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Munk Lauridsen M, Jonasson E, Bajaj JS. Microbial Approaches to Treat and Prevent Hepatic Encephalopathy. Gastroenterol Clin North Am 2025; 54:429-451. [PMID: 40348497 PMCID: PMC12066833 DOI: 10.1016/j.gtc.2024.12.006] [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] [Indexed: 05/14/2025]
Abstract
This review articulates the significance of the gut-liver-brain axis in understanding hepatic encephalopathy (HE), emphasizing the role of gut microbiota in influencing liver and brain health. Key treatments like lactulose, rifaximin, probiotics, and fecal microbiota transplantation are examined for their ability to modulate the gut microbiome, thereby mitigating HE symptoms through reduced neurotoxin production and enhanced gut barrier integrity. The synopsis highlights both established and emerging microbial therapies, presenting them as crucial to the management and future strategies of HE. This comprehensive overview explores current therapeutic approaches alongside promising future interventions, suggesting that personalized microbiome-focused treatments may revolutionize HE management.
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Affiliation(s)
- Mette Munk Lauridsen
- Department for Regional Health Research, University Hospital of Southern Denmark, Finsensgade 35 6700, Esbjerg, Denmark
| | - Elise Jonasson
- Department for Regional Health Research, University Hospital of Southern Denmark, Finsensgade 35 6700, Esbjerg, Denmark
| | - Jasmohan S Bajaj
- Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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2
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Narayanan S, Sneller L, Mathur P. To be or not to be: the non-antimicrobial properties of common antimicrobials. J Antimicrob Chemother 2025:dkaf150. [PMID: 40376834 DOI: 10.1093/jac/dkaf150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025] Open
Abstract
Antibiotics are diverse in their utility in clinical care. They are widely prescribed for their antimicrobial effect and used as modulators, although rarely, of non-infectious conditions, to influence immune responses, to decrease morbidity and improve quality of life. This review provides a concise summary of different classes of antibiotics and their unique properties that allow them to be used in the treatment of non-infectious conditions.
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Affiliation(s)
- Shivakumar Narayanan
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Laura Sneller
- Drexel University College of Medicine, Philadelphia, PA, USA
| | - Poonam Mathur
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
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3
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Mishra AK, Dhiman RK. Hepatic encephalopathy in cirrhosis: therapies and developments. Metab Brain Dis 2025; 40:198. [PMID: 40332628 DOI: 10.1007/s11011-025-01598-7] [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: 07/07/2024] [Accepted: 03/30/2025] [Indexed: 05/08/2025]
Abstract
Hepatic encephalopathy (HE) is a frequent decompensation in patients with cirrhosis, which significantly affects morbidity and mortality. Ammonia is a major neurotoxin implicated in the pathogenesis, progression, and severity of HE, and various organs including the gut, muscle, kidney, and brain are involved in its metabolism. Therefore, therapeutic management involves reducing ammonia production and increasing its elimination from the blood and the brain. Prevention of HE in patients at high risk of first and recurrent episodes is important for prolonging survival. Various anti-ammonia therapies with synergistic and complementary actions have been attempted for overt HE and for prophylaxis of the first and recurrent episodes of HE. In the current review, we summarize the currently used and under-development pharmacotherapies/procedure(s) for HE in cirrhosis and their mechanism of action. Primary and secondary prophylaxis with monotherapies and combination therapies are also discussed.
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Affiliation(s)
- Ajay Kumar Mishra
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India
| | - Radha Krishan Dhiman
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India.
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Worland T, Hey P, Wong D, Apostolov R, Chan RK, Sinclair M, Gow P. Rifaximin-α use is associated with improved muscle mass in patients with cirrhosis. World J Hepatol 2025; 17:104056. [PMID: 40308826 PMCID: PMC12038419 DOI: 10.4254/wjh.v17.i4.104056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/21/2025] [Accepted: 04/03/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Sarcopaenia is associated with a two-fold higher mortality rate in patients with cirrhosis independent of liver disease severity. Few treatments for cirrhosis related sarcopaenia exist beyond optimal nutritional management. AIM To assess if rifaximin-α, a minimally absorbed antimicrobial used to manage hepatic encephalopathy (HE), may improve sarcopaenia in cirrhosis through its ammonia lowering and anti-inflammatory properties. METHODS This single-centre retrospective cohort study of patients with prior HE compared patients treated with lactulose alone to those on combination therapy with rifaximin-α. The primary outcome was a change in skeletal muscle area (SMA) as measured by computed tomography over two time points. Secondary outcomes included episodes of spontaneous bacterial peritonitis, variceal bleeding, and gastrointestinal Clostridium difficile infection. RESULTS Of the 142 patients included, 63 were on rifaximin-α [35% female, median age 57 (51, 62)], and 79 were on lactulose without rifaximin-α [20% female, median age 55 (51, 60)]. Univariate analysis for SMA found that male sex (P < 0.001), hepatocellular carcinoma presence (P = 0.024), and greater baseline body mass index (P = 0.001) were associated with improvement of SMA. Multivariate analysis that adjusted for baseline SMA was performed and found only use of rifaximin-α (P = 0.029) to be associated with improvement of SMA. CONCLUSION This study demonstrates a significant independent association between rifaximin-α therapy and muscle mass in patients with cirrhosis and HE. Prospective studies of rifaximin-α therapy examining its impact on sarcopenia are required to assess its potential therapeutic role in this cohort.
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Affiliation(s)
- Thomas Worland
- Department of Gastroenterology, Monash Health, Clayton 3168, Victoria, Australia.
| | - Penelope Hey
- Liver Transplant Unit, Austin Health, Heidelberg 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3000, Victoria, Australia
| | - Darren Wong
- Department of Medicine, University of Melbourne, Melbourne 3000, Victoria, Australia
- Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia
| | - Ross Apostolov
- Liver Transplant Unit, Austin Health, Heidelberg 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3000, Victoria, Australia
| | | | - Marie Sinclair
- Liver Transplant Unit, Austin Health, Heidelberg 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3000, Victoria, Australia
| | - Paul Gow
- Liver Transplant Unit, Austin Health, Heidelberg 3084, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne 3000, Victoria, Australia
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5
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Li Y, Wu YT, Wu H. Management of hepatic encephalopathy following transjugular intrahepatic portosystemic shunts: Current strategies and future directions. World J Gastroenterol 2025; 31:103512. [PMID: 40309228 PMCID: PMC12038546 DOI: 10.3748/wjg.v31.i15.103512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/04/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
Transjugular intrahepatic portosystemic shunts (TIPSs) are generally used for the management of complications of portal hypertension in patients with decompensated cirrhosis. However, hepatic encephalopathy (HE), which impairs neuropsychiatric function and motor control, remains the primary adverse effect of TIPS, limiting its utility. Prompt prevention and treatment of post-TIPS HE are critical, as they are strongly associated with readmission rates and poor quality of life. This review focuses on the main pathophysiological mechanisms underlying post-TIPS HE, explores advanced biomarkers and predictive tools, and discusses current management strategies and future directions to prevent or reverse HE following TIPS. These strategies include preoperative patient assessment, individualized shunt diameter optimization, spontaneous portosystemic shunt embolization during the TIPS procedure, postoperative preventive and therapeutic measures such as nutrition management, medical therapy, fecal microbiota transplantation, and stent reduction.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Tong Wu
- Chongqing Medical University-University of Leicester Joint Institute, Chongqing Medical University, Chongqing 400016, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Yakut A. Gut microbiota in the development and progression of chronic liver diseases: Gut microbiota-liver axis. World J Hepatol 2025; 17:104167. [PMID: 40177197 PMCID: PMC11959663 DOI: 10.4254/wjh.v17.i3.104167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, "How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?" has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.
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Affiliation(s)
- Aysun Yakut
- Department of Gastroenterology, İstanbul Medipol University Sefakoy Health Practice Research Center, İstanbul 38000, Türkiye.
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Xu X, Zhu T, Jing C, Jiang M, Fu Y, Xie F, Meng Q, Li J. Hepatic encephalopathy treatment after transjugular intrahepatic portosystemic shunt: a new perspective on the gut microbiota. Front Med (Lausanne) 2025; 12:1423780. [PMID: 40124683 PMCID: PMC11926149 DOI: 10.3389/fmed.2025.1423780] [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: 11/23/2024] [Accepted: 02/24/2025] [Indexed: 03/25/2025] Open
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) placement alleviates portal hypertension symptoms. Hepatic encephalopathy (HE) is a common complication of TIPS, impacting patient quality of life and the healthcare burden. Post-TIPS HE is associated with portosystemic shunting, elevated blood ammonia levels, and inflammation. Increasing attention has been given to the liver and intestinal circulation in recent years. An imbalance in intestinal microecology plays a role in the occurrence of HE and may be a new target for treatment. This review discusses the causes, diagnosis, and treatment strategies for post-TIPS HE and focuses on exploring treatment strategies and their relationships with the gut microbiota, suggesting an innovative approach to address this complication.
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Affiliation(s)
- Xiaotong Xu
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhu
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Changyou Jing
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Minjie Jiang
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yunlai Fu
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Fang Xie
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Qinghua Meng
- Department of Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jianjun Li
- Interventional Therapy Center for Oncology, Beijing Youan Hospital, Capital Medical University, Beijing, China
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8
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Morrison MA, Artru F, Trovato FM, Triantafyllou E, McPhail MJ. Potential therapies for acute-on-chronic liver failure. Liver Int 2025; 45:e15545. [PMID: 36800487 PMCID: PMC11815631 DOI: 10.1111/liv.15545] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 02/19/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.
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Affiliation(s)
- Maura A. Morrison
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Florent Artru
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Francesca M. Trovato
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Mark J. McPhail
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
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Meroni M, Longo M, Paolini E, Dongiovanni P. A narrative review about cognitive impairment in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Another matter to face through a holistic approach. J Adv Res 2025; 68:231-240. [PMID: 38369241 PMCID: PMC11785580 DOI: 10.1016/j.jare.2024.02.007] [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] [Received: 11/20/2023] [Revised: 01/28/2024] [Accepted: 02/15/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic disorder worldwide in both adults and children. It is well established that MASLD represents the hepatic manifestation of the metabolic syndrome whose definition includes the presence of obesity, type 2 diabetes (T2D), dyslipidemia, hypertension and hypercoagulability. All these conditions contribute to a chronic inflammatory status which may impact on blood brain barrier (BBB) integrity leading to an impaired function of central nervous system (CNS). AIM OF REVIEW Since the mechanisms underlying the brain-liver-gut axis derangement are still inconclusive, the present narrative review aims to make a roundup of the most recent studies regarding the cognitive decline in MASLD also highlighting possible therapeutic strategies to reach a holistic advantage for the patients. KEY SCIENTIFIC CONCEPTS OF REVIEW Due to its ever-growing prevalence, the MASLD-related mental dysfunction represents an enormous socio-economic burden since it largely impacts on the quality of life of patients as well as on their working productivity. Indeed, cognitive decline in MASLD translates in low concentration and processing speed, reduced memory, sleepiness but also anxiety and depression. Chronic systemic inflammation, hyperammonemia, genetic background and intestinal dysbiosis possibly contribute to the cognitive decline in MASLD patients. However, its diagnosis is still underestimated since the leading mechanisms are multi-faceted and unexplained and do not exist standardized diagnostic tools or cognitive test strategies. In this scenario, nutritional and lifestyle interventions as well as intestinal microbiota manipulation (probiotics, fecal transplantation) may represent new approaches to counteract mental impairment in these subjects. In sum, to face the "mental aspect" of this multifactorial disease which is almost unexplored, cognitive tools should be introduced in the management of MASLD patients.
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Affiliation(s)
- Marica Meroni
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Miriam Longo
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Erika Paolini
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paola Dongiovanni
- Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
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10
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Xu XT, Jiang MJ, Fu YL, Xie F, Li JJ, Meng QH. Gut microbiome composition in patients with liver cirrhosis with and without hepatic encephalopathy: A systematic review and meta-analysis. World J Hepatol 2025; 17:100377. [PMID: 39871903 PMCID: PMC11736471 DOI: 10.4254/wjh.v17.i1.100377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/26/2024] [Accepted: 11/19/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND The gut microbiome is associated with hepatic encephalopathy (HE), but research results on the gut microbiome characteristics of patients with liver cirrhosis with and without HE are inconsistent. AIM To study the gut microbiota characteristics of patients with liver cirrhosis with and without HE. METHODS We searched the PubMed, Web of Science, EMBASE, and Cochrane databases using two keywords, HE, and gut microbiome. According to the inclusion and exclusion criteria, suitable literature was screened to extract data on the diversity and composition of the fecal microbiota in patients with liver cirrhosis with and without HE. The data were analyzed using RevMan and STATA. RESULTS Seventeen studies were included: (1) A meta-analysis of 7 studies revealed that the Shannon index in liver cirrhosis patients with HE was significantly lower than that in patients without HE [-0.20, 95% confidence interval (CI): -0.28 to -0.13, I2 = 20%]; (2) The relative abundances of Lachnospiraceae (-2.73, 95%CI: -4.58 to -0.87, I2 = 38%) and Ruminococcaceae (-2.93, 95%CI: -4.29 to -1.56, I2 = 0%) in liver cirrhosis patients with HE was significantly lower than those in patients without HE; (3) In patients with HE, Enterococcus, Proteobacteria, Enterococcaceae, and Enterobacteriaceae proportions increased, but Ruminococcaceae, Lachnospiraceae, Prevotellaceae, and Bacteroidetes proportions decreased; (4) Differences in the fecal metabolome between liver cirrhosis patients with and without HE were detected; and (5) Differential gut microbiomes may serve as diagnostic and prognostic tools. CONCLUSION The gut microbiomes of patients with liver cirrhosis with and without HE differ. Some gut microbiomes may distinguish liver cirrhosis patients with or without HE and determine patient prognosis.
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Affiliation(s)
- Xiao-Tong Xu
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Interventional Therapy Center for Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Min-Jie Jiang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250000, Shandong Province, China
| | - Yun-Lai Fu
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
- Interventional Therapy Center for Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Fang Xie
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Jian-Jun Li
- Interventional Therapy Center for Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Interventional Therapy Center for Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China.
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Hackstein CP. Liver damage and immune responses. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:56-64. [PMID: 39793602 DOI: 10.1055/a-2365-3796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2025]
Abstract
Chronic liver disease (CLD) has massive systemic repercussions including major impacts on the body's immune system. Abnormalities in phenotype, function and numbers of various immune cell subsets have been established by a large number of clinical and pre-clinical studies. The loss of essential immune functions renders CLD-patients exceptionally susceptible to bacterial and viral infections and also impairs the efficacy of vaccination. Consequently, infections represent a major clinical issue causing significant morbidity and mortality in these patients. Mechanistically, the immune dysfunction associated with CLD results from the increased translocation of bacteria and bacterial cues from the intestine. These trigger a signaling axis around the cytokines IFN I and IL-10 in hepatic myeloid cells, which aside from impairing the function of the myeloid cells themselves, also has notable negative impacts on the functionality of other immune cells. T cells in CLD-patients and -models are especially affected by this signaling axis and display a variety of quantitative and qualitative defects. Due to the high clinical relevance, understanding the mechanisms underlaying CED-associated immune dysfunction is of critical importance to discover and develop new therapeutic targets.
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Affiliation(s)
- Carl-Philipp Hackstein
- Institut für Molekulare Immunologie, Technische Universität München, München, Germany
- Zentrum für Infektionsprävention (ZIP), Technische Universität München, Freising, Germany
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12
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Bloom PP, Chung RT. The future of clinical trials of gut microbiome therapeutics in cirrhosis. JHEP Rep 2025; 7:101234. [PMID: 39717506 PMCID: PMC11663965 DOI: 10.1016/j.jhepr.2024.101234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 12/25/2024] Open
Abstract
The last two decades have witnessed an explosion of microbiome research, including in hepatology, with studies demonstrating altered microbial composition in liver disease. More recently, efforts have been made to understand the association of microbiome features with clinical outcomes and to develop therapeutics targeting the microbiome. While microbiome therapeutics hold much promise, their unique features pose certain challenges for the design and conduct of clinical trials. Herein, we will briefly review indications for microbiome therapeutics in cirrhosis, currently available microbiome therapeutics, and the biological pathways targeted by these therapies. We will then focus on the best practices and important considerations for clinical trials of gut microbiome therapeutics in cirrhosis.
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Affiliation(s)
- Patricia P. Bloom
- University of Michigan, Division of Gastroenterology, Ann Arbor, MI, USA
| | - Raymond T. Chung
- Massachusetts General Hospital, Division of Gastroenterology, Boston, MA, USA
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13
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Song DS, Yang JM, Jung YK, Yim HJ, Kim HY, Kim CW, Kim SS, Cheong JY, Lee HL, Lee SW, Yoo JJ, Kim SG, Kim YS. Rifaximin treatment in patients with severe alcoholic hepatitis: A multicenter, randomized controlled, open-label, pilot trial. Ann Hepatol 2024; 30:101749. [PMID: 39662593 DOI: 10.1016/j.aohep.2024.101749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/10/2024] [Accepted: 09/30/2024] [Indexed: 12/13/2024]
Abstract
INTRODUCTION AND OBJECTIVES The short-term mortality of severe alcoholic-associated hepatitis (SAH) is high, but there are no effective treatments to improve short-term mortality other than corticosteroids. This study investigated the effects of adding rifaximin to standard treatment in patients with SAH. MATERIAL AND METHODS In this randomized controlled open-label trial, patients with SAH (Maddrey's discriminant function≥32) were randomized to the rifaximin or control group. Patients were simultaneously treated with corticosteroid or pentoxifylline as standard treatment for 4 weeks. Randomization was stratified by SAH treatment. RESULTS A total of 50 patients were enrolled in this study (29 in the control group and 21 in the rifaximin group). The mean Model for End-stage Liver Disease (MELD) scores were 24.4 and 27.5 in the control and rifaximin groups, respectively (P = 0.106). There were no significant differences in 6-month Liver Transplantation (LT)-free survival rate between the two groups (P = 0.502). When stratified by SAH treatment, there was no significant difference in 6-month LT-free survival rate between the control and rifaximin treatment groups (P = 0.186 in the corticosteroid group and P = 0.548 in the pentoxifylline group). There were no significant differences in the occurrence of liver-related complications between the two groups (all Ps>0.05). The MELD score was the only independent factor for 6-month LT-free survival (hazard ratio 1.188, 95 % confidence interval 1.094-1.289, P<0.001), and rifaximin was not. CONCLUSIONS In patients with SAH, adding rifaximin to corticosteroid or pentoxifylline had no survival benefit and no preventive effect on the development of liver-related complications. The MELD score was the only significant factor for short-term mortality. CLINICAL TRIAL REGISTRATION The study was registered on ClinicalTrials.gov (number: NCT02485106).
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Affiliation(s)
- Do Seon Song
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Jin Mo Yang
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea.
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea
| | - Hee Yeon Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Chang Wook Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Soon Sun Kim
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Jae Youn Cheong
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Hae Lim Lee
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Sung Won Lee
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
| | - Young Seok Kim
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
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Airola C, Severino A, Spinelli I, Gasbarrini A, Cammarota G, Ianiro G, Ponziani FR. "Pleiotropic" Effects of Antibiotics: New Modulators in Human Diseases. Antibiotics (Basel) 2024; 13:1176. [PMID: 39766566 PMCID: PMC11727521 DOI: 10.3390/antibiotics13121176] [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: 10/23/2024] [Revised: 11/22/2024] [Accepted: 11/29/2024] [Indexed: 01/15/2025] Open
Abstract
Antibiotics, widely used medications that have significantly increased life expectancy, possess a broad range of effects beyond their primary antibacterial activity. While some are recognized as adverse events, others have demonstrated unexpected benefits. These adjunctive effects, which have been defined as "pleiotropic" in the case of other pharmacological classes, include immunomodulatory properties and the modulation of the microbiota. Specifically, macrolides, tetracyclines, and fluoroquinolones have been shown to modulate the immune system in both acute and chronic conditions, including autoimmune disorders (e.g., rheumatoid arthritis, spondyloarthritis) and chronic inflammatory pulmonary diseases (e.g., asthma, chronic obstructive pulmonary disease). Azithromycin, in particular, is recommended for the long-term treatment of chronic inflammatory pulmonary diseases due to its well-established immunomodulatory effects. Furthermore, antibiotics influence the human microbiota. Rifaximin, for example, exerts a eubiotic effect that enhances the balance between the gut microbiota and the host immune cells and epithelial cells. These pleiotropic effects offer new therapeutic opportunities by interacting with human cells, signaling molecules, and bacteria involved in non-infectious diseases like spondyloarthritis and inflammatory bowel diseases. The aim of this review is to explore the pleiotropic potential of antibiotics, from molecular and cellular evidence to their clinical application, in order to optimize their use. Understanding these effects is essential to ensure careful use, particularly in consideration of the threat of antimicrobial resistance.
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Affiliation(s)
- Carlo Airola
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (A.S.); (I.S.); (A.G.); (G.C.); (G.I.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Andrea Severino
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (A.S.); (I.S.); (A.G.); (G.C.); (G.I.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Irene Spinelli
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (A.S.); (I.S.); (A.G.); (G.C.); (G.I.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (A.S.); (I.S.); (A.G.); (G.C.); (G.I.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Giovanni Cammarota
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (A.S.); (I.S.); (A.G.); (G.C.); (G.I.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Gianluca Ianiro
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (A.S.); (I.S.); (A.G.); (G.C.); (G.I.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (A.S.); (I.S.); (A.G.); (G.C.); (G.I.)
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
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15
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Bajaj JS, Pompili E, Caraceni P. The burden of hepatic encephalopathy and the use of albumin as a potential treatment. Ann Hepatol 2024; 30:101751. [PMID: 39631456 DOI: 10.1016/j.aohep.2024.101751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 09/30/2024] [Indexed: 12/07/2024]
Abstract
As a potential sequela of cirrhosis, hepatic encephalopathy (HE) significantly impacts the lives of patients and caregivers and places a substantial burden on the healthcare system. With an increasing incidence over time and a cumulative effect on cognition, HE adversely effects quality of life, morbidity and mortality in patients with cirrhosis. HE can range from minimal or covert (MHE/CHE) to overt and symptomatic (OHE). HE has profound impacts on the health and wellbeing of patients and their families and caregivers. Effective treatments could improve the quality of life for all those affected. In this article, we discuss the existing treatments for HE and focus on the potential role of albumin in the treatment of HE. Currently approved therapies for HE (lactulose and rifaximin) are focused on decreasing the formation of ammonia in the gastrointestinal tract. Among the many agents with alternative mechanisms being investigated for treatment of HE, albumin has been studied in clinical trials with acute (≤ 3 days), short-term (up to 2 weeks) prolonged (> 2 weeks) and long-term administration (months). Current studies indicate that acute or short-term administration of albumin does not provide significant benefit for patients with OHE. However, there is increasing evidence that prolonged or long-term albumin therapy can help improve cognition in OHE and prevent recurrence. Additional studies are needed to substantiate these positive findings for longer term administration of albumin in HE and to increase our comprehension of the pharmacologic basis of the effects of albumin.
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Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Healthcare System, Richmond, Virginia, USA.
| | - Enrico Pompili
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy; Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy; Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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16
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Hurtado-Díaz-de-León I, Tapper EB. Systems of care that improve outcomes for people with hepatic encephalopathy. Metab Brain Dis 2024; 40:50. [PMID: 39621162 DOI: 10.1007/s11011-024-01430-8] [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: 04/06/2024] [Accepted: 10/31/2024] [Indexed: 12/11/2024]
Abstract
Hepatic encephalopathy (HE) is a critical neuropsychiatric complication of liver cirrhosis with a significant impact on patient quality of life and survival. The global prevalence of cirrhosis and associated HE necessitates a comprehensive understanding of the condition and effective systems of care to optimize outcomes. This review addresses the epidemiology, classification, diagnosis, and management of HE, with an emphasis on systems of care that improve outcomes for people with HE. Current diagnostic challenges include differentiating cognitive deficits attributable to HE from those caused by other etiologies, highlighting the need for accurate diagnostic methods. Traditional psychometric tests, while valuable for diagnosing covert HE (CHE), are limited in their ability to predict overt HE (OHE) due to various confounding factors. As a result, non-psychometric tools have been developed to provide outcome-based predictions aligned with the clinical course of HE. The management of HE includes addressing precipitating factors, pharmacologic interventions to reduce ammonia levels, and supportive care, with lactulose and rifaximin playing a central role. Preventive strategies with the use of remote monitoring in the outpatient management of HE, integrating technology for real-time tracking of therapy compliance and symptom evolution, could contribute to reducing hospital readmissions and improving patient care.
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Affiliation(s)
- Ivonne Hurtado-Díaz-de-León
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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17
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Prasad SK, Acharjee A, Singh VV, Trigun SK, Acharjee P. Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction. Metab Brain Dis 2024; 39:1649-1665. [PMID: 39120853 DOI: 10.1007/s11011-024-01407-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
Cerebral function is linked to a high level of metabolic activity and relies on glucose as its primary energy source. Glucose aids in the maintenance of physiological brain activities; as a result, a disruption in metabolism has a significant impact on brain function, launching a chain of events that leads to neuronal death. This metabolic insufficiency has been observed in a variety of brain diseases and neuroexcitotoxicity disorders, including hepatic encephalopathy. It is a significant neurological complication that develops in people with liver disease, ranging from asymptomatic abnormalities to coma. Hyperammonemia is the main neurotoxic villain in the development of hepatic encephalopathy and induces a wide range of complications in the brain. The neurotoxic effects of ammonia on brain function are thought to be mediated by impaired glucose metabolism. Accordingly, in this review, we provide an understanding of deranged brain energy metabolism, emphasizing the role of glucose metabolic dysfunction in the pathogenesis of hepatic encephalopathy. We also highlighted the differential metabolic profiles of brain cells and the status of metabolic cooperation between them. The major metabolic pathways that have been explored are glycolysis, glycogen metabolism, lactate metabolism, the pentose phosphate pathway, and the Krebs cycle. Furthermore, the lack of efficacy in current hepatic encephalopathy treatment methods highlights the need to investigate potential therapeutic targets for hepatic encephalopathy, with regulating deficient bioenergetics being a viable alternative in this case. This review also demonstrates the importance of the development of glucose metabolism-focused disease diagnostics and treatments, which are now being pursued for many ailments.
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Affiliation(s)
- Shambhu Kumar Prasad
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Arup Acharjee
- Department of Zoology, University of Allahabad, Prayagraj, 211002, India.
| | - Vishal Vikram Singh
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Surendra Kumar Trigun
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
| | - Papia Acharjee
- Biochemistry and Molecular Biology Unit, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
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18
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Ntuli Y, Shawcross DL. Infection, inflammation and hepatic encephalopathy from a clinical perspective. Metab Brain Dis 2024; 39:1689-1703. [PMID: 39212845 PMCID: PMC11535002 DOI: 10.1007/s11011-024-01402-y] [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: 04/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024]
Abstract
Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.
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Affiliation(s)
- Yevedzo Ntuli
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Debbie L Shawcross
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK.
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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19
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Llansola M, Izquierdo-Altarejos P, Montoliu C, Mincheva G, Palomares-Rodriguez A, Pedrosa MA, Arenas YM, Felipo V. Role of peripheral inflammation in minimal hepatic encephalopathy. Metab Brain Dis 2024; 39:1667-1677. [PMID: 39177864 DOI: 10.1007/s11011-024-01417-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/16/2024] [Indexed: 08/24/2024]
Abstract
Many patients with liver cirrhosis show minimal hepatic encephalopathy (MHE) with mild cognitive impairment (MCI) and motor alterations that reduce their quality of life. Some patients with steatotic liver disease also suffer MCI. To design treatments to improve MHE/MCI it is necessary to understand the mechanisms by which liver disease induce them. This review summarizes studies showing that appearance of MHE/MCI is associated with a shift in the immunophenotype leading to an "autoimmune-like" form with increased pro-inflammatory monocytes, enhanced CD4 T and B lymphocytes activation and increased plasma levels of pro-inflammatory cytokines, including IL-17, IL-21, TNFα, IL-15 and CCL20. The contribution of peripheral inflammation to trigger MHE is supported by studies in animal models and by the fact that rifaximin treatment reverses MHE in around 60% of patients in parallel with reversal of the changes in peripheral inflammation. MHE does not improve in patients in which peripheral inflammation is not improved by rifaximin. The process by which peripheral inflammation induces MHE involves induction of neuroinflammation in brain, with activation of microglia and astrocytes and increased pro-inflammatory TNFα and IL-1β, which is observed in patients who died with steatotic liver disease (SLD) or liver cirrhosis and in animal models of MHE. Neuroinflammation alters glutamatergic and GABAergic neurotransmission, leading to cognitive and motor impairment. Transmission of peripheral alterations into the brain is mediated by infiltration in brain of extracellular vesicles from plasma and of cells from the peripheral immune system. Acting on any step of the process peripheral inflammation - neuroinflammation - altered neurotransmission may improve MHE.
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Affiliation(s)
- Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | | | - Carmina Montoliu
- Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Gergana Mincheva
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | | | - María A Pedrosa
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Yaiza M Arenas
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
- Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
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20
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Raya Tonetti F, Eguileor A, Mrdjen M, Pathak V, Travers J, Nagy LE, Llorente C. Gut-liver axis: Recent concepts in pathophysiology in alcohol-associated liver disease. Hepatology 2024; 80:1342-1371. [PMID: 38691396 PMCID: PMC11801230 DOI: 10.1097/hep.0000000000000924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/20/2024] [Indexed: 05/03/2024]
Abstract
The growing recognition of the role of the gut microbiome's impact on alcohol-associated diseases, especially in alcohol-associated liver disease, emphasizes the need to understand molecular mechanisms involved in governing organ-organ communication to identify novel avenues to combat alcohol-associated diseases. The gut-liver axis refers to the bidirectional communication and interaction between the gut and the liver. Intestinal microbiota plays a pivotal role in maintaining homeostasis within the gut-liver axis, and this axis plays a significant role in alcohol-associated liver disease. The intricate communication between intestine and liver involves communication between multiple cellular components in each organ that enable them to carry out their physiological functions. In this review, we focus on novel approaches to understanding how chronic alcohol exposure impacts the microbiome and individual cells within the liver and intestine, as well as the impact of ethanol on the molecular machinery required for intraorgan and interorgan communication.
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Affiliation(s)
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Marko Mrdjen
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Vai Pathak
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jared Travers
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, University Hospital, Cleveland OH
| | - Laura E Nagy
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland OH
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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21
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Li S, Cai Y, Wang S, Luo L, Zhang Y, Huang K, Guan X. Gut microbiota: the indispensable player in neurodegenerative diseases. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:7096-7108. [PMID: 38572789 DOI: 10.1002/jsfa.13509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/26/2024] [Accepted: 04/04/2024] [Indexed: 04/05/2024]
Abstract
As one of the most urgent social and health problems in the world, neurodegenerative diseases have always been of interest to researchers. However, the pathological mechanisms and therapeutic approaches are not achieved. In addition to the established roles of oxidative stress, inflammation and immune response, changes of gut microbiota are also closely related to the pathogenesis of neurodegenerative diseases. Gut microbiota is the central player of the gut-brain axis, the dynamic bidirectional communication pathway between gut microbiota and central nervous system, and emerging insights have confirmed its indispensability in the development of neurodegenerative diseases. In this review, we discuss the complex relationship between gut microbiota and the central nervous system from the perspective of the gut-brain axis; review the mechanism of microbiota for the modulation different neurodegenerative diseases and discuss how different dietary patterns affect neurodegenerative diseases via gut microbiota; and prospect the employment of gut microbiota in the therapeutic approach to those diseases. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Sen Li
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, China
| | - Yuwei Cai
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, China
| | - Shuo Wang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, China
| | - Lei Luo
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, China
| | - Yu Zhang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, China
| | - Kai Huang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, China
| | - Xiao Guan
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- National Grain Industry (Urban Grain and Oil Security) Technology Innovation Center, Shanghai, China
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22
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Wu S, Li L, Xi H, Wu X, He Y, Sun X, Wu L. Bibliometrics and knowledge mapping of the pathogenesis of hepatic encephalopathy in patients with liver cirrhosis. Heliyon 2024; 10:e34330. [PMID: 39145014 PMCID: PMC11320160 DOI: 10.1016/j.heliyon.2024.e34330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 08/16/2024] Open
Abstract
Background Hepatic encephalopathy is a common and serious complication of decompensated cirrhosis. It can considerably contribute to economic burden and impaired quality of life. However, its pathogenesis remains unclear. Method In this study, we aimed to visually analyse the research status and development trends in hepatic encephalopathy pathogenesis using bibliometrics and knowledge mapping. Information regarding publications between 1978 and 2022 were obtained from the Web of Science Core Collection. CiteSpace was used to analyse and present data by year, author, institution, country, journal, reference, and keyword. Results A total of 1578 publications on hepatic encephalopathy pathogenesis in patients with cirrhosis were retrieved from Web of Science Core Collection. A gradual increasing trend in annual publications has occurred. The collaborative network analysis results suggest the United States of America, the University of London, and Bajaj, Jasmohan S as the most influential country, institution, and author, respectively, in this research field. Notably, China appeariiuis to be the most promising country. Research on 'hepatology' garners the most significant papers in the field. Combined with reference co-citation and keyword co-occurrence analyses, we found that ammonia metabolism, gut microbiota, sarcopenia, and trace elements will become future research frontiers that are likely to be explored for a considerable length of time. Conclusion Future research directions in HE pathogenesis may target modulating the ammonia metabolism, the gut microbiota, sarcopenia, and trace elements.
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Affiliation(s)
- Shiyan Wu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
- Department of Gastroenterology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
| | - Lu Li
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
- Department of Gastroenterology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
| | - Heng Xi
- Department of Pharmacy, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
| | - Xiaoping Wu
- Department of Gastroenterology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
| | - Yumei He
- North Sichuan Medical College, Nanchong, 623300, Sichuan Province, China
| | - Xiaobin Sun
- Department of Gastroenterology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
| | - Liping Wu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan Province, China
- Department of Gastroenterology, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, Sichuan Province, China
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23
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Mantovani A, Longo L, Thoen RU, Rampelotto PH, Salinas R, Guerreiro GTS, Álvares-da-Silva MR. Firmicutes/Bacteroidetes and Firmicutes/Proteobacteria ratios are associated with worse prognosis in a cohort of Latin American patients with cirrhosis. Clinics (Sao Paulo) 2024; 79:100471. [PMID: 39098143 PMCID: PMC11345307 DOI: 10.1016/j.clinsp.2024.100471] [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: 04/06/2024] [Revised: 07/04/2024] [Accepted: 07/19/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND Some evidence suggests an association between gut dysbiosis and cirrhosis progression. The authors investigated Gut Microbiome (GM) influence on 90-day mortality and hospitalization/rehospitalization rates in cirrhotic patients. METHODS Compensated/decompensated outpatients and decompensated inpatients were prospectively included and compared to healthy controls. Clinical, laboratory, GM, and two ratios between phyla were evaluated. Patients were followed up for 90 days for hospitalization/rehospitalization and mortality. RESULTS 165 individuals were included (50 compensated, 49 decompensated outpatients; 36 decompensated inpatients; 30 healthy), 48.5 % female, mean age was 61, main cirrhosis etiology was hepatitis C (27.3 %), and mostly Child-Pugh (CP) B patients, median MELD of 13. As liver disease progressed, microbiota diversity decreased between the groups (p = 0.05; p < 0.004). There were 9 deaths and 22 hospitalizations or rehospitalizations. GM composition had correlation with norfloxacin (p = 0.36, p = 0.04), encephalopathy (p = 0.31, p = 0.01), lactulose (p = 0.26, p = 0.01), 90-day mortality (p = 0.22, p = 0.04), CP (p = 0.17, p = 0.01), previous 6-month antibiotic use (p = 0.16, p = 0.01), MELD (p = 0.145, p = 0.01), ALBI (p = 0.1, p = 0.04) and 90-day hospitalization/rehospitalization (p = 0.08, p = 0.03). Firmicutes/Bacteroidetes (F/B) and Firmicutes/Proteobacteria (F/P) ratios were progressively lower and more significant and had an association with 90-day mortality (p < 0.001). Three MELD set-points (≥ 15, 18 and 20) were significantly associated with both ratios, with similar accuracies. CONCLUSIONS GM dysbiosis was associated with higher CP, MELD, 90-day mortality and hospitalization/rehospitalization. F/B and F/P ratios were associated with 90-day mortality.
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Affiliation(s)
- Augusto Mantovani
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Larisse Longo
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil
| | - Rutiane Ullmann Thoen
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil
| | - Pabulo Henrique Rampelotto
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; Bioinformatics and Biostatistics Core Facility, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Raul Salinas
- Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil
| | | | - Mário Reis Álvares-da-Silva
- Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Experimental Laboratory of Hepatology and Gastroenterology, Center for Experimental Research, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq Researcher, Brazil; Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
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24
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Maharshi S, Sharma BC. Prophylaxis of hepatic encephalopathy: current and future drug targets. Hepatol Int 2024; 18:1096-1109. [PMID: 38492132 DOI: 10.1007/s12072-024-10647-9] [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: 09/21/2023] [Accepted: 01/18/2024] [Indexed: 03/18/2024]
Abstract
Hepatic encephalopathy is described by a broad spectrum of neurological and psychiatric aberrations resulting due to advanced liver dysfunction. It is a neurological disorder due to hepatic insufficiency and/or portosystemic shunts. Its clinical presentation includes neuropsychiatric dysfunction ranging from subclinical changes to comatose state. It is a sign of poor prognosis in cirrhotics with a high 1-year mortality. Each episode of hepatic encephalopathy leads to high hospitalization rate, poor prognosis and raised burden of healthcare. Primary prophylaxis is prevention of initial occurrence and secondary prophylaxis is prevention of reappearance of hepatic encephalopathy in subjects who had prior history. Early detection and management of triggers is very important in the treatment of hepatic encephalopathy. The initial choice of treatment is still lactulose, as it is effective in minimal, overt, and recurrent hepatic encephalopathy. Rifaximin is equally effective as lactulose in managing hepatic encephalopathy and is better tolerated. Branch chain amino acids are beneficial in subjects who are protein intolerant. L-ornithine L-aspartate and probiotics are also useful in the management of hepatic encephalopathy. Rifaximin along with lactulose is effective in managing overt and recurrent hepatic encephalopathy. Large portosystemic shunts embolization and liver transplant is efficacious in certain group of patients. Nutritional therapy and fecal microbiota transplantation are newer therapies for hepatic encephalopathy but the evidences are limited, more research is required to prove their efficacy. Involvement of hospital pharmacists, telemedicine, and providing education are also beneficial in managing hepatic encephalopathy.
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Affiliation(s)
- Sudhir Maharshi
- Department of Gastroenterology, SMS Medical College and Hospitals, Jaipur, India
| | - Barjesh Chander Sharma
- Department of Gastroenterology, G.B. Pant Hospital, Room No. 201, Academic Block, New Delhi, 110002, India.
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25
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Smith ML, Wade JB, Wolstenholme J, Bajaj JS. Gut microbiome-brain-cirrhosis axis. Hepatology 2024; 80:465-485. [PMID: 36866864 PMCID: PMC10480351 DOI: 10.1097/hep.0000000000000344] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/10/2023] [Indexed: 03/04/2023]
Abstract
Cirrhosis is characterized by inflammation, degeneration, and fibrosis of liver tissue. Along with being the most common cause of liver failure and liver transplant, cirrhosis is a significant risk factor for several neuropsychiatric conditions. The most common of these is HE, which is characterized by cognitive and ataxic symptoms, resulting from the buildup of metabolic toxins with liver failure. However, cirrhosis patients also show a significantly increased risk for neurodegenerative diseases such as Alzheimer and Parkinson diseases, and for mood disorders such as anxiety and depression. In recent years, more attention has been played to communication between the ways the gut and liver communicate with each other and with the central nervous system, and the way these organs influence each other's function. This bidirectional communication has come to be known as the gut-liver-brain axis. The gut microbiome has emerged as a key mechanism affecting gut-liver, gut-brain, and brain-liver communication. Clinical studies and animal models have demonstrated the significant patterns of gut dysbiosis when cirrhosis is present, both with or without concomitant alcohol use disorder, and have provided compelling evidence that this dysbiosis also influences the cognitive and mood-related behaviors. In this review, we have summarized the pathophysiological and cognitive effects associated with cirrhosis, links to cirrhosis-associated disruption of the gut microbiome, and the current evidence from clinical and preclinical studies for the modulation of the gut microbiome as a treatment for cirrhosis and associated neuropsychiatric conditions.
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Affiliation(s)
- Maren L Smith
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - James B Wade
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jennifer Wolstenholme
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
- Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
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26
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Guevara-Cruz M, Hernández-Gómez KG, Condado-Huerta C, González-Salazar LE, Peña-Flores AK, Pichardo-Ontiveros E, Serralde-Zúñiga AE, Sánchez-Tapia M, Maya O, Medina-Vera I, Noriega LG, López-Barradas A, Rodríguez-Lima O, Mata I, Olin-Sandoval V, Torres N, Tovar AR, Velázquez-Villegas LA. Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial. Clin Nutr 2024; 43:1914-1928. [PMID: 39003957 DOI: 10.1016/j.clnu.2024.06.036] [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: 02/27/2024] [Revised: 06/24/2024] [Accepted: 06/30/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND Mitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota. METHODS AND FINDINGS A randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p = 0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p = 0.0001), enriched the abundance of Phascolarctobacterium faecium (p = 0.019) in the CR group and Ruminococcus bromii (p = 0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman's correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p = 0.002; IF, p = 0.001; and KD, p = 0.001) compared to those in the AL group at the end of the study. CONCLUSIONS We conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials. TRIAL REGISTRATION This trial was registered with ClinicalTrials.gov (NCT05200468).
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Affiliation(s)
- Martha Guevara-Cruz
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Karla G Hernández-Gómez
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Citlally Condado-Huerta
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Luis E González-Salazar
- Servicio de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Ana Karen Peña-Flores
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Edgar Pichardo-Ontiveros
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Aurora E Serralde-Zúñiga
- Servicio de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Mónica Sánchez-Tapia
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Otoniel Maya
- Chalmers e-Commons. Chalmers University of Technology, Gotemburg, Vastra Gotaland, Sweden
| | - Isabel Medina-Vera
- Departamento de Metodología de la Investigación, Instituto Nacional de Pediatría, Ciudad de México, Mexico
| | - Lilia G Noriega
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Adriana López-Barradas
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Oscar Rodríguez-Lima
- Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Irma Mata
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Viridiana Olin-Sandoval
- Laboratorio 43. Departamento de Biotecnología y Bioingeniería, Cinvestav-Zacatenco, Ciudad de México, Mexico
| | - Nimbe Torres
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Armando R Tovar
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Laura A Velázquez-Villegas
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico.
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Ahmed Z, Gangwani MK, Iqbal U, Kazi AI, Arif SF, Priyanka F, Lee-Smith W, Aziz M, Jaber F, Dahiya DS, Ali H, Inamdar S, Confer B. Role of Rifaximin in the Prevention of Variceal Bleeding: Systematic Review and Meta-Analysis. Am J Ther 2024; 31:e511-e514. [PMID: 38810173 DOI: 10.1097/mjt.0000000000001712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Affiliation(s)
- Zohaib Ahmed
- Department of Medicine, University of Toledo Medical Center, Toledo, OH
| | | | - Umair Iqbal
- Department of Gastroenterology and Hepatology, Geisenger Medical Center, Danville, PA
| | - Amal Iqbal Kazi
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Syeda Faiza Arif
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Fnu Priyanka
- Department of Medicine, University of Toledo Medical Center, Toledo, OH
| | - Wade Lee-Smith
- Depatment of Toledo Libraries, University of Toledo, Toledo, OH
| | - Muhammad Aziz
- Department of Medicine, University of Toledo Medical Center, Toledo, OH
| | - Fouad Jaber
- Department of Medicine, University of Missouri-Kansas City, Kansas, MO
| | | | - Hassam Ali
- Department of Gastroenterology and Hepatology, East Carolina University Health, Greenville, NC
| | - Sumant Inamdar
- Department of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Texarkana, AR
| | - Bradley Confer
- Department of Gastroenterology and Hepatology, Geisenger Medical Center, Danville, PA
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28
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Garg P, Verma N, Angrup A, Taneja N, Valsan A, Reddy VD, Agarwal J, Chaudhary R, Kaur P, Rathi S, De A, Premkumar M, Taneja S, Duseja A. Exploring the Prevalence, Predictors, and Impact of Bacterial Infections to Guide Empiric Antimicrobial Decisions in Cirrhosis (EPIC-AD). J Clin Exp Hepatol 2024; 14:101352. [PMID: 38449507 PMCID: PMC10914474 DOI: 10.1016/j.jceh.2024.101352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 01/25/2024] [Indexed: 03/08/2024] Open
Abstract
Background/Aims This study delved into cirrhosis-related infections to unveil their epidemiology, risk factors, and implications for antimicrobial decisions. Methods We analyzed acutely decompensated cirrhosis patients (n = 971) from North India between 2013-2023 at a tertiary center. Microbiological and clinical features based on infection sites (EASL criteria) and patient outcomes were assessed. Results Median age was 45 years; 87% were males with 47% having alcoholic hepatitis. Of these, 675 (69.5%) had infections; 305 (45%) were culture-confirmed. Notably, 71% of confirmed cases were multi-drug resistant organisms (MDRO)-related, chiefly carbapenem-resistant (48%). MDRO prevalence was highest in pulmonary (80.5%) and skin-soft-tissue infections (76.5%). Site-specific distribution and antimicrobials were suggested. Predