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1
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Zhang X, Lau HCH, Yu J. Pharmacological treatment for metabolic dysfunction-associated steatotic liver disease and related disorders: Current and emerging therapeutic options. Pharmacol Rev 2025; 77:100018. [PMID: 40148030 DOI: 10.1016/j.pharmr.2024.100018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.
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Affiliation(s)
- Xiang Zhang
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Harry Cheuk-Hay Lau
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
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2
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Banerjee A, Farci P. Fibrosis and Hepatocarcinogenesis: Role of Gene-Environment Interactions in Liver Disease Progression. Int J Mol Sci 2024; 25:8641. [PMID: 39201329 PMCID: PMC11354981 DOI: 10.3390/ijms25168641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
The liver is a complex organ that performs vital functions in the body. Despite its extraordinary regenerative capacity compared to other organs, exposure to chemical, infectious, metabolic and immunologic insults and toxins renders the liver vulnerable to inflammation, degeneration and fibrosis. Abnormal wound healing response mediated by aberrant signaling pathways causes chronic activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM), leading to hepatic fibrosis and cirrhosis. Fibrosis plays a key role in liver carcinogenesis. Once thought to be irreversible, recent clinical studies show that hepatic fibrosis can be reversed, even in the advanced stage. Experimental evidence shows that removal of the insult or injury can inactivate HSCs and reduce the inflammatory response, eventually leading to activation of fibrolysis and degradation of ECM. Thus, it is critical to understand the role of gene-environment interactions in the context of liver fibrosis progression and regression in order to identify specific therapeutic targets for optimized treatment to induce fibrosis regression, prevent HCC development and, ultimately, improve the clinical outcome.
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Affiliation(s)
- Anindita Banerjee
- Department of Transfusion Transmitted Diseases, ICMR-National Institute of Immunohaematology, Mumbai 400012, Maharashtra, India;
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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3
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Feng S, Cheng Y, Sheng C, Yang C, Li Y. Biliary atresia: the role of gut microbiome, and microbial metabolites. Front Cell Infect Microbiol 2024; 14:1411843. [PMID: 39104854 PMCID: PMC11298464 DOI: 10.3389/fcimb.2024.1411843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 07/05/2024] [Indexed: 08/07/2024] Open
Abstract
Biliary atresia (BA) is a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, potentially leading to chronic cholestasis and biliary cirrhosis. Despite its prevalence, the exact mechanisms behind BA development remain incompletely understood. Recent research suggests that the gut microbiota and its metabolites may play significant roles in BA development. This paper offers a comprehensive review of the changing characteristics of gut microbiota and their metabolites at different stages of BA in children. It discusses their influence on the host's inflammatory response, immune system, and bile acid metabolism. The review also explores the potential of gut microbiota and metabolites as a therapeutic target for BA, with interventions like butyrate and gut microbiota preparations showing promise in alleviating BA symptoms. While progress has been made, further research is necessary to untangle the complex interactions between gut microbiota and BA, paving the way for more effective prevention and treatment strategies for this challenging condition.
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Affiliation(s)
| | | | | | | | - Yumei Li
- Department of pediatric intensive care unit, Children’s Medical Center, The First Hospital of Jilin University, Changchun, China
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4
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Vesković M, Pejović M, Šutulović N, Hrnčić D, Rašić-Marković A, Stanojlović O, Mladenović D. Exploring Fibrosis Pathophysiology in Lean and Obese Metabolic-Associated Fatty Liver Disease: An In-Depth Comparison. Int J Mol Sci 2024; 25:7405. [PMID: 39000518 PMCID: PMC11242866 DOI: 10.3390/ijms25137405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-β, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients.
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Affiliation(s)
- Milena Vesković
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotića 9, 11000 Belgrade, Serbia
| | - Milka Pejović
- Primary Health Center “Vračar”, Velimira Bate Živojinovića 16, 11000 Belgrade, Serbia
| | - Nikola Šutulović
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Dragan Hrnčić
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Aleksandra Rašić-Marković
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Olivera Stanojlović
- Institute of Medical Physiology, Faculty of Medicine, University of Belgrade, Višegradska 26, 11000 Belgrade, Serbia
| | - Dušan Mladenović
- Institute of Pathophysiology, Faculty of Medicine, University of Belgrade, Dr Subotića 9, 11000 Belgrade, Serbia
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5
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Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
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6
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Maslennikov R, Poluektova E, Zolnikova O, Sedova A, Kurbatova A, Shulpekova Y, Dzhakhaya N, Kardasheva S, Nadinskaia M, Bueverova E, Nechaev V, Karchevskaya A, Ivashkin V. Gut Microbiota and Bacterial Translocation in the Pathogenesis of Liver Fibrosis. Int J Mol Sci 2023; 24:16502. [PMID: 38003692 PMCID: PMC10671141 DOI: 10.3390/ijms242216502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/11/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Cirrhosis is the end result of liver fibrosis in chronic liver diseases. Studying the mechanisms of its development and developing measures to slow down and regress it based on this knowledge seem to be important tasks for medicine. Currently, disorders of the gut-liver axis have great importance in the pathogenesis of cirrhosis. However, gut dysbiosis, which manifests as increased proportions in the gut microbiota of Bacilli and Proteobacteria that are capable of bacterial translocation and a decreased proportion of Clostridia that strengthen the intestinal barrier, occurs even at the pre-cirrhotic stage of chronic liver disease. This leads to the development of bacterial translocation, a process by which those microbes enter the blood of the portal vein and then the liver tissue, where they activate Kupffer cells through Toll-like receptor 4. In response, the Kupffer cells produce profibrogenic cytokines, which activate hepatic stellate cells, stimulating their transformation into myofibroblasts that produce collagen and other elements of the extracellular matrix. Blocking bacterial translocation with antibiotics, probiotics, synbiotics, and other methods could slow down the progression of liver fibrosis. This was shown in a number of animal models but requires further verification in long-term randomized controlled trials with humans.
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Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study of the Human Microbiome”, 119048 Moscow, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study of the Human Microbiome”, 119048 Moscow, Russia
| | - Oxana Zolnikova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Alla Sedova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Anastasia Kurbatova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Yulia Shulpekova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Natyia Dzhakhaya
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Svetlana Kardasheva
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Maria Nadinskaia
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Elena Bueverova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Vladimir Nechaev
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Anna Karchevskaya
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study of the Human Microbiome”, 119048 Moscow, Russia
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7
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Huang C, Mei S, Zhang X, Tian X. Inflammatory Milieu Related to Dysbiotic Gut Microbiota Promotes Tumorigenesis of Hepatocellular Carcinoma. J Clin Gastroenterol 2023; 57:782-788. [PMID: 37406184 DOI: 10.1097/mcg.0000000000001883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is an invasive primary liver cancer caused by multiple pathogenic factors and is a significant global health concern. With few effective therapeutic options, HCC is a heterogeneous carcinoma that typically arises in an inflammatory environment. Recent studies have suggested that dysbiotic gut microbiota is involved in hepatocarcinogenesis via multiple mechanisms. In this review, we discuss the effects of gut microbiota, microbial components, and microbiota-derived metabolites on the promotion and progression of HCC by feeding a persistent inflammatory milieu. In addition, we discuss the potential therapeutic modalities for HCC targeting the inflammatory status induced by gut microbiota. A better understanding of the correlation between the inflammatory milieu and gut microbiota in HCC may be beneficial for developing new therapeutic strategies and managing the disease.
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Affiliation(s)
- Caizhi Huang
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Department of Laboratory Medicine, Hunan Children's Hospital
| | - Si Mei
- Department of Physiology, Hunan University of Chinese Medicine
| | - Xue Zhang
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
| | - Xuefei Tian
- Department of Internal Medicine, College of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine
- Key Laboratory of Traditional Chinese Medicine for Mechanism of Tumor Prevention & Treatment, Hunan University of Chinese Medicine
- Hunan Province University Key Laboratory of Oncology of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China
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8
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Zhang J, Zao X, Zhang J, Guo Z, Jin Q, Chen G, Gan D, Du H, Ye Y. Is it possible to intervene early cirrhosis by targeting toll-like receptors to rebalance the intestinal microbiome? Int Immunopharmacol 2023; 115:109627. [PMID: 36577151 DOI: 10.1016/j.intimp.2022.109627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/27/2022]
Abstract
Cirrhosis is a progressive chronic liver disease caused by one or more causes and characterized by diffuse fibrosis, pseudolobules, and regenerated nodules. Once progression to hepatic decompensation, the function of the liver and other organs is impaired and almost impossible to reverse and recover, which often results in hospitalization, impaired quality of life, and high mortality. However, in the early stage of cirrhosis, there seems to be a possibility of cirrhosis reversal. The development of cirrhosis is related to the intestinal microbiota and activation of toll-like receptors (TLRs) pathways, which could regulate cell proliferation, apoptosis, expression of the hepatomitogen epiregulin, and liver inflammation. Targeting regulation of intestinal microbiota and TLRs pathways could affect the occurrence and development of cirrhosis and its complications. In this paper, we first reviewed the dynamic change of intestinal microbiota and TLRs during cirrhosis progression. And further discussed the interaction between them and potential therapeutic targets to reverse early staged cirrhosis.
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Affiliation(s)
- Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaying Zhang
- School of Mechanical Engineering and Automation, Beihang University, Beijing, China
| | - Ziwei Guo
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qian Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Da'nan Gan
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Yong'an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China; Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China.
