.04.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 04/08/2019] [Accepted: 04/27/2019] [Indexed: 02/07/2023] Open
Abstract
Recent research has suggested a role for the intestinal microbiota in the pathogenesis and potential treatment of a wide range of liver diseases. The intestinal microbiota and bacterial products may contribute to the development of liver diseases through multiple mechanisms including increased intestinal permeability, chronic systemic inflammation, production of short-chain fatty acids and changes in metabolism. This suggests a potential role for pre-, pro- and synbiotic products in the prevention or treatment of some liver diseases. In addition, there is emerging evidence on the effects of faecal microbial transplant. Herein, we discuss the relationship between the intestinal microbiota and liver diseases, as well as reviewing intestinal microbiota-based treatment options that are currently being investigated.
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Affiliation(s)
- Katherine Jp Schwenger
- Toronto General Hospital, University Health Network, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, Canada
| | | | - Johane P Allard
- Toronto General Hospital, University Health Network, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, Canada.,Department of Nutritional Sciences, University of Toronto, Toronto, Canada
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8
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Monnig MA, Cohen R, Ramratnam B, McAdams M, Tashima K, Monti PM. HIV Infection, HCV Coinfection, and Alcohol Use: Associations with Microbial Translocation and Immune Activation. Alcohol Clin Exp Res 2019; 43:1126-1134. [PMID: 30908642 DOI: 10.1111/acer.14032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 03/14/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Human immunodeficiency virus (HIV) infection and heavy drinking independently promote microbial translocation and inflammation. However, it is not known how alcohol use may affect these processes in people living with HIV (PLWH). This study tested the hypothesis that alcohol exacerbates innate immune dysfunction in PLWH. METHODS Participants were 75 PLWH and 34 uninfected controls. Groups were recruited to have similar proportions of nondrinkers, moderate drinkers, and heavy drinkers. Substance use data and plasma samples were collected at up to 3 visits over a 5-year study period. Recent alcohol use was assessed with the Timeline Followback Interview. Biomarkers of microbial translocation (lipopolysaccharide, LPS) and immune activation (lipopolysaccharide binding protein, LBP; soluble CD14, sCD14; soluble CD163, sCD163) were quantified using enzyme-linked immunosorbent assays. Analyses tested 2 hypotheses: (i) that biomarker levels would be significantly higher in PLWH than controls with comparable alcohol use and (ii) that current alcohol use would exacerbate biomarker elevations in PLWH. The second analysis included the interaction of alcohol use with hepatitis C virus (HCV) coinfection. RESULTS Groups were matched on alcohol use, smoking, and other drug use. All biomarkers were significantly higher in PLWH relative to controls (LBP: p = 0.005; LPS: p = 0.014; sCD14: p < 0.001; sCD163: p < 0.001). In PLWH, alcohol use showed a significant, positive association with sCD163, but not with other biomarkers. However, the interaction of alcohol use with HCV coinfection was significant for all biomarkers (LBP: p = 0.002; LPS: p = 0.026; sCD14: p = 0.0004; sCD163: p = 0.001). In pairwise tests with sequential Bonferroni correction, HIV/HCV coinfected individuals who drank heavily had significantly higher sCD163 compared to coinfected nondrinkers and to HIV monoinfected nondrinkers, moderate drinkers, and heavy drinkers (ps < 0.005). Coinfected moderate drinkers had significantly higher sCD163 than each monoinfected group (ps < 0.003). In addition, sCD14 was significantly higher in coinfected moderate drinkers than coinfected nondrinkers (p = 0.027). CONCLUSIONS As predicted, PLWH had higher levels of LBP, LPS, sCD14, and sCD163 than uninfected individuals with similar alcohol use. In PLWH, alcohol by itself was significantly associated only with higher sCD163. However, heavy or moderate alcohol use was associated with elevations in macrophage activation (sCD163) and monocyte activation (sCD14) in HIV/HCV coinfected individuals.
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Affiliation(s)
- Mollie A Monnig
- Center for Alcohol and Addiction Studies , Brown University, Providence, Rhode Island
| | - Ronald Cohen
- Center for Cognitive Aging and Memory , University of Florida, Gainesville, Florida
| | - Bharat Ramratnam
- COBRE Center for Cancer Research Development, Rhode Island Hospital, Providence, Rhode Island.,Division of Infectious Diseases , Department of Medicine, Alpert Medical School, Brown University, Providence, Rhode Island
| | - Mikayla McAdams
- The Immunology Center , The Miriam Hospital, Providence, Rhode Island
| | - Karen Tashima
- Division of Infectious Diseases , Department of Medicine, Alpert Medical School, Brown University, Providence, Rhode Island.,The Immunology Center , The Miriam Hospital, Providence, Rhode Island
| | - Peter M Monti
- Center for Alcohol and Addiction Studies , Brown University, Providence, Rhode Island
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9
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Burra P, Zanetto A, Germani G. Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma. Cancers (Basel) 2018; 10:E46. [PMID: 29425151 PMCID: PMC5836078 DOI: 10.3390/cancers10020046] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 02/01/2018] [Accepted: 02/07/2018] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma.
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Affiliation(s)
- Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padua, Italy.
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padua, Italy.
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 Padua, Italy.
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10
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Markers of Microbial Translocation and Immune Activation Predict Cognitive Processing Speed in Heavy-Drinking Men Living with HIV. Microorganisms 2017; 5:microorganisms5040064. [PMID: 28934108 PMCID: PMC5748573 DOI: 10.3390/microorganisms5040064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 09/15/2017] [Accepted: 09/20/2017] [Indexed: 01/06/2023] Open
Abstract
HIV infection and alcohol use disorder are associated with deficits in neurocognitive function. Emerging evidence points to pro-inflammatory perturbations of the gut-brain axis as potentially contributing to neurocognitive impairment in the context of HIV and chronic heavy alcohol use. This study examined whether plasma markers of microbial translocation (LPS) from the gastrointestinal tract and related immune activation (sCD14, EndoCAb) were associated with neurocognition in 21 men living with HIV who were virally suppressed on antiretroviral therapy. All participants met federal criteria for heavy drinking and were enrolled in a randomized controlled trial (RCT) of a brief alcohol intervention. This secondary analysis utilized blood samples and cognitive scores (learning, memory, executive function, verbal fluency, and processing speed) obtained at baseline and three-month follow-up of the RCT. In generalized estimating equation models, LPS, sCD14, and EndoCAb individually were significant predictors of processing speed. In a model with all biomarkers, higher LPS and sCD14 both remained significant predictors of lower processing speed. These preliminary findings suggest that inflammation stemming from HIV and/or alcohol could have negative effects on the gut-brain axis, manifested as diminished processing speed. Associations of microbial translocation and immune activation with processing speed in heavy-drinking PLWH warrant further investigation in larger-scale studies.
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11
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Gorelick FS, Lerch MM. Do Animal Models of Acute Pancreatitis Reproduce Human Disease? Cell Mol Gastroenterol Hepatol 2017; 4:251-262. [PMID: 28752114 PMCID: PMC5518169 DOI: 10.1016/j.jcmgh.2017.05.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 05/26/2017] [Indexed: 12/10/2022]
Abstract
Acute pancreatitis is currently the most common cause of hospital admission among all nonmalignant gastrointestinal diseases. To understand the pathophysiology of the disease and as a potential step toward developing targeted therapies, attempts to induce the disease experimentally began more than 100 years ago. Recent decades have seen progress in developing new experimental pancreatitis models as well as elucidating many underlying cell biological and pathophysiological disease mechanisms. Some models have been developed to reflect specific causes of acute pancreatitis in human beings. However, the paucity of data relating to the molecular mechanisms of human disease, the likelihood that multiple genetic and environmental factors affect the risk of disease development and its severity, and the limited information regarding the natural history of disease in human beings make it difficult to evaluate the value of disease models. Here, we provide an overview of key models and discuss our views on their strengths for characterizing cell biological disease mechanisms or for identifying potential therapeutic targets. We also acknowledge their limitations.
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Affiliation(s)
- Fred S. Gorelick
- Yale University Medical School and Veterans Affairs Medical Center, West Haven, Connecticut
- Correspondence Address correspondence to: Fred S. Gorelick, MD, VA Connecticut Healthcare System/Yale University Medical School, 950 Campbell Avenue, West Haven, Connecticut 06516. fax: (203) 937-3852.VA Connecticut Healthcare System/Yale University Medical School950 Campbell AvenueWest HavenConnecticut 06516
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
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12
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Kirpich IA, McClain CJ, Vatsalya V, Schwandt M, Phillips M, Falkner KC, Zhang L, Harwell C, George DT, Umhau JC. Liver Injury and Endotoxemia in Male and Female Alcohol-Dependent Individuals Admitted to an Alcohol Treatment Program. Alcohol Clin Exp Res 2017; 41:747-757. [PMID: 28166367 DOI: 10.1111/acer.13346] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 01/30/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Interactions between the liver, the gut, and the immune system are critical components of alcoholic liver disease (ALD). The aim of this study was to explore the associations between alcohol-induced liver injury, endotoxemia, and inflammation at admission and over time during abstinence, as well as to examine the sex-related differences in these parameters in alcohol-dependent individuals admitted to an alcohol treatment program. METHODS A cohort of 48 otherwise healthy participants with alcohol use disorder, but no clinical signs of alcoholic liver injury (34 males [M]/14 females [F]) admitted to an alcohol detoxification program, was stratified into 2 groups based on baseline plasma alanine aminotransferase (ALT) levels (as a marker of liver injury). Group 1 (ALT < 40 U/l, 7M/8F) and Group 2 (ALT ≥ 40 U/l, 27M/6F) were identified. Plasma biomarkers of liver damage, endotoxemia, and inflammation were examined at baseline, day 8, and day 15 of the admission. The drinking history was also evaluated. RESULTS Sixty-nine percent of patients had elevated ALT and other markers of liver damage, including aspartate aminotransferase and cytokeratin 18 (CK18 M65 and CK M30) at baseline, indicating the presence of mild ALD. Elevated CK18 M65:M30 ratio suggested a greater contribution of necrotic rather than apoptotic hepatocyte cell death in the liver injury observed in these individuals. Females showed greater elevations of liver injury markers compared to males, although they had fewer drinks per day and shorter lifetime duration of heavy drinking. Liver injury was associated with systemic inflammation, specifically, elevated plasma tumor necrosis factor-alpha levels. Compared to patients without liver injury, patients with mild ALD had greater endotoxemia (increased serum lipopolysaccharide levels), which decreased with abstinence and this decrease preceded the drop in CK18 M65 levels. CONCLUSIONS The study documented the association of mild alcohol-induced liver injury and endotoxemia, which improved with 2 weeks of abstinence, in a subset of individuals admitted to an alcohol detoxification program.
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Affiliation(s)
- Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.,Robley Rex Veterans Medical Center, Louisville, Kentucky.,University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky.,University of Louisville Hepatobiology & Toxicology Program, University of Louisville, Louisville, Kentucky
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.,Robley Rex Veterans Medical Center, Louisville, Kentucky.,University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky.,University of Louisville Hepatobiology & Toxicology Program, University of Louisville, Louisville, Kentucky
| | - Vatsalya Vatsalya
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.,University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky.,University of Louisville Hepatobiology & Toxicology Program, University of Louisville, Louisville, Kentucky.,National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Melanie Schwandt
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Monte Phillips
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Keith Cameron Falkner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.,University of Louisville Alcohol Research Center, University of Louisville, Louisville, Kentucky.,University of Louisville Hepatobiology & Toxicology Program, University of Louisville, Louisville, Kentucky
| | - Lucy Zhang
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - Catey Harwell
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky
| | - David T George
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.,George Washington University Hospital, Washington, District of Columbia
| | - John C Umhau
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.,Food and Drug Administration, Silver Spring, Maryland
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13
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Host defenses against metabolic endotoxaemia and their impact on lipopolysaccharide detection. Int Rev Immunol 2017; 36:125-144. [PMID: 28783409 DOI: 10.1080/08830185.2017.1280483] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Monnig MA. Immune activation and neuroinflammation in alcohol use and HIV infection: evidence for shared mechanisms. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2017; 43:7-23. [PMID: 27532935 PMCID: PMC5250549 DOI: 10.1080/00952990.2016.1211667] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 07/07/2016] [Accepted: 07/07/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Emerging research points to innate immune mechanisms in the neuropathological and behavioral consequences of heavy alcohol use. Alcohol use is common among people living with HIV infection (PLWH), a chronic condition that carries its own set of long-term effects on brain and behavior. Notably, neurobiological and cognitive profiles associated with heavy alcohol use and HIV infection share several prominent features. This observation raises questions about interacting biological mechanisms as well as compounded impairment when HIV infection and heavy drinking co-occur. OBJECTIVE AND METHOD This narrative overview discusses peer-reviewed research on specific immune mechanisms of alcohol that exhibit apparent potential to compound the neurobiological and psychiatric sequelae of HIV infection. These include microbial translocation, systemic immune activation, blood-brain barrier compromise, microglial activation, and neuroinflammation. RESULTS Clinical and preclinical evidence supports overlapping mechanistic actions of HIV and alcohol use on peripheral and neural immune systems. In preclinical studies, innate immune signaling mediates many of the detrimental neurocognitive and behavioral effects of alcohol use. Neuropsychopharmacological research suggests potential for a feed-forward cycle in which heavy drinking induces innate immune signaling, which in turn stimulates subsequent alcohol use behavior. CONCLUSION Alcohol-induced immune activation and neuroinflammation are a serious health concern for PLWH. Future research to investigate specific immune effects of alcohol in the context of HIV infection has potential to identify novel targets for therapeutic intervention.
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Affiliation(s)
- Mollie A. Monnig
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI
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15
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Ronis MJJ, Hakkak R, Korourian S, Albano E, Yoon S, Ingelman-Sundberg M, Lindros KO, Badger TM. Alcoholic Liver Disease in Rats Fed Ethanol as Part of Oral or Intragastric Low-Carbohydrate Liquid Diets. Exp Biol Med (Maywood) 2016; 229:351-60. [PMID: 15044719 DOI: 10.1177/153537020422900410] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The intragastric administration of ethanol as part of a lowcarbohydrate diet results in alcohol hepatotoxicity. We aimed to investigate whether comparable liver injury can be achieved by oral diet intake. Male Sprague-Dawley rats were fed ethanol as part of low-carbohydrate diets for 36–42 days either intragastrically or orally. Liver pathology, blood ethanol concentration, serum alanine amino transferase (ALT), endotoxin level, hepatic CYP2E1 induction, and cytokine profiles were assessed. Both oral and intragastric low-carbohydrate ethanol diets resulted in marked steatosis with additional inflammation and necrosis accompanied by significantly increased serum ALT, high levels of CYP2E1 expression, and production of auto-antibodies against malondialdehyde and hydroxyethyl free radical protein adducts. However, cytokine profiles differed substantially between the groups, with significantly lower mRNA expression of the anti-inflammatory cytokine interleukin 4 observed in rats fed low-carbohydrate diets orally. Inflammation and necrosis were significantly greater in rats receiving low-carbohydrate alcohol diets intragastrically than orally. This was associated with a significant increase in liver tumor necrosis factor α and interleukin 1β gene expression in the intragastric model. Thus, oral low-carbohydrate diets produce more ethanol-induced liver pathology than oral high-carbohydrate diets, but hepatotoxicity is more severe when a low-carbohydrate diet plus ethanol is infused intragastrically and is accompanied by significant increases in levels of proinflammatory cytokines.
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Affiliation(s)
- Martin J J Ronis
- Department of Pharmacology and Toxicology, UAMS, Arkansas Children's Nutrition Center, Little Rock Arkansas, 72205, USA.
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16
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Gnauck A, Lentle RG, Kruger MC. Chasing a ghost?--Issues with the determination of circulating levels of endotoxin in human blood. Crit Rev Clin Lab Sci 2016; 53:197-215. [PMID: 26732012 DOI: 10.3109/10408363.2015.1123215] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Reliable quantification of bacterial products such as endotoxin is important for the diagnosis of Gram-negative infection and for the monitoring of its treatment. Further, it is important to identify patients with persistent subclinical level of bacterial products in their systemic circulation as data from animal studies also suggest this may be correlated with the onset of metabolic syndrome. In this review, we first aim to describe the principles of the Limulus amoebocyte lysate (LAL) test, an assay that is used to quantify endotoxin, and the various shortcomings that must be addressed before it can become a reliable means of quantifying endotoxin in samples derived from blood. We then review published data regarding endotoxin levels in healthy subjects and those with sepsis, inflammatory bowel disease, liver disorders and metabolic disorders such as obesity and diabetes. We also review the evidence regarding influence of macronutrients in augmenting the levels of systemic endotoxin. The results of this review show that reported mean levels of endotoxin in the systemic circulation of healthy humans and of those with various clinical disorders vary over a wide range. Further, this review shows that a significant proportion of this variation can be related to the method that was used to prepare plasma and serum samples prior to assay and its ability to reduce the effect of various blood borne factors that interfere with the LAL assay.
