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1
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Kronsten VT, Shawcross DL. Clinical Implications of Inflammation in Patients With Cirrhosis. Am J Gastroenterol 2025; 120:65-74. [PMID: 39194320 PMCID: PMC11676607 DOI: 10.14309/ajg.0000000000003056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.
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Affiliation(s)
- Victoria T. Kronsten
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
| | - Debbie L. Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
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2
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Gallego-Durán R, Hadjihambi A, Ampuero J, Rose CF, Jalan R, Romero-Gómez M. Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 2024; 21:774-791. [PMID: 39251708 DOI: 10.1038/s41575-024-00970-9] [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] [Accepted: 07/24/2024] [Indexed: 09/11/2024]
Abstract
Ammonia levels are orchestrated by a series of complex interrelated pathways in which the urea cycle has a central role. Liver dysfunction leads to an accumulation of ammonia, which is toxic and is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation, hypoxaemia and dysregulation of neurotransmission. Hyperammonaemia is a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure. In addition to the established role of ammonia as a neurotoxin in the pathogenesis of hepatic encephalopathy, an increasing number of studies suggest that it can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction and cancer. However, elevated systemic ammonia levels are uncommon in patients with metabolic dysfunction-associated steatotic liver disease. A clear causal relationship between ammonia-induced immune dysfunction and risk of infection has not yet been definitively proven. In this Review, we discuss the mechanisms by which ammonia produces its diverse deleterious effects and their clinical relevance in liver diseases, the importance of measuring ammonia levels for the diagnosis of hepatic encephalopathy, the prognosis of patients with cirrhosis and liver failure, and how our knowledge of inter-organ ammonia metabolism is leading to the development of novel therapeutic approaches.
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Affiliation(s)
- Rocío Gallego-Durán
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Anna Hadjihambi
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Javier Ampuero
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Rajiv Jalan
- Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London, UK
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Manuel Romero-Gómez
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
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3
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Incicco S, Angeli P, Piano S. Infectious Complications of Portal Hypertension. Clin Liver Dis 2024; 28:525-539. [PMID: 38945641 DOI: 10.1016/j.cld.2024.03.007] [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] [Indexed: 07/02/2024]
Abstract
Patients with cirrhosis and clinically significant portal hypertension are at high risk of developing bacterial infections (BIs) that are the most common trigger of acute decompensation and acute-on-chronic liver failure. Furthermore, after decompensation, the risk of developing BIs further increases in an ominous vicious circle. BIs may be subtle, and they should be ruled out in all patients at admission and in case of deterioration. Timely administration of adequate empirical antibiotics is the cornerstone of treatment. Herein, we reviewed current evidences about pathogenesis, clinical implications and management of BIs in patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Simone Incicco
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy.
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4
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Oyelade T, Moore KP, Mani AR. Physiological network approach to prognosis in cirrhosis: A shifting paradigm. Physiol Rep 2024; 12:e16133. [PMID: 38961593 PMCID: PMC11222171 DOI: 10.14814/phy2.16133] [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: 04/30/2024] [Revised: 06/12/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024] Open
Abstract
Decompensated liver disease is complicated by multi-organ failure and poor prognosis. The prognosis of patients with liver failure often dictates clinical management. Current prognostic models have focused on biomarkers considered as individual isolated units. Network physiology assesses the interactions among multiple physiological systems in health and disease irrespective of anatomical connectivity and defines the influence or dependence of one organ system on another. Indeed, recent applications of network mapping methods to patient data have shown improved prediction of response to therapy or prognosis in cirrhosis. Initially, different physical markers have been used to assess physiological coupling in cirrhosis including heart rate variability, heart rate turbulence, and skin temperature variability measures. Further, the parenclitic network analysis was recently applied showing that organ systems connectivity is impaired in patients with decompensated cirrhosis and can predict mortality in cirrhosis independent of current prognostic models while also providing valuable insights into the associated pathological pathways. Moreover, network mapping also predicts response to intravenous albumin in patients hospitalized with decompensated cirrhosis. Thus, this review highlights the importance of evaluating decompensated cirrhosis through the network physiologic prism. It emphasizes the limitations of current prognostic models and the values of network physiologic techniques in cirrhosis.
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Affiliation(s)
- Tope Oyelade
- Institute for Liver and Digestive Health, Division of MedicineUCLLondonUK
- Network Physiology Laboratory, Division of MedicineUCLLondonUK
| | - Kevin P. Moore
- Institute for Liver and Digestive Health, Division of MedicineUCLLondonUK
| | - Ali R. Mani
- Institute for Liver and Digestive Health, Division of MedicineUCLLondonUK
- Network Physiology Laboratory, Division of MedicineUCLLondonUK
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5
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Sriram S, Carstens K, Dewing W, Fiacco TA. Astrocyte regulation of extracellular space parameters across the sleep-wake cycle. Front Cell Neurosci 2024; 18:1401698. [PMID: 38988660 PMCID: PMC11233815 DOI: 10.3389/fncel.2024.1401698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/07/2024] [Indexed: 07/12/2024] Open
Abstract
Multiple subfields of neuroscience research are beginning to incorporate astrocytes into current frameworks of understanding overall brain physiology, neuronal circuitry, and disease etiology that underlie sleep and sleep-related disorders. Astrocytes have emerged as a dynamic regulator of neuronal activity through control of extracellular space (ECS) volume and composition, both of which can vary dramatically during different levels of sleep and arousal. Astrocytes are also an attractive target of sleep research due to their prominent role in the glymphatic system, a method by which toxic metabolites generated during wakefulness are cleared away. In this review we assess the literature surrounding glial influences on fluctuations in ECS volume and composition across the sleep-wake cycle. We also examine mechanisms of astrocyte volume regulation in glymphatic solute clearance and their role in sleep and wake states. Overall, findings highlight the importance of astrocytes in sleep and sleep research.
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Affiliation(s)
- Sandhya Sriram
- Interdepartmental Graduate Program in Neuroscience, University of California, Riverside, Riverside, CA, United States
- Department of Biochemistry and Molecular Biology, University of California, Riverside, Riverside, CA, United States
| | - Kaira Carstens
- Department of Biochemistry and Molecular Biology, University of California, Riverside, Riverside, CA, United States
| | - Wayne Dewing
- Undergraduate Major in Neuroscience, University of California, Riverside, Riverside, CA, United States
| | - Todd A Fiacco
- Interdepartmental Graduate Program in Neuroscience, University of California, Riverside, Riverside, CA, United States
- Department of Biochemistry and Molecular Biology, University of California, Riverside, Riverside, CA, United States
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Milewski K, Orzeł-Gajowik K, Zielińska M. Mitochondrial Changes in Rat Brain Endothelial Cells Associated with Hepatic Encephalopathy: Relation to the Blood-Brain Barrier Dysfunction. Neurochem Res 2024; 49:1489-1504. [PMID: 35917006 PMCID: PMC11106209 DOI: 10.1007/s11064-022-03698-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 02/17/2022] [Accepted: 07/14/2022] [Indexed: 12/06/2022]
Abstract
The mechanisms underlying cerebral vascular dysfunction and edema during hepatic encephalopathy (HE) are unclear. Blood-brain barrier (BBB) impairment, resulting from increased vascular permeability, has been reported in acute and chronic HE. Mitochondrial dysfunction is a well-documented result of HE mainly affecting astrocytes, but much less so in the BBB-forming endothelial cells. Here we review literature reports and own experimental data obtained in HE models emphasizing alterations in mitochondrial dynamics and function as a possible contributor to the status of brain endothelial cell mitochondria in HE. Own studies on the expression of the mitochondrial fusion-fission controlling genes rendered HE animal model-dependent effects: increase of mitochondrial fusion controlling genes opa1, mfn1 in cerebral vessels in ammonium acetate-induced hyperammonemia, but a decrease of the two former genes and increase of fis1 in vessels in thioacetamide-induced HE. In endothelial cell line (RBE4) after 24 h ammonia and/or TNFα treatment, conditions mimicking crucial aspects of HE in vivo, we observed altered expression of mitochondrial fission/fusion genes: a decrease of opa1, mfn1, and, increase of the fission related fis1 gene. The effect in vitro was paralleled by the generation of reactive oxygen species, decreased total antioxidant capacity, decreased mitochondrial membrane potential, as well as increased permeability of RBE4 cell monolayer to fluorescein isothiocyanate dextran. Electron microscopy documented enlarged mitochondria in the brain endothelial cells of rats in both in vivo models. Collectively, the here observed alterations of cerebral endothelial mitochondria are indicative of their fission, and decreased potential of endothelial mitochondria are likely to contribute to BBB dysfunction in HE.
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Affiliation(s)
- Krzysztof Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.
| | - Karolina Orzeł-Gajowik
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.
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7
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Pierzchala K, Hadjihambi A, Mosso J, Jalan R, Rose CF, Cudalbu C. Lessons on brain edema in HE: from cellular to animal models and clinical studies. Metab Brain Dis 2024; 39:403-437. [PMID: 37606786 PMCID: PMC10957693 DOI: 10.1007/s11011-023-01269-5] [Citation(s) in RCA: 4] [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: 03/09/2023] [Accepted: 07/24/2023] [Indexed: 08/23/2023]
Abstract
Brain edema is considered as a common feature associated with hepatic encephalopathy (HE). However, its central role as cause or consequence of HE and its implication in the development of the neurological alterations linked to HE are still under debate. It is now well accepted that type A and type C HE are biologically and clinically different, leading to different manifestations of brain edema. As a result, the findings on brain edema/swelling in type C HE are variable and sometimes controversial. In the light of the changing natural history of liver disease, better description of the clinical trajectory of cirrhosis and understanding of molecular mechanisms of HE, and the role of brain edema as a central component in the pathogenesis of HE is revisited in the current review. Furthermore, this review highlights the main techniques to measure brain edema and their advantages/disadvantages together with an in-depth description of the main ex-vivo/in-vivo findings using cell cultures, animal models and humans with HE. These findings are instrumental in elucidating the role of brain edema in HE and also in designing new multimodal studies by performing in-vivo combined with ex-vivo experiments for a better characterization of brain edema longitudinally and of its role in HE, especially in type C HE where water content changes are small.
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Affiliation(s)
- Katarzyna Pierzchala
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland.
- Animal Imaging and Technology, EPFL, Lausanne, Switzerland.
| | - Anna Hadjihambi
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Jessie Mosso
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, EPFL, Lausanne, Switzerland
- Laboratory for Functional and Metabolic Imaging (LIFMET), EPFL, Lausanne, Switzerland
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain
| | - Christopher F Rose
- Hépato-Neuro Laboratory, Centre de Recherche du Centre Hospitalier de l', Université de Montréal (CRCHUM), Montreal, QC, H2X 0A9, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, QC, Montreal, H3T 1J4, Canada
| | - Cristina Cudalbu
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland.
- Animal Imaging and Technology, EPFL, Lausanne, Switzerland.
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8
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Bloom PP, Tapper EB. Lactulose in cirrhosis: Current understanding of efficacy, mechanism, and practical considerations. Hepatol Commun 2023; 7:e0295. [PMID: 37820287 PMCID: PMC10578757 DOI: 10.1097/hc9.0000000000000295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/04/2023] [Indexed: 10/13/2023] Open
Abstract
HE is a complication of cirrhosis characterized by neuropsychiatric and motor dysfunction, and results in decreased quality of life and increased mortality. Lactulose is a synthetic disaccharide used to treat HE since 1966, though many questions about its use remain unanswered. Lactulose reverses minimal HE, prevents overt HE, improves quality of life, increases the rate of recovery from overt HE, and improves survival rates. Lactulose's clinical effect appears to be derived from its impact on intestinal microbes, likely a result of its enteric acidifying effect, positive pressure on beneficial taxa, and improvement of gut barrier function. There are several practical considerations with lactulose including (1) a need to avoid excessive bowel movements and subsequent dehydration, (2) treatment titration protocols need further investigation, (3) baseline or treatment-induced gastrointestinal side effects limit adherence in some cases, and (4) the utility of monitoring stool consistency or pH remains unknown. Further research is needed to optimize our use of this effective treatment for HE.
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Tu H, Liu R, Zhang A, Yang S, Liu C. Risk factors for the mortality of hepatitis B virus-associated acute-on-chronic liver failure: a systematic review and meta-analysis. BMC Gastroenterol 2023; 23:342. [PMID: 37789279 PMCID: PMC10548554 DOI: 10.1186/s12876-023-02980-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 09/27/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) has been confirmed as a prevalent form of end-stage liver disease in people subjected to chronic HBV infection. However, there has been rare in-depth research on the risk factors for the mortality of HBV-ACLF. This study aimed at determining the risk factors for the mortality of HBV-ACLF. METHODS The relevant research was selected from four electronic databases that have been published as of August 2023. The existing research was reviewed in accordance with the inclusion and exclusion criteria. The level of quality of previous research was evaluated using the Newcastle-Ottawa scale. Moreover, a pooled estimate of the odds ratios (ORs) with their associated 95% confidence intervals (CIs) was provided through a meta-analysis. The data were combined, and the risk variables that at least two studies had considered were analyzed. The publication bias was examined through Egger's test and Begg's test. RESULTS Twenty two studies that conformed to the inclusion criteria were selected from 560 trials. Eight risk variables in terms of HBV-ACLF mortality were determined, which covered INR (OR = 1.923, 95% CI = 1.664-2.221, P < 0.001), Monocytes (OR = 1.201, 95% CI = 1.113-1.296, P < 0.001), Cirrhosis (OR = 1.432, 95% CI = 1.210-1.696, P < 0.001), HE (OR = 2.553, 95% CI = 1.968-3.312, P < 0.001), HE grade (OR = 2.059, 95% CI = 1.561-2.717, P < 0.001), SBP (OR = 1.383, 95% CI = 1.080-1.769, P = 0.010), Hyponatremia (OR = 1.941, 95% CI = 1.614-2.334, P < 0.001), as well as HRS (OR = 2.610, 95% CI = 1.669-4.080, P < 0.001). CONCLUSION The most significant risk factors for HBV-ACLF mortality comprise HRS, HE, and HE grade, followed by INR and hyponatremia. The Monocytes, cirrhosis, and SBP have been confirmed as the additional key risk factors for HBV-ACLF mortality.
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Affiliation(s)
- Hanyun Tu
- School of Medicine, Jinan University, Guangzhou, 510632, China.
| | - Rong Liu
- Sichuan Institute of Product Quality Supervision and Inspection, Chengdu, 610100, China
| | - Anni Zhang
- School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Sufei Yang
- Department of Cardiology, Daping Hospital, Army Medical University), Third Military Medical University, Chongqing, 400042, China
| | - Chengjiang Liu
- Department of General Medicine, Affiliated Anqing First People's Hospital of Anhui Medical University, Anqing, 246004, China
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Di Vincenzo F, Nicoletti A, Negri M, Vitale F, Zileri Dal Verme L, Gasbarrini A, Ponziani FR, Cerrito L. Gut Microbiota and Antibiotic Treatments for the Main Non-Oncologic Hepato-Biliary-Pancreatic Disorders. Antibiotics (Basel) 2023; 12:1068. [PMID: 37370387 DOI: 10.3390/antibiotics12061068] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/10/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
The gut microbiota is a pivotal actor in the maintenance of the balance in the complex interconnections of hepato-biliary-pancreatic system. It has both metabolic and immunologic functions, with an influence on the homeostasis of the whole organism and on the pathogenesis of a wide range of diseases, from non-neoplastic ones to tumorigenesis. The continuous bidirectional metabolic communication between gut and hepato-pancreatic district, through bile ducts and portal vein, leads to a continuous interaction with translocated bacteria and their products. Chronic liver disease and pancreatic disorders can lead to reduced intestinal motility, decreased bile acid synthesis and intestinal immune dysfunction, determining a compositional and functional imbalance in gut microbiota (dysbiosis), with potentially harmful consequences on the host's health. The modulation of the gut microbiota by antibiotics represents a pioneering challenge with striking future therapeutic opportunities, even in non-infectious diseases. In this setting, antibiotics are aimed at harmonizing gut microbial function and, sometimes, composition. A more targeted and specific approach should be the goal to pursue in the future, tailoring the treatment according to the type of microbiota modulation to be achieved and using combined strategies.
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Affiliation(s)
- Federica Di Vincenzo
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Alberto Nicoletti
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Marcantonio Negri
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Federica Vitale
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Lorenzo Zileri Dal Verme
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Lucia Cerrito
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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11
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Sepehrinezhad A, Stolze Larsen F, Ashayeri Ahmadabad R, Shahbazi A, Sahab Negah S. The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review. Cells 2023; 12:cells12070979. [PMID: 37048052 PMCID: PMC10093707 DOI: 10.3390/cells12070979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, 999017 Copenhagen, Denmark
| | | | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1449614535, Iran
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12
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Zhai H, Zhang J, Shang D, Zhu C, Xiang X. The progress to establish optimal animal models for the study of acute-on-chronic liver failure. Front Med (Lausanne) 2023; 10:1087274. [PMID: 36844207 PMCID: PMC9947362 DOI: 10.3389/fmed.2023.1087274] [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: 11/02/2022] [Accepted: 01/23/2023] [Indexed: 02/11/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) defines a complicated and multifaceted syndrome characterized by acute liver dysfunction following an acute insult on the basis of chronic liver diseases. It is usually concurrent with bacterial infection and multi-organ failure resulting in high short-term mortality. Based on the cohort studies in ACLF worldwide, the clinical course of ACLF was demonstrated to comprise three major stages including chronic liver injury, acute hepatic/extrahepatic insult, and systemic inflammatory response caused by over-reactive immune system especially bacterial infection. However, due to the lack of optimal experimental animal models for ACLF, the progress of basic study on ACLF is limping. Though several experimental ACLF models were established, none of them can recapitulate and simulate the whole pathological process of ACLF patients. Recently, we have developed a novel mouse model for ACLF combining chronic liver injury [injection of carbon tetrachloride (CCl4) for 8 weeks], acute hepatic insult (injection of a double dose CCl4), and bacterial infection (intraperitoneal injection of Klebsiella pneumoniae), which could recapitulate the major clinical features of patients with ACLF worsened by bacterial infection.
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Affiliation(s)
- Hengben Zhai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinming Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dabao Shang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Fifth People’s Hospital of Suzhou, Suzhou, China,Chuanwu Zhu,
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,Translational Lab of Liver Diseases, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China,*Correspondence: Xiaogang Xiang,
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13
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Luo M, Xin RJ, Hu FR, Yao L, Hu SJ, Bai FH. Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis. World J Gastroenterol 2023; 29:144-156. [PMID: 36683714 PMCID: PMC9850958 DOI: 10.3748/wjg.v29.i1.144] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/23/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Minimal hepatic encephalopathy (MHE) is a frequent neurological and psychiatric complication of liver cirrhosis. The precise pathogenesis of MHE is complicated and has yet to be fully elucidated. Studies in cirrhotic patients and experimental animals with MHE have indicated that gut microbiota dysbiosis induces systemic inflammation, hyperammonemia, and endotoxemia, subsequently leading to neuroinflammation in the brain via the gut-liver-brain axis. Related mechanisms initiated by gut microbiota dysbiosis have significant roles in MHE pathogenesis. The currently available therapeutic strategies for MHE in clinical practice, including lactulose, rifaximin, probiotics, synbiotics, and fecal microbiota transplantation, exert their effects mainly by modulating gut microbiota dysbiosis. Microbiome therapies for MHE have shown promised efficacy and safety; however, several controversies and challenges regarding their clinical use deserve to be intensively discussed. We have summarized the latest research findings concerning the roles of gut microbiota dysbiosis in the pathogenesis of MHE via the gut-liver-brain axis as well as the potential mechanisms by which microbiome therapies regulate gut microbiota dysbiosis in MHE patients.
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Affiliation(s)
- Ming Luo
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Rui-Juan Xin
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Fang-Rui Hu
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Li Yao
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Sheng-Juan Hu
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, China
| | - Fei-Hu Bai
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750021, Ningxia Hui Autonomous Region, 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: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [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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Mpabanzi L, Wainwright J, Boonen B, van Eijk H, Dhar D, Karssemeijer E, Dejong CHC, Jalan R, Schwartz JM, Olde Damink SWM, Soons Z. Fluxomics reveals cellular and molecular basis of increased renal ammoniagenesis. NPJ Syst Biol Appl 2022; 8:49. [PMID: 36539425 PMCID: PMC9768161 DOI: 10.1038/s41540-022-00257-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 11/07/2022] [Indexed: 12/24/2022] Open
Abstract
The kidney plays a critical role in excreting ammonia during metabolic acidosis and liver failure. The mechanisms behind this process have been poorly explored. The present study combines results of in vivo experiments of increased total ammoniagenesis with systems biology modeling, in which eight rats were fed an amino acid-rich diet (HD group) and eight a normal chow diet (AL group). We developed a method based on elementary mode analysis to study changes in amino acid flux occurring across the kidney in increased ammoniagenesis. Elementary modes represent minimal feasible metabolic paths in steady state. The model was used to predict amino acid fluxes in healthy and pre-hyperammonemic conditions, which were compared to experimental fluxes in rats. First, we found that total renal ammoniagenesis increased from 264 ± 68 to 612 ± 87 nmol (100 g body weight)-1 min-1 in the HD group (P = 0.021) and a concomitated upregulation of NKCC2 ammonia and other transporters in the kidney. In the kidney metabolic model, the best predictions were obtained with ammonia transport as an objective. Other objectives resulting in a fair correlation with the measured fluxes (correlation coefficient >0.5) were growth, protein uptake, urea excretion, and lysine and phenylalanine transport. These predictions were improved when specific gene expression data were considered in HD conditions, suggesting a role for the mitochondrial glycine pathway. Further studies are needed to determine if regulation through the mitochondrial glycine pathway and ammonia transporters can be modulated and how to use the kidney as a therapeutic target in hyperammonemia.
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Affiliation(s)
- Liliane Mpabanzi
- grid.5012.60000 0001 0481 6099Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands ,grid.83440.3b0000000121901201Hepato-Pancreato-Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, Pond Street, London, NW3 2QG UK ,grid.83440.3b0000000121901201Liver Failure Group, UCL Hepatology, Royal Free Hospital, University College London, Pond Street, London, NW3 2QG UK
| | - Jessica Wainwright
- grid.5379.80000000121662407School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT UK
| | - Bas Boonen
- grid.5012.60000 0001 0481 6099Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands
| | - Hans van Eijk
- grid.5012.60000 0001 0481 6099Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands
| | - Dipok Dhar
- grid.83440.3b0000000121901201Hepato-Pancreato-Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, Pond Street, London, NW3 2QG UK
| | - Esther Karssemeijer
- grid.5012.60000 0001 0481 6099Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands
| | - Cees H. C. Dejong
- grid.5012.60000 0001 0481 6099Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands ,grid.412301.50000 0000 8653 1507Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Rajiv Jalan
- grid.83440.3b0000000121901201Liver Failure Group, UCL Hepatology, Royal Free Hospital, University College London, Pond Street, London, NW3 2QG UK
| | - Jean-Marc Schwartz
- grid.5379.80000000121662407School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT UK
| | - Steven W. M. Olde Damink
- grid.5012.60000 0001 0481 6099Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands ,grid.83440.3b0000000121901201Hepato-Pancreato-Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, Pond Street, London, NW3 2QG UK ,grid.412301.50000 0000 8653 1507Department of General, Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany
| | - Zita Soons
- grid.5012.60000 0001 0481 6099Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands ,grid.412301.50000 0000 8653 1507Research Center for Computational Biomedicine, University Hospital RWTH Aachen, Aachen, Germany
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Li X, Kiprowska M, Kansara T, Kansara P, Li P. Neuroinflammation: A Distal Consequence of Periodontitis. J Dent Res 2022; 101:1441-1449. [PMID: 35708472 PMCID: PMC9608094 DOI: 10.1177/00220345221102084] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Periodontitis, a chronic, inflammatory disease, induces systemic inflammation and contributes to the development of neurodegenerative diseases. The precise etiology of the most common neurodegenerative disorders, such as sporadic Alzheimer's, Parkinson's diseases and multiple sclerosis (AD, PD, and MS, respectively), remains to be revealed. Chronic neuroinflammation is a well-recognized component of these disorders, and evidence suggests that systemic inflammation is a possible stimulus for neuroinflammation development. Systemic inflammation can lead to deleterious consequences on the brain if the inflammation is sufficiently severe or if the brain shows vulnerabilities due to genetic predisposition, aging, or neurodegenerative diseases. It has been proposed that periodontal disease can initiate or contribute to the AD pathogenesis through multiple pathways, including key periodontal pathogens. Dysbiotic oral bacteria can release bacterial products into the bloodstream and eventually cross the brain-blood barrier; these bacteria can also cause alterations to gut microbiota that enhance inflammation and potentially affect brain function via the gut-brain axis. The trigeminal nerve has been suggested as another route for connecting oral bacterial products to the brain. PD and MS are often preceded by gastrointestinal symptoms or aberrant gut microbiome composition, and alterations in the enteric nervous system accompany the disease. Clinical evidence has suggested that patients with periodontitis are at a higher risk of developing PD and MS. This nexus among the brain, periodontal disease, and systemic inflammation heralds new ways in which microglial cells, the main innate immune cells, and astrocytes, the crucial regulators of innate and adaptive immune responses in the brain, contribute to brain pathology. Currently, the lack of understanding of the pathogenesis of neurodegeneration is hindering treatment development. However, we may prevent this pathogenesis by tackling one of its possible contributors (periodontitis) for systemic inflammation through simple preventive oral hygiene measures.
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Affiliation(s)
- X. Li
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA
- Department of Urology, New York University Grossman School of Medicine, New York, NY, USA
- Perlmutter Cancer Institute, New York University Langone Medical Center, New York, NY, USA
| | - M. Kiprowska
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA
| | - T. Kansara
- Cleveland Clinic- Union hospital, Dover, OH, USA
| | - P. Kansara
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA
| | - P. Li
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA
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Yang B, Sun T, Chen Y, Xiang H, Xiong J, Bao S. The Role of Gut Microbiota in Mice With Bile Duct Ligation-Evoked Cholestatic Liver Disease-Related Cognitive Dysfunction. Front Microbiol 2022; 13:909461. [PMID: 35620109 PMCID: PMC9127770 DOI: 10.3389/fmicb.2022.909461] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
The pathogenesis of Hepatic Encephalopathy (HE) is complex and multifactorial. The development of metagenomics sequencing technology led to show the significant role of gut microbiota in the pathogenesis of cognitive dysfunction, which paved the way for further research in this field. However, it is unknown whether gut microbiota plays a role in bile duct ligation (BDL)-evoked cholestatic liver disease-related cognitive dysfunction. The aim of this investigation is to assess BDL mice induced cognitive dysfunction and meanwhile to delineate the alteration of gut microbiota in cognitive dysfunction mice, which may underline the role of gut microbiota in BDL mice induced cognitive dysfunction. Our study was carried out in male C57BL/6 J mice with bile duct ligation. The liver functions were assessed via different biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), and total bile acid (TBA)] and a histopathological examination of the liver tissue. We used the novel object recognition test (NORT) to assess cognitive dysfunction. And BDL mice were divided into BDL with cognitive dysfunction (BDL-CD) or BDL without cognitive dysfunction (BDL-NCD groups) by the result of hierarchical cluster analysis of NORT. Then, 16S ribosomal RNA (rRNA) gene sequencing was used to compare the gut bacterial composition between BDL-CD and BDL-NCD groups. According to our results, we concluded that bile duct ligation can significantly change the gut microbiota composition, and Bacteroides fragilis, Bacteroides ovatus V975, and Bacteroides thetaiotaomicron play a vital role in BDL-evoked cholestatic liver disease-related cognitive dysfunction.
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Affiliation(s)
- Bowen Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Tianning Sun
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingle Chen
- Department of Anesthesiology, The First Affiliated Quanzhou Hospital of Fujian Medical University, Quanzhou, China
| | - Hongbing Xiang
- Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Xiong
- Hepatobiliary Surgery Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiting Bao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Guth I, Matos-Pardal C, Ferreira-Lima R, Loureiro-Rebouças R, Sobral A, Moraes-Marques C, Kubrusly L. Caffeine attenuates liver damage and improves neurologic signs in a rat model of hepatic encephalopathy. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:159-169. [DOI: 10.1016/j.rgmxen.2022.03.004] [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: 07/01/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
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19
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Guth I, Matos-Pardal C, Ferreira-Lima R, Loureiro-Rebouças R, Sobral A, Moraes-Marques C, Kubrusly L. La cafeína atenúa daño hepático y mejora signos neurológicos en un modelo de encefalopatía hepática con ratas. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2022. [DOI: 10.1016/j.rgmx.2020.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Manzhalii E, Moyseyenko V, Kondratiuk V, Molochek N, Falalyeyeva T, Kobyliak N. Effect of a specific Escherichia coli Nissle 1917 strain on minimal/mild hepatic encephalopathy treatment. World J Hepatol 2022; 14:634-646. [PMID: 35582294 PMCID: PMC9055191 DOI: 10.4254/wjh.v14.i3.634] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 02/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) can be considered a result of dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as the administration of nonabsorbable disaccharides, nonabsorbable antibiotics, probiotics and prebiotics. AIM To assess the short-term efficacy and safety of the probiotic Escherichia coli Nissle (EcN) 1917 strain compared to lactulose and rifaximin in patients with minimal/mild HE. METHODS From January 2017 to March 2020, a total of 45 patients with HE were enrolled in this prospective, single-centre, open-label, randomized study. Participants were randomly assigned at a ratio of 1:1:1 to one of the treatment groups: The EcN group (n = 15), lactulose group (n = 15) or rifaximin group (n = 15) for a 1 mo intervention period. The main primary outcomes of the study were changes in serum ammonia and Stroop test score. The secondary outcomes were markers of a chronic systemic inflammatory response (ІL-6, ІL-8, and IFN-γ) and bacteriology of the stool flora evaluated by specialized nonculture techniques after a 1 mo intervention period. RESULTS Patients who were given rifaximin or EcN showed a more significant reduction in serum ammonia and normalization of Bifidobacteria and Lactobacilli abundance compared to the lactulose group. However, the most pronounced restoration of the symbiotic microflora was associated with EcN administration and characterized by the absence of E. coli with altered properties and pathogenic enterobacteria in patient faeces. In the primary outcome analysis, improvements in the Stroop test parameters in all intervention groups were observed. Moreover, EcN-treated patients performed 15% faster on the Stroop test than the lactulose group patients (P = 0.017). Both EcN and rifaximin produced similar significant reductions in the proinflammatory cytokines INF-γ, IL-6 and IL-8. EcN was more efficient than lactulose in reducing proinflammatory cytokine levels. CONCLUSION The use of the probiotic EcN strain was safe and quite efficient for HE treatment. The probiotic reduced the ammonia content and the level of serum proinflammatory cytokines, normalized the gut microbiota composition and improved the cognitive function of patients with HE. The application of the EcN strain was more effective than lactulose treatment.
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Affiliation(s)
- Elina Manzhalii
- Department of Propedeutics of Internal Medicine, Bogomolets National Medical University, Kyiv 01601, Ukraine.
| | - Valentyna Moyseyenko
- Department of Propedeutics of Internal Medicine, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Vitalii Kondratiuk
- Department of Propedeutics of Internal Medicine, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Nataliia Molochek
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
- Department of Pediatrics, Bogomolets National Medical University, Kyiv 01601, Ukraine
| | - Tetyana Falalyeyeva
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
- Department of Scientific, Medical Laboratory CSD, Kyiv 01004, Ukraine
| | - Nazarii Kobyliak
- Department of Endocrinology, Bogomolets National Medical University, Kyiv 01601, Ukraine
- Department of Scientific, Medical Laboratory CSD, Kyiv 01004, Ukraine.
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Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives. Biomolecules 2021; 12:biom12010056. [PMID: 35053205 PMCID: PMC8774162 DOI: 10.3390/biom12010056] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/24/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors—genetic, metabolic, and dietary—intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.
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Kronsten VT, Shawcross DL. Hepatic encephalopathy and depression in chronic liver disease: is the common link systemic inflammation? Anal Biochem 2021; 636:114437. [PMID: 34715068 DOI: 10.1016/j.ab.2021.114437] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/26/2021] [Accepted: 10/22/2021] [Indexed: 02/08/2023]
Abstract
Hepatic encephalopathy and depression share a number of clinical features, such as cognitive impairment and psychomotor retardation, and are highly prevalent in patients with chronic liver disease. Both conditions signify a poor prognosis, carry an increased mortality and are major determinants of reduced health related quality of life. The pathophysiology of hepatic encephalopathy is complex. Whilst cerebral accumulation of ammonia is well-recognised as being central to the development of hepatic encephalopathy, systemic inflammation, which acts in synergy with hyperammonaemia, is emerging as a key driver in its development. The pro-inflammatory state is also widely documented in depression, and peripheral to brain communication occurs resulting in central inflammation, behavioural changes and depressive symptoms. Gut dysbiosis, with a similar reduction in beneficial bacteria, increase in pathogens and decreased bacterial diversity, has been observed in both hepatic encephalopathy and depression, and it may be that the resultant increased bacterial translocation causes their shared inflammatory pathophysiology. Whilst the literature on a positive association between hepatic encephalopathy and depression in cirrhosis remains to be substantiated, there is evolving evidence that treatment with psychobiotics may be of dual benefit, improving cognition and mood in cirrhosis.
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Affiliation(s)
- Victoria Tatiana Kronsten
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK.
| | - Debbie Lindsay Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
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23
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Claeys W, Van Hoecke L, Lefere S, Geerts A, Verhelst X, Van Vlierberghe H, Degroote H, Devisscher L, Vandenbroucke RE, Van Steenkiste C. The neurogliovascular unit in hepatic encephalopathy. JHEP Rep 2021; 3:100352. [PMID: 34611619 PMCID: PMC8476774 DOI: 10.1016/j.jhepr.2021.100352] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/14/2021] [Accepted: 07/23/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of hepatic dysfunction and portosystemic shunting. It is highly prevalent in patients with cirrhosis and is associated with poor outcomes. New insights into the role of peripheral origins in HE have led to the development of innovative treatment strategies like faecal microbiota transplantation. However, this broadening of view has not been applied fully to perturbations in the central nervous system. The old paradigm that HE is the clinical manifestation of ammonia-induced astrocyte dysfunction and its secondary neuronal consequences requires updating. In this review, we will use the holistic concept of the neurogliovascular unit to describe central nervous system disturbances in HE, an approach that has proven instrumental in other neurological disorders. We will describe HE as a global dysfunction of the neurogliovascular unit, where blood flow and nutrient supply to the brain, as well as the function of the blood-brain barrier, are impaired. This leads to an accumulation of neurotoxic substances, chief among them ammonia and inflammatory mediators, causing dysfunction of astrocytes and microglia. Finally, glymphatic dysfunction impairs the clearance of these neurotoxins, further aggravating their effect on the brain. Taking a broader view of central nervous system alterations in liver disease could serve as the basis for further research into the specific brain pathophysiology of HE, as well as the development of therapeutic strategies specifically aimed at counteracting the often irreversible central nervous system damage seen in these patients.
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Key Words
- ABC, ATP-binding cassette
- ACLF, acute-on-chronic liver failure
- AD, acute decompensation
- ALF, acute liver failure
- AOM, azoxymethane
- AQP4, aquaporin 4
- Acute Liver Failure
- Ammonia
- BBB, blood-brain barrier
- BCRP, breast cancer resistance protein
- BDL, bile duct ligation
- Blood-brain barrier
- Brain edema
- CCL, chemokine ligand
- CCR, C-C chemokine receptor
- CE, cerebral oedema
- CLD, chronic liver disease
- CLDN, claudin
- CNS, central nervous system
- CSF, cerebrospinal fluid
- Cirrhosis
- Energy metabolism
- GS, glutamine synthetase
- Glymphatic system
- HE, hepatic encephalopathy
- HO-1, heme oxygenase 1
- IL-, interleukin
- MMP-9, matrix metalloproteinase 9
- MRP, multidrug resistance associated protein
- NGVU
- NGVU, neurogliovascular unit
- NKCC1, Na-K-2Cl cotransporter 1
- Neuroinflammation
- OCLN, occludin
- ONS, oxidative and nitrosative stress
- Oxidative stress
- P-gp, P-glycoprotein
- PCA, portacaval anastomosis
- PSS, portosystemic shunt
- S1PR2, sphingosine-1-phosphate receptor 2
- SUR1, sulfonylurea receptor 1
- Systemic inflammation
- TAA, thioacetamide
- TGFβ, transforming growth factor beta
- TJ, tight junction
- TNF, tumour necrosis factor
- TNFR1, tumour necrosis factor receptor 1
- ZO, zonula occludens
- mPT, mitochondrial pore transition
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Affiliation(s)
- Wouter Claeys
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
- Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Lien Van Hoecke
- Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Sander Lefere
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences; Liver Research Center Ghent; Ghent University, Ghent, Belgium
| | - Anja Geerts
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Xavier Verhelst
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Helena Degroote
- Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences; Liver Research Center Ghent; Ghent University, Ghent, Belgium
| | - Roosmarijn E. Vandenbroucke
- Barriers in Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Christophe Van Steenkiste
- Antwerp University, Department of Gastroenterology and Hepatology, Antwerp, Belgium
- Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium
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Vipani A, Lindenmeyer CC, Sundaram V. Treatment of Severe Acute on Chronic Liver Failure: Management of Organ Failures, Investigational Therapeutics, and the Role of Liver Transplantation. J Clin Gastroenterol 2021; 55:667-676. [PMID: 34028394 DOI: 10.1097/mcg.0000000000001568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Acute on chronic liver failure (ACLF) is a unique syndrome that afflicts patients with chronic liver disease and results in high short-term mortality, in the setting of organ system failures. Given this prognosis, there is an urgent need to understand risk factors for this condition, for appropriate medical management of organ failures, and for selection criteria for patients who may benefit from liver transplantation (LT). Although several definitions exist to identify ACLF, all of them are designed to identify patients with uniquely high mortality. Currently, management of severe ACLF relies on best supportive care for specific organ failures. Thromboelastography should guide the evaluation of coagulation pathways and hyperfibrinolysis in ACLF; prophylactic blood product transfusions and thrombopoetin agonists are not recommended. Combination therapy with terlipressin and albumin has been shown to be efficacious in the management of the hepatorenal syndrome but should be administered with caution in patients with ACLF-3. Recent data have characterized the role of beta-blockers and transjugular intrahepatic portosystemic shunt placement in the management of ACLF. Investigational therapies such as extracorporeal liver support and hepatocyte stem cell therapies have shown promise; larger scale studies may better define the subpopulations of patients with ACLF mostly likely to benefit from these evolving therapeutics. Regarding LT in ACLF, data suggest that even patients with 3 or more organ system failures may have a 1-year survival >80%. However, further efforts are needed to understand the predictors of post-LT survival to facilitate LT criteria for this condition.
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Affiliation(s)
| | | | - Vinay Sundaram
- Division of Gastroenterology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
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25
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The Gut Microbiota-Derived Immune Response in Chronic Liver Disease. Int J Mol Sci 2021; 22:ijms22158309. [PMID: 34361075 PMCID: PMC8347749 DOI: 10.3390/ijms22158309] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut–liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.
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DeMorrow S, Cudalbu C, Davies N, Jayakumar AR, Rose CF. 2021 ISHEN guidelines on animal models of hepatic encephalopathy. Liver Int 2021; 41:1474-1488. [PMID: 33900013 PMCID: PMC9812338 DOI: 10.1111/liv.14911] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/05/2021] [Accepted: 04/01/2021] [Indexed: 02/07/2023]
Abstract
This working group of the International Society of Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) was commissioned to summarize and update current efforts in the development and characterization of animal models of hepatic encephalopathy (HE). As defined in humans, HE in animal models is based on the underlying degree and severity of liver pathology. Although hyperammonemia remains the key focus in the pathogenesis of HE, other factors associated with HE have been identified, together with recommended animal models, to help explore the pathogenesis and pathophysiological mechanisms of HE. While numerous methods to induce liver failure and disease exist, less have been characterized with neurological and neurobehavioural impairments. Moreover, there still remains a paucity of adequate animal models of Type C HE induced by alcohol, viruses and non-alcoholic fatty liver disease; the most common etiologies of chronic liver disease.
