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He X, Hu M, Xu Y, Xia F, Tan Y, Wang Y, Xiang H, Wu H, Ji T, Xu Q, Wang L, Huang Z, Sun M, Wan Y, Cui P, Liang S, Pan Y, Xiao S, He Y, Song R, Yan J, Quan X, Wei Y, Hong C, Liao W, Li F, El-Omar E, Chen J, Qi X, Gao J, Zhou H. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nat Med 2025; 31:627-638. [PMID: 39779925 DOI: 10.1038/s41591-024-03405-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025]
Abstract
Up to 50-70% of patients with liver cirrhosis develop hepatic encephalopathy (HE), which is closely related to gut microbiota dysbiosis, with an unclear mechanism. Here, by constructing gut-brain modules to assess bacterial neurotoxins from metagenomic datasets, we found that phenylalanine decarboxylase (PDC) genes, mainly from Ruminococcus gnavus, increased approximately tenfold in patients with cirrhosis and higher in patients with HE. Cirrhotic, not healthy, mice colonized with R. gnavus showed brain phenylethylamine (PEA) accumulation, along with memory impairment, symmetrical tremors and cortex-specific neuron loss, typically found in patients with HE. This accumulation of PEA was primarily driven by decreased monoamine oxidase-B activity in both the liver and serum due to cirrhosis. Targeting PDC or PEA reversed the neurological symptoms induced by R. gnavus. Furthermore, fecal microbiota transplantation from patients with HE to germ-free cirrhotic mice replicated these symptoms and further corroborated the efficacy of targeting PDC or PEA. Clinically, high baseline PEA levels were linked to a sevenfold increased risk of HE after intrahepatic portosystemic shunt procedures. Our findings expand the understanding of the gut-liver-brain axis and identify a promising therapeutic and predictive target for HE.
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Affiliation(s)
- Xiaolong He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Mengyao Hu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yi Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fangbo Xia
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Tan
- Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao C1 Refinery Engineering Research Center, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
| | - Yuqing Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Huiling Xiang
- Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Tengfei Ji
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qian Xu
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Wang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhenhe Huang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Meiling Sun
- Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Wan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peng Cui
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Shaocong Liang
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Pan
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Siyu Xiao
- Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan He
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China
- Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China
| | - Ruixin Song
- The Third Central Clinical College of Tianjin Medical University, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Junqing Yan
- Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China
| | - Xin Quan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yingge Wei
- Department of Hepatology, Third People's Hospital of Linfen City, Linfen, China
| | - Changze Hong
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weizuo Liao
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, the State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Fuli Li
- Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao C1 Refinery Engineering Research Center, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
| | - Emad El-Omar
- UNSW Microbiome Research Centre, School of Clinical Medicine, UNSW Medicine & Health, UNSW SYDNEY, Sydney, New South Wales, Australia
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
| | - Jie Gao
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
- Department of Gastroenterology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
- The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, the State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
| | - Hongwei Zhou
- Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
- State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
- Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Clinical Research Center for Laboratory Medicine, Guangzhou, China.
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
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Assimakopoulos SF, Bhagani S, Aggeletopoulou I, Tsounis EP, Tsochatzis EA. The role of gut barrier dysfunction in postoperative complications in liver transplantation: pathophysiological and therapeutic considerations. Infection 2024; 52:723-736. [PMID: 38324146 PMCID: PMC11143052 DOI: 10.1007/s15010-024-02182-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/11/2024] [Indexed: 02/08/2024]
Abstract
PURPOSE Gut barrier dysfunction is a pivotal pathophysiological alteration in cirrhosis and end-stage liver disease, which is further aggravated during and after the operational procedures for liver transplantation (LT). In this review, we analyze the multifactorial disruption of all major levels of defense of the gut barrier (biological, mechanical, and immunological) and correlate with clinical implications. METHODS A narrative review of the literature was performed using PubMed, PubMed Central and Google from inception until November 29th, 2023. RESULTS Systemic translocation of indigenous bacteria through this dysfunctional barrier contributes to the early post-LT infectious complications, while endotoxin translocation, through activation of the systemic inflammatory response, is implicated in non-infectious complications including renal dysfunction and graft rejection. Bacterial infections are the main cause of early in-hospital mortality of LT patients and unraveling the pathophysiology of gut barrier failure is of outmost importance. CONCLUSION A pathophysiology-based approach to prophylactic or therapeutic interventions may lead to enhancement of gut barrier function eliminating its detrimental consequences and leading to better outcomes for LT patients.
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Affiliation(s)
- Stelios F Assimakopoulos
- Division of Infectious Diseases, Department of Internal Medicine, Medical School, University of Patras, University Hospital of Patras, Rion, 26504, Patras, Greece.
| | - Sanjay Bhagani
- Department of Infectious Diseases/HIV Medicine, Royal Free Hospital, London, UK
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
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Terbah R, Testro A, Gow P, Majumdar A, Sinclair M. Portal Hypertension in Malnutrition and Sarcopenia in Decompensated Cirrhosis-Pathogenesis, Implications and Therapeutic Opportunities. Nutrients 2023; 16:35. [PMID: 38201864 PMCID: PMC10780673 DOI: 10.3390/nu16010035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Malnutrition and sarcopenia are highly prevalent in patients with decompensated cirrhosis and are associated with poorer clinical outcomes. Their pathophysiology is complex and multifactorial, with protein-calorie malnutrition, systemic inflammation, reduced glycogen stores and hormonal imbalances all well reported. The direct contribution of portal hypertension to these driving factors is however not widely documented in the literature. This review details the specific mechanisms by which portal hypertension directly contributes to the development of malnutrition and sarcopenia in cirrhosis. We summarise the existing literature describing treatment strategies that specifically aim to reduce portal pressures and their impact on nutritional and muscle outcomes, which is particularly relevant to those with end-stage disease awaiting liver transplantation.
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Affiliation(s)
- Ryma Terbah
- Liver Transplant Unit, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia; (R.T.); (A.T.); (P.G.); (A.M.)
- Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia
| | - Adam Testro
- Liver Transplant Unit, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia; (R.T.); (A.T.); (P.G.); (A.M.)
- Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia
| | - Paul Gow
- Liver Transplant Unit, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia; (R.T.); (A.T.); (P.G.); (A.M.)
- Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia
| | - Avik Majumdar
- Liver Transplant Unit, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia; (R.T.); (A.T.); (P.G.); (A.M.)
- Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia
| | - Marie Sinclair
- Liver Transplant Unit, Austin Health, 145 Studley Road, Heidelberg, VIC 3084, Australia; (R.T.); (A.T.); (P.G.); (A.M.)
- Department of Medicine, The University of Melbourne, Parkville, VIC 3050, Australia
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Liu H, Nguyen HH, Hwang SY, Lee SS. Oxidative Mechanisms and Cardiovascular Abnormalities of Cirrhosis and Portal Hypertension. Int J Mol Sci 2023; 24:16805. [PMID: 38069125 PMCID: PMC10706054 DOI: 10.3390/ijms242316805] [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: 11/03/2023] [Revised: 11/19/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
In patients with portal hypertension, there are many complications including cardiovascular abnormalities, hepatorenal syndrome, ascites, variceal bleeding, and hepatic encephalopathy. The underlying mechanisms are not yet completely clarified. It is well known that portal hypertension causes mesenteric congestion which produces reactive oxygen species (ROS). ROS has been associated with intestinal mucosal injury, increased intestinal permeability, enhanced gut bacterial overgrowth, and translocation; all these changes result in increased endotoxin and inflammation. Portal hypertension also results in the development of collateral circulation and reduces liver mass resulting in an overall increase in endotoxin/bacteria bypassing detoxication and immune clearance in the liver. Endotoxemia can in turn aggravate oxidative stress and inflammation, leading to a cycle of gut barrier dysfunction → endotoxemia → organ injury. The phenotype of cardiovascular abnormalities includes hyperdynamic circulation and cirrhotic cardiomyopathy. Oxidative stress is often accompanied by inflammation; thus, blocking oxidative stress can minimize the systemic inflammatory response and alleviate the severity of cardiovascular diseases. The present review aims to elucidate the role of oxidative stress in cirrhosis-associated cardiovascular abnormalities and discusses possible therapeutic effects of antioxidants on cardiovascular complications of cirrhosis including hyperdynamic circulation, cirrhotic cardiomyopathy, and hepatorenal syndrome.
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Affiliation(s)
| | | | | | - Samuel S. Lee
- Liver Unit, University of Calgary Cumming School of Medicine, Calgary, AB T2N 4N1, Canada (H.H.N.); (S.Y.H.)
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Luo M, Xu Y, Li J, Luo D, Zhu L, Wu Y, Liu X, Wu P. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Open Med (Wars) 2023; 18:20230714. [PMID: 37273916 PMCID: PMC10238812 DOI: 10.1515/med-2023-0714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 03/14/2023] [Accepted: 04/15/2023] [Indexed: 06/06/2023] Open
Abstract
Liver cirrhosis affects the structures and physiological functions of the intestine. Our previous study revealed that liver injury inhibited 25-hydroxylation of vitamin D (25(OH)-VD). The aim of this study was to investigate the roles and mechanisms of vitamin D in liver cirrhosis-induced intestinal injury. The rat liver cirrhosis model was established through the administration of carbon tetrachloride (CCl4) for 8 weeks. Hematoxylin-eosin staining was performed to unveil the intestinal injury induced by liver cirrhosis. Enzyme-linked immunosorbent and reverse transcription PCR (RT-PCR) analysis were used to determine the levels of 25(OH)-VD, vitamin D receptor, Cytochrome P450 24A1 (CYP24A1), and α-defensin 5 (DEFA5) in rat and human serum of liver cirrhosis. Furthermore, liver cirrhosis rats were treated with low-dose (500 IU/kg) and high-dose (2,000 IU/kg) vitamin D intraperitoneally. The expression levels of TLR4/MyD88/NF-κB signaling pathway were evaluated by RT-PCR and Western blot. In conclusion, we determined the deficiency of vitamin D and down-regulation of DEFA5 and intestinal damage induced by liver cirrhosis. Moreover, vitamin D effectively inhibited liver cirrhosis-induced intestinal inflammation and oxidative stress through the TLR4/MyD88/NF-κB pathway. Vitamin D might be a promising therapeutic strategy for future treatment of liver-induced intestinal injury.
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Affiliation(s)
- Mei Luo
- Infectious Disease Laboratory, Chengdu Public Health Clinical Center, Chengdu, 610061, China
| | - Yuanhong Xu
- Clinical Laboratory, Chengdu Public Health Clinical Center, Chengdu, 610061, China
| | - Jike Li
- Infectious Disease Laboratory, Chengdu Public Health Clinical Center, Chengdu, 610061, China
| | - Dongxia Luo
- Infectious Disease Laboratory, Chengdu Public Health Clinical Center, Chengdu, 610061, China
| | - Li Zhu
- Hepatology Clinic, Chengdu Public Health Clinical Center, Chengdu, 610061, China
| | - Yanxi Wu
- Infectious Disease Laboratory, Chengdu Public Health Clinical Center, Chengdu, 610061, China
| | - Xiaodong Liu
- Clinical Laboratory, Chengdu Public Health Clinical Center, Chengdu, 610061, China
| | - Pengfei Wu
- Infectious Disease Laboratory, Chengdu Public Health Clinical Center, Chengdu, 610061, China
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Muñoz L, Caparrós E, Albillos A, Francés R. The shaping of gut immunity in cirrhosis. Front Immunol 2023; 14:1139554. [PMID: 37122743 PMCID: PMC10141304 DOI: 10.3389/fimmu.2023.1139554] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
Cirrhosis is the common end-stage of chronic liver diseases of different etiology. The altered bile acids metabolism in the cirrhotic liver and the increase in the blood-brain barrier permeability, along with the progressive dysbiosis of intestinal microbiota, contribute to gut immunity changes, from compromised antimicrobial host defense to pro-inflammatory adaptive responses. In turn, these changes elicit a disruption in the epithelial and gut vascular barriers, promoting the increased access of potential pathogenic microbial antigens to portal circulation, further aggravating liver disease. After summarizing the key aspects of gut immunity during homeostasis, this review is intended to update the contribution of liver and brain metabolites in shaping the intestinal immune status and, in turn, to understand how the loss of homeostasis in the gut-associated lymphoid tissue, as present in cirrhosis, cooperates in the advanced chronic liver disease progression. Finally, several therapeutic approaches targeting the intestinal homeostasis in cirrhosis are discussed.