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Affiliation(s)
- Anne Gnauck
- a Physiology Group, School of Food and Nutrition, College of Health, Massey University , Palmerston North , New Zealand
| | - Roger Graham Lentle
- a Physiology Group, School of Food and Nutrition, College of Health, Massey University , Palmerston North , New Zealand
| | - Marlena Cathorina Kruger
- a Physiology Group, School of Food and Nutrition, College of Health, Massey University , Palmerston North , New Zealand
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17
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Zhong W, Li Q, Sun Q, Zhang W, Zhang J, Sun X, Yin X, Zhang X, Zhou Z. Preventing Gut Leakiness and Endotoxemia Contributes to the Protective Effect of Zinc on Alcohol-Induced Steatohepatitis in Rats. J Nutr 2015; 145:2690-8. [PMID: 26468492 PMCID: PMC4656905 DOI: 10.3945/jn.115.216093] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 09/18/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Zinc deficiency has been well documented in alcoholic liver disease. OBJECTIVE This study was undertaken to determine whether dietary zinc supplementation provides beneficial effects in treating alcohol-induced gut leakiness and endotoxemia. METHODS Male Sprague Dawley rats were divided into 3 groups and pair-fed (PF) Lieber-DeCarli liquid diet for 8 wk: 1) control (PF); 2) alcohol-fed (AF; 5.00-5.42% wt:vol ethanol); and 3) AF with zinc supplementation (AF/Zn) at 220 ppm zinc sulfate heptahydrate. The PF and AF/Zn groups were pair-fed with the AF group. Hepatic inflammation and endotoxin signaling were determined by immunofluorescence and quantitative polymerase chain reaction (qPCR). Alterations in intestinal tight junctions and aldehyde dehydrogenases were assessed by qPCR and Western blot analysis. RESULTS The AF rats had greater macrophage activation and cytokine production (P < 0.05) in the liver compared with the PF rats, whereas the AF/Zn rats showed no significant differences (P > 0.05). Plasma endotoxin concentrations of the AF rats were 136% greater than those of the PF rats, whereas the AF/Zn rats did not differ from the PF rats. Ileal permeability was 255% greater in the AF rats and 19% greater in the AF/Zn rats than in the PF rats. The AF group had reduced intestinal claudin-1, occludin, and zona occludens-1 (ZO-1) expression, and the AF/Zn group had upregulated claudin-1 and ZO-1 expression (P < 0.05) compared with the PF group. The intestinal epithelial expression and activity of aldehyde dehydrogenases were elevated (P < 0.05) in the AF/Zn rats compared with those of the AF rats. Furthermore, the ileal expression and function of hepatocyte nuclear factor 4α, which was impaired in the AF group, was significantly elevated in the AF/Zn group compared with the PF group. CONCLUSIONS The results demonstrate that attenuating hepatic endotoxin signaling by preserving the intestinal barrier contributes to the protective effect of zinc on alcohol-induced steatohepatitis in rats.
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Affiliation(s)
- Wei Zhong
- Center for Translational Biomedical Research and
| | - Qiong Li
- Center for Translational Biomedical Research and
| | - Qian Sun
- Center for Translational Biomedical Research and,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC; and
| | | | - Jiayang Zhang
- Department of Chemistry, University of Louisville, Louisville, KY
| | - Xinguo Sun
- Center for Translational Biomedical Research and
| | - Xinmin Yin
- Department of Chemistry, University of Louisville, Louisville, KY
| | - Xiang Zhang
- Department of Chemistry, University of Louisville, Louisville, KY
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research and Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC; and
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18
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Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats. Biomolecules 2015; 5:2643-58. [PMID: 26501337 PMCID: PMC4693251 DOI: 10.3390/biom5042643] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/21/2015] [Accepted: 09/23/2015] [Indexed: 12/12/2022] Open
Abstract
Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation.
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19
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Abstract
Chronic alcohol abuse is a major risk factor for hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide. Alcohol can also function synergistically with other risk factors to cause HCC. Hence, alcohol consumption is a major factor affecting hepatic carcinogenesis in millions and the cause of a substantial public health burden. Chronic alcohol consumption interferes with several host anti-tumor mechanisms, thereby facilitating hepatocyte proliferation and tumorigenesis. This review summarizes the major mechanisms of alcohol-induced HCC. These include pathways of ethanol metabolism, alcohol-induced oxidative stress and hypomethylation of DNA, and interplay of alcohol with iron elevation, retinoid metabolism, the immune system, inflammatory pathways, and neoangiogenesis. The relevance of each pathway in affecting HCC transformation is a topic of intense investigation. Ongoing research will enhance our insight into the alcohol-induced occurrence of HCC and offer hope in developing better therapeutics.
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Affiliation(s)
- Sreetha Sidharthan
- Critical Care Medicine Department, Department of Health and Human Services, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Shyam Kottilil
- Laboratory of Immunoregulation, Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg10, Rm.11N204, Bethesda, MD 20892, USA
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20
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Vassallo G, Mirijello A, Ferrulli A, Antonelli M, Landolfi R, Gasbarrini A, Addolorato G. Review article: Alcohol and gut microbiota - the possible role of gut microbiota modulation in the treatment of alcoholic liver disease. Aliment Pharmacol Ther 2015; 41:917-27. [PMID: 25809237 DOI: 10.1111/apt.13164] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 07/25/2014] [Accepted: 02/27/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Alcohol abuse represents the most common cause of liver disease in the Western countries. Pre-clinical and clinical studies showed that alcohol consumption affects amount and composition of gut microbiota. Moreover, gut flora plays an important role in the pathogenesis of alcoholic liver injury. AIM To review the relationship between alcohol administration and changes on gut microbiota, its involvement in the pathogenesis of alcoholic liver disease, and how gut microbiota modulation could be a target for the treatment of alcoholic liver disease. METHODS Articles were identified using the PubMed database with the search terms 'Alcohol', 'Gut Microbiota', 'Alcoholic liver disease', 'Probiotic', 'Prebiotic', 'Symbiotic' and 'Antibiotic'. English-language articles were screened for relevance. Full review of publications for the relevant studies was conducted, including additional publications that were identified from individual article reference lists. RESULTS Alcohol abuse induces changes in the composition of gut microbiota, although the exact mechanism for this alteration is not well known. The translocation of bacterial products into the portal blood appears to play a key role in alcohol-induced liver damage. Several studies show that the modulation of gut microbiota seem to be a promising strategy to reduce alcohol-induced liver injury. CONCLUSIONS Further studies are needed to better understand the relationship between alcohol administration and changes in gut microbiota, and its involvement in alcoholic liver disease. Moreover larger studies are needed to confirm the preliminary results on the therapeutic effects of gut microbiota modulation.
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Affiliation(s)
- G Vassallo
- Department of Internal Medicine, Catholic University of Rome, Rome, Italy
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21
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Nyström J, Stenkvist J, Häggblom A, Weiland O, Nowak P. Low levels of microbial translocation marker LBP are associated with sustained viral response after anti-HCV treatment in HIV-1/HCV co-infected patients. PLoS One 2015; 10:e0118643. [PMID: 25785448 PMCID: PMC4364767 DOI: 10.1371/journal.pone.0118643] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 01/08/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Microbial translocation (MT) contributes to immune activation during HIV and HCV infections. We investigated the kinetics of MT markers during anti-HCV and anti-HIV treatments, and if baseline plasma levels of lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) could predict anti-HCV treatment outcome. METHODS Plasma from 78 HIV-infected patients was evaluated for LPS, LBP and sCD14. The patients starting anti-HCV treatment (with ongoing antiretroviral (ART) treatment) were categorized into sustained viral responders (SVR; n = 21) or non-responders (NR; n = 15) based on treatment outcome. ART starting subjects--were categorized into chronically HCV-infected (CH; n = 24) and mono-infected (HIV; n = 18), based on the HCV infection status. Samples were collected before start (at baseline) of pegylated-interferon-alpha/ribavirin (peg-IFN/RBV) or antiretroviral-therapy and two years after treatment start (at follow up). χ2-test, non-parametric statistics and logistic regression were applied to determine the associations with treatment response and changes of the soluble markers. RESULTS Plasma levels of LPS and sCD14 were elevated in all subjects before antiviral-treatment but remained unchanged at follow-up. Elevated levels of LBP were present in patients with HIV and HIV/HCV co-infection and were reduced by ART. Additionally, higher levels of LBP were present at baseline in NR vs. SVR. Higher levels of LBP at baseline were associated with non-response to peg-IFN/RBV treatment in both bivariate (OR: 0.19 95% CI: 0.06-0.31, p = 0.004) and multivariate analysis (OR: 1.43, 95% CI: 1.1-1.86, p = 0.07). CONCLUSION In HIV/HCV co-infected patients high baseline LBP levels are associated with non-response to peg-IFN/RBV therapy. Plasma LBP (decreased by ART) may be a more relevant MT marker than LPS and sCD14.