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Affiliation(s)
- S DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Texas, USA; Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Texas, USA; Research division, Central Texas Veterans Healthcare System, Temple Texas USA.,Correspondance: Sharon DeMorrow, PhD, ; tel: +1-512-495-5779
| | - C Cudalbu
- Center for Biomedical Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - N Davies
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - AR Jayakumar
- General Medical Research, Neuropathology Section, R&D Service and South Florida VA Foundation for Research and Education Inc; Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami FL, USA
| | - CF Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
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27
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Jalan R, D'Amico G, Trebicka J, Moreau R, Angeli P, Arroyo V. New clinical and pathophysiological perspectives defining the trajectory of cirrhosis. J Hepatol 2021; 75 Suppl 1:S14-S26. [PMID: 34039485 DOI: 10.1016/j.jhep.2021.01.018] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023]
Abstract
Traditionally, the complications of cirrhosis, namely variceal bleeding, ascites and hepatic encephalopathy, were thought to result predominantly from circulatory dysfunction and altered organ perfusion arising as a result of portal hypertension. Over the past 20 years, large, international prospective studies have indicated the importance of systemic inflammation and organ immunopathology as additional determinants of organ dysfunction in cirrhosis, which not only manifests in the liver, brain, circulation and the kidneys, but also the immune system, gut, muscles, adrenal glands, reproductive organs, heart and lungs. This review provides an overview of the traditional and emerging concepts around the initiation and maintenance of organ dysfunction in cirrhosis and proposes a new paradigm based upon a better understanding of acute decompensation of cirrhosis. The interaction between the traditional concepts and the emerging perspectives remains a matter of great interest and the basis for future research.
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Affiliation(s)
- Rajiv Jalan
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom.
| | - Gennaro D'Amico
- Gastroenterology Unit, Ospedale Cervello and University of Palermo, Italy
| | - Jonel Trebicka
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; JW Goethe University Hospital, Frankfurt, Germany
| | - Richard Moreau
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; APHP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France; Inserm, Université de Paris, Centre de Recherche sur L'Inflammation, Paris, France
| | - Paolo Angeli
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; University of Padova, Padova, Italy
| | - Vicente Arroyo
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain
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28
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Piano S, Angeli P. Bacterial Infections in Cirrhosis as a Cause or Consequence of Decompensation? Clin Liver Dis 2021; 25:357-372. [PMID: 33838855 DOI: 10.1016/j.cld.2021.01.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Bacterial infections are ominous events in liver cirrhosis. Cirrhosis-associated immune dysfunction and pathologic bacterial translocation are responsible for the increased risk of infections. Bacteria induce systemic inflammation, which worsens circulatory dysfunction and induces oxidative stress and mitochondrial dysfunction. Bacterial infections, frequently associated with decompensation, are the most common precipitating event of acute-on-chronic liver failure (ACLF). After decompensation, patients with cirrhosis have an increased risk of developing infections. Bacterial infections should be ruled out in these patients and strategies to prevent infections should be implemented to prevent further decompensation. We review infections as a cause and consequence of decompensation in cirrhosis.
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Affiliation(s)
- Salvatore Piano
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine - DIMED, University and Hospital of Padova, Via Giustiniani 2, Padova 35100, Italy.
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine - DIMED, University and Hospital of Padova, Via Giustiniani 2, Padova 35100, Italy
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29
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Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease-Current Knowledge, Mechanisms and Perspectives. J Clin Med 2021; 10:jcm10040673. [PMID: 33572481 PMCID: PMC7916374 DOI: 10.3390/jcm10040673] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/29/2021] [Accepted: 01/31/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the hepatic component of the metabolic syndrome and now seemingly affects one-fourth of the world population. Features associated with NAFLD and the metabolic syndrome have frequently been linked to cognitive dysfunction, i.e. systemic inflammation, vascular dysfunction, and sleep apnoea. However, emerging evidence suggests that NAFLD may be a cause of cognitive dysfunction independent of these factors. NAFLD in addition exhibits dysbiosis of the gut microbiota and impaired urea cycle function, favouring systemic ammonia accumulation and further promotes systemic inflammation. Such disruption of the gut–liver–brain axis is essential in the pathogenesis of hepatic encephalopathy, the neuropsychiatric syndrome associated with progressive liver disease. Considering the growing burden of NAFLD, the morbidity from cognitive impairment is expected to have huge societal and economic impact. The present paper provides a review of the available evidence for cognitive dysfunction in NAFLD and outlines its possible mechanisms. Moreover, the clinical challenges of characterizing and diagnosing cognitive dysfunction in NAFLD are discussed.
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30
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Betaine alleviates cholestasis-associated renal injury by mitigating oxidative stress and enhancing mitochondrial function. Biologia (Bratisl) 2021. [DOI: 10.2478/s11756-020-00576-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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31
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Kitzbichler MG, Aruldass AR, Barker GJ, Wood TC, Dowell NG, Hurley SA, McLean J, Correia M, Clarke C, Pointon L, Cavanagh J, Cowen P, Pariante C, Cercignani M, Bullmore ET, Harrison NA. Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks. Mol Psychiatry 2021; 26:7346-7354. [PMID: 34535766 PMCID: PMC8872995 DOI: 10.1038/s41380-021-01272-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 07/15/2021] [Accepted: 08/19/2021] [Indexed: 02/08/2023]
Abstract
Inflammation is associated with depressive symptoms and innate immune mechanisms are likely causal in some cases of major depression. Systemic inflammation also perturbs brain function and microstructure, though how these are related remains unclear. We recruited N = 46 healthy controls, and N = 83 depressed cases stratified by CRP (> 3 mg/L: N = 33; < 3 mg/L: N = 50). All completed clinical assessment, venous blood sampling for C-reactive protein (CRP) assay, and brain magnetic resonance imaging (MRI). Micro-structural MRI parameters including proton density (PD), a measure of tissue water content, were measured at 360 cortical and 16 subcortical regions. Resting-state fMRI time series were correlated to estimate functional connectivity between individual regions, as well as the sum of connectivity (weighted degree) of each region. Multiple tests for regional analysis were controlled by the false discovery rate (FDR = 5%). We found that CRP was significantly associated with PD in precuneus, posterior cingulate cortex (pC/pCC) and medial prefrontal cortex (mPFC); and with functional connectivity between pC/pCC, mPFC and hippocampus. Depression was associated with reduced weighted degree of pC/pCC, mPFC, and other nodes of the default mode network (DMN). Thus CRP-related increases in proton density-a plausible marker of extracellular oedema-and changes in functional connectivity were anatomically co-localised with DMN nodes that also demonstrated significantly reduced hubness in depression. We suggest that effects of peripheral inflammation on DMN node micro-structure and connectivity may mediate inflammatory effects on depression.
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Affiliation(s)
- Manfred G. Kitzbichler
- grid.5335.00000000121885934University of Cambridge, Brain Mapping Unit, Department of Psychiatry, Downing Site, Cambridge, UK
| | - Athina R. Aruldass
- grid.5335.00000000121885934University of Cambridge, Brain Mapping Unit, Department of Psychiatry, Downing Site, Cambridge, UK
| | - Gareth J. Barker
- grid.13097.3c0000 0001 2322 6764Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King’s College London, London, UK
| | - Tobias C. Wood
- grid.13097.3c0000 0001 2322 6764Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King’s College London, London, UK
| | - Nicholas G. Dowell
- grid.414601.60000 0000 8853 076XUniversity of Sussex, Brighton and Sussex Medical School, Clinical Imaging Sciences Centre, Brighton, UK
| | - Samuel A. Hurley
- grid.416938.10000 0004 0641 5119University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK ,grid.14003.360000 0001 2167 3675University of Wisconsin, Department of Radiology, Madison, WI USA
| | - John McLean
- grid.8756.c0000 0001 2193 314XCollege of MVLS, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Marta Correia
- grid.415036.50000 0001 2177 2032MRC Cognition and Brain Sciences Unit, Cambridge, UK
| | - Charlotte Clarke
- grid.414601.60000 0000 8853 076XUniversity of Sussex, Brighton and Sussex Medical School, Clinical Imaging Sciences Centre, Brighton, UK
| | - Linda Pointon
- grid.5335.00000000121885934University of Cambridge, Brain Mapping Unit, Department of Psychiatry, Downing Site, Cambridge, UK
| | - Jonathan Cavanagh
- grid.511123.50000 0004 5988 7216Centre for Immunobiology, University of Glasgow and Queen Elizabeth University Hospital, Glasgow, UK
| | - Phil Cowen
- grid.416938.10000 0004 0641 5119University of Oxford Department of Psychiatry, Warneford Hospital, Oxford, UK
| | - Carmine Pariante
- grid.13097.3c0000 0001 2322 6764Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King’s College London, London, UK
| | - Mara Cercignani
- grid.414601.60000 0000 8853 076XUniversity of Sussex, Brighton and Sussex Medical School, Clinical Imaging Sciences Centre, Brighton, UK
| | | | - Edward T. Bullmore
- grid.5335.00000000121885934University of Cambridge, Brain Mapping Unit, Department of Psychiatry, Downing Site, Cambridge, UK
| | - Neil A. Harrison
- grid.414601.60000 0000 8853 076XUniversity of Sussex, Brighton and Sussex Medical School, Clinical Imaging Sciences Centre, Brighton, UK ,grid.5600.30000 0001 0807 5670Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK
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Rose CF, Amodio P, Bajaj JS, Dhiman RK, Montagnese S, Taylor-Robinson SD, Vilstrup H, Jalan R. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J Hepatol 2020; 73:1526-1547. [PMID: 33097308 DOI: 10.1016/j.jhep.2020.07.013] [Citation(s) in RCA: 244] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 07/01/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed.
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Affiliation(s)
- Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada.
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Radha Krishan Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Simon D Taylor-Robinson
- Department of Surgery and Cancer, St. Mary's Hospital Campus, Imperial College London, London, United Kingdom
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.