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Affiliation(s)
- Leticia Muñoz
- Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Esther Caparrós
- Grupo de Inmunobiología Hepática e Intestinal, Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan, Spain
- Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | - Agustín Albillos
- Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Departamento de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- *Correspondence: Agustín Albillos, ; Rubén Frances,
| | - Rubén Francés
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Grupo de Inmunobiología Hepática e Intestinal, Departamento Medicina Clínica, Universidad Miguel Hernández, San Juan, Spain
- Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnologiía Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain
- *Correspondence: Agustín Albillos, ; Rubén Frances,
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Bloom P, Rao K, Bassis C, Zhou S, Nojkov B, Owyang C, Young V, Lok A. Duodenal Permeability Is Associated With Mucosal Microbiota in Compensated Cirrhosis. Clin Transl Gastroenterol 2022; 13:e00522. [PMID: 36000993 PMCID: PMC9624490 DOI: 10.14309/ctg.0000000000000522] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/02/2022] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Several complications of decompensated cirrhosis are believed to result from increased intestinal permeability. However, little is known about the relationship between mucosal bacteria and epithelial permeability in cirrhosis. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with compensated cirrhosis. METHODS We obtained duodenal tissue biopsies from patients with compensated cirrhosis and controls. Patients were excluded if they used antibiotics or immunosuppression. The composition of mucosal microbiota was determined by 16S rRNA gene sequencing and epithelial permeability by transepithelial electrical resistance (TEER) and tight junction protein expression. RESULTS We studied 24 patients with compensated cirrhosis and 20 controls. Patients with cirrhosis were older than controls (62 vs 52 years, P = 0.02) but had a similar number of extrahepatic comorbidities (2.2 vs 1.4, P = 0.13). Patients with compensated cirrhosis had lower duodenal TEER (i.e., increased epithelial permeability; 13.3 Ω/cm 2 ± 3.4 vs 18.9 Ω/cm 2 ± 7.1; P = 0.004). Patients with compensated cirrhosis trended toward a distinct mucosal microbiota community structure relative to controls ( P = 0.09). Clustering analysis identified two unique enterotypes. These enterotypes differed in bacterial composition and also TEER. A beta-binomial model found 13 individual bacteria associated with TEER, including Lactobacillus and Bifidobacterium taxa. Thirty-six taxa were associated with tight junction protein expression, including Lactobacillus and Bifidobacterium. DISCUSSION Compensated cirrhosis is characterized by increased duodenal epithelial permeability with a distinct mucosal microbial community. Intriguingly, bacteria previously associated with health were protective of duodenal permeability.
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Affiliation(s)
- P.P. Bloom
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - K. Rao
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | - C.M. Bassis
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | - S.Y. Zhou
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - B. Nojkov
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - C. Owyang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - V.B. Young
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - A.S. Lok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
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Maslennikov R, Ivashkin V, Efremova I, Poluektova E, Shirokova E. Gut-liver axis in cirrhosis: Are hemodynamic changes a missing link? World J Clin Cases 2021; 9:9320-9332. [PMID: 34877269 PMCID: PMC8610853 DOI: 10.12998/wjcc.v9.i31.9320] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/03/2021] [Accepted: 09/07/2021] [Indexed: 02/06/2023] Open
Abstract
Recent evidence suggests that the condition of the gut and its microbiota greatly influence the course of liver disease, especially cirrhosis. This introduces the concept of the gut-liver axis, which can be imagined as a chain connected by several links. Gut dysbiosis, small intestinal bacterial overgrowth, and intestinal barrier alteration lead to bacterial translocation, resulting in systemic inflammation. Systemic inflammation further causes vasodilation, arterial hypotension, and hyperdynamic circulation, leading to the aggravation of portal hypertension, which contributes to the development of complications of cirrhosis, resulting in a poorer prognosis. The majority of the data underlying this model were obtained initially from animal experiments, and most of these correlations were further reproduced in studies including patients with cirrhosis. However, despite the published data on the relationship of the disorders of the gut microbiota with the complications of cirrhosis and the proposed pathogenetic role of hemodynamic disorders in their development, the direct relations between gut dysbiosis and hemodynamic changes in this disease are poorly studied. They remain a missing link in the gut-liver axis and a challenge for future research.
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Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Interregional Public Organization "Scientific Community for the Promotion of the Clinical Study of the Human Microbiome", Moscow 119435, Russia
- Department of Internal Medicine, Consultative and Diagnostic Center of the Moscow City Health Department, Moscow 107564, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Interregional Public Organization "Scientific Community for the Promotion of the Clinical Study of the Human Microbiome", Moscow 119435, Russia
| | - Elena Shirokova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
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Hsu CF, Lin MW, Huang CC, Li TH, Liu CW, Huang SF, Yang YY, Huang YH, Hou MC, Lin HC. Roles and mechanisms of circulating CEACAM1 in the cirrhosis-related intestinal hyperpermeability: in vitro approach. J Chin Med Assoc 2021; 84:851-859. [PMID: 34261981 DOI: 10.1097/jcma.0000000000000582] [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: 11/27/2022] Open
Abstract
BACKGROUND Cirrhosis-related intestinal hyperpermeability and endotoxemia are characterized by intestinal epithelial cell apoptosis, impaired restitution (proliferation and migration), decreased tight junction protein levels, and subsequent barrier dysfunction. In addition to endotoxin and tumor necrosis factor-α (TNFα), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) plays crucial roles in the regulation of apoptosis, restitution, tight junction protein-maintained barrier function of intestinal epithelial cells. METHODS This study aims to explore the roles and underlying mechanisms of CEACAM1 in cirrhosis-related intestinal hyperpermeability through in vitro approach. RESULTS In cirrhotic patients, high serum levels of intestinal hyperpermeability (zonulin and endotoxin) markers were accompanied by elevated serum levels of TNFα and soluble CEACAM1. In in vitro experiments, we evaluated the individual and interacted roles of TNFα and human recombinant CEACAM1 (hrCEACAM1) in LC-sera (sera of cirrhotic patients)-induced intestinal hyperpermeability-related pathogenic signals. In the cell Line human from human colon (Caucasian colon adenocarcinoma) (Caco-2) cell culture, LC-sera, TNFα, and hrCEACAM1 increased apoptosis (measured by Terminal deoxynucleotidyl transferase [TdT] dUTP nick end labeling+/annexin-5+propidium iodide+ cells and caspase-3 activity), decreased restitution capacity (proliferation and migration), and disrupted tight junction protein-maintained barrier function in Caco-2 cells. The pathogenic changes mentioned above were accompanied by an increase in intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase release, and endoplasmic reticulum stress-related signals in the LC-sera or TNFα-pretreated Caco-2 cells. Concomitant incubation of Caco-2 cells with anti-CEACAM1 suppressed these LC-sera or TNFα-induced negative effects on restitution, barrier function, and cell viability. CONCLUSION This study demonstrated that sera from cirrhotic patients contain soluble CEACAM1, which is involved in the pathogenesis of intestinal hyperpermeability. Accordingly, it is noteworthy to explore the potential use of anti-CEACAM1 treatment for cirrhosis-related intestinal hyperpermeability and endotoxemia.