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9
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Abstract
Sucrose, the primary circulating sugar in plants, contains equal amounts of fructose and glucose. The latter is the predominant circulating sugar in animals and thus the primary fuel source for various tissue and cell types in the body. Chronic excessive energy intake has, however, emerged as a major driver of obesity and associated pathologies including nonalcoholic fatty liver diseases (NAFLD) and the more severe nonalcoholic steatohepatitis (NASH). Consumption of a high-caloric, western-style diet induces gut dysbiosis and inflammation resulting in leaky gut. Translocation of gut-derived bacterial content promotes hepatic inflammation and ER stress, and when either or both of these are combined with steatosis, it can cause NASH. Here, we review the metabolic links between diet-induced changes in the gut and NASH. Furthermore, therapeutic interventions for the treatment of obesity and liver metabolic diseases are also discussed with a focus on restoring the gut-liver axis.
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10
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Tourkochristou E, Assimakopoulos SF, Thomopoulos K, Marangos M, Triantos C. NAFLD and HBV interplay - related mechanisms underlying liver disease progression. Front Immunol 2022; 13:965548. [PMID: 36544761 PMCID: PMC9760931 DOI: 10.3389/fimmu.2022.965548] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/15/2022] [Indexed: 12/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Stelios F. Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Markos Marangos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
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11
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Spanu D, Pretta A, Lai E, Persano M, Donisi C, Mariani S, Dubois M, Migliari M, Saba G, Ziranu P, Pusceddu V, Puzzoni M, Astara G, Scartozzi M. Hepatocellular carcinoma and microbiota: Implications for clinical management and treatment. World J Hepatol 2022; 14:1319-1332. [PMID: 36158925 PMCID: PMC9376771 DOI: 10.4254/wjh.v14.i7.1319] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/11/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Gut microbiota plays an essential role in host homeostasis. It is involved in several physiological processes such as nutrients digestion and absorption, maintenance of intestinal epithelial barrier integrity and immune system self-tolerance. Especially the gut microbiota is assumed to play a crucial role in many gastrointestinal, pancreatic and liver disorders. Its role in hepatic carcinogenesis is also gaining increasing interest, especially regarding the development of therapeutic strategies. Different studies are highlighting a link between some bacterial strains and liver disease, including hepatocellular carcinoma (HCC). Indeed, HCC represents an interesting field of research in this perspective, due to the gut-liver axis, to the implication of microbiota in the immune system and to the increasing number of immunotherapy agents investigated in this tumour. Thus, the assessment of the role of microbiota in influencing clinical outcome for patients treated with these drugs is becoming of increasing importance. Our review aims to give an overview on the relationship between microbiota and HCC development/progression and treatment. We focus on potential implications on the available treatment strategies and those under study in the various stages of disease. We highlight the pathogenic mechanisms and investigate the underlying molecular pathways involved. Moreover, we investigate the potential prognostic and/or predictive role of microbiota for target therapies, immune checkpoint inhibitors and loco-regional treatment. Finally, given the limitation of current treatments, we analyze the gut microbiota-mediated therapies and its potential options for HCC treatment focusing on fecal microbiota transplantation.
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Affiliation(s)
- Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Dubois
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Migliari
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Giorgio Astara
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato 09042, Cagliari, Italy
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12
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Albuquerque-Souza E, Sahingur SE. Periodontitis, chronic liver diseases, and the emerging oral-gut-liver axis. Periodontol 2000 2022; 89:125-141. [PMID: 35244954 PMCID: PMC9314012 DOI: 10.1111/prd.12427] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver carries out a wide range of functions ranging from the control of metabolites, nutrient storage, and detoxification to immunosurveillance. While inflammation is essential for the tissue remodeling and maintenance of homeostasis and normal liver physiology, constant exposure to dietary and microbial products creates a niche for potentially prolonged immune activation and unresolved inflammation in susceptible host. Failure to restrain inflammation can lead to development of chronic liver diseases characterized by fibrosis, cirrhosis and eventually liver failure. The liver maintains close interactions with numerous organs which can influence its metabolism and physiology. It is also known that oral cavity microenvironment can influence the physiological conditions of other organs and emerging evidence implicates that this could be true for the liver as well. Presence of chronic inflammation and dysbiotic microbiota is a common feature leading to clinical pathology both in periodontitis and chronic liver diseases (CLDs). In fact, known CLDs appear to have some relationship with periodontitis, which impacts the onset or progression of these conditions in a bidirectional crosstalk. In this review, we explore the emerging association between oral‐gut‐liver axis focusing on periodontitis and common CLDs including nonalcoholic fatty liver disease, chronic viral hepatitis, liver cirrhosis, and hepatocellular cancer. We highlight the immune pathways and oral microbiome interactions which can link oral cavity and liver health and offer perspectives for future research.
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Affiliation(s)
- Emmanuel Albuquerque-Souza
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sinem E Sahingur
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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13
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Antifibrotic Effects of Kangxian Ruangan Capsule on Rats with Nonalcoholic Fatty Liver Fibrosis and Hepatic Stellate Cells through Regulation of TGF- β and TLR4 Signaling Pathways. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5649575. [PMID: 34422075 PMCID: PMC8371615 DOI: 10.1155/2021/5649575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 05/07/2021] [Accepted: 07/22/2021] [Indexed: 01/18/2023]
Abstract
Kangxian ruangan (KXRG) is a traditional Chinese medicine (TCM) formula consisting of 12 herbs. TCM syndrome differentiation proposes that KXRG exerts pharmacological effects against nonalcoholic fatty liver disease (NAFLD) fibrosis. This work investigates the effect of KXRG on NAFLD fibrosis in vivo and in vitro. In vivo, the NAFLD fibrosis model was constructed in Wistar rats using methionine- and choline-deficient (MCD) diet, followed by KXRG (0.92 g/kg/d) treatment for 8 weeks. In vitro, primary hepatic stellate cells (HSCs) were activated using platelet-derived growth factor (PDGF) and treated with KXRG. Molecular mechanisms underlying fibrosis were investigated. After 8 weeks, compared with the control groups, the histological lesions, degree of fibrosis, and inflammatory reaction increased with the MCD diet as demonstrated by histological changes and increased fibrosis-related (α-SMA, TGF-β, COL1A1, and desmin, P < 0.01) and inflammation-related factors (TNF-α, MCP-1, and F4/80, P < 0.01), whereas they decreased with KXRG treatment (P < 0.01). KXRG not only inhibited the proliferation of activated HSCs and promoted their apoptosis but also resulted in G0-G1 arrest. Furthermore, KXRG suppressed HSC activation (P < 0.01), collagen synthesis (P < 0.01), and α-SMA expression (P < 0.01) with PDGF stimulation. In both the MCD diet-induced animal model and PDGF-induced cell model, KXRG inhibited TGF-β and TLR4 signaling (P < 0.01), similar to corresponding small-molecule inhibitors. These results demonstrated that KXRG might exert suppressive effects against NAFLD fibrosis via regulating TGF-β and TLR4 signaling. KXRG may act as a natural and potent therapeutic agent against NAFLD.
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Hrncir T, Hrncirova L, Kverka M, Hromadka R, Machova V, Trckova E, Kostovcikova K, Kralickova P, Krejsek J, Tlaskalova-Hogenova H. Gut Microbiota and NAFLD: Pathogenetic Mechanisms, Microbiota Signatures, and Therapeutic Interventions. Microorganisms 2021; 9:microorganisms9050957. [PMID: 33946843 PMCID: PMC8146698 DOI: 10.3390/microorganisms9050957] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Its worldwide prevalence is rapidly increasing and is currently estimated at 24%. NAFLD is highly associated with many features of the metabolic syndrome, including obesity, insulin resistance, hyperlipidaemia, and hypertension. The pathogenesis of NAFLD is complex and not fully understood, but there is increasing evidence that the gut microbiota is strongly implicated in the development of NAFLD. In this review, we discuss the major factors that induce dysbiosis of the gut microbiota and disrupt intestinal permeability, as well as possible mechanisms leading to the development of NAFLD. We also discuss the most consistent NAFLD-associated gut microbiota signatures and immunological mechanisms involved in maintaining the gut barrier and liver tolerance to gut-derived factors. Gut-derived factors, including microbial, dietary, and host-derived factors involved in NAFLD pathogenesis, are discussed in detail. Finally, we review currently available diagnostic and prognostic methods, summarise latest knowledge on promising microbiota-based biomarkers, and discuss therapeutic strategies to manipulate the microbiota, including faecal microbiota transplantation, probiotics and prebiotics, deletions of individual strains with bacteriophages, and blocking the production of harmful metabolites.
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Affiliation(s)
- Tomas Hrncir
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
- Correspondence:
| | - Lucia Hrncirova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
- The Faculty of Medicine in Hradec Kralove, Charles University in Prague, 500 03 Hradec Kralove, Czech Republic; (P.K.); (J.K.)
| | - Miloslav Kverka
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Robert Hromadka
- NEXARS (C2P), The Campus Science Park, 625 00 Brno, Czech Republic;
| | - Vladimira Machova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Eva Trckova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Klara Kostovcikova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
| | - Pavlina Kralickova
- The Faculty of Medicine in Hradec Kralove, Charles University in Prague, 500 03 Hradec Kralove, Czech Republic; (P.K.); (J.K.)
| | - Jan Krejsek
- The Faculty of Medicine in Hradec Kralove, Charles University in Prague, 500 03 Hradec Kralove, Czech Republic; (P.K.); (J.K.)
| | - Helena Tlaskalova-Hogenova
- Czech Academy of Sciences, Institute of Microbiology, 142 20 Prague, Czech Republic; (L.H.); (M.K.); (V.M.); (E.T.); (K.K.); (H.T.-H.)
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15
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Blesl A, Stadlbauer V. The Gut-Liver Axis in Cholestatic Liver Diseases. Nutrients 2021; 13:nu13031018. [PMID: 33801133 PMCID: PMC8004151 DOI: 10.3390/nu13031018] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
The gut-liver axis describes the physiological interplay between the gut and the liver and has important implications for the maintenance of health. Disruptions of this equilibrium are an important factor in the evolution and progression of many liver diseases. The composition of the gut microbiome, the gut barrier, bacterial translocation, and bile acid metabolism are the key features of this cycle. Chronic cholestatic liver diseases include primary sclerosing cholangitis, the generic term secondary sclerosing cholangitis implying the disease secondary sclerosing cholangitis in critically ill patients and primary biliary cirrhosis. Pathophysiology of these diseases is not fully understood but seems to be multifactorial. Knowledge about the alterations of the gut-liver axis influencing the pathogenesis and the outcome of these diseases has considerably increased. Therefore, this review aims to describe the function of the healthy gut-liver axis and to sum up the pathological changes in these cholestatic liver diseases. The review compromises the actual level of knowledge about the gut microbiome (including the mycobiome and the virome), the gut barrier and the consequences of increased gut permeability, the effects of bacterial translocation, and the influence of bile acid composition and pool size in chronic cholestatic liver diseases. Furthermore, therapeutic implications and future scientific objectives are outlined.
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Affiliation(s)
- Andreas Blesl
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Correspondence:
| | - Vanessa Stadlbauer
- Division for Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria;
- Center for Biomarker Research in Medicine (CBmed), 8010 Graz, Austria
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16
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Kwong EK, Puri P. Gut microbiome changes in Nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol 2021; 6:3. [PMID: 33409398 DOI: 10.21037/tgh.2020.02.18] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 02/11/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are some of the most common liver diseases worldwide. The human gut microbiome is dynamic and shifts in bacterial composition have been implicated in many diseases. Studies have shown that there is a shift in bacterial overgrowth favoring pro-inflammatory mediators in patients with advanced disease progression such as cirrhosis. Further investigation demonstrated that the transplantation of gut microbiota from advanced liver disease patients can reproduce severe liver inflammation and injury in mice. Various techniques in manipulating the gut microbiota have been attempted including fecal transplantation and probiotics. This review focuses on the changes in the gut microbiota as well as emerging lines of microbiome work with respect to NAFLD and ALD.
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Affiliation(s)
- Eric K Kwong
- Department of Microbiology and Immunology, McGuire VA Medical Center, Richmond, VA, USA
| | - Puneet Puri
- Section of Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center, Richmond, VA, USA.,Virginia Commonwealth University, Richmond, VA, USA
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17
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Gandhi CR. Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver. Front Med (Lausanne) 2020; 7:130. [PMID: 32373617 PMCID: PMC7186417 DOI: 10.3389/fmed.2020.00130] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Extensive research performed over several decades has identified cells participating in the initiation and progression of fibrosis, and the numerous underlying inter- and intra-cellular signaling pathways. However, liver fibrosis continues to be a major clinical challenge as the precise targets of treatment are still elusive. Activation of physiologically quiescent perisinusoidal hepatic stellate cells (HSCs) to a myofibroblastic proliferating, contractile and fibrogenic phenotype is a critical event in the pathogenesis of chronic liver disease. Thus, elucidation of the mechanisms of the reversal to quiescence or inhibition of activated HSCs, and/or their elimination via apoptosis has been the focus of intense investigation. Lipopolysaccharide (LPS), a gut-resident Gram-negative bacterial endotoxin, is a powerful pro-inflammatory molecule implicated in hepatic injury, inflammation and fibrosis. In both acute and chronic liver injury, portal venous levels of LPS are elevated due to increased intestinal permeability. LPS, via CD14 and Toll-like receptor 4 (TLR4) and its adapter molecules, stimulates macrophages, neutrophils and several other cell types to produce inflammatory mediators as well as factors that can activate HSCs and stimulate their fibrogenic activity. LPS also stimulates synthesis of pro- and anti-inflammatory cytokines/chemokines, growth mediators and molecules of immune regulation by HSCs. However, LPS was found to arrest proliferation of activated HSCs and to convert them into non-fibrogenic phenotype. Interestingly, LPS can elicit responses in HSCs independent of CD14 and TLR4. Identifying and/or developing non-inflammatory but anti-fibrogenic mimetics of LPS could be relevant for treating liver fibrosis.
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Affiliation(s)
- Chandrashekhar R Gandhi
- Divisions of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Cincinnati VA Medical Center, Cincinnati, OH, United States
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18
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Endotoxin Producers Overgrowing in Human Gut Microbiota as the Causative Agents for Nonalcoholic Fatty Liver Disease. mBio 2020; 11:mBio.03263-19. [PMID: 32019793 PMCID: PMC7002352 DOI: 10.1128/mbio.03263-19] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Recent studies have reported a link between gut microbiota and nonalcoholic fatty liver disease (NAFLD), showing that germfree (GF) mice do not develop metabolic syndromes, including NAFLD. However, the specific bacterial species causing NAFLD, as well as their molecular cross talk with the host for driving liver disease, remain elusive. Here, we found that nonvirulent endotoxin-producing strains of pathogenic species overgrowing in obese human gut can act as causative agents for induction of NAFLD and related metabolic disorders. The cross talk between endotoxin from these specific producers and the host’s TLR4 receptor is the most upstream and essential molecular event for inducing all phenotypes in NAFLD and related metabolic disorders. These nonvirulent endotoxin-producing strains of gut pathogenic species overgrowing in human gut may collectively become a predictive biomarker or serve as a novel therapeutic target for NAFLD and related metabolic disorders. Gut microbiota-derived endotoxin has been linked to human nonalcoholic fatty liver disease (NAFLD), but the specific causative agents and their molecular mechanisms remain elusive. In this study, we investigated whether bacterial strains of endotoxin-producing pathogenic species overgrowing in obese human gut can work as causative agents for NAFLD. We further assessed the role of lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) cross talk in this pathogenicity. Nonvirulent strains of Gram-negative pathobionts were isolated from obese human gut and monoassociated with C57BL/6J germfree (GF) mice fed a high-fat diet (HFD). Deletion of waaG in the bacterial endotoxin synthetic pathway and knockout of TLR4 in GF mice were used to further study the underlying mechanism for a causal relationship between these strains and the development of NAFLD. Three endotoxin-producing strains, Enterobacter cloacae B29, Escherichia coli PY102, and Klebsiella pneumoniae A7, overgrowing in the gut of morbidly obese volunteers with severe fatty liver, induced NAFLD when monoassociated with GF mice on HFD, while HFD alone did not induce the disease in GF mice. The commensal Bacteroides thetaiotaomicron (ATCC 29148), whose endotoxin activity was markedly lower than that of Enterobacteriaceae strains, did not induce NAFLD in GF mice. B29 lost its proinflammatory properties and NAFLD-inducing capacity upon deletion of the waaG gene. Moreover, E. cloacae B29 did not induce NAFLD in TLR4-deficient GF mice. These nonvirulent endotoxin-producing strains in pathobiont species overgrowing in human gut may work as causative agents, with LPS-TLR4 cross talk as the most upstream and essential molecular event for NAFLD.
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19
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Peng JL, Techasatian W, Hato T, Liangpunsakul S. Role of endotoxemia in causing renal dysfunction in cirrhosis. J Investig Med 2019; 68:26-29. [PMID: 31324695 DOI: 10.1136/jim-2019-001056] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2019] [Indexed: 12/18/2022]
Abstract
Renal failure is a challenging problem in patients with cirrhosis since mortality increases with worsening renal function, hence the inclusion of serum creatinine in calculating the Model for End-Stage Liver Disease score for liver transplant evaluation. Among the various causes, infection is the leading etiology of mortality associated with cirrhosis. Bacterial infection frequently precipitates renal failure in patients with cirrhosis with the reported prevalence around 34%. Patients with cirrhosis are at increased risk of infections due to impaired immunity and increased gut permeability leading to bacterial translocation in the setting of portal hypertension. One of the most feared complications of severely decompensated liver and renal failure is hepatorenal syndrome, of which liver transplant may be the only available treatment. Furthermore, in those with spontaneous bacterial peritonitis and urinary tract infection, progressive renal failure occurs despite resolution of infection. Thus, the effects of endotoxemia on renal function in cirrhosis have become a major focus of research. The mechanisms of the damaging effects of endotoxin on renal function are complex but, in essence, involve dysregulated inflammation, circulatory dysfunction, poor clearance of endotoxin burden, as well as vasomotor nephropathy. In this article, we will review the mechanisms of endotoxemia-induced renal dysfunction in the setting of cirrhosis through the effects on renal blood flow, renal vascular endothelium, glomerular filtration rate, and tubular function.
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Affiliation(s)
- Jennifer L Peng
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Witina Techasatian
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Takashi Hato
- Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
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20
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Immunobiotics Beneficially Modulate TLR4 Signaling Triggered by Lipopolysaccharide and Reduce Hepatic Steatosis In Vitro. J Immunol Res 2019; 2019:3876896. [PMID: 31001563 PMCID: PMC6437725 DOI: 10.1155/2019/3876896] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 01/02/2019] [Accepted: 01/30/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatic inflammation and injury may result from the translocation of pathological bacteria and their proinflammatory mediators. Probiotics attenuate hepatic diseases related to inflammation by exhibiting immunoregulatory effects. Therefore, this study was conducted to evaluate lipid reduction and immunoregulatory potentials of probiotic bacteria in vitro. HepG2 cells treated with total cellular fluid (TCF) of LABs reduced lipid accumulation. Moreover, cells responded to lipopolysaccharide (LPS) by producing higher levels of IL-6, IL-8, MCP-1, and TNF-α. TCF of LABs treatment showed remarkably diminished levels of the expression of these cytokines via modulation of the expression of TLR-negative regulators, as well as MAPK and NF-κB pathways. Moreover, heat-killed LABs were able to diminish TGF-β, IL-1β, and IL-6 and to increase IL-10 and TLR4 levels in THP-1 cells. LABs also decreased the protein level of TNF-α. These results demonstrated that immunobiotics exhibit potent immunoregulatory activity and may be used as effective therapeutic agents to alleviate inflammatory response.