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33
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Fritz M, Klawonn AM, Zhao Q, Sullivan EV, Zahr NM, Pfefferbaum A. Structural and biochemical imaging reveals systemic LPS-induced changes in the rat brain. J Neuroimmunol 2020; 348:577367. [PMID: 32866714 DOI: 10.1016/j.jneuroim.2020.577367] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/11/2022]
Abstract
Despite mounting evidence for the role of inflammation in Major Depressive Disorder (MDD), in vivo preclinical investigations of inflammation-induced negative affect using whole brain imaging modalities are scarce, precluding a valid model within which to evaluate pharmacological interventions. Here we used an E. coli lipopolysaccharide (LPS)-based model of inflammation-induced depressive signs in rats to explore brain changes using multimodal neuroimaging methods. During the acute phase of the LPS response (2 h post injection), prior to the emergence of a task-quantifiable depressive phenotype, striatal glutamine levels and splenial, retrosplenial, and peri-callosal hippocampal cortex volumes were greater than at baseline. LPS-induced depressive behaviors observed at 24 h, however, occurred concurrently with lower than control levels of striatal glutamine and a reversibility of volume expansion (i.e., shrinkage of splenial, retrosplenial, and peri-callosal hippocampal cortex to baseline volumes). In both striatum and hippocampus at 24 h, mRNA expression in LPS relative to control animals demonstrated alterations in enzymes and transporters regulating glutamine homeostasis. Collectively, the observed behavioral, in vivo structural and metabolic, and mRNA expression alterations suggest a critical role for astrocytic regulation of inflammation-induced depressive behaviors.
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Affiliation(s)
- Michael Fritz
- Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, Stanford, CA 94304, United States of America
| | - Anna M Klawonn
- Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, Stanford, CA 94304, United States of America
| | - Qingyu Zhao
- Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, Stanford, CA 94304, United States of America
| | - Edith V Sullivan
- Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, Stanford, CA 94304, United States of America; Neuroscience Program, SRI International, Menlo Park, CA 94025, United States of America
| | - Natalie M Zahr
- Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, Stanford, CA 94304, United States of America; Neuroscience Program, SRI International, Menlo Park, CA 94025, United States of America.
| | - Adolf Pfefferbaum
- Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, Stanford, CA 94304, United States of America; Neuroscience Program, SRI International, Menlo Park, CA 94025, United States of America
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Ommati MM, Farshad O, Mousavi K, Jamshidzadeh A, Azmoon M, Heidari S, Azarpira N, Niknahad H, Heidari R. Betaine supplementation mitigates intestinal damage and decreases serum bacterial endotoxin in cirrhotic rats. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100179] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Kerbert AJC, Jalan R. Recent advances in understanding and managing hepatic encephalopathy in chronic liver disease. F1000Res 2020; 9. [PMID: 32399191 PMCID: PMC7194462 DOI: 10.12688/f1000research.22183.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a common, severe complication of advanced chronic liver disease (CLD) and has a devastating impact on the patient’s quality of life and prognosis. The neurotoxin ammonia and the presence of systemic and neurological inflammation are considered the key drivers of this neuropsychiatric syndrome. Treatment options available in routine clinical practice are limited, and the development of novel therapies is hampered owing to the complexity and heterogeneity of HE. This review article aims to outline the current understanding of the pathomechanisms of HE and the recent advances in the identification and development of novel therapeutic targets.
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Affiliation(s)
- Annarein J C Kerbert
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Rajiv Jalan
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
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Zamanian G, Partoazar A, Tavangar SM, Rashidian A, Mirzaei P, Niaz Q, Sharifi K, Dehpour AR, Jazaeri F. Effect of phosphatidylserine on cirrhosis-induced hepatic encephalopathy: Response to acute endotoxemia in cirrhotic rats. Life Sci 2020; 253:117606. [PMID: 32320707 DOI: 10.1016/j.lfs.2020.117606] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/22/2020] [Accepted: 03/23/2020] [Indexed: 11/16/2022]
Abstract
BACKGROUND/AIMS In cirrhosis, the levels of proinflammatory cytokines are high in the liver and blood. Endotoxin decreases level of consciousness in cirrhotic rats. Phosphatidylserine exists in the cell membrane structure and is essential for the survival of neurons. Phosphatidylserine receptor is found in phagocytic cells and also activates the signaling of membrane proteins in apoptotic process. Therefore this study was aimed to explore the hypothesis that hepatic encephalopathy is prevented by phosphatidylserine treatment and if so, whether this is associated with altered level of proinflammatory cytokines in the brain. METHODS Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. The groups were treated with phosphatidylserine and saline for 4 weeks. Brain IL6, TNFα and the expression of phosphatidylserine receptor were assessed. Intraperitoneal injections of either saline or lipopolysaccharide (0.1 mg/kg) were administered to each group. Finally, animal behavior, blood ammonia and the expression of toll like receptor 4 were examined in the brain. RESULTS Cirrhosis in rats was associated with altered expression of toll-like receptor4 in brain cortex and phosphatidylserine treatment increases toll-like receptor4 receptor expression. Phosphatidylserine had anti-inflammatory effect in healthy rats but no effect in cirrhotic rats. Chronic phosphatidylserine treatment decreased blood ammonia in BDL cirrhotic rats treated with lipopolysaccharide. CONCLUSION The brain of cirrhotic rat is more susceptible to acute endotoxemia and chronic phosphatidylserine treatment decreases blood ammonia and encephalopathy in cirrhotic rats by encountering endotoxin. Phosphatidylserine may boost immune system against endotoxin.
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Affiliation(s)
- Golnaz Zamanian
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Partoazar
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Rashidian
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parto Mirzaei
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Qamar Niaz
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Khadijeh Sharifi
- School of Advanced Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farahnaz Jazaeri
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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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: 21] [Impact Index Per Article: 4.2] [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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Liotta EM, Kimberly WT. Cerebral edema and liver disease: Classic perspectives and contemporary hypotheses on mechanism. Neurosci Lett 2020; 721:134818. [PMID: 32035166 DOI: 10.1016/j.neulet.2020.134818] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 02/01/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Liver disease is a growing public health concern. Hepatic encephalopathy, the syndrome of brain dysfunction secondary to liver disease, is a frequent complication of both acute and chronic liver disease and cerebral edema (CE) is a key feature. While altered ammonia metabolism is a key contributor to hepatic encephalopathy and CE in liver disease, there is a growing appreciation that additional mechanisms contribute to CE. In this review we will begin by presenting three classic perspectives that form a foundation for a discussion of CE in liver disease: 1) CE is unique to acute liver failure, 2) CE in liver disease is only cytotoxic, and 3) CE in liver disease is primarily an osmotically mediated consequence of ammonia and glutamine metabolism. We will present each classic perspective along with more recent observations that call in to question that classic perspective. After highlighting these areas of debate, we will explore the leading contemporary mechanisms hypothesized to contribute to CE during liver disease.
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Affiliation(s)
- Eric M Liotta
- Northwestern University-Feinberg School of Medicine, Department of Neurology, United States; Northwestern University-Feinberg School of Medicine, Department of Surgery, Division of Organ Transplantation, United States; Northwestern University Transplant Outcomes Research Collaboration, United States.
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Recombinant Alkaline Phosphatase Prevents Acute on Chronic Liver Failure. Sci Rep 2020; 10:389. [PMID: 31942020 PMCID: PMC6962206 DOI: 10.1038/s41598-019-57284-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/09/2019] [Indexed: 12/11/2022] Open
Abstract
The lipopolysaccharide (LPS)– toll-like receptor-4 (TLR4) pathway plays an important role in liver failure. Recombinant alkaline phosphatase (recAP) deactivates LPS. The aim of this study was to determine whether recAP prevents the progression of acute and acute-on-chronic liver failure (ACLF). Eight groups of rats were studied 4-weeks after sham surgery or bile duct ligation and were injected with saline or LPS to mimic ACLF. Acute liver failure was induced with Galactosamine-LPS and in both models animals were treated with recAP prior to LPS administration. In the ACLF model, the severity of liver dysfunction and brain edema was attenuated by recAP, associated with reduction in cytokines, chemokines, liver cell death, and brain water. The activity of LPS was reduced by recAP. The treatment was not effective in acute liver failure. Hepatic TLR4 expression was reduced by recAP in ACLF but not acute liver failure. Increased sensitivity to endotoxins in cirrhosis is associated with upregulation of hepatic TLR4, which explains susceptibility to development of ACLF whereas acute liver failure is likely due to direct hepatoxicity. RecAP prevents multiple organ injury by reducing receptor expression and is a potential novel treatment option for prevention of ACLF but not acute liver failure.
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Vairappan B, Sundhar M, Srinivas BH. Resveratrol Restores Neuronal Tight Junction Proteins Through Correction of Ammonia and Inflammation in CCl 4-Induced Cirrhotic Mice. Mol Neurobiol 2019; 56:4718-4729. [PMID: 30377987 DOI: 10.1007/s12035-018-1389-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 10/11/2018] [Indexed: 12/31/2022]
Abstract
Systemic inflammation and ammonia (hyperammonemia) act synergistically in the pathogenesis of hepatic encephalopathy (HE), the neurobehavioral sequelae of advanced liver disease. In cirrhotic patients, we have recently observed elevated levels of circulating neuronal tight junction (TJ) protein, zonula occludens 1 (ZO-1), reflective of a change to blood-brain barrier (BBB) integrity. Moreover, ZO-1 levels positively correlated with hyperammonemia, although any potential relationship remains unclear. Using a carbon tetrachloride (CCl4)-induced mouse model of cirrhosis, we primarily looked to explore the relationship between neuronal TJ protein expression and hyperammonemia. Secondarily, we assessed the potential role of a natural antioxidant, resveratrol, on neuronal TJ protein expression and hyperammonemia. Over 12 weeks, male Swiss mice were randomized (n = 8/group) to either naïve controls or induced cirrhosis, using two doses of intraperitoneal CCl4 (0.5 ml/kg/week). After 12 weeks, naïve and cirrhotic mice were randomized to receive either 2 weeks of par-oral resveratrol (10 mg/kg). Plasma samples were analyzed for ammonia, liver biochemistry (ALT, AST, albumin, and bilirubin), and pro-inflammatory cytokines (TNF-α and IL-1β), and brain tissue for brain water content, TJ protein expression (e.g., ZO-1, claudin 5, and occludin), and tissue oxidative stress and inflammatory markers (NF-κB and iNOS) using western blotting. Compared to naïve mice, cirrhosis significantly increased circulating ammonia, brain water, ALT, AST, TNF-α, IL-1β, 4HNE, NF-κB, and iNOS levels, with a concomitant reduction in all TJ proteins (P < 0.05, respectively). In cirrhotic mice, resveratrol treatment ameliorated these changes significantly (P < 0.05, respectively). Our findings provide evidence for a causal association between hyperammonemia and inflammation in cirrhosis linked to TJ protein alterations, BBB disruption, and HE predilection. Moreover, this is the first report of a potential role for resveratrol as a novel therapeutic approach to managing neurological sequelae complicating cirrhosis.