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Affiliation(s)
- Chien-Fu Hsu
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
| | - Ming-Wei Lin
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Preventive Medicine, Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chia-Chang Huang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Tzu-Hao Li
- Division of Preventive Medicine, Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC
| | - Chih-Wei Liu
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Allergy, Immunology and Rheumatology Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shiang-Fen Huang
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Infection, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ying-Ying Yang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, Department of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Han-Chieh Lin
- Faculty of Medicine, National Yang Ming Chiao Tung Universityl, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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10
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Cao YY, Wang ZH, Xu QC, Chen Q, Wang Z, Lu WH. Sepsis induces variation of intestinal barrier function in different phase through nuclear factor kappa B signaling. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2021; 25:375-383. [PMID: 34187954 PMCID: PMC8255122 DOI: 10.4196/kjpp.2021.25.4.375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 11/15/2022]
Abstract
The intestinal barrier function disrupted in sepsis, while little is known about the variation in different phases of sepsis. In this study, mouse models of sepsis were established by caecal ligation and puncture (CLP). The H&E staining of sections and serum diamine oxidase concentration were evaluated at different timepoint after CLP. TUNEL assay and EdU staining were performed to evaluate the apoptosis and proliferation of intestinal epithelium. Relative protein expression was assessed by Western blotting and serum concentrations of pro-inflammatory cytokines was measured by ELISA. The disruption of intestinal barrier worsened in the first 24 h after the onset of sepsis and gradually recovered over the next 24 h. The percentage of apoptotic cell increased in the first 24 h and dropped at 48 h, accompanied with the proliferative rate of intestinal epithelium inhibited in the first 6 h and regained in the later period. Furthermore, the activity of nuclear factor kappa B (NF-κB) presented similar trend with the intestinal barrier function, shared positive correction with apoptosis of intestinal epithelium. These findings reveal the conversion process of intestinal barrier function in sepsis and this process is closely correlated with the activity of NF-κB signaling.
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Affiliation(s)
- Ying-Ya Cao
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - Zhong-Han Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - Qian-Cheng Xu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - Qun Chen
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - Zhen Wang
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - Wei-Hua Lu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
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Current Status and Prospects of Spontaneous Peritonitis in Patients with Cirrhosis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3743962. [PMID: 32724800 PMCID: PMC7364234 DOI: 10.1155/2020/3743962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/03/2020] [Indexed: 12/14/2022]
Abstract
Spontaneous bacterial peritonitis (SBP) is a common cirrhotic ascites complication which exacerbates the patient's condition. SBP is caused by gram-negative bacilli and, to a lesser extent, gram-positive cocci. Hospital-acquired infections show higher levels of drug-resistant bacteria. Geographical location influences pathogenic bacteria distribution; therefore, different hospitals in the same country record different bacteria strains. Intestinal changes and a weak immune system in patients with liver cirrhosis lead to bacterial translocation thus causing SBP. Early diagnosis and timely treatment are important in SBP management. When the treatment effect is not effective, other rare pathogens should be explored.
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Ommati MM, Farshad O, Niknahad H, Mousavi K, Moein M, Azarpira N, Mohammadi H, Jamshidzadeh A, Heidari R. Oral administration of thiol-reducing agents mitigates gut barrier disintegrity and bacterial lipopolysaccharide translocation in a rat model of biliary obstruction. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2020; 1:10-18. [PMID: 34909638 PMCID: PMC8663936 DOI: 10.1016/j.crphar.2020.06.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/28/2020] [Accepted: 06/10/2020] [Indexed: 12/15/2022] Open
Abstract
It has been well documented that cirrhosis is associated with the intestinal injury. Intestinal injury in cirrhosis could lead to bacterial lipopolysaccharide (LPS) translocation to the systemic circulation. It has been found that high plasma LPS is connected with higher morbidity and mortality in cirrhotic patients. Therefore, finding therapeutic approaches to mitigate this complication has great clinical value. Several investigations mentioned the pivotal role of oxidative stress in cirrhosis-associated intestinal injury. It has been well-known that the redox balance of enterocytes is disturbed in cirrhotic patients. In the current study, the effects of thiol-reducing agents N-acetylcysteine (NAC) (0.5 and 1% w: v) and dithiothreitol (DTT) (0.5 and 1% w: v) on biomarkers of oxidative stress, tissue histopathological alterations, and LPS translocation is investigated in a rat model of cirrhosis. Bile duct ligation (BDL) surgery was used to induce cirrhosis in male Sprague-Dawley rats. Animals (n = 48; 8 animals/group) were supplemented with NAC and DTT for 28 consecutive days. Significant changes in ileum and colon markers of oxidative stress were evident in BDL rats as judged by increased reactive oxygen species (ROS), lipid peroxidation, oxidized glutathione (GSSG), and protein carbonylation along with decreased antioxidant capacity and glutathione (GSH) content. Blunted villus, decreased villus number, and inflammation was also detected in the intestine of BDL animals. Moreover, serum LPS level was also significantly higher in BDL rats. NAC and DTT administration (0.5 and 1% w: v, gavage) significantly decreased biomarkers of oxidative stress, mitigated intestinal histopathological alterations, and restored tissue antioxidant capacity. Moreover, NAC and/or DTT significantly suppressed LPS translocation to the systemic circulation. The protective effects of thiol reducing agents in the intestine of cirrhotic rats could be attributed to the effect of these chemicals on the cellular redox environment and biomarkers of oxidative stress.
Gut permeability is a clinical complication in cholestasis/cirrhosis Intestinal injury leads to lipopolysaccharide (LPS) translocation to the bloodstream LPS translocation to the systemic circulation could cause systemic inflammation Oxidative stress is involved in the mechanisms of cirrhosis-induced gut permeability Oral administration of thiol-reducing agents mitigated intestinal tissue oxidative stress Serum LPS levels were lower in thiol reducing agents-treated animals
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Affiliation(s)
- Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Omid Farshad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Khadijeh Mousavi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Marjan Moein
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamidreza Mohammadi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
- Corresponding author. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Fax: +987132424127.
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Corresponding author. Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Fax: +987132424127.