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21
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Kanmani P, Kim H. Protective Effects of Lactic Acid Bacteria Against TLR4 Induced Inflammatory Response in Hepatoma HepG2 Cells Through Modulation of Toll-Like Receptor Negative Regulators of Mitogen-Activated Protein Kinase and NF-κB Signaling. Front Immunol 2018; 9:1537. [PMID: 30022981 PMCID: PMC6039550 DOI: 10.3389/fimmu.2018.01537] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/21/2018] [Indexed: 12/12/2022] Open
Abstract
The beneficial effects of probiotics in several liver diseases have been investigated in both animal and clinical models; however, the precise mechanisms responsible for their effects have not yet been elucidated. Gut transmitted endotoxins such as LPS have been shown to play critical roles in hepatic inflammation and injury. Therefore, in this study, we investigated the beneficial role of selected lactic acid bacteria (LABs) on reduction of hepatic steatosis (HS) and attenuation of LPS induced inflammatory response in vitro. Total cellular fluid (TCF) of LABs treatment reduced HS by decreasing the amount of lipid accumulation in vitro. Additionally, HepG2 cells exposed to LPS showed increased expression of exacerbated inflammatory cytokines, such as IL-6, CXCL8, CCL2, and TNF-α, but these effects were counteracted when cells were treated with TCF of LABs prior to LPS challenge. Moreover, TCF of LABs was able to modulate mRNA levels of TLR negative regulators and protein levels of p38 MAPK and p65 NF-κB transcription factors. However, these modulations were differed remarkably between both free fatty acid treated and untreated HepG2 cells. Heat-killed LABs were also indirectly suppressed THP-1 cells to produce higher level of IL-10, TLR4, and lower at genes level of TGF-β, IL-1β, and IL-6, and at protein level of TNF-α in response to LPS. Taken together, our findings indicate that selected LABs exhibit profound immunoregulatory effects on liver cells via modulation of TLR negative regulators of the MAPK and NF-κB pathways.
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Affiliation(s)
- Paulraj Kanmani
- Department of Korean Medicine, Dongguk University, Goyang, South Korea
| | - Hojun Kim
- Department of Korean Medicine, Dongguk University, Goyang, South Korea
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22
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Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018; 15:397-411. [PMID: 29748586 PMCID: PMC6319369 DOI: 10.1038/s41575-018-0011-z] [Citation(s) in RCA: 935] [Impact Index Per Article: 133.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In the past decade, an exciting realization has been that diverse liver diseases - ranging from nonalcoholic steatohepatitis, alcoholic steatohepatitis and cirrhosis to hepatocellular carcinoma - fall along a spectrum. Work on the biology of the gut-liver axis has assisted in understanding the basic biology of both alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). Of immense importance is the advancement in understanding the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that enable the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review gut-liver communications in liver disease, exploring the molecular, genetic and microbiome relationships and discussing prospects for exploiting the microbiome to determine liver disease stage and to predict the effects of pharmaceutical, dietary and other interventions at a population and individual level. Although much work remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These 'avatar mice' could be especially useful for guiding new microbiome-based or microbiome-informed therapies.
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Affiliation(s)
- Anupriya Tripathi
- Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
- Department of Pediatrics, University of California, San Diego, CA, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA
| | - Justine Debelius
- Department of Pediatrics, University of California, San Diego, CA, USA
| | - David A Brenner
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California, San Diego, CA, USA
| | - Michael Karin
- Department of Pediatrics, University of California, San Diego, CA, USA
- Department of Computer Science and Engineering, University of California, San Diego, CA, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California, San Diego, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, CA, USA
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
- Center for Microbiome Innovation, University of California, San Diego, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, CA, USA.
- Department of Computer Science and Engineering, University of California, San Diego, CA, USA.
- Center for Microbiome Innovation, University of California, San Diego, CA, USA.
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23
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Mohamadkhani A. On the potential role of intestinal microbial community in hepatocarcinogenesis in chronic hepatitis B. Cancer Med 2018; 7:3095-3100. [PMID: 29761927 PMCID: PMC6051233 DOI: 10.1002/cam4.1550] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 03/17/2018] [Accepted: 04/19/2018] [Indexed: 12/12/2022] Open
Abstract
The chronic infection of hepatitis B virus (HBV) is the most potent risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The association of intestinal microbiota alteration with progressive liver disease has been investigated in recent studies. Overgrowth of potentially pathogenic bacteria of gram‐negative species and, in particular, a significant increase in the fecal count of Escherichia coli (E. coli) are characterized in the presence of HCC. This study was conducted to describe the characteristics of the intestinal microbiota related to the presence of HCC in HBV‐carrier patients. The available literature indicates the colonization of E. coli as principal source of portal vein lipopolysaccharide (LPS), in the gut may contribute to the carcinogenesis process by inducing chronic inflammation. This understanding could help to predict the clinical outcomes in HBV‐carrier patients and innovative strategies to reduce the virulence of liver disease from intestinal dysbiosis.
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Affiliation(s)
- Ashraf Mohamadkhani
- Liver and Pancreatobiliary Disease Research Center, Digestive Disease Research institute, Shariati Hospital, Tehran University of Medical Science, Tehran, Iran
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24
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Liu Y, Li J, Jin Y, Zhao L, Zhao F, Feng J, Li A, Wei Y. Splenectomy Leads to Amelioration of Altered Gut Microbiota and Metabolome in Liver Cirrhosis Patients. Front Microbiol 2018; 9:963. [PMID: 29867867 PMCID: PMC5962811 DOI: 10.3389/fmicb.2018.00963] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 04/24/2018] [Indexed: 12/12/2022] Open
Abstract
Dysbiosis of gut microbiota and metabolome is a frequently encountered condition in liver cirrhosis (LC) patients. The severity of liver dysfunction was found to be correlated with the degree of microbial dysbiosis. Several clinical studies have indicated liver function improvement after therapeutic splenectomy for LC-induced hypersplenism. We sought to determine whether such post-splenectomy outcome is pertinent to modulation of the abnormal gut microenvironment in LC patients. A cross-sectional study including 12 LC patients and 16 healthy volunteers was first conducted, then a before-after study in the cohort of patients was carried out before and 6 months after splenectomy. Fecal samples were collected in hospital. Temporal bacterial (n = 40) and metabolomics (n = 30) profiling was performed using 16s rRNA gene sequencing and ultra performance liquid chromatography/mass spectrometer (UPLC/MS), respectively. Our results revealed that microbial composition in patients was clearly different from that in healthy controls (HCs), evidenced by considerable taxonomic variation. Along with improved liver function (Child-Pugh score), the patients also displayed similar gut microbiota profile and predicted metagenome function to that of HCs after splenectomy. Enterobacteriaceae and Streptococcaceae, two LC-enriched families showing positive relation with Child-Pugh score, exhibited significantly decreased abundance after splenectomy. At the genus level, 11 genera were differentially abundant between patients and HCs, but 9 genera of them restituted to normal levels by certain degree after splenectomy. PICRUSt analysis showed that the relative abundance of 17 KEGG pathways was partially restored after splenectomy. Four of them were amino acid-related pathways: lysine degradation, tryptophan degradation, amino acid metabolism, and protein digestion and absorption. These findings were supported by metabonomics results which showed that relative abundance of amino acid and corresponding catabolites changed toward normal. In addition to the variations in the relative abundances of bacteria and metabolites, the correlation between them also altered in patients after splenectomy. Dysbiosis in gut microbiome and related metabolism of LC patients was partially corrected after splenectomy. Whether the improved gut microenvironment could prevent LC-related complications and delay the progress of LC is a propitious objective for future study. TRIAL REGISTRATION ChiCTR-OOB-15007409. Registered November 15, 2015.