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Affiliation(s)
- Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Pondicherry, 605 006, India.
| | - M Sundhar
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Pondicherry, 605 006, India
| | - B H Srinivas
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
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Cudalbu C, Taylor-Robinson SD. Brain Edema in Chronic Hepatic Encephalopathy. J Clin Exp Hepatol 2019; 9:362-382. [PMID: 31360029 PMCID: PMC6637228 DOI: 10.1016/j.jceh.2019.02.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 01/15/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023] Open
Abstract
Brain edema is a common feature associated with hepatic encephalopathy (HE). In patients with acute HE, brain edema has been shown to play a crucial role in the associated neurological deterioration. In chronic HE, advanced magnetic resonance imaging (MRI) techniques have demonstrated that low-grade brain edema appears also to be an important pathological feature. This review explores the different methods used to measure brain edema ex vivo and in vivo in animal models and in humans with chronic HE. In addition, an in-depth description of the main studies performed to date is provided. The role of brain edema in the neurological alterations linked to HE and whether HE and brain edema are the manifestations of the same pathophysiological mechanism or two different cerebral manifestations of brain dysfunction in liver disease are still under debate. In vivo MRI/magnetic resonance spectroscopy studies have allowed insight into the development of brain edema in chronic HE. However, additional in vivo longitudinal and multiparametric/multimodal studies are required (in humans and animal models) to elucidate the relationship between liver function, brain metabolic changes, cellular changes, cell swelling, and neurological manifestations in chronic HE.
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Key Words
- 1H MRS, proton magnetic resonance spectroscopy
- ADC, apparent diffusion coefficient
- ALF, acute liver failure
- AQP, aquaporins
- BBB, blood-brain barrier
- BDL, bile duct ligation
- CNS, central nervous system
- CSF, cerebrospinal fluid
- Cr, creatine
- DTI, diffusion tensor imaging
- DWI, diffusion-weighted imaging
- FLAIR, fluid-attenuated inversion recovery
- GM, gray matter
- Gln, glutamine
- Glx, sum of glutamine and glutamate
- HE, hepatic encephalopathy
- Ins, inositol
- LPS, lipopolysaccharide
- Lac, lactate
- MD, mean diffusivity
- MRI, magnetic resonance imaging
- MRS, magnetic resonance spectroscopy
- MT, magnetization transfer
- MTR, MT ratio
- NMR, nuclear magnetic resonance
- PCA, portocaval anastomosis
- TE, echo time
- WM, white matter
- brain edema
- chronic hepatic encephalopathy
- in vivo magnetic resonance imaging
- in vivo magnetic resonance spectroscopy
- liver cirrhosis
- mIns, myo-inositol
- tCho, total choline
- tCr, total creatine
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Affiliation(s)
- Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Simon D. Taylor-Robinson
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, St Mary's Hospital Campus, Imperial College London, London, United Kingdom
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Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2019; 51:190-205. [PMID: 30606696 DOI: 10.1016/j.dld.2018.11.035] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/27/2018] [Accepted: 11/28/2018] [Indexed: 12/11/2022]
Abstract
Hepatic encephalopathy (HE) is a common, worrisome and sometimes difficult to manage complication of end-stage liver disease. HE is often recurrent, requiring multiple hospital admissions. It can have serious implications in terms of a patient's ability to perform complex tasks (for example driving), their earning capacity, their social and family roles. This guideline reviews current knowledge on HE definition, pathophysiology, diagnosis and treatment, both by general principles and by way of a summary of available drugs and treatment strategies. The quality of the published, pertinent evidence is graded, and practical recommendations are made. Where possible, these are placed within the Italian health service context, with reference to local diagnosis and management experience.
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Weil D, Pais de Barros JP, Mourey G, Laheurte C, Cypriani B, Badet N, Delabrousse E, Grandclément E, Di Martino V, Saas P, Lagrost L, Thévenot T. Circulating levels of 3-hydroxymyristate, a direct quantification of endotoxaemia in noninfected cirrhotic patients. Liver Int 2019; 39:106-114. [PMID: 29931819 DOI: 10.1111/liv.13916] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 06/15/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The quantification of lipopolysaccharide (LPS) in biological fluids is challenging. We aimed to measure plasma LPS concentration using a new method of direct quantification of 3-hydroxymyristate (3-HM), a lipid component of LPS, and to evaluate correlations between 3-HM and markers of liver function, endothelial activation, portal hypertension and enterocyte damage. METHODS Plasma from 90 noninfected cirrhotic patients (30 Child-Pugh [CP]-A, 30 CP-B, 30 CP-C) was prospectively collected. The concentration of 3-HM was determined by high-performance liquid chromatography coupled with mass spectrometry. RESULTS 3-HM levels were higher in CP-C patients (CP-A/CP-B/CP-C: 68/70/103 ng/mL, P = 0.005). Patients with severe acute alcoholic hepatitis (n = 16; 113 vs 74 ng/mL, P = 0.012), diabetic patients (n = 22; 99 vs 70 ng/mL, P = 0.028) and those not receiving beta blockers (n = 44; 98 vs 72 ng/mL, P = 0.034) had higher levels of 3-HM. We observed a trend towards higher baseline levels of 3-HM in patients with hepatic encephalopathy (n = 7; 144 vs 76 ng/mL, P = 0.45) or SIRS (n = 10; 106 vs 75 ng/mL, P = 0.114). In multivariate analysis, high levels of 3-HM were associated with CP (OR = 4.39; 95%CI = 1.79-10.76) or MELD (OR = 8.24; 95%CI = 3.19-21.32) scores. Patients dying from liver insufficiency (n = 6) during a 12-month follow-up had higher baseline levels of 3-HM (106 vs 75 ng/mL, P = 0.089). CONCLUSIONS In noninfected cirrhotic patients, 3-HM arises more frequently with impairment of liver function, heavy alcohol consumption, diabetic status, nonuse of beta blockers and a trend towards poorer outcome is also observed. The direct mass measurement of LPS using 3-HM appears reliable to detect transient endotoxaemia and promising to manage the follow-up of cirrhotic patients.
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Affiliation(s)
- Delphine Weil
- Service d'Hépatologie, CHU Jean Minjoz, Besançon, France.,UPRES EA4266, Laboratoire Pathogènes & Inflammation/EPILAB, Université de Bourgogne Franche-Comté, Besançon, France
| | - Jean-Paul Pais de Barros
- INSERM, LNC UMR 1231, Université de Bourgogne Franche-Comté, Dijon, France.,LipSTIC LabEx, Plateforme de BioMonitoring, Besançon, France
| | - Guillaume Mourey
- INSERM Etablissement Français du Sang Bourgogne Franche-Comté, UMR 1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LipSTIC LabEx, Plateforme de BioMonitoring, Univ.Bourgogne Franche-Comté, Besançon, France
| | - Caroline Laheurte
- INSERM Etablissement Français du Sang Bourgogne Franche-Comté, UMR 1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LipSTIC LabEx, Plateforme de BioMonitoring, Univ.Bourgogne Franche-Comté, Besançon, France
| | - Benoit Cypriani
- Service de Biochimie Médicale, CHU Jean Minjoz, Besançon, France
| | - Nicolas Badet
- Service de Radiologie, CHU Jean Minjoz, Besançon, France
| | | | | | - Vincent Di Martino
- Service d'Hépatologie, CHU Jean Minjoz, Besançon, France.,UPRES EA4266, Laboratoire Pathogènes & Inflammation/EPILAB, Université de Bourgogne Franche-Comté, Besançon, France
| | - Philippe Saas
- INSERM Etablissement Français du Sang Bourgogne Franche-Comté, UMR 1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LipSTIC LabEx, Plateforme de BioMonitoring, Univ.Bourgogne Franche-Comté, Besançon, France
| | - Laurent Lagrost
- INSERM, LNC UMR 1231, Université de Bourgogne Franche-Comté, Dijon, France.,LipSTIC LabEx, Plateforme de BioMonitoring, Besançon, France
| | - Thierry Thévenot
- Service d'Hépatologie, CHU Jean Minjoz, Besançon, France.,UPRES EA4266, Laboratoire Pathogènes & Inflammation/EPILAB, Université de Bourgogne Franche-Comté, Besançon, France
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Nataj A, Eftekhari G, Raoufy MR, Mani AR. The effect of fractal-like mechanical ventilation on vital signs in a rat model of acute-on-chronic liver failure. Physiol Meas 2018; 39:114008. [PMID: 30475741 DOI: 10.1088/1361-6579/aaea10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE The network of interactions between different organs is impaired in liver cirrhosis. Liver cirrhosis is associated with multi-system involvement, which eventually leads to multiple organ failure. This process is accelerated by a precipitating factor such as bacterial infection, which leads to respiratory distress, circulatory shock, neural dysfunction and very high mortality. Cirrhotic patients often have blunted respiratory sinus arrhythmia and impaired cardio-respiratory variability. Fractal-like mechanical ventilation is reported to enhance respiratory sinus arrhythmia and attenuate respiratory distress in experimental models. In the present study we hypothesise that fractal-like mechanical ventilation may improve the outcome of cirrhotic rats with multiple organ failure. APPROACH Cirrhosis was induced by chronic biliary obstruction in rats. Acute multiple organ failure was induced by intraperitoneal injection of bacterial endotoxin in cirrhotic rats. The effect of conventional mechanical ventilation (with constant tidal volume and respiratory rate) or fractal-like ventilation (with the same average but variable tidal volume and respiratory rate) were assessed on vital signs, oxygen saturation and plasma alanine aminotransferase in anaesthetised cirrhotic rats. MAIN RESULTS We demonstrated that fractal-like mechanical ventilation was accompanied by improved oxygen saturation, reduced heart rate and decreased liver injury following injection of bacterial endotoxin. Moreover, variable mechanical ventilation in cirrhotic rats reduced mortality and prevented a fall in short-term heart rate variability following endotoxin challenge in comparison with rats with constant mechanical ventilation. SIGNIFICANCE We suggest further investigations into the beneficial effects of fractal-like ventilation strategy in critically ill patients with liver failure requiring organ support and mechanical ventilation.