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Ke J, Bian X, Liu H, Li B, Huo R. Edaravone reduces oxidative stress and intestinal cell apoptosis after burn through up-regulating miR-320 expression. Mol Med 2019; 25:54. [PMID: 31829167 PMCID: PMC6907153 DOI: 10.1186/s10020-019-0122-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 11/21/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Intestinal mucosa barrier dysfunction after burn injury is an important factor for causing mortality of burn patients. The current study established a burn model in rats and used a free radical scavenger edaravone (ED) to treat the rats, so as to investigate the effect of edaravone on intestinal mucosa barrier after burn injury. METHODS Anesthetized rats were subjected to 40% total body surface area water burn immediately, followed by treatment with ED, scrambled antagomir, or antagomiR-320. Intestinal mucosa damage was observed by hematoxylin-eosin staining and graded by colon mucosal damage index (CMDI) score. The contents of total sulfhydryl (TSH), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) were determined by spectrophotometry. Cell apoptosis, protein relative expression,and the in situ expressions of p-Akt and p-Bad were detected by flow cytometry, Western blotting and immunohistochemistry, respectively. The miR-320 expression was determined by quantitative real-time polymerase chain reaction. RESULTS ED alleviated intestinal mucosal damage caused by burn injury, down-regulated the levels of MDA, cytochrome C, cleaved caspase-9 and cleaved caspase-3, but up-regulated the levels of TSH, SOD, CAT and Bcl-2. We also found that ED could reduce oxidative stress, inhibit cell apoptosis, increase the expressions of p-Akt, p-Bad and miR-320, and decrease PTEN expression. PTEN was predicted to be the target gene for miR-320, and cell apoptosis could be promoted by inhibiting miR-320 expression. CONCLUSION ED regulates Akt/Bad/Caspase signaling cascade to reduce apoptosis and oxidative stress through up-regulating miR-320 expression and down-regulating PTEN expression, thus protecting the intestinal mucosal barrier of rats from burn injury.
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Affiliation(s)
- Jiaxiang Ke
- Burn and Plastic Section, Qingdao Municipal Hospital Affiliated to Shandong University, Qingdao, China
| | - Xi Bian
- Burn and Plastic Section, Qingdao Municipal Hospital Affiliated to Shandong University, Qingdao, China
| | - Hu Liu
- Burn and Plastic Section, Qingdao Municipal Hospital Affiliated to Shandong University, Qingdao, China
| | - Bei Li
- Burn and Plastic Section, Qingdao Municipal Hospital Affiliated to Shandong University, Qingdao, China
| | - Ran Huo
- Burn and Plastic Section, Shandong Province Hospital Affiliated to Shandong University, Jiaozhou Road, Shibei District, Qingdao, 266011, Shandong Province, China.
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Sawada Y, Kawaratani H, Kubo T, Fujinaga Y, Furukawa M, Saikawa S, Sato S, Seki K, Takaya H, Okura Y, Kaji K, Shimozato N, Mashitani T, Kitade M, Moriya K, Namisaki T, Akahane T, Mitoro A, Yamao J, Yoshiji H. Combining probiotics and an angiotensin-II type 1 receptor blocker has beneficial effects on hepatic fibrogenesis in a rat model of non-alcoholic steatohepatitis. Hepatol Res 2019; 49:284-295. [PMID: 30365236 DOI: 10.1111/hepr.13281] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 09/28/2018] [Accepted: 10/22/2018] [Indexed: 02/08/2023]
Abstract
AIM Intestinal endotoxin is important for the progression of non-alcoholic steatohepatitis (NASH). Circulating endotoxin levels are elevated in most animal models of diet-induced non-alcoholic fatty liver disease (NAFLD) and NASH. Furthermore, plasma endotoxin levels are significantly higher in NAFLD patients, which is associated with small intestinal bacterial overgrowth and increased intestinal permeability. By improving the gut microbiota environment and restoring gut-barrier functions, probiotics are effective for NASH treatment in animal models. It is also widely known that hepatic fibrosis and suppression of activated hepatic stellate cells (Ac-HSCs) can be attenuated using an angiotensin-II type 1 receptor blocker (ARB). We thus evaluated the effect of combination probiotics and ARB treatment on liver fibrosis using a rat model of NASH. METHODS Fisher 344 rats were fed a choline-deficient/L-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. Animals were divided into ARB, probiotics, and ARB plus probiotics groups. Therapeutic efficacy was assessed by evaluating liver fibrosis, the lipopolysaccharide Toll-like receptor (TLR)4 regulatory cascade, and intestinal barrier function. RESULTS Both probiotics and ARB inhibited liver fibrosis, with concomitant HSC activation and suppression of liver-specific transforming growth factor-β and TLR4 expression. Probiotics reduced intestinal permeability by rescuing zonula occludens-1 disruption induced by the CDAA diet. Angiotensin-II type 1 receptor blocker was found to directly suppress Ac-HSCs. CONCLUSIONS Probiotics and ARB are effective in suppressing liver fibrosis through different mechanisms. Currently both drugs are in clinical use; therefore, the combination of probiotics and ARB is a promising new therapy for NASH.
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Affiliation(s)
- Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takuya Kubo
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yukihisa Fujinaga
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Masanori Furukawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Yasushi Okura
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Tsuyoshi Mashitani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Junichi Yamao
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
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15
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Antimicrobial proteins: intestinal guards to protect against liver disease. J Gastroenterol 2019; 54:209-217. [PMID: 30392013 PMCID: PMC6391196 DOI: 10.1007/s00535-018-1521-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 10/19/2018] [Indexed: 02/07/2023]
Abstract
Alterations of gut microbes play a role in the pathogenesis and progression of many disorders including liver and gastrointestinal diseases. Both qualitative and quantitative changes in gut microbiota have been associated with liver disease. Intestinal dysbiosis can disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In order to sustain symbiosis and protect from pathological bacterial translocation, antimicrobial proteins (AMPs) such as a-defensins and C-type lectins are expressed in the gastrointestinal tract. In this review, we provide an overview of the role of AMPs in different chronic liver disease such as alcoholic steatohepatitis, non-alcoholic fatty liver disease, and cirrhosis. In addition, potential approaches to modulate the function of AMPs and prevent bacterial translocation are discussed.