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Affiliation(s)
| | | | | | | | | | | | | | - Yunwei Wei
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Liu Y, Jin Y, Li J, Zhao L, Li Z, Xu J, Zhao F, Feng J, Chen H, Fang C, Shilpakar R, Wei Y. Small Bowel Transit and Altered Gut Microbiota in Patients With Liver Cirrhosis. Front Physiol 2018; 9:470. [PMID: 29780327 PMCID: PMC5946013 DOI: 10.3389/fphys.2018.00470] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/13/2018] [Indexed: 12/13/2022] Open
Abstract
Disturbance of the gut microbiota is common in liver cirrhosis (LC) patients, the underlying mechanisms of which are yet to be unfolded. This study aims to explore the relationship between small bowel transit (SBT) and gut microbiota in LC patients. Cross-sectional design was applied with 36 LC patients and 20 healthy controls (HCs). The gut microbiota was characterized by 16S rRNA gene sequencing. The Firmicutes/Bacteroidetes (F/B) ratio and the Microbial Dysbiosis index (MDI) were used to evaluate the severity of microbiota dysbiosis. The scintigraphy method was performed in patients to describe the objective values of SBT. Patients were then subdivided according to the Child–Pugh score (threshold = 5) or SBT value (threshold = 0.6) for microbiota analysis. LC patients were characterized by an altered gut microbiota; F/B ratios and MDI were higher than HC in both Child_5 (14.00 ± 14.69 vs. 2.86 ± 0.99, p < 0.01; 0.49 ± 0.80 vs. -0.47 ± 0.69, p < 0.01) and Child_5+ (15.81 ± 15.11 vs. 2.86±0.99, p < 0.01; 1.11 ± 1.05 vs. -0.47 ± 0.69, p < 0.01) sub-groups in patients. Difference in the gut microbiota between Child_ 5 and Child_5+ patients was inappreciable, but the SBT was relatively slower in Child_5+ patients (43 ± 26% vs. 80 ± 15%, p < 0.05). Compared with the Child–Pugh score indicators, SBT showed stronger associations with bacterial genera. A clear difference in the gut microbiota was observed between SBT_0.6- and SBT_0.6+ patients [Pr(>F) = 0.0068, pMANOVA], with higher F/B ratios and MDI in SBT_0.6- patients (19.71 ± 16.62 vs. 7.33 ± 6.65, p < 0.01; 1.02 ± 0.97 vs. 0.20 ± 0.58, p < 0.01). Similar results were observed between the SBT_0.6- and SBT_0.6+ sub-groups of patients with normal liver function and a Child–Pugh score of 5. SBT was negatively correlated with both the F/B ratio and MDI (r = -0.34, p < 0.05; r = -0.38, p < 0.05). Interestingly, an increased capacity for the inferred pathway “bacterial invasion of epithelial cells” in patients, was highly negatively correlated with SBT (r = -0.57, p < 0.01). The severity of microbiota dysbiosis in LC patients depends on SBT rather than Child–Pugh score. SBT per se might be significantly related to the gut microbiota abnormalities observed in patients with LC.
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Affiliation(s)
- Yang Liu
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ye Jin
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jun Li
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Lei Zhao
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhengtian Li
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jun Xu
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fuya Zhao
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jing Feng
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huinan Chen
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chengyuan Fang
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rojina Shilpakar
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yunwei Wei
- Department of Oncological and Laparoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Sharma A, Gandhi CR. "CHOP"ing intestinal stem cells on way to cholestatic liver injury. Hepatology 2018; 67:1216-1218. [PMID: 29144555 DOI: 10.1002/hep.29656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 10/31/2017] [Accepted: 11/14/2017] [Indexed: 12/07/2022]
Affiliation(s)
- Akanksha Sharma
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Chandrashekhar R Gandhi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Cincinnati VA Medical Center, Cincinnati, OH.,Department of Surgery, University of Cincinnati, Cincinnati, OH
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Mogroside IVE attenuates experimental liver fibrosis in mice and inhibits HSC activation through downregulating TLR4-mediated pathways. Int Immunopharmacol 2018; 55:183-192. [DOI: 10.1016/j.intimp.2017.12.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 12/15/2017] [Accepted: 12/16/2017] [Indexed: 12/20/2022]
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Lin YC, Wang FS, Yang YL, Chuang YT, Huang YH. MicroRNA-29a mitigation of toll-like receptor 2 and 4 signaling and alleviation of obstructive jaundice-induced fibrosis in mice. Biochem Biophys Res Commun 2018; 496:880-886. [PMID: 29366780 DOI: 10.1016/j.bbrc.2018.01.132] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 01/20/2018] [Indexed: 12/17/2022]
Abstract
Cholestasis and hepatitis can cause continuous liver damage that may ultimately result in liver fibrosis. In a previous study, we demonstrated that microRNA-29a (miR-29a) protects against liver fibrosis. Toll-like receptor 2 (TLR2) and TLR4 are pattern recognition receptors of bacterial lipoprotein and lipopolysaccharide, both of which participate in activating hepatic stellate cells and liver fibrosis. The purpose of this study is to characterize the biological influence of miR-29a on TLR2 and TLR4 signaling in livers injured with bile duct ligation (BDL). We performed BDL on both miR-29a transgenic mice (miR-29aTg) and wild-type mice to induce cholestatic liver injury. Primary HSCs were transfected with a miR-29a mimic and inhibitor. In the wild-type mice, the BDL demonstrated significant α-smooth muscle actin fibrotic matrix formation and hepatic high mobility group box-1 expression. However, in the miR-29aTg mice, these factors were significantly reduced. Furthermore, miR-29a overexpression reduced the BDL exaggeration of TLR2, TLR4, MyD88, bromodomain-containing protein 4 (BRD4), phospho-p65 as well as proinflammatory cytokines, IL-1β, MCP-1, TGF-β, and TNF-α. In vitro, miR-29a mimic transfection reduced α-SMA, BRD4,TLR2, and TLR4 expressions in HSCs. This study provides new molecular insight into the ability of miR-29a to inhibit TLR2 and TLR4 signaling, which thus slows the progression of cholestatic liver deterioration.
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Affiliation(s)
- Yen-Cheng Lin
- Department of Pediatrics, Chiayi Chang Gung Memorial Hospital, Taiwan
| | - Feng-Sheng Wang
- Genomics and Proteomics Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College, Taiwan
| | - Ya-Ling Yang
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yuan-Ting Chuang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ying-Hsien Huang
- Department of Pediatrics, Chiayi Chang Gung Memorial Hospital, Taiwan; Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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29
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Cong M, Jia J, Kisseleva T, Brenner DA. The Liver's Response to Injury. ZAKIM AND BOYER'S HEPATOLOGY 2018:77-83.e5. [DOI: 10.1016/b978-0-323-37591-7.00005-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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30
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Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of worldwide cancer mortality. HCC almost exclusively develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation and regeneration that typically spans decades. Increasing evidence points towards a key role of the bacterial microbiome in promoting the progression of liver disease and the development of HCC. Here, we will review mechanisms by which the gut microbiota promotes hepatocarcinogenesis, focusing on the leaky gut, bacterial dysbiosis, microbe-associated molecular patterns and bacterial metabolites as key pathways that drive cancer-promoting liver inflammation, fibrosis and genotoxicity. On the basis of accumulating evidence from preclinical studies, we propose the intestinal-microbiota-liver axis as a promising target for the simultaneous prevention of chronic liver disease progression and HCC development in patients with advanced liver disease. We will review in detail therapeutic modalities and discuss clinical settings in which targeting the gut-microbiota-liver axis for the prevention of disease progression and HCC development seems promising.
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Affiliation(s)
- Le-Xing Yu
- Department of Medicine, Columbia University, 1130 St. Nicholas Avenue, Room 926, New York, New York 10032, USA
| | - Robert F Schwabe
- Department of Medicine, Columbia University, 1130 St. Nicholas Avenue, Room 926, New York, New York 10032, USA
- Institute of Human Nutrition, 1130 St. Nicholas Avenue, Room 926, New York, New York 10032, USA
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31
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Breitkopf-Heinlein K, Meyer C, König C, Gaitantzi H, Addante A, Thomas M, Wiercinska E, Cai C, Li Q, Wan F, Hellerbrand C, Valous NA, Hahnel M, Ehlting C, Bode JG, Müller-Bohl S, Klingmüller U, Altenöder J, Ilkavets I, Goumans MJ, Hawinkels LJAC, Lee SJ, Wieland M, Mogler C, Ebert MP, Herrera B, Augustin H, Sánchez A, Dooley S, Ten Dijke P. BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut 2017; 66:939-954. [PMID: 28336518 DOI: 10.1136/gutjnl-2016-313314] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 02/22/2017] [Accepted: 03/02/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-β family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues including bone and endothelium, but little is known about its hepatic functions in health and disease. DESIGN Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice. RESULTS Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis. CONCLUSIONS Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.
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Affiliation(s)
| | - Christoph Meyer
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Courtney König
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Haristi Gaitantzi
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Annalisa Addante
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain
| | - Maria Thomas
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany
| | - Eliza Wiercinska
- German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, Frankfurt, Germany
| | - Chen Cai
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Qi Li
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Fengqi Wan
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Claus Hellerbrand
- Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany
| | - Nektarios A Valous
- Applied Tumor Immunity Clinical Cooperation Unit, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany
| | - Maximilian Hahnel
- University Hospital of the Heinrich-Heine University, Duesseldorf, Germany
| | - Christian Ehlting
- University Hospital of the Heinrich-Heine University, Duesseldorf, Germany
| | - Johannes G Bode
- University Hospital of the Heinrich-Heine University, Duesseldorf, Germany
| | - Stephanie Müller-Bohl
- Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ursula Klingmüller
- Division Systems Biology of Signal Transduction, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jutta Altenöder
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Iryna Ilkavets
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Marie-José Goumans
- Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Lukas J A C Hawinkels
- Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Se-Jin Lee
- Johns Hopkins University School of Medicine, Molecular Biology and Genetics, Baltimore, USA
| | - Matthias Wieland
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany
| | - Carolin Mogler
- Institute of Pathology, Technical University of Munich, München, Germany
| | - Matthias P Ebert
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Blanca Herrera
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain
| | - Hellmut Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany.,Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,German Cancer Consortium, Heidelberg, Germany
| | - Aránzazu Sánchez
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, Complutense University of Madrid, San Carlos Clinical Hospital Health Research Institute (IdISSC), Madrid, Spain
| | - Steven Dooley
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Peter Ten Dijke
- Department of Molecular Cell Biology and Centre for Cancer Genomics, Leiden University Medical Center, Leiden, The Netherlands
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Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol 2016; 8:1354-1369. [PMID: 27917262 PMCID: PMC5114472 DOI: 10.4254/wjh.v8.i32.1354] [Citation(s) in RCA: 125] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Revised: 08/17/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors that participate in host defense by recognizing pathogen-associated molecular patterns alongside inflammatory processes by recognizing damage associated molecular patterns. Given constant exposure to pathogens from gut, strict control of TLR-associated signaling pathways is essential in the liver, which otherwise may lead to inappropriate production of pro-inflammatory cytokines and interferons and may generate a predisposition to several autoimmune and chronic inflammatory diseases. The liver is considered to be a site of tolerance induction rather than immunity induction, with specificity in hepatic cell functions and distribution of TLR. Recent data emphasize significant contribution of TLR signaling in chronic liver diseases via complex immune responses mediating hepatocyte (i.e., hepatocellular injury and regeneration) or hepatic stellate cell (i.e., fibrosis and cirrhosis) inflammatory or immune pathologies. Herein, we review the available data on TLR signaling, hepatic expression of TLRs and associated ligands, as well as the contribution of TLRs to the pathophysiology of hepatic diseases.