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Affiliation(s)
- Jessica Nyström
- Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Jenny Stenkvist
- Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Amanda Häggblom
- Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
- Department of Infectious Diseases, County Council of Gävleborg, Gävle, Sweden
| | - Ola Weiland
- Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Piotr Nowak
- Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
- Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
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23
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French AL, Evans CT, Agniel DM, Cohen MH, Peters M, Landay AL, Desai SN. Microbial translocation and liver disease progression in women coinfected with HIV and hepatitis C virus. J Infect Dis 2013; 208:679-89. [PMID: 23687224 PMCID: PMC3719907 DOI: 10.1093/infdis/jit225] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 02/13/2013] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Microbial translocation has been implicated in the pathogenesis of liver fibrosis and cirrhosis. We sought to determine whether markers of microbial translocation are associated with liver disease progression during coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS We measured serial plasma lipopolysaccharide (LPS), endotoxin core antibody, intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), interleukin 10, and tumor necrosis factor α (TNF-α) levels over a 5-year period in 44 HIV/HCV-coinfected women, 21 of whom experienced liver disease progression and 23 were nonprogressors. RESULTS While LPS levels did not differ significantly over time between progressors and nonprogressors (P = .60), progressors had significantly higher plasma levels of sCD14, a marker of monocyte activation by LPS, at the first time point measured (P = .03) and throughout the study period (P = .001); progressors also had higher IL-6 and I-FABP levels over the 5-year study period (P = .02 and .03, respectively). The associations between progression and sCD14, I-FABP, and IL-6 levels were unchanged in models controlling for HIV RNA and CD4(+) T-cell count. CONCLUSIONS Although LPS levels did not differ between liver disease progressors and nonprogressors, the association of sCD14, I-FABP, and IL-6 levels with liver disease progression suggests that impairment of gut epithelial integrity and consequent microbial translocation may play a role in the complex interaction of HIV and HCV pathogenesis.
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Affiliation(s)
- Audrey L French
- Department of Medicine, CORE Center/Stroger Hospital of Cook County, Chicago, IL 60612, USA.
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24
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Hartmann P, Chen P, Wang HJ, Wang L, McCole DF, Brandl K, Stärkel P, Belzer C, Hellerbrand C, Tsukamoto H, Ho SB, Schnabl B. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 2013; 58:108-19. [PMID: 23408358 PMCID: PMC3695050 DOI: 10.1002/hep.26321] [Citation(s) in RCA: 189] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 02/07/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED 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 (Muc) 2, 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 than 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 antimicrobial proteins regenerating islet-derived 3 beta and gamma 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.
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Affiliation(s)
- Phillipp Hartmann
- Department of Medicine, University of California San Diego, La Jolla, CA,Department of Internal Medicine I, University Regensburg, Regensburg, Germany
| | - Peng Chen
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - Hui J. Wang
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - Lirui Wang
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - Declan F. McCole
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - Katharina Brandl
- Department of Genetics, The Scripps Research Institute, La Jolla, CA
| | - Peter Stärkel
- St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | - Clara Belzer
- Laboratory of Microbiology, Wageningen, The Netherlands
| | - Claus Hellerbrand
- Department of Internal Medicine I, University Regensburg, Regensburg, Germany
| | - Hidekazu Tsukamoto
- Department of Pathology, Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA,Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA
| | - Samuel B. Ho
- Department of Medicine, University of California San Diego, La Jolla, CA,Department of Medicine, VA San Diego Healthcare System, San Diego, CA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA
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Wlazlo N, van Greevenbroek MMJ, Ferreira I, Jansen EHJM, Feskens EJM, van der Kallen CJH, Schalkwijk CG, Bravenboer B, Stehouwer CDA. Activated complement factor 3 is associated with liver fat and liver enzymes: the CODAM study. Eur J Clin Invest 2013; 43:679-88. [PMID: 23586841 DOI: 10.1111/eci.12093] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Accepted: 03/16/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND The complement system may be involved in the pathogenesis of alcoholic and nonalcoholic liver disease, although studies in humans are scarce. For this reason, we investigated whether circulating levels of activated complement factor 3 (C3a) were associated with hepatic steatosis and hepatocellular damage. MATERIALS AND METHODS Plasma C3a, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were determined in 523 individuals (61% men, age 59 ± 7 years). Liver enzymes (LEs) were standardized and compiled into a LE score. Liver fat content was estimated using a predictive equation that has recently been validated with magnetic resonance spectrometry. Cross-sectional associations between C3a and liver fat or LE s were investigated with multiple linear regression analyses, stratified in no-to-moderate vs. heavy alcohol consumers (men: > 30 g/day; women: > 20 g/day). RESULTS C3a was associated with liver fat percentage both in the no-to-moderate (β = 0.223; 95%CI 0.036; 0.409) and in the heavy alcohol consumers (β = 0.632; 95%CI 0.259-1.004; P-interaction = 0.047). C3a was also associated with the LE score in heavy alcohol consumers (β = 0.917; 95%CI 0.443-1.392), but not in no-to-moderate alcohol consumers (β = 0.042; 95%CI -0.198 to 0.281; P-interaction = 0.001). CONCLUSIONS C3a levels, as a marker of complement activation, were associated with liver fat content and hepatocellular injury, at least in subjects who consume considerable amounts of alcohol daily.
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Affiliation(s)
- Nick Wlazlo
- Department of Internal Medicine, Catharina Hospital, Eindhoven, the Netherlands.
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Litzman J, Nechvatalova J, Xu J, Ticha O, Vlkova M, Hel Z. Chronic immune activation in common variable immunodeficiency (CVID) is associated with elevated serum levels of soluble CD14 and CD25 but not endotoxaemia. Clin Exp Immunol 2013; 170:321-32. [PMID: 23121673 DOI: 10.1111/j.1365-2249.2012.04655.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Common variable immunodeficiency (CVID), the most frequent symptomatic immunoglobulin primary immunodeficiency, is associated with chronic T cell activation and reduced frequency of CD4(+) T cells. The underlying cause of immune activation in CVID is unknown. Microbial translocation indicated by elevated serum levels of lipopolysaccharide and soluble CD14 (sCD14) has been linked previously to systemic immune activation in human immunodeficiency virus/acquired immune deficiency syndrome (HIV-1/AIDS), alcoholic cirrhosis and other conditions. To address the mechanisms of chronic immune activation in CVID, we performed a detailed analysis of immune cell populations and serum levels of sCD14, soluble CD25 (sCD25), lipopolysaccharide and markers of liver function in 35 patients with CVID, 53 patients with selective immunoglobulin (Ig)A deficiency (IgAD) and 63 control healthy subjects. In CVID subjects, the concentration of serum sCD14 was increased significantly and correlated with the level of sCD25, C-reactive protein and the extent of T cell activation. Importantly, no increase in serum lipopolysaccharide concentration was observed in patients with CVID or IgAD. Collectively, the data presented suggest that chronic T cell activation in CVID is associated with elevated levels of sCD14 and sCD25, but not with systemic endotoxaemia, and suggest involvement of lipopolysaccharide-independent mechanisms of induction of sCD14 production.