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16
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Meng X, Li S, Li Y, Gan RY, Li HB. Gut Microbiota's Relationship with Liver Disease and Role in Hepatoprotection by Dietary Natural Products and Probiotics. Nutrients 2018; 10:E1457. [PMID: 30297615 PMCID: PMC6213031 DOI: 10.3390/nu10101457] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 09/17/2018] [Accepted: 09/26/2018] [Indexed: 12/14/2022] Open
Abstract
A variety of dietary natural products have shown hepatoprotective effects. Increasing evidence has also demonstrated that gut microorganisms play an important role in the hepatoprotection contributed by natural products. Gut dysbiosis could increase permeability of the gut barrier, resulting in translocated bacteria and leaked gut-derived products, which can reach the liver through the portal vein and might lead to increased oxidative stress and inflammation, thereby threatening liver health. Targeting gut microbiota modulation represents a promising strategy for hepatoprotection. Many natural products could protect the liver from various injuries or mitigate hepatic disorders by reverting gut dysbiosis, improving intestinal permeability, altering the primary bile acid, and inhibiting hepatic fatty acid accumulation. The mechanisms underlying their beneficial effects also include reducing oxidative stress, suppressing inflammation, attenuating fibrosis, and decreasing apoptosis. This review discusses the hepatoprotective effects of dietary natural products via modulating the gut microbiota, mainly focusing on the mechanisms of action.
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Affiliation(s)
- Xiao Meng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 999077, China.
| | - Ya Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
| | - Ren-You Gan
- Department of Food Science & Technology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Hua-Bin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangdong Engineering Technology Research Center of Nutrition Translation, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
- South China Sea Bioresource Exploitation and Utilization Collaborative Innovation Center, Sun Yat-sen University, Guangzhou 510006, China.
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17
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Utsunomiya H, Yamamoto Y, Takeshita E, Tokumoto Y, Tada F, Miyake T, Hirooka M, Abe M, Kumagi T, Matsuura B, Ikeda Y, Hiasa Y. Upregulated absorption of dietary palmitic acids with changes in intestinal transporters in non-alcoholic steatohepatitis (NASH). J Gastroenterol 2017; 52:940-954. [PMID: 28062946 DOI: 10.1007/s00535-016-1298-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 12/14/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Palmitic acid is an important risk factor for the pathogenesis of non-alcoholic steatohepatitis (NASH), but changes in palmitic acid intestinal absorption in NASH are unclear. The aim of this study was to clarify changes in palmitic acid intestinal absorption and their association with the pathogenesis of NASH. METHODS A total of 106 participants were recruited to the study, of whom 33 were control subjects (control group), 32 were patients with NASH Brunt stage 1-2 [early NASH (e-NASH)], and 41 were patients with NASH Brunt stage 3-4 [advanced NASH (a-NASH)]. 13C-labeled palmitate was administered directly into the duodenum of all participants by gastrointestinal endoscopy. Breath 13CO2 levels were measured to quantify palmitic acid absorption, and serum Apolipoprotein B-48 (ApoB-48) concentrations were measured after a test meal to quantify absorbed chylomicrons. Expressions of fatty acid (FA) transporters were also examined. The associations of breath 13CO2 levels with hepatic steatosis, fibrosis and insulin resistance was evaluated using laboratory data, elastography results and liver histology findings. RESULTS Overall, 13CO2 excretion was significantly higher in e-NASH patients than in the control subjects and a-NASH patients (P < 0.01). e-NASH patients had higher serum ApoB-48 levels, indicating increased palmitic acid transport via chylomicrons in these patients. Jejunal mRNA and protein expressions of microsomal triglyceride transfer protein and cluster of differentiation 36 were also increased in both NASH patient groups. The 13CO2 excretion of e-NASH patients was significantly correlated with the degree of hepatic steatosis, fibrosis and insulin resistance (P = 0.005, P < 0.001, P = 0.019, respectively). CONCLUSIONS Significantly upregulated palmitic acid absorption by activation of its transporters was evident in patients with NASH, and clinical progression of NASH was related to palmitic acid absorption. These dietary changes are associated with the onset and progression of NASH.
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Affiliation(s)
- Hiroki Utsunomiya
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Eiji Takeshita
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Fujimasa Tada
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Teru Kumagi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Bunzo Matsuura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoshio Ikeda
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
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18
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Pijls KE, Jonkers DMAE, Elizalde M, Drittij-Reijnders MJ, Haenen GR, Bast A, Masclee AAM, Koek GH. Is intestinal oxidative stress involved in patients with compensated liver cirrhosis? Ann Hepatol 2017; 15:402-9. [PMID: 27049494 DOI: 10.5604/16652681.1198816] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Liver cirrhosis is associated with intestinal epithelial barrier dysfunction, which may be affected by oxidative stress. Studies in cirrhotic rats provided evidence for intestinal oxidative stress, but studies in cirrhotic patients are scarce. We have shown intestinal barrier dysfunction in patients with compensated cirrhosis. AIM The present study aimed to investigate whether oxidative stress occurs in the intestinal mucosa of compensated cirrhotic patients and may contribute to barrier dysfunction. MATERIAL AND METHODS Oxidative stress was studied in duodenal and sigmoid biopsies from 15 cirrhotic patients and 22 controls by analyzing transcription of genes involved in glutathione and uric acid metabolism using quantitative real-time polymerase chain reaction. Protein levels of glutathione and glutathione disulphide were measured and the glutathione/glutathione disulphide ratio was calculated as marker of oxidative stress. In addition, intestinal myeloperoxidase and fecal calprotectin were determined. RESULTS Gene transcription of glutathione synthetase and glutathione reductase were significantly different in duodenal and sigmoid biopsies of cirrhotic patients vs. controls, but no alterations were found for other genes nor for glutathione, glutathione disulphide, glutathione/glutathione disulphide ratio and intestinal myeloperoxidase and fecal calprotectin concentrations. CONCLUSION This study did not find indications for oxidative stress and low-grade inflammation in the small and large intestine of stable compensated cirrhotic patients. Although these preliminary findings need further validation, we found intestinal oxidative stress not to be a major mechanism contributing to epithelial barrier dysfunction in patients with compensated cirrhosis.