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Affiliation(s)
- Safak Kiziltas
- Safak Kiziltas, Department of Gastroenterology, Baskent University Istanbul Hospital, 34662 Istanbul, Turkey
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33
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Evans TI, Li H, Schafer JL, Klatt NR, Hao XP, Traslavina RP, Estes JD, Brenchley JM, Reeves RK. SIV-induced Translocation of Bacterial Products in the Liver Mobilizes Myeloid Dendritic and Natural Killer Cells Associated With Liver Damage. J Infect Dis 2016; 213:361-9. [PMID: 26238685 PMCID: PMC4704667 DOI: 10.1093/infdis/jiv404] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 07/24/2015] [Indexed: 12/25/2022] Open
Abstract
Disruption of the mucosal epithelium during lentivirus infections permits translocation of microbial products into circulation, causing immune activation and driving disease. Although the liver directly filters blood from the intestine and is the first line of defense against gut-derived antigens, the effects of microbial products on the liver are unclear. In livers of normal macaques, minute levels of bacterial products were detectable, but increased 20-fold in simian immunodeficiency virus (SIV)-infected animals. Increased microbial products in the liver induced production of the chemoattractant CXCL16 by myeloid dendritic cells (mDCs), causing subsequent recruitment of hypercytotoxic natural killer (NK) cells expressing the CXCL16 receptor, CXCR6. Microbial accumulation, mDC activation, and cytotoxic NK cell frequencies were significantly correlated with markers of liver damage, and SIV-infected animals consistently had evidence of hepatitis and fibrosis. Collectively, these data indicate that SIV-associated accumulation of microbial products in the liver initiates a cascade of innate immune activation, resulting in liver damage.
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Affiliation(s)
- Tristan I. Evans
- Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough
| | - Haiying Li
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Jamie L. Schafer
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Nichole R. Klatt
- Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle
| | - Xing-Pei Hao
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory
| | - Ryan P. Traslavina
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory
| | - Jacob D. Estes
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory
| | - Jason M. Brenchley
- Program in Barrier Immunity and Repair, Immunopathogenesis Section, LMM, NIAID NIH, Bethesda, Maryland
| | - R. Keith Reeves
- Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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34
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Hellweg CE. The Nuclear Factor κB pathway: A link to the immune system in the radiation response. Cancer Lett 2015; 368:275-89. [DOI: 10.1016/j.canlet.2015.02.019] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 02/08/2015] [Accepted: 02/10/2015] [Indexed: 01/01/2023]
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35
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Liu LH, Lai QN, Chen JY, Zhang JX, Cheng B. Overexpression of pim-3 and protective role in lipopolysaccharide-stimulated hepatic stellate cells. World J Gastroenterol 2015; 21:8858-8867. [PMID: 26269675 PMCID: PMC4528028 DOI: 10.3748/wjg.v21.i29.8858] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 05/01/2015] [Accepted: 05/27/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate pim-3 expression in hepatic stellate cells (HSCs) stimulated by lipopolysaccharide (LPS), and its protective effect on HSCs.
METHODS: Rat HSC-T6 cells were stimulated by LPS. The effect of LPS on proliferation and apoptosis of HSC-T6 cells was investigated by methyl thiazoyltetrazolium (MTT) assay and flow cytometry after annexin V-fluorescein isothiocyanate/propidium iodide double staining. pim-3 mRNA and protein were detected by reverse transcriptase polymerase chain reaction and Western blotting at 48 h when HSC-T6 cells were stimulated with 1 μg/mL LPS for 0, 3, 6, 12, 24 and 48 h. The cells without stimulation served as controls. To study the effect of pim-3 kinase on HSC-T6 cells, si-pim3 (siRNA against pim-3) was transfected into HSC-T6 cells. HSC-T6 cells were subjected to different treatments, including LPS, si-pim3, or si-pim3 plus LPS, and control cells were untreated. Protein expression of pim-3 was detected at 48 h after treatment, and cell proliferation at 24 and 48 h by MTT assay. Apoptosis was detected by flow cytometry, and confirmed with caspase-3 activity assay.
RESULTS: LPS promoted HSC-T6 cell proliferation and protected against apoptosis. Significantly delayed upregulation of pim-3 expression induced by LPS occurred at 24 and 48 h for mRNA expression (pim-3/β-actin RNA, 24 or 48 h vs 0 h, 0.81 ± 0.20 or 0.78 ± 0.21 vs 0.42 ± 0.13, P < 0.05), and occurred at 12 h and peaked at 24 and 48 h for protein expression (pim-3/GAPDH protein, 12, or 24 or 48 h vs 0 h, 0.68 ± 0.12, 1.47 ± 0.25 or 1.51 ± 0.23 vs 0.34 ± 0.04, P < 0.01). pim-3 protein was ablated by si-pim3 and upregulated by LPS in HSC-T6 cells at 48 h after treatment (pim-3/GAPDH: si-pim3, si-pim3 plus LPS or LPS vs control, 0.11 ± 0.05, 0.12 ± 0.05 or 1.08 ± 0.02 vs 0.39 ± 0.03, P < 0.01). Ablation of pim-3 by si-pim3 in HSC-T6 cells partly abolished proliferation (OD at 24 h, si-pim3 group or si-pim3 plus LPS vs control, 0.2987 ± 0.050 or 0.4063 ± 0.051 vs 0.5267 ± 0.030, P < 0.01; at 48 h 0.4634 ± 0.056 or 0.5433 ± 0.031 vs 0.8435 ± 0.028, P < 0.01; si-pim3 group vs si-pim3 plus LPS, P < 0.01 at 24 h and P < 0.05 at 48 h), and overexpression of pim-3 in the LPS group increased cell proliferation (OD: LPS vs control, at 24 h, 0.7435 ± 0.028 vs 0.5267 ± 0.030, P < 0.01; at 48 h, 1.2136 ± 0.048 vs 0.8435 ± 0.028, P < 0.01). Ablation of pim3 with si-pim3 in HSC-T6 cells aggravated apoptosis (si-pim3 or si-pim3 plus LPS vs control, 42.3% ±1.1% or 40.6% ± 1.3% vs 16.8% ± 3.3%, P < 0.01; si-pim3 vs si-pim3 plus LPS, P > 0.05), and overexpression of pim-3 in the LPS group attenuated apoptosis (LPS vs control, 7.32% ± 2.1% vs 16.8% ± 3.3%, P < 0.05). These results were confirmed by caspase-3 activity assay.
CONCLUSION: Overexpression of pim-3 plays a protective role in LPS-stimulated HSC-T6 cells.
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Thapa M, Chinnadurai R, Velazquez VM, Tedesco D, Elrod E, Han JH, Sharma P, Ibegbu C, Gewirtz A, Anania F, Pulendran B, Suthar MS, Grakoui A. Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. Hepatology 2015; 61:2067-79. [PMID: 25711908 PMCID: PMC4441566 DOI: 10.1002/hep.27761] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 02/23/2015] [Indexed: 12/18/2022]
Abstract
UNLABELLED Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Here, we postulated that the immune regulatory properties of HSCs might promote the profibrogenic activity of B cells. Fibrosis is completely attenuated in carbon tetrachloride-treated, B cell-deficient µMT mice, showing that B cells are required. The retinoic acid produced by HSCs augmented B-cell survival, plasma cell marker CD138 expression, and immunoglobulin G production. These activities were reversed following addition of the retinoic acid inhibitor LE540. Transcriptional profiling of fibrotic liver B cells revealed increased expression of genes related to activation of nuclear factor κ light chain enhancer of activated B cells, proinflammatory cytokine production, and CD40 signaling, suggesting that these B cells are activated and may be acting as inflammatory cells. Biological validation experiments also revealed increased activation (CD44 and CD86 expression), constitutive immunoglobulin G production, and secretion of the proinflammatory cytokines tumor necrosis factor-α, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α. Likewise, targeted deletion of B-cell-intrinsic myeloid differentiation primary response gene 88 signaling, an innate adaptor with involvement in retinoic acid signaling, resulted in reduced infiltration of migratory CD11c(+) dendritic cells and Ly6C(++) monocytes and, hence, reduced liver pathology. CONCLUSION Liver fibrosis occurs through a mechanism of HSC-mediated augmentation of innate B-cell activity. These findings highlight B cells as important "first responders" of the intrahepatic immune environment.