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Affiliation(s)
- J Litzman
- Department of Clinical Immunology and Allergology, Faculty of Medicine, Masaryk University and St Anne's University Hospital, Brno, Czech Republic
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Seo YS, Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol 2012; 18:337-46. [PMID: 23323248 PMCID: PMC3540369 DOI: 10.3350/cmh.2012.18.4.337] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Revised: 10/03/2012] [Accepted: 10/17/2012] [Indexed: 12/12/2022] Open
Abstract
Because of the anatomical position and its unique vascular system, the liver is susceptible to the exposure to the microbial products from the gut. Although large amount of microbes colonize in the gut, translocation of the microbes or microbial products into the liver and systemic circulation is prevented by gut epithelial barrier function and cleansing and detoxifying functions of the liver in healthy subjects. However, when the intestinal barrier function is disrupted, large amount of bacterial products can enter into the liver and systemic circulation and induce inflammation through their receptors. Nowadays, there have been various reports suggesting the role of gut flora and bacterial translocation in the pathogenesis of chronic liver disease and portal hypertension. This review summarizes the current knowledge about bacterial translocation and its contribution to the pathogenesis of chronic liver diseases and portal hypertension.
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Affiliation(s)
- Yeon Seok Seo
- Gastroenterology Research Unit, Mayo Clinic, Rochester, MN 55905, USA
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28
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EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57:399-420. [PMID: 22633836 DOI: 10.1016/j.jhep.2012.04.004] [Citation(s) in RCA: 450] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Accepted: 04/04/2012] [Indexed: 12/12/2022]
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Kirpich IA, Feng W, Wang Y, Liu Y, Barker DF, Barve SS, McClain CJ. The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res 2011; 36:835-46. [PMID: 22150547 DOI: 10.1111/j.1530-0277.2011.01673.x] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Interactions between the gut, immune system, and the liver, as well as the type of fat in the diet, are critical components of alcoholic liver disease (ALD). The goal of the present study was to determine the effects of saturated fat (SF) and unsaturated fat (USF) on ethanol (EtOH)-induced gut-liver interactions in a mouse model of ALD. METHODS C57BL/6N mice were fed Lieber-DeCarli liquid diets containing EtOH and enriched in USF (corn oil) or SF (medium chain triglycerides:beef tallow). Control mice were pair-fed on an isocaloric basis. Liver injury and steatosis, blood endotoxin levels, intestinal permeability, and tight junction (TJ) integrity, as well as hepatic Toll-like receptor (TLR) gene expression, were evaluated. RESULTS After 8 weeks of EtOH feeding, liver injury and steatosis were observed in USF + EtOH group compared with control and SF + EtOH. Significantly increased intestinal permeability in conjunction with elevated blood endotoxin levels were observed in the ileal segments of the mice fed USF + EtOH. USF diet alone resulted in down-regulation of intestinal TJ protein mRNA expression compared with SF. Importantly, alcohol further suppressed TJ proteins in USF + EtOH, but did not affect intestinal TJ in SF + EtOH group. The type of fat in the diet alone did not affect hepatic TLR expression. Compared with control animals, hepatic TLR (TLR 1, 2, 3, 4, 7, 8, 9) mRNA expression was significantly (p < 0.05) increased in USF + EtOH, but not in SF + EtOH group. Notably, TLR5 was the only up-regulated TLR in both SF + EtOH and USF + EtOH groups. CONCLUSIONS Dietary fat is an important cofactor in alcohol-associated liver injury. We demonstrate that USF (corn oil/linoleic acid) by itself results in dysregulation of intestinal TJ integrity leading to increased gut permeability, and alcohol further exacerbates these alterations. We postulate that elevated blood endotoxin levels in response to USF and alcohol in conjunction with up-regulation of hepatic TLRs combine to cause hepatic injury in ALD.
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Affiliation(s)
- Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Kentucky, USA
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Sandler NG, Koh C, Roque A, Eccleston JL, Siegel RB, DeMino M, Kleiner DE, Deeks SG, Liang TJ, Heller T, Douek DC. Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection. Gastroenterology 2011; 141:1220-30, 1230.e1-3. [PMID: 21726511 PMCID: PMC3186837 DOI: 10.1053/j.gastro.2011.06.063] [Citation(s) in RCA: 238] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Revised: 06/10/2011] [Accepted: 06/24/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes. METHODS In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment. RESULTS Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively). CONCLUSIONS LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection.
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MESH Headings
- Bacterial Translocation
- Biomarkers/blood
- Biopsy
- Cell Death
- Disease Progression
- End Stage Liver Disease/microbiology
- End Stage Liver Disease/virology
- Enterocytes/microbiology
- Enterocytes/pathology
- Enterocytes/virology
- Enzyme-Linked Immunosorbent Assay
- Fatty Acid-Binding Proteins/blood
- Female
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/microbiology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/microbiology
- Host-Pathogen Interactions
- Humans
- Hypertension, Portal/microbiology
- Hypertension, Portal/virology
- Interleukin-6/blood
- Intestines/immunology
- Intestines/microbiology
- Intestines/pathology
- Intestines/virology
- Kupffer Cells/microbiology
- Kupffer Cells/virology
- Limulus Test
- Lipopolysaccharide Receptors/blood
- Lipopolysaccharides/blood
- Liver Cirrhosis/diagnosis
- Liver Cirrhosis/immunology
- Liver Cirrhosis/microbiology
- Liver Cirrhosis/virology
- Logistic Models
- Male
- Maryland
- Middle Aged
- Monocytes/immunology
- Monocytes/microbiology
- Monocytes/virology
- Odds Ratio
- Retrospective Studies
- Severity of Illness Index
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Affiliation(s)
- Netanya G. Sandler
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - Annelys Roque
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Jason L. Eccleston
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - Rebecca B. Siegel
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892
| | - Mary DeMino
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892
| | - Steven G. Deeks
- HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA, USA
| | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892
| | - Daniel C. Douek
- Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892
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Basra G, Basra S, Parupudi S. Symptoms and signs of acute alcoholic hepatitis. World J Hepatol 2011; 3:118-20. [PMID: 21731904 PMCID: PMC3124878 DOI: 10.4254/wjh.v3.i5.118] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 03/08/2011] [Accepted: 03/15/2011] [Indexed: 02/06/2023] Open
Abstract
Although there is not one specific sign or symptom related to alcoholic hepatitis (AH), a constellation of symptoms and signs can help make the diagnosis of AH with reasonable accuracy. Documentation of chronic and active alcohol abuse is paramount in making a diagnosis of AH. Clinical presentation after abstinence for more than 3 m should raise doubts about the diagnosis of AH and dictate the need for considering other causes of liver disease, decompensation of alcoholic cirrhosis, sepsis and malignancy as the cause of patient's clinical profile.
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Affiliation(s)
- Gurjot Basra
- Gurjot Basra, Sarpreet Basra, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
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Pimentel-Nunes P, Roncon-Albuquerque R, Gonçalves N, Fernandes-Cerqueira C, Cardoso H, Bastos RP, Marques M, Marques C, Alexandre Sarmento J, Costa-Santos C, Macedo G, Pestana M, Dinis-Ribeiro M, Leite-Moreira AF. Attenuation of toll-like receptor 2-mediated innate immune response in patients with alcoholic chronic liver disease. Liver Int 2010; 30:1003-11. [PMID: 20492495 DOI: 10.1111/j.1478-3231.2010.02251.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Alcoholic chronic liver disease (ACLD) is a common form of acquired immunodeficiency. AIM To evaluate ex vivo toll-like receptor (TLR) 2 and TLR4 innate immune response in stable ACLD. METHODS Blood was collected from 26 males with stable ACLD and from 17 controls. Serum was used for lipopolysaccharide (LPS), sCD14, LPS-binding protein (LBP), tumour necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL-10) quantification. Peripheral blood monocytes (PBM) protein expression of TLR2 and TLR4 was determined by flow cytometry. Primary cultures of anti-CD11b positive selected PBM were stimulated with the TLR2/TLR6 ligand zymosan (Zym), with TLR2/TLR1 ligand lipopeptide (Lp) and with TLR4 ligand LPS. PBM TLR1, TLR2, TLR4, TLR6, MD2, CD14, TNF-alpha and IL-10 gene expression was evaluated by reverse transcription-polymerase chain reaction. RESULTS Stable ACLD patients showed increased circulating LPS (+22.5+/-4.1%), LBP (+60.6+/-12.2%) and sCD14 (+23.5+/-4.6%), with no differences in TNF-alpha and IL-10. Zym and Lp, but not LPS, induced TNF-alpha production by monocytes was blunted in ACLD (-66+/-20.4% Zym; -40.1+/-13.5% Lp; P<0.05). Basal TNF-alpha mRNA expression was decreased in PBM from ACLD patients (-50.1+/-21.0%; P<0.05), with no significant differences in the other studied genes. Results were similar in Child-Pugh A and B/C patients. CONCLUSIONS Patients with stable ACLD show an attenuation of TLR2-mediated innate immune response in PBM, which may represent an important mechanism for acquired immunodeficiency. This was neither related with decreased TLR2 or its co-receptors expression nor with impaired TLR4 activation, being already present in the early stages of disease.
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Affiliation(s)
- Pedro Pimentel-Nunes
- Department of Physiology, Cardiovascular Research & Development Unit, Faculty of Medicine, University of Porto, Porto, Portugal
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Leber B, Mayrhauser U, Rybczynski M, Stadlbauer V. Innate immune dysfunction in acute and chronic liver disease. Wien Klin Wochenschr 2010; 121:732-44. [PMID: 20047110 DOI: 10.1007/s00508-009-1288-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2009] [Accepted: 11/26/2009] [Indexed: 12/19/2022]
Abstract
Liver cirrhosis is a common disease causing great public-health concern because of the frequent complications requiring hospital care. Acute liver failure is also prone to several complications but is rare. One of the main complications for both acute and chronic liver diseases is infection, which regularly causes decompensation of cirrhosis, possibly leading to organ failure and death. This review focuses on innate immune function in cirrhosis, acute-on-chronic liver failure and acute liver failure. The known defects of Kupffer cells, neutrophils and monocytes are discussed, together with the pathophysiological importance of gut permeability, portal hypertension and intrinsic cellular defects, and the role of endotoxin, albumin, lipoproteins and toll-like receptors. Based on these different pathomechanisms, the available information on therapeutic strategies is presented. Antibiotic and probiotic treatment, nutritional support, artificial liver support, and experimental strategies such as inhibition of toll-like receptors and use of albumin and colony-stimulating factors are highlighted.
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Affiliation(s)
- Bettina Leber
- Division of Surgery, Medical University of Graz, Graz, Austria
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34
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Low-grade endotoxemia in patients with severe autism. Neurosci Lett 2010; 471:162-5. [PMID: 20097267 DOI: 10.1016/j.neulet.2010.01.033] [Citation(s) in RCA: 158] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 12/25/2009] [Accepted: 01/15/2010] [Indexed: 02/07/2023]
Abstract
The objective of this study was to examine whether levels of endotoxin and other markers of immuno-inflammatory activation are altered in adult patients with severe autism. We determined circulating serum endotoxin levels, its soluble receptor (sCD14), and markers of immuno-inflammatory activation (IL-1beta, IL-6, and IL-10) in 22 adult patients with severe autism and 28 age- and gender-matched healthy controls. Compared with healthy subjects, serum levels of endotoxin were significantly higher in autistic patients and inversely and independently correlated with Socialization scores on the Vineland Adaptive Behavior Scales (VABS) and ADI-R Domain A score (social). Whether increased endotoxin may contribute to the pathophysiology of inflammation and impaired reciprocal social interaction in autism should be further explored in future studies.
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Moriya T, Naito H, Ito Y, Nakajima T. "Hypothesis of seven balances": molecular mechanisms behind alcoholic liver diseases and association with PPARalpha. J Occup Health 2009; 51:391-403. [PMID: 19706994 DOI: 10.1539/joh.k9001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVES The purpose of this review to collate current leading scientific advances of molecular mechanisms in alcoholic liver diseases and to propose a working "hypothesis of seven balances" in relation to peroxisome proliferator activated receptor alpha (PPARalpha), which has important roles in fatty acid oxidation, oxidative stress, inflammatory responses, and possibly liver fibrosis. METHODS We conducted an extensive literature review of over a hundred publications and collated the findings with evidence generated in our laboratory. RESULTS Our research points to a working hypothesis of seven balances for alcoholic liver diseases consisting of: 1) ethanol oxidation balance in hepatocytes; 2) PPAR alpha activities in liver; 3) fatty acid metabolism balance in hepatic mitochondria; 4) gastrointestinal response to ethanol, acetaldehyde and lipopolysaccharide (LPS); 5) Kupffer cells response to LPS, oxidative stress and inflammatory cytokines; 6) adiponectin levels in plasma interchangeably regulated by tumor necrosis factor-alpha (TNF-alpha); and 7) stellate cells response to all of the above promoting hepatic fibrosis. Cellular mechanisms behind alcoholic liver diseases reveal close temporal associations of PPARalpha, adiponectin, TNF-alpha, cellular inflammation, proliferation, and potentially fibrosis as illustrated in "the hypothesis of seven balances." CONCLUSIONS The regulation and adjustment of PPARalpha activation underlying the balance of molecular cascades might resolve the progression of alcoholic liver diseases by reducing oxidative stress and inflammatory effects induced by nuclear factor-kappaB as well as the associated adiponectin pathway. Further elucidation of these pathways would reveal exciting new prospects for treating alcoholic liver diseases and other related liver disorders.
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Affiliation(s)
- Takashi Moriya
- Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Aichi, Japan
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Oz HS, Chen TS, Neuman M. Nutrition intervention: a strategy against systemic inflammatory syndrome. JPEN J Parenter Enteral Nutr 2009; 33:380-9. [PMID: 19380752 PMCID: PMC3063840 DOI: 10.1177/0148607108327194] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Sepsis and septic shock syndrome are the leading causes of death in critically ill patients. Lipopolysaccharide (LPS) released by the colonic microorganisms may translocate across a compromised lumen, leading to upregulated reactive oxidative stress, inflammation, and sepsis. The authors examined an enteral formula high in cysteine (antioxidant precursor), omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and prebiotic fructooligosaccharides (FOS) against systemic inflammatory syndrome. METHODS Rats were allocated to (1) standard soy-based diet high in cysteine and crude fiber and devoid of EPA-DHA (CHOW); (2) whey-peptide-based liquid diet high in cysteine, EPA-DHA, and FOS (CYSPUFA); or (3) casein-based liquid isonitrogenous diet, low in cysteine and devoid of EPA-DHA-FOS (CASN). Liquid diets provided 25% and CHOW, 23% of calories as protein. After 6 days on diets, rats received an intraperitoneal injection of LPS or saline. Animals gained weight on their respective diets and lost weight after LPS administration. The CYSPUFA group lost considerably less weight (vs CASN or CHOW, P < .05). Inflammatory cytokines significantly increased by 4 hours and subsided 18 hours after assault. The CASN group showed elevated liver enzyme alanine aminotransferase release from damaged hepatocytes and developed severe hepatic pathology with low hematocrit. The CHOW group developed more severe hepatic lesions compared with those on liquid diets. Concentration of liver enzyme and pathology were improved in rats receiving CYSPUFA. CONCLUSIONS Data indicate that CYSPUFA, a diet rich in EPA-DHA-FOS, protects against LPS-induced systemic inflammatory responses and warrants clinical studies in critically ill patients.
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Affiliation(s)
- Helieh S Oz
- Center for Oral Health Research, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
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Affiliation(s)
- Michael R Lucey
- Section of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
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Petrásek J, Hubácek JA, Stickel F, Sperl J, Berg T, Ruf E, Wichmann HE, Pfeufer A, Meitinger T, Trunecka P, Spicák J, Jirsa M. Do common genetic variants in endotoxin signaling pathway contribute to predisposition to alcoholic liver cirrhosis? Clin Chem Lab Med 2009; 47:398-404. [PMID: 19278365 DOI: 10.1515/cclm.2009.112] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), produced by endotoxin-activated Kupffer cells, play a key role in the pathogenesis of alcoholic liver cirrhosis (ALC). Alleles TNFA -238A, IL1B -31T and variant IL1RN*2 of repeat polymorphism in the gene encoding the IL-1 receptor antagonist increase production of TNF-alpha and IL-1beta, respectively. Alleles CD14 -159T, TLR4 c.896G and TLR4 c.1196T modify activation of Kupffer cells by endotoxin. We confirmed the published associations between these common variants and genetic predisposition to ALC by means of a large case-control association study conducted on two Central European populations. METHODS The study population comprised a Czech sample of 198 ALC patients and 370 controls (MONICA project), and a German sample of 173 ALC patients and 331 controls (KORA-Augsburg), and 109 heavy drinkers without liver disease. RESULTS Single locus analysis revealed no significant difference between patients and controls in all tested loci. Diplotype [IL1RN 2/ 2; IL1B -31T+] was associated with increased risk of ALC in the pilot study, but not in the validation samples. CONCLUSIONS Although cytokine mediated immune reactions play a role in the pathogenesis of ALC, hereditary susceptibility caused by variants in the corresponding genes is low in Central European populations.