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Affiliation(s)
- Kirsten E Pijls
- Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
| | - Daisy M A E Jonkers
- Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
| | - Montserrat Elizalde
- Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
| | - Marie-Jose Drittij-Reijnders
- Department of Toxicology, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
| | - Guido R Haenen
- Department of Toxicology, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
| | - Aalt Bast
- Department of Toxicology, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
| | - Ad A M Masclee
- Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
| | - Ger H Koek
- Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, the Netherlands; School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Center, the Netherlands
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Bihari C, Anand L, Rooge S, Kumar D, Saxena P, Shubham S, Sukriti, Trehanpati N, Kumar G, Pamecha V, Sharma S, Rastogi A, Kumar A, Sarin SK. Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver. Hepatology 2016; 64:1273-88. [PMID: 27486864 DOI: 10.1002/hep.28754] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 07/10/2016] [Indexed: 12/13/2022]
Abstract
UNLABELLED Bone marrow (BM) is a reservoir for immune and hematopoietic cells and critical for tissue repair and regeneration. All of these functions are severely altered in cirrhosis. We investigated the cellular and functional state of BM in cirrhosis patients. We studied the histological, cellular, and molecular changes in BM of cirrhosis patients (n = 168) and controls (n = 44). Hematopoietic stem cells (HSCs) and associated niche cells, mesenchymal stem cells, Schwann cells, neural fibers, and endothelial cells were evaluated by immunohistochemistry. Cytokines and growth factors were analyzed in peripheral blood and BM plasma. Cirrhotic BM showed an inverse correlation between cluster of differentiation 34+HSCs and Model of End-Stage Liver Disease (ρ = -0.582, P < 0.001) and Child's scores (P < 0.038). BMs of cirrhosis patients with higher Model of End-Stage Liver Disease (>15) showed significantly decreased HSCs, mesenchymal stem cells, Schwann cells, and neural fibers; increased interleukin-1β (P = 0.004), tumor necrosis factor-α (P = 0.040), and interferon-γ (P = 0.03); and decreased oncostatin M (P = 0.04), stem cell factor (P = 0.05), and stromal cell-derived factor 1 (P = 0.03) compared to those with lower Model of End-Stage Liver Disease scores (≤15). The cluster of differentiation 34+ cell population was a predictor for the development of sepsis (P < 0.001), and per unit loss increased the probability of sepsis by 16%. Cirrhosis patients with fewer HSCs had lower hemoglobin (P = 0.05) and platelet counts (P = 0.05) and showed early graft dysfunction. CONCLUSIONS Increasing severity of cirrhosis causes derangement of the hematopoietic niche and loss of HSCs, contributing to the hematological and immunological dysfunctions and reduced potential for regeneration; restoring BM functions could provide new therapeutic options in cirrhosis. (Hepatology 2016;64:1273-1288).
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Affiliation(s)
- Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Lovkesh Anand
- Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Sheetalnath Rooge
- Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India
| | - Dhananjay Kumar
- Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India
| | - Priyanka Saxena
- Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Smriti Shubham
- Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India
| | - Sukriti
- Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India
| | - Nirupma Trehanpati
- Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India
| | - Guresh Kumar
- Department of Clinical Research, Institute of Liver and Biliary Sciences, Delhi, India
| | - Viniyendra Pamecha
- Department of Liver Transplant & Hepato-pancreatico-biliary Surgery, Institute of Liver and Biliary Sciences, Delhi, India
| | - Shvetank Sharma
- Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India
| | - Anupam Kumar
- Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India. .,Department of Research (Cellular and Molecular Medicine), Institute of Liver and Biliary Sciences, Delhi, India.
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Varma MC, Kusminski CM, Azharian S, Gilardini L, Kumar S, Invitti C, McTernan PG. Metabolic endotoxaemia in childhood obesity. BMC OBESITY 2016; 3:3. [PMID: 26819711 PMCID: PMC4728817 DOI: 10.1186/s40608-016-0083-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 01/19/2016] [Indexed: 12/26/2022]
Abstract
Background Childhood obesity is associated with chronic low-grade inflammation considered as a precursor to metabolic disease; however, the underlying mechanisms for this remain unclear. Studies in adults have implicated gut derived gram-negative bacterial fragments known as lipopolysaccharide or endotoxin, activating the inflammatory response, whilst the importance in childhood obesity is unclear. The aim of this research is to understand the relationship between circulating endotoxin in childhood obesity, and its’ association with inflammatory and cardiovascular (CV) injury biomarkers. Methods Fasted blood was obtained from children with varying degrees of obesity (age: 13.9 ± 2.3Yr; BMI: 35.1 ± 5.2 Kg/m2; n = 60). Multiplex CVD biomarker immunoassays were used to determine systemic levels of inflammatory and vascular injury biomarkers, such as tumour necrosis factor-α (TNF-α), interleukin (IL-) 1β, 6, 8 and 10, plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule type-1 (sICAM-1), matrix metalloproteinase-9 (MMP-9), myeloperoxidase (MPO) and vascular endothelial growth factor (VEGF) as well as endotoxin levels. Results Endotoxin levels demonstrated a significant and positive correlation with the markers for inflammation, vascular injury and atherogenesis (TNF-α: r2 = 0.077, p < 0.05; PAI-1: r2 = 0.215, p < 0.01; sICAM-1: r2 = 0.159, p < 0.01; MMP-9: r2 = 0.159, p < 0.01; MPO: r2 = 0.07, p < 0.05; VEGF: r2 = 0.161, p < 0.01). Males demonstrated significantly higher circulating endotoxin than females (Males: 9.63 ± 5.34 EU/ml; p = 0.004; Females: 5.56 ± 4.06 EU/ml; n = 60) in these BMI and age-matched cohorts. Conclusion The present study demonstrates for the first time a significant association between circulating endotoxin and biomarkers of metabolic risk in children as young as 11 years. Thus, endotoxin-mediated sub-clinical inflammation during childhood obesity may be a key contributor to T2DM and CVD development later in life.