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Affiliation(s)
- Arman Nataj
- Faculty of Medical Sciences, Department of Physiology, Tarbiat Modares University, Tehran, Iran. These authors are joint first authors
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Ochoa-Sanchez R, Rose CF. Pathogenesis of Hepatic Encephalopathy in Chronic Liver Disease. J Clin Exp Hepatol 2018; 8:262-271. [PMID: 30302043 PMCID: PMC6175755 DOI: 10.1016/j.jceh.2018.08.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs during chronic liver disease (CLD). While ammonia and other precipitating factors in liver disease including inflammation, bile acids, oxidative stress, and lactate play a role in the pathogenesis of HE, the exact mechanism that leads to HE is not fully understood. Notably, accumulating evidence points toward a synergic effect rather than independent actions among precipitating factors that contributes to the development and severity of HE in CLD. Hence, this review is aimed to briefly discuss the single and synergic interplay of pathological factors in the progression and severity of HE.
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Key Words
- AQP4, Aquaporin 4
- BAs, Bile Acids
- BBB, Blood-Brain Barrier
- BDL, Bile Duct Ligation
- CLD, Chronic Liver Disease
- CSF, Cerebrospinal Fluid
- GABA, Gamma-Aminobutyric Acid
- GAMSAs, GABAA Receptor Modulating Steroid Antagonists
- GFAP, Glial Fibrillary Acid Protein
- GLAST, Glial Glutamate-Aspartate Transporter
- GPR81, G-Protein-Coupled Receptor 81
- GS, Glutamine Synthetase
- HE, Hepatic Encephalopathy
- ICP, Intracranial Pressure
- ILs, Interleukins
- MRI, Magnetic Resonance Imaging
- NF-?B, Nuclear Factor Kappa B
- NMDA, N-Methyl-d-Aspartate Glutamate Receptor
- NO, Nitric Oxide
- PCA, Portacaval Anastomosis
- ROS, Reactive Oxygen Species
- TJ, Tight Junction
- TNF-a, Tumor Necrosis Alpha
- ammonia
- astrocyte swelling
- bile acids
- brain edema
- cGMP, Cyclic Guanosine Monophosphate
- cirrhosis
- hepatic encephalopathy
- inflammation
- lactate
- mGluR, Metabotropic Glutamate Receptor
- neurotransmission
- oxidative stress
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Affiliation(s)
| | - Christopher F. Rose
- Address for correspondence. Christopher F. Rose Professor, Dept. Medicine, Université de Montréal, CRCHUM, 900 Saint-Denis Street, Montréal, Québec, H2X 0A9, Canada.
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Ponziani FR, Zocco MA, Cerrito L, Gasbarrini A, Pompili M. Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications. Expert Rev Gastroenterol Hepatol 2018; 12:641-656. [PMID: 29806487 DOI: 10.1080/17474124.2018.1481747] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gut liver axis is an operative unit that works to protect the human body against potentially harmful substances and microorganisms, maintaining the homeostasis of the immune system. Liver cirrhosis profoundly alters this complex system. The intestine becomes more permeable allowing the translocation of bacteria, bacterial products and fragments into the portal circulation, triggering an abnormal local and systemic inflammatory response and a condition of perpetual immunologic alarm. This immune-inflammatory disorder related to dysbiosis is involved in the development of liver damage and liver cirrhosis complications and increases intestinal permeability in a vicious circle. Areas covered: The most relevant studies on bacterial translocation, the mechanism of intestinal barrier dysfunction and its consequences in patients with liver cirrhosis have been revised through a PubMed search. Data have been discussed with particular regard to their significance in clinical practice. Expert commentary: The assessment of bacterial translocation and intestinal permeability is not currently used in clinical practice but may be useful to stratify patients' prognosis.
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Affiliation(s)
- Francesca Romana Ponziani
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maria Assunta Zocco
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Lucia Cerrito
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Antonio Gasbarrini
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maurizio Pompili
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
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Mancini A, Campagna F, Amodio P, Tuohy KM. Gut : liver : brain axis: the microbial challenge in the hepatic encephalopathy. Food Funct 2018; 9:1373-1388. [PMID: 29485654 DOI: 10.1039/c7fo01528c] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) is a debilitating neuropsychiatric condition often associated with acute liver failure or cirrhosis. Advanced liver diseases are characterized by a leaky gut and systemic inflammation. There is strong evidence that the pathogenesis of HE is linked to a dysbiotic gut microbiota and to harmful microbial by-products, such as ammonia, indoles, oxindoles and endotoxins. Increased concentrations of these toxic metabolites together with the inability of the diseased liver to clear such products is thought to play an important patho-ethiological role. Current first line clinical treatments target microbiota dysbiosis by decreasing the counts of pathogenic bacteria, blood endotoxemia and ammonia levels. This review will focus on the role of the gut microbiota and its metabolism in HE and advanced cirrhosis. It will critically assess data from different clinical trials measuring the efficacy of the prebiotic lactulose, the probiotic VSL#3 and the antibiotic rifaximin in treating HE and advanced cirrhosis, through gut microbiota modulation. Additionally data from Randomised Controlled Trials using pre-, pro- and synbiotic will be also considered by reporting meta-analysis studies. The large amount of existing data showed that HE is a clear example of how an altered gut microbiota homeostasis can influence and impact on physiological functions outside the intestine, with implication for host health at the systems level. Nevertheless, a strong effort should be made to increase the information on gut microbiota ecology and its metabolic function in liver diseases and HE.
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Affiliation(s)
- Andrea Mancini
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all'Adige, Trento, Italy.
| | - Francesca Campagna
- Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy
| | - Piero Amodio
- Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy
| | - Kieran M Tuohy
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all'Adige, Trento, Italy.
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48
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Hajiasgharzadeh K, Baradaran B. Cholinergic Anti-Inflammatory Pathway and the Liver. Adv Pharm Bull 2017; 7:507-513. [PMID: 29399541 PMCID: PMC5788206 DOI: 10.15171/apb.2017.063] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/08/2017] [Accepted: 11/17/2017] [Indexed: 01/06/2023] Open
Abstract
The hepatic vagus branches innervate the liver and serve an important role in liver-brain connection. It appears that brain modulates inflammatory responses by activation of vagal efferent fibers. This activation and subsequent acetylcholine releases from vagus nerve terminals leads to inhibition of inflammatory cytokines through α7 nicotinic acetylcholine receptors (α7nAChRs) which located on the surface of different cell types such as liver Kupffer cells. This protective role of vagus-α7nAChR axis in liver diseases has been shown in several experimental studies. On the other hand, accumulated evidence clearly demonstrate that, autonomic dysfunction which is reduced functioning of both vagal and sympathetic nervous system, occurs during chronic liver disease and is well-known complication of patients suffering from cirrhosis. This review describes the impact and significance of cholinergic anti-inflammatory pathway in the liver and discusses about its disease-related dysfunction on the progression of cirrhosis. Considering the fact that sepsis is major cause of death in cirrhotic patients, convergence of these findings, may lead to designing novel therapeutic strategies in the field of chronic liver diseases management involving selective drug targeting and electrical nerve stimulation.
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Affiliation(s)
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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49
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Kaji K, Takaya H, Saikawa S, Furukawa M, Sato S, Kawaratani H, Kitade M, Moriya K, Namisaki T, Akahane T, Mitoro A, Yoshiji H. Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity. World J Gastroenterol 2017; 23:8355-8366. [PMID: 29307995 PMCID: PMC5743506 DOI: 10.3748/wjg.v23.i47.8355] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 10/30/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the efficacy of rifaximin for hepatic encephalopathy (HE) with the linkage of gut microbiome in decompensated cirrhotic patients.
METHODS Twenty patients (12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis (Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test (NCT)-A. Changes in whole blood endotoxin activity (EA) was analyzed by endotoxin activity assay. Fecal microbiome was assessed by 16S ribosome RNA (rRNA) gene sequencing.
RESULTS Treatment with rifaximin for 4 wk improved hyperammonemia (from 90.6 ± 23.9 μg/dL to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT (from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced (from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels (r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator (Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups (3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were lowered.
CONCLUSION Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.
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Affiliation(s)
- Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Masanori Furukawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara 634-8522, Japan
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50
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Balasubramanian V, Mehta G, Jones H, Sharma V, Davies NA, Jalan R, Mookerjee RP. Post-Transcriptional Regulation of Hepatic DDAH1 with TNF Blockade Leads to Improved eNOS Function and Reduced Portal Pressure In Cirrhotic Rats. Sci Rep 2017; 7:17900. [PMID: 29263339 PMCID: PMC5738445 DOI: 10.1038/s41598-017-18094-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 11/13/2017] [Indexed: 12/19/2022] Open
Abstract
Portal hypertension (PH) is a major cause of morbidity and mortality in chronic liver disease. Infection and inflammation play a role in potentiating PH and pro-inflammatory cytokines, including TNF, are associated with severity of PH. In this study, cirrhotic bile duct ligated (BDL) rats with PH were treated with Infliximab (IFX, a monoclonal antibody against TNF) and its impact on modulation of vascular tone was assessed. BDL rats had increased TNF and NFkB compared to sham operated rats, and their reduction by IFX was associated with a reduction in portal pressure. IFX treatment also reduced hepatic oxidative stress, and biochemical markers of hepatic inflammation and injury. IFX treatment was associated with an improvement in eNOS activity and increased l-arginine/ADMA ratio and DDAH1 expression. In vitro analysis of HepG2 hepatocytes showed that DDAH1 protein expression is reduced by oxidative stress, and this is in part mediated by post-transcriptional regulation by the 3′UTR. This study supports a role for the DDAH1/ADMA axis on the effect of inflammation and oxidative stress in PH and provides insight for new therapies.
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Affiliation(s)
- V Balasubramanian
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - G Mehta
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - H Jones
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - V Sharma
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - N A Davies
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - R Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - R P Mookerjee
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.
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