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Affiliation(s)
- Jan Petrásek
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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El-Mas MM, Fan M, Abdel-Rahman AA. Facilitation of myocardial PI3K/Akt/nNOS signaling contributes to ethanol-evoked hypotension in female rats. Alcohol Clin Exp Res 2009; 33:1158-68. [PMID: 19389198 DOI: 10.1111/j.1530-0277.2009.00939.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND The mechanism by which ethanol reduces cardiac output (CO) and blood pressure (BP) in female rats remains unclear. We tested the hypothesis that enhancement of myocardial phosphatidylinositol 3-kinase (PI3K)/Akt signaling and related neuronal nitric oxide synthase (nNOS) and/or endothelial nitric oxide synthase (eNOS) activity constitutes a cellular mechanism for the hemodynamic effects of ethanol. METHODS We measured the level of phosphorylated eNOS (p-eNOS) and p-nNOS in the myocardium of ethanol (1 g/kg intragastric, i.g.) treated female rats along with hemodynamic responses [BP, CO, stroke volume, (SV), total peripheral resistance, (TPR)], and myocardial nitrate/nitrite levels (NOx) levels. Further, we investigated the effect of selective pharmacological inhibition of nNOS with N(omega)-propyl-l-arginine (NPLA) or eNOS with N(5)-(1-iminoethyl)-l-ornithine (l-NIO) on cellular, hemodynamic, and biochemical effects of ethanol. The effects of PI3K inhibition by wortmannin on the cardiovascular actions of ethanol and myocardial Akt phosphorylation were also investigated. RESULTS The hemodynamic effects of ethanol (reductions in BP, CO, and SV) were associated with significant increases in myocardial NOx and myocardial p-nNOS and p-Akt expressions while myocardial p-eNOS remained unchanged. Prior nNOS inhibition by NPLA (2.5 or 12.5 microg/kg) attenuated hemodynamic effects of ethanol and abrogated associated increases in myocardial NOx and cardiac p-nNOS contents. The hemodynamic effects of ethanol and increases in myocardial p-Akt phosphorylation were reduced by wortmannin (15 microg/kg). On the other hand, although eNOS inhibition by l-NIO (4 or 20 mg/kg) in a dose-dependent manner attenuated ethanol-evoked hypotension, the concomitant reductions in CO and SV remained unaltered. Also, selective eNOS inhibition uncovered dramatic increases in TPR in response to ethanol, which appeared to have offset the reduction in CO. Neither NPLA nor l-NIO altered plasma ethanol levels. CONCLUSIONS These findings implicate the myocardial PI3K/Akt/nNOS signaling in the reductions in BP and CO produced by ethanol in female rats.
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Affiliation(s)
- Mahmoud M El-Mas
- Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina, USA
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Abstract
Although per capita alcohol consumption, and thus the prevalence of alcoholic liver disease, decreases generally with age in Europe and in the United States, recently an increase in alcohol consumption has been reported in individuals over 65 years. Reasons explaining this observation may include an increase in life expectancy or a loss of life partners and, thus, loneliness and depression. Although ethanol metabolism and ethanol distribution change with age, and an elderly person's liver is more susceptible to the toxic effect of ethanol, the spectrum of alcoholic liver diseases and their symptoms and signs is similar to that seen in patients of all ages. However, prognosis of alcoholic liver disease in the elderly is poor. In addition, chronic alcohol consumption may enhance drug associated liver disease and may also act as a cofactor in other liver diseases, such as viral hepatitis and nonalcoholic fatty liver disease.
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Affiliation(s)
- Helmut K Seitz
- Department of Medicine & Center of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Zeppelinstrasse 11-33, D - 69121 Heidelberg, Germany.
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MICROCIRCULATORY ALTERATIONS OF HEPATIC AND MESENTERIC MICROCIRCULATION IN ENDOTOXIN TOLERANCE. Shock 2008; 29:223-31. [DOI: 10.1097/shk.0b013e3180ca9ef3] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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El-Mas MM, Fan M, Abdel-Rahman AA. Endotoxemia-mediated induction of cardiac inducible nitric-oxide synthase expression accounts for the hypotensive effect of ethanol in female rats. J Pharmacol Exp Ther 2008; 324:368-75. [PMID: 17925480 DOI: 10.1124/jpet.107.127498] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
We have recently shown that intragastric (i.g.) ethanol lowers blood pressure (BP) in conscious female rats via a reduction in cardiac output (CO). However, the mechanisms implicated in these hemodynamic effects of ethanol are not known. Therefore, we tested the hypothesis that ethanol-evoked endotoxemia mediates the reduction in CO via enhanced myocardial inducible nitric-oxide synthase (iNOS) expression. Immunoblot (myocardial iNOS), biochemical (plasma endotoxin and nitrite/nitrate), and integrative [BP, heart rate, CO, stroke volume (SV), and total peripheral resistance (TPR)] studies were conducted in conscious female rats that received i.g. ethanol (1 g/kg) in the absence or presence of 1400W (N-(3-[aminomethyl]benzyl) acetamidine) or ampicillin to selectively inhibit iNOS and to eliminate endogenous endotoxin, respectively. Ethanol-evoked hypotension coincided with reductions in CO and SV and increases in: 1) TPR, 2) plasma endotoxin and nitrite/nitrate, and 3) myocardial iNOS expression. These effects of ethanol were virtually abolished in rats pretreated with ampicillin (200 mg/kg/day for 2 days by gavage) or with 1400W (5 mg/kg i.p.) except for the increase in plasma endotoxin, which persisted in 1400W-pretreated rats. These findings yield insight into the mechanistic role of endotoxin-myocardial iNOS signaling in the cardiodepressant action of ethanol, which accounts for its hypotensive effect in conscious female rats.
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Affiliation(s)
- Mahmoud M El-Mas
- Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27834, USA
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Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 2007; 86:1286-92. [PMID: 17991637 DOI: 10.1093/ajcn/86.5.1286] [Citation(s) in RCA: 532] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Bacterial endotoxin is a potently inflammatory antigen that is abundant in the human gut. Endotoxin circulates at low concentrations in the blood of all healthy individuals, although elevated concentrations are associated with an increased risk of atherosclerosis. OBJECTIVE We sought to determine whether a high-fat meal or smoking increases plasma endotoxin concentrations and whether such concentrations are of physiologic relevance. DESIGN Plasma endotoxin and endotoxin neutralization capacity were measured for 4 h in 12 healthy men after no meal, 3 cigarettes, a high-fat meal, or a high-fat meal with 3 cigarettes by using the limulus assay. RESULTS Baseline endotoxin concentrations were 8.2 pg/mL (interquartile range: 3.4-13.5 pg/mL) but increased significantly (P < 0.05) by approximately 50% after a high-fat meal or after a high-fat meal with cigarettes but not after no meal or cigarettes alone. These results were validated by the observations that a high-fat meal with or without cigarettes, but not no meal or smoking, also significantly (P < 0.05) reduced plasma endotoxin neutralization capacity, which is an indirect measure of endotoxin exposure. Human monocytes, but not aortic endothelial cells, were responsive to transient (30 s) or low-dose (10 pg/mL) exposure to endotoxin. However, plasma from whole blood treated with as little as 10 pg endotoxin/mL increased the endothelial cell expression of E-selectin, at least partly via tumor necrosis factor-alpha-induced cellular activation. CONCLUSIONS Low-grade endotoxemia may contribute to the postprandial inflammatory state and could represent a novel potential contributor to endothelial activation and the development of atherosclerosis.
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Affiliation(s)
- Clett Erridge
- Strathclyde Institute of Pharmacy and Biomedical Science, University of Strathclyde, Glasgow, United Kingdom.
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Stadlbauer V, Davies NA, Wright G, Jalan R. Endotoxin measures in patients' sample: how valid are the results? J Hepatol 2007; 47:726-7; author reply 727-3. [PMID: 17850915 DOI: 10.1016/j.jhep.2007.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Mookerjee RP, Stadlbauer V, Lidder S, Wright GAK, Hodges SJ, Davies NA, Jalan R. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007; 46:831-40. [PMID: 17680644 DOI: 10.1002/hep.21737] [Citation(s) in RCA: 257] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Mortality in patients with alcoholic hepatitis (AH) remains high, and although corticosteroids are widely used for treatment, the results vary considerably. In AH, neutrophils are primed and infiltrate the liver to produce injury, but paradoxically, the main cause of death in such patients is infection. Our prospective study addressed this paradox of primed neutrophils on the one hand and increased risk of infection on the other. We hypothesized that the full activation of neutrophils by a humoral factor such as endotoxin renders them unable to respond to further bacterial challenge. We analyzed neutrophil oxidative burst and phagocytosis in whole blood by fluorescence-activated cell sorting analysis in 63 alcoholic patients with cirrhosis and patients with cirrhosis with superimposed AH (cirrhosis+AH). In 16 patients, ex vivo studies determined whether the removal of endotoxin restored neutrophil function. A resting burst greater than or equal to 55[corrected]%, indicating neutrophil activation and a reduced phagocytic capacity lower than 42%, was associated with significantly greater risk of infection, organ failure, and mortality. This defective neutrophil function was transmissible through patients' plasma to normal neutrophils, and patients' neutrophil function could be restored by normal plasma. The ex vivo removal of endotoxin from patients' plasma decreased the resting burst and increased the phagocytic function. CONCLUSIONS Our study provides the rationale for a goal-directed approach to the management of patients with cirrhosis and AH, in which the assessment of neutrophil function may be an important biomarker to select patients for immunosuppressive therapy. The neutrophil dysfunction in cirrhosis and AH is reversible, with endotoxin-removal strategies providing new targets for intervention.
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Affiliation(s)
- Rajeshwar P Mookerjee
- Liver Failure Group, Institute of Hepatology, Division of Medicine, University College London, London, UK
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Seitz HK, Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 2006; 387:349-60. [PMID: 16606331 DOI: 10.1515/bc.2006.047] [Citation(s) in RCA: 197] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular cancer is the fifth most frequent cancer in men and the eighth in women worldwide. Established risk factors are chronic hepatitis B and C infection, chronic heavy alcohol consumption, obesity and type 2 diabetes, tobacco use, use of oral contraceptives, and aflatoxin-contaminated food. Almost 90% of all hepatocellular carcinomas develop in cirrhotic livers. In Western countries, attributable risks are highest for cirrhosis due to chronic alcohol abuse and viral hepatitis B and C infection. Among those with alcoholic cirrhosis, the annual incidence of hepatocellular cancer is 1-2%. An important mechanism implicated in alcohol-related hepatocarcinogenesis is oxidative stress from alcohol metabolism, inflammation, and increased iron storage. Ethanol-induced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis. Chronic alcohol exposure elicits hepatocyte hyperregeneration due to the activation of survival factors and interference with retinoid metabolism. Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA etheno adducts. Finally, chronic alcohol abuse interferes with methyl group transfer and may thereby alter gene expression.
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Affiliation(s)
- Helmut K Seitz
- Department of Medicine and Laboratory of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, D-69121 Heidelberg, Germany.
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Meuleman P, Steyaert S, Libbrecht L, Couvent S, Van Houtte F, Clinckspoor F, de Hemptinne B, Roskams T, Vanlandschoot P, Leroux-Roels G. Human hepatocytes secrete soluble CD14, a process not directly influenced by HBV and HCV infection. Clin Chim Acta 2005; 366:156-62. [PMID: 16253217 DOI: 10.1016/j.cca.2005.09.022] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2005] [Revised: 09/22/2005] [Accepted: 09/22/2005] [Indexed: 11/30/2022]
Abstract
BACKGROUND Chronic hepatitis B (HBV) and hepatitis C (HCV) patients have elevated plasma levels of soluble CD14 (sCD14). We examined whether human hepatocytes produce sCD14 in vivo, and whether HBV or HCV infections influence this chimeric production. METHODS uPA-SCID mice were transplanted with primary human hepatocytes and some animals were subsequently infected with HBV or HCV. Plasma from these mice was analyzed for the presence of human sCD14. The liver was examined via immunohistochemistry. RESULTS A soluble form of human CD14 could be detected in the plasma from successfully transplanted mice, while it was completely absent in non-transplanted control animals. The isoform of this human sCD14 corresponded with the most abundant isoform found in human plasma. CD14 levels in circulation were not significantly different between non-infected, HBV infected and HCV infected animals. CONCLUSIONS Our data indicate that human hepatocytes produce sCD14 in vivo, and that liver cells might be the major source of sCD14 in normal human plasma. In addition we demonstrate that HBV and HCV infections have no direct influence on the production of sCD14 by human hepatocytes in this chimeric model.
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Affiliation(s)
- Philip Meuleman
- Center for Vaccinology, Ghent University and Hospital, Building A, 1st floor, De Pintelaan 185, B-9000 Ghent, Belgium
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Echtenacher B, Urbaschek R, Weigl K, Freudenberg MA, Männel DN. Treatment of experimental sepsis-induced immunoparalysis with TNF. Immunobiology 2004; 208:381-9. [PMID: 14748511 DOI: 10.1078/0171-2985-00282] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Following a severe septic abdominal infection induced by sublethal cecal ligation and puncture (CLP) in mice, a phase of depressed immune reactivity occurred two days after CLP characterized by a reduced capacity to produce TNF. To determine whether this reduced TNF production causes immunoparalysis as determined by increased susceptibility to bacterial infection and whether therapeutic TNF substitution can be beneficial during this phase, a super-infection with Salmonella enterica Serovar typhimurium or Listeria monocytogenes was induced two days after sublethal CLP. After CLP a state of true immunoparalysis developed during which Salmonella or Listeria super-infection led to increased lethality paralleled by increased bacterial numbers in spleens and livers. Injection of recombinant human TNF before or at the time of super-infection conferred protection to Salmonella but not to Listeria. In the latter case, the infection mortality was even enhanced. Thus, super-infection during the state of sepsis-induced immunoparalysis leads to increased lethality. TNF substitution during this state of immunoparalysis can be beneficial or deleterious, depending on the location of TNF activity in the animal, timing of TNF administration, or the type of super-infection. These results demonstrate that impaired TNF production capacity can account for some aspects of immunoparalysis, however, diagnostic parameters are required for a safe TNF substitution therapy.
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Affiliation(s)
- Bernd Echtenacher
- Institute for Pathology/Tumor Immunology, University of Regensburg, Regensburg, Germany
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Spahr L, Giostra E, Frossard JL, Bresson-Hadni S, Rubbia-Brandt L, Hadengue A. Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis. J Hepatol 2004; 41:229-34. [PMID: 15288471 DOI: 10.1016/j.jhep.2004.04.028] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2003] [Revised: 04/05/2004] [Accepted: 04/13/2004] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIMS In alcoholic hepatitis (AH), soluble TNF alpha receptor-1 (sTNF-R1) is increased. Elevated TNF alpha predicts mortality, but infection influences TNF alpha values. In patients with AH, we determined the prognostic value of TNF alpha, sTNF-R1, and lipopolysaccharide binding protein (LBP) and CD14, both involved in endotoxemia-associated inflammation. METHODS One hundred and eight cirrhotic patients (Pugh score 10 [6-13]) and biopsy-proven AH (Maddrey's DF <32: n=46; > or =32: n=62) without associated infection were included within 8 days of admission and followed-up for 3 months. Cytokines were measured using specific immunoassays. Patients with severe AH received steroids. RESULTS Twenty four patients died at a median time of 35 days (range: 3-89). The overall survival was 78%. Multivariate Cox regression analysis showed that sTNF-R1 was an independent predictor of mortality, (OR 4.33: 95% CI [1.12-16.75]). Pugh's score (P=0.618), Maddrey's DF (P=0.182), creatinine (P=0.197), TNF alpha (P=0.319), LBP (P=0.362), and CD14 (P=0.347) were not related to survival. CONCLUSIONS In patients with AH, sTNF-R1 measured at admission is an independent predictor of survival at 3 months. Provided that TNF-R1 mediates the cytotoxic actions of TNFalpha, these results support the concept of dysregulated TNF alpha metabolism in AH.
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Affiliation(s)
- Laurent Spahr
- Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland.
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