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Affiliation(s)
- Manoj Thapa
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
| | - Raghavan Chinnadurai
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
| | - Victoria M. Velazquez
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
| | - Dana Tedesco
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
| | - Elizabeth Elrod
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
| | - Jin-Hwan Han
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
| | - Prachi Sharma
- Division of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Chris Ibegbu
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
| | - Andrew Gewirtz
- Department of Biology, Georgia State University, Atlanta, GA 30303
| | - Frank Anania
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA 30322
| | - Bali Pulendran
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322
| | - Mehul S. Suthar
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322,Department of Pediatrics and Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322
| | - Arash Grakoui
- Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322,Division of Infectious diseases, Emory University School of Medicine, Atlanta, Georgia 30322
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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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Ma CY, Chang WE, Shi GY, Chang BY, Cheng SE, Shih YT, Wu HL. Recombinant Thrombomodulin Inhibits Lipopolysaccharide-Induced Inflammatory Response by Blocking the Functions of CD14. THE JOURNAL OF IMMUNOLOGY 2015; 194:1905-15. [DOI: 10.4049/jimmunol.1400923] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Yao HW, Li J. Epigenetic modifications in fibrotic diseases: implications for pathogenesis and pharmacological targets. J Pharmacol Exp Ther 2015; 352:2-13. [PMID: 25362107 DOI: 10.1124/jpet.114.219816] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Organ fibrosis is a complex and chronic disorder that results from a variety of acute injuries and contributes to thirty percent of naturally occurring deaths worldwide. The main feature of organ fibrosis is the excessive accumulation and deposit of extracellular matrix, thereby leading to organ dysfunction, loss of elasticity, and development of a rigid organ. Accumulating evidence shows that epigenetic remodeling, including aberrant DNA methylation and noncoding RNA expression as well as histone post-translational modifications, play important roles in the pathogenesis of fibrosis through the regulation of fibroblast activation, differentiation, and apoptosis, as well as collagen synthesis and profibrotic gene transcription. In this review, we discuss the basic regulation of DNA methylation, noncoding RNA expression, and histone post-translational modification, and their participation in the pathogenesis and development of organ fibrosis. This review also provides the latest insights into the novel biomarkers and therapeutic targets for fibrosis through modulation of epigenetic remodeling.
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Affiliation(s)
- Hong-Wei Yao
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China
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Giannelli V, Di Gregorio V, Iebba V, Giusto M, Schippa S, Merli M, Thalheimer U. Microbiota and the gut-liver axis: Bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol 2014; 20:16795-16810. [PMID: 25492994 PMCID: PMC4258550 DOI: 10.3748/wjg.v20.i45.16795] [Citation(s) in RCA: 166] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/26/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota. In cirrhotic patients the alteration in gut microbiota is characterized by an overgrowth of potentially pathogenic bacteria (i.e., gram negative species) and a decrease in autochthonous familiae. Here we summarize the available literature on the risk of gut dysbiosis in liver cirrhosis and its clinical consequences. We therefore described the features of the complex interaction between gut microbiota and cirrhotic host, the so called “gut-liver axis”, with a particular attention to the acquired risk of bacterial translocation, systemic inflammation and the relationship with systemic infections in the cirrhotic patient. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of gut dysbiosis and its complication in liver cirrhosis.
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Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, Eckmann L, Dhungana S, Pathmasiri W, Sumner S, Westwater C, Brenner DA, Schnabl B. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 2014; 29:1043-55. [PMID: 25466902 DOI: 10.1096/fj.14-259515] [Citation(s) in RCA: 129] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Translocation of bacteria and their products across the intestinal barrier is common in patients with liver disease, and there is evidence that experimental liver fibrosis depends on bacterial translocation. The purpose of our study was to investigate liver fibrosis in conventional and germ-free (GF) C57BL/6 mice. Chronic liver injury was induced by administration of thioacetamide (TAA) in the drinking water for 21 wk or by repeated intraperitoneal injections of carbon tetrachloride (CCl4). Increased liver fibrosis was observed in GF mice compared with conventional mice. Hepatocytes showed more toxin-induced oxidative stress and cell death. This was accompanied by increased activation of hepatic stellate cells, but hepatic mediators of inflammation were not significantly different. Similarly, a genetic model using Myd88/Trif-deficient mice, which lack downstream innate immunity signaling, had more severe fibrosis than wild-type mice. Isolated Myd88/Trif-deficient hepatocytes were more susceptible to toxin-induced cell death in culture. In conclusion, the commensal microbiota prevents fibrosis upon chronic liver injury in mice. This is the first study describing a beneficial role of the commensal microbiota in maintaining liver homeostasis and preventing liver fibrosis.
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Affiliation(s)
- Magdalena Mazagova
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lirui Wang
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Andrew T Anfora
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Max Wissmueller
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Scott A Lesley
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Yukiko Miyamoto
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lars Eckmann
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Suraj Dhungana
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Wimal Pathmasiri
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Susan Sumner
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Caroline Westwater
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - David A Brenner
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Bernd Schnabl
- *Department of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA; Genomics Institute of the Novartis Research Foundation, San Diego, California, USA; Systems and Translational Science, RTI International, Research Triangle Park, North Carolina, USA; and Department of Oral Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
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Giorgio V, Alisi A, Kazem HM, Monti S, Nobili V. NASH and the Cross-Talk Between the Gut and Liver. CURRENT PEDIATRICS REPORTS 2014. [DOI: 10.1007/s40124-014-0047-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Garcia-Irigoyen O, Carotti S, Latasa MU, Uriarte I, Fernández-Barrena MG, Elizalde M, Urtasun R, Vespasiani-Gentilucci U, Morini S, Banales JM, Parks WC, Rodriguez JA, Orbe J, Prieto J, Páramo JA, Berasain C, Ávila MA. Matrix metalloproteinase-10 expression is induced during hepatic injury and plays a fundamental role in liver tissue repair. Liver Int 2014; 34:e257-e270. [PMID: 24119197 DOI: 10.1111/liv.12337] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 09/15/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Upon tissue injury, the liver mounts a potent reparative and regenerative response. A role for proteases, including serine and matrix metalloproteinases (MMPs), in this process is increasingly recognized. We have evaluated the expression and function of MMP10 (stromelysin-2) in liver wound healing and regeneration. METHODS The hepatic expression of MMP10 was examined in two murine models: liver regeneration after two-thirds partial hepatectomy (PH) and bile duct ligation (BDL). MMP10 was detected in liver tissues by qPCR, western blotting and immunohistochemistry. The effect of growth factors and toll-like receptor 4 (TLR4) agonists on MMP10 expression was studied in cultured parenchymal and biliary epithelial cells and macrophages respectively. The role of MMP10 was evaluated by comparing the response of Mmp10+/+ and Mmp10-/- mice to PH and BDL. The intrahepatic turnover of the extracellular matrix proteins fibrin (ogen) and fibronectin was examined. RESULTS MMP10 mRNA was readily induced after PH and BDL. MMP10 protein was detected in hepatocytes, cholangiocytes and macrophages. In cultured liver epithelial cells, MMP10 expression was additively induced by transforming growth factor-β and epidermal growth factor receptor ligands. TLR4 ligands also stimulated MMP10 expression in macrophages. Lack of MMP10 resulted in increased liver injury upon PH and BDL. Resolution of necrotic areas was impaired, and Mmp10-/- mice showed increased fibrogenesis and defective turnover of fibrin (ogen) and fibronectin. CONCLUSIONS MMP10 expression is induced during mouse liver injury and participates in the hepatic wound healing response. The profibrinolytic activity of MMP10 may be essential in this novel hepatoprotective role.
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Affiliation(s)
- Oihane Garcia-Irigoyen
- Centro de Investigación Médica Aplicada (CIMA), Division of Hepatology and Gene Therapy, Universidad de Navarra, Pamplona, Spain
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Roderburg C, Luedde T. The role of the gut microbiome in the development and progression of liver cirrhosis and hepatocellular carcinoma. Gut Microbes 2014; 5:441-5. [PMID: 25006881 DOI: 10.4161/gmic.29599] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver cirrhosis and hepatocellular carcinoma (HCC) represent the endstage of most chronic liver diseases and are a major global health burden. It has been consistently shown that both liver cirrhosis and HCC are triggered by inflammatory processes, but the molecular mechanisms linking chronic hepatitis with cirrhosis and HCC are only poorly understood. Recent studies suggested that the intestinal microflora as a main source of portal-vein LPS might play a critical role in this process. Here we summarize the available literature on the role of the gut microbiome in hepatofibrogenesis and -carcinogenesis. Such knowledge might help to develop novel, innovative strategies for the prevention and therapy of liver disease.
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Affiliation(s)
| | - Tom Luedde
- Department of Medicine III; University of Aachen (RWTH); Aachen, Germany
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Shi W, Su L, Li Q, Sun L, Lv J, Li J, Cheng B. Suppression of toll-like receptor 2 expression inhibits the bioactivity of human hepatocellular carcinoma. Tumour Biol 2014; 35:9627-37. [PMID: 24964964 DOI: 10.1007/s13277-014-2268-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 06/19/2014] [Indexed: 12/11/2022] Open
Abstract
Toll-like receptor (TLR) 2 signaling is regarded as one of the mechanisms of chronic inflammation, but it can also mediate tumor cell immune escape and tumor progression. However, the role of TLR2 in the progression of human hepatocellular carcinoma (HCC) remains unclear. The objective of the study was to examine the effect of TLR2 on the bioactivity of HCC cell lines, HepG2 and BEL-7402, and the relationship between high mobility group box1 (HMGB1) and TLR2. The expression of TLR2 and nuclear factor-kappaB/P65 (NF-κB/P65) in HepG2 and BEL-7402 was assayed by Western blot. Cells were transfected with specific small interfering RNAs of TLR2 (TLR2-siRNAs), then TLR2-siRNA-transfected cells were treated with recombinant HMGB1 (rHMGB1). Apoptosis was determined by flow cytometry. Results showed that TLR2 was expressed in HepG2 and BEL-7402 cells. The ability of proliferation, invasion, and migration in siRNA group was lower than that in blank group, and the apoptosis ratio was higher than that in blank group, respectively. NF-κB/P65 expression was declined in contrast with blank group. Downregulation of TLR2 by siRNA resulted in a significant inhibition of proliferation, invasion, migration, and NF-κB/P65 expression, and elevated apoptotic ratio. Conversely, rHMGB1 promoted proliferation, invasion, and migration, induced NF-κB/P65 expression, and inhibited cells apoptosis. Furthermore, downregulation of TLR2 weakened the role of rHMGB1. This study suggests TLR2 and HMGB1 are important targets for therapeutic intervention of HCC.