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Affiliation(s)
- Madhusudhan C Varma
- Division of Biomedical sciences,, Warwick Medical School, University of Warwick, UHCW Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX UK
| | - Christine M Kusminski
- Division of Biomedical sciences,, Warwick Medical School, University of Warwick, UHCW Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX UK
| | - Sahar Azharian
- Division of Biomedical sciences,, Warwick Medical School, University of Warwick, UHCW Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX UK
| | - Luisa Gilardini
- Department of Medical Sciences & Rehabilitation, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy
| | - Sudhesh Kumar
- Division of Biomedical sciences,, Warwick Medical School, University of Warwick, UHCW Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX UK
| | - Cecilia Invitti
- Department of Medical Sciences & Rehabilitation, IRCCS Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy
| | - Philip G McTernan
- Division of Biomedical sciences,, Warwick Medical School, University of Warwick, UHCW Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX UK
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Liu Y, Ye F, Zou WJ, Sun Y, Wang R, Han PP, Zhang Z, Yang XL, Liu X. Baicalein reduces the occurrence of cirrhotic endotoxemia by reducing intestinal mucosal apoptosis. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 15:161. [PMID: 26021373 PMCID: PMC4448291 DOI: 10.1186/s12906-015-0682-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2015] [Accepted: 05/20/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND The dried roots of Scutellaria baicalensis Georgi, is known in traditional Chinese medicine as Huang Qin (H. qin), and it has been officially and traditionally used in treatment of various diseases such as hepatitis in China. Baicalein (BA), a flavonoid originally isolated from H. qin, has shown a wide range of biological activities. This study was to evaluate whether baicalein, can reduce the intestinal mucosal cell apoptosis caused by cirrhotic endotoxemia and its possible mechanisms. METHODS For this purpose, compound factors modeling was used to establish endotoxemic cirrhotic rat model. Firstly, we evaluated endotoxin, ALT, AST and TBIL levels after the baicalein treatment (20 mg/kg, i.v.). To investigate the mechanism of baicalein effect on apoptosis, TUNEL assay was used to detect intestinal mucosal apoptosis. RT-PCR was used to detect the expression levels of gene Bcl-2 mRNA and Bax mRNA in intestinal mucosal tissues. Caspase-3 activity of intestinal tissue was detected with colorimetric method in our experiments. RESULTS After treatment with BA, the serum endotoxin concentration, the intestinal mucosal apoptosis rate and the activity of caspase-3 of the baicalein group were significantly lower than that of the model and the glutamine group. The serum ALT, AST and TBIL concentration of the BA group were significantly lower than that of the model group. The body weight of the baicalein group was significantly lower than that of the normal group, but it was higher than that of the model group. Among the treatment groups, the mRNA level of anti-apoptotic gene Bcl-2 was the lowest in the model group and the highest in the baicalein group while the mRNA level of pro-apoptotic gene Bax was the lowest in the baicalein group and the highest in the model group. CONCLUSION The present results demonstrated that baicalein could reduce the occurrence of cirrhotic endotoxemia partly by reducing intestinal mucosal apoptosis.
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DOUHARA AKITOSHI, MORIYA KEI, YOSHIJI HITOSHI, NOGUCHI RYUICHI, NAMISAKI TADASHI, KITADE MITSUTERU, KAJI KOSUKE, AIHARA YOSUKE, NISHIMURA NORIHISA, TAKEDA KOSUKE, OKURA YASUSHI, KAWARATANI HIDETO, FUKUI HIROSHI. Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat non-alcoholic steatohepatitis model. Mol Med Rep 2015; 11:1693-1700. [PMID: 25421042 PMCID: PMC4270343 DOI: 10.3892/mmr.2014.2995] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 11/05/2014] [Indexed: 02/07/2023] Open
Abstract
Previous clinical studies have demonstrated that endotoxin/toll‑like receptor 4 (TLR4) signaling is critical in the inflammatory pathways associated with non‑alcoholic steatohepatitis (NASH). In human and animal studies, NASH was associated with portal lipopolysaccharide (LPS) and the plasma LPS level was hypothesized to be associated with small intestinal bacterial overgrowth, change in composition of the microbiota and increased intestinal permeability. The aim of the present study was to investigate the roles of endogenous endotoxin and TLR4 in the pathogenesis of NASH. The effects of antibiotics were assessed in vivo using a choline deficiency amino acid (CDAA)‑induced experimental liver fibrosis model. Antibiotics, including polymyxins and neomycins, were orally administered in drinking water. Antibiotics attenuated hepatic stellate cell (HSC) activation and liver fibrosis via TGF‑β and collagen in an experimental hepatic fibrosis model. The mechanism by which antibiotics attenuated LPS‑TLR4 signaling and liver fibrosis was assessed. Notably, TLR4 mRNA level in the liver was elevated in the CDAA group and the CDAA‑induced increase was significantly reduced by antibiotics. However, no significant differences were observed in the intestine among all groups. Elevated mRNA levels of LPS binding protein, which was correlated with serum endotoxin levels, were recognized in the CDAA group and the CDAA‑induced increase was significantly reduced by antibiotics. The intestinal permeability of the CDAA group was increased compared with the choline‑supplemented amino acid group. The tight junction protein (TJP) in the intestine, determined by immunohistochemical analysis was inversely associated with intestinal permeability. Antibiotics improved the intestinal permeability and enhanced TJP expression. Inhibition of LPS‑TLR4 signaling with antibiotics attenuated liver fibrosis development associated with NASH via the inhibition of HSC activation. These results indicated that reduction of LPS and restoration of intestinal TJP may be a novel therapeutic strategy for treatment of liver fibrosis development in NASH.
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Affiliation(s)
- AKITOSHI DOUHARA
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - KEI MORIYA
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - HITOSHI YOSHIJI
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - RYUICHI NOGUCHI
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - TADASHI NAMISAKI
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - MITSUTERU KITADE
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - KOSUKE KAJI
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - YOSUKE AIHARA
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - NORIHISA NISHIMURA
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - KOSUKE TAKEDA
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - YASUSHI OKURA
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - HIDETO KAWARATANI
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - HIROSHI FUKUI
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
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Verschoor CP, Naidoo A, Wallace JG, Johnstone J, Loeb M, Bramson JL, Bowdish DME. Circulating Muramyl Dipeptide Is Negatively Associated with Interleukin-10 in the Frail Elderly. Inflammation 2014; 38:272-7. [DOI: 10.1007/s10753-014-0030-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Sheen JM, Chen YC, Tain YL, Huang LT. Increased circulatory asymmetric dimethylarginine and multiple organ failure: bile duct ligation in rat as a model. Int J Mol Sci 2014; 15:3989-4006. [PMID: 24603538 PMCID: PMC3975379 DOI: 10.3390/ijms15033989] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 02/04/2014] [Accepted: 02/26/2014] [Indexed: 02/06/2023] Open
Abstract
Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher plasma and hepatic ADMA levels, which may be due to increased hepatic protein arginine methyltransferase-1 and decreased dimethylarginine dimethylaminohydrolase expression. BDL rats also exhibit renal and brain damage characterized by increased tissue ADMA concentrations. The increased plasma ADMA levels and multiple organ damages seen here are also observed following multiple organ failures associated with critical illness. This review discusses the dysregulation of ADMA in major organs in BDL rats and the role of increased ADMA in multiple organ damages.
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Affiliation(s)
- Jiunn-Ming Sheen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Yu-Chieh Chen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Li-Tung Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
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