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Affiliation(s)
- Wenna Shi
- Department of Gastroenterology, Qilu Hospital, School of Medicine, Shandong University, 107#, Wenhua Xi Road, Jinan, 250012, People's Republic of China,
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Siddiqi NJ, Zargar S. Effect of quercetin on cadmium fluoride-induced alterations in hydroxyproline/collagen content in mice liver. Connect Tissue Res 2014; 55:234-8. [PMID: 24588693 DOI: 10.3109/03008207.2014.900551] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
PURPOSE/AIM OF THE STUDY To study the effect of quercetin, a flavanoid on cadmium fluoride-induced alterations in hydroxyproline and collagen content in mice liver. MATERIALS AND METHODS Following experimental groups were studied: Group 1, normal mice; Group 2, CdF2-treated mice administered single intraperitoneal (i.p.) injections of CdF2 1 mg/kg bw (body weight); Group 3, CdF2-treated mice administered single i.p. injections of CdF2 2 mg/kg bw; Group 4, mice-injected i.p. with 100 mg quercetin/kg bw; and Group 5, mice-injected i.p. with 100 mg quercetin/kg bw followed by 2 mg CdF2/kg bw after 2 h. Mice were sacrificed 24 h after CdF injection by asphyxiation with carbon dioxide. RESULTS 1 mg/kg and 2 mg/kg body weight (bw) of CdF2 caused a significant increase in hepatic total Hyp and collagen when compared with the liver of control mice. This was associated with significant changes in free, peptide bound, and protein bound Hyp fraction in the livers of treated mice. Quercetin treatment alone and with CdF2 also caused a significant increase in total Hyp and total collagen in mice liver. CONCLUSION We conclude that quercetin has a synergestic effect with CdF2 on the total Hyp and collagen content in mice liver.
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Affiliation(s)
- Nikhat J Siddiqi
- Department of Biochemistry, College of Science, King Saud University , Riyadh , Saudi Arabia
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Kremer M, Son G, Zhang K, Moore SM, Norris A, Manzini G, Wheeler MD, Hines IN. Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression. Transpl Int 2014; 27:748-58. [PMID: 24649805 DOI: 10.1111/tri.12322] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 11/24/2013] [Accepted: 03/16/2014] [Indexed: 12/12/2022]
Abstract
Liver regeneration is vital for graft survival and adequate organ function. Smad activation regulates hepatocyte proliferation and macrophage function. The aim of the current study was to evaluate the impact of Smad3 signaling during liver regeneration in the mouse. Male C57Bl/6 wild-type (wt) mice or mice deficient in Smad3 (Smad3(-/-) ) were subjected to a 70% partial hepatectomy (pHx) or sham surgery and sacrificed 24, 42, or 48 h later. Tissue was analyzed for TGF-β signaling, the mitogenic cytokine response [i.e., tumor necrosis factor alpha, TNF-α; interleukin (IL)-6], and liver regeneration. Partial hepatectomy stimulated a strong regenerative response measured by proliferating cell nuclear antigen-positive hepatocytes 42 and 48 h post-pHx in conjunction with an increased expression of IL-6, TNF-α, and Smad2/3 phosphorylation 24 h post-pHx in both hepatocytes and nonparenchymal cells. Surprisingly, Smad3 deficiency led to reduced hepatocyte proliferation 42 h post-pHx which recovered by 48 h, a process that correlated with and was preceded by significant reductions in IL-6 expression and signal transducer and activator of transcription 3 phosphorylation, and cyclin D1 induction 24 h post-pHx. Loss of Smad3 signaling suppresses the expression of key mitogenic cytokines and delays hepatocellular regeneration. Therapies directed at finely regulating Smad3 activation early within the regenerating liver may prove useful in promoting liver cell proliferation and restoration of liver mass.
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Affiliation(s)
- Michael Kremer
- Department of General Surgery, University of Ulm, Ulm, Germany; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA
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Nakamoto N, Kanai T. Role of toll-like receptors in immune activation and tolerance in the liver. Front Immunol 2014; 5:221. [PMID: 24904576 PMCID: PMC4032908 DOI: 10.3389/fimmu.2014.00221] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Accepted: 04/30/2014] [Indexed: 12/11/2022] Open
Abstract
Liver has a unique vascular system receiving the majority of the blood supply from the gastrointestinal tract through the portal vein and faces continuous exposure to foreign pathogens and commensal bacterial products. These gut-derived antigens stimulate liver cells and result in a distinctive immune response via a family of pattern recognition receptors, the Toll-like receptors (TLRs). TLRs are expressed on Kupffer cells, dendritic cells, hepatic stellate cells, endothelial cells, and hepatocytes in the liver. The crosstalk between gut-derived antigens and TLRs on immune cells trigger a distinctive set of mechanisms to induce immunity, contributing to various acute and chronic liver diseases including liver cirrhosis and hepatocellular carcinoma. Accumulating evidence has shown that TLRs stimulation by foreign antigens induces the production of immunoactivating and immunoregulatory cytokines. Furthermore, the immunoregulatory arm of TLR stimulation can also control excessive tissue damage. With this knowledge at hand, it is important to clarify the dual role of disease-specific TLRs as activators and regulators, especially in the liver. We will review the current understanding of TLR signaling and subsequent immune activation and tolerance by the innate immune system in the liver.
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Affiliation(s)
- Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine , Tokyo , Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine , Tokyo , Japan
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Saito S, Hata K, Iwaisako K, Yanagida A, Takeiri M, Tanaka H, Kageyama S, Hirao H, Ikeda K, Asagiri M, Uemoto S. Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis. Hepatol Res 2014; 44:460-73. [PMID: 23607402 DOI: 10.1111/hepr.12140] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Revised: 04/08/2013] [Accepted: 04/15/2013] [Indexed: 01/28/2023]
Abstract
AIM Liver fibrosis is a common pathway leading to cirrhosis. Cilostazol, a clinically available oral phosphodiesterase-3 inhibitor, has been shown to have antifibrotic potential in experimental non-alcoholic fatty liver disease. However, the detailed mechanisms of the antifibrotic effect and its efficacy in a different experimental model remain elusive. METHODS Male C57BL/6J mice were assigned to five groups: mice fed a normal diet (groups 1 and 2); 0.1% or 0.3% cilostazol-containing diet (groups 3 and 4, respectively); and 0.125% clopidogrel-containing diet (group 5). Two weeks after feeding, groups 2-5 were intraperitoneally administered carbon tetrachloride (CCl4 ) twice a week for 6 weeks, while group 1 was treated with the vehicle alone. To investigate the effects of cilostazol on hepatic cells, in vitro studies were conducted using primary hepatic stellate cells (HSC), Kupffer cells and hepatocytes with cilostazol supplementation. RESULTS Sirius red staining revealed that groups 3 and 4 exhibited a lesser fibrotic area (2.49 ± 0.43% and 2.31 ± 0.30%, respectively) than group 2 (3.17 ± 0.67%, P < 0.05 and P < 0.001, respectively). In vitro studies showed cilostazol dose-dependently suppressed HSC activation (assessed by morphological change, cell proliferation, and the expression of HSC activation markers), suggesting the therapeutic effect of cilostazol is mediated by its direct action on HSC. CONCLUSION Cilostazol could alleviate CCl4 -induced hepatic fibrogenesis in vivo, presumably due, at least partly, to its direct effect to suppress HSC activation. Given its clinical availability and safety, it may be a novel therapeutic intervention for chronic liver diseases.
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Affiliation(s)
- Shunichi Saito
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiko Iwaisako
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Atsuko Yanagida
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masatoshi Takeiri
- Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hirokazu Tanaka
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shoichi Kageyama
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hirofumi Hirao
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuo Ikeda
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Masataka Asagiri
- Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Sun X, Yang Y, Zhu D, Qian H, Duan Y, He X, Gu X, Sun W, Zhu Y. Expression of Septin4 in human hepatic stellate cells LX-2 stimulated by LPS. Inflammation 2014. [PMID: 23180367 DOI: 10.1007/s10753-012-9575-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Septin4, a member of polymerizing GTP-binding proteins family, is reported to be involved in cytoskeletal organization in mitosis, apoptosis, fibrosis, and other cellular processes. Since various Septin4 expression patterns were reported in different diseases, this study aimed to investigate Septin4 expression in human LX-2 cell line stimulated by lipopolysaccharides (LPS) and attempted to clarify the relationship between Septin4 and hepatic inflammatory injury and fibrosis. In this subject, human stellate cell line LX-2 was stimulated by LPS. The expression of Septin4 was analyzed by Western blot and quantitative real-time PCR. To observe the relationship among Toll-like receptor 4 (TLR4), TGF-β, and Septin4, proteins from the anti-TLR4 antibody blocked cells, as well as the TGF-β-induced cells, were analyzed by the method of Western blot. As the results, LPS could induce the alteration of α-smooth muscle actin and Septin4 expression in LX-2 cells. Septin4 expression was regulated by LPS stimulation through TLR4 and TGF-β pathway. These results therefore suggest that Septin4 may be involved in the process of activation of hepatic stellate cells by LPS stimulation. Further work would focus on the function of Septin4 in hepatic inflammatory injury and fibrosis.
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Affiliation(s)
- Xiaolei Sun
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu, People's Republic of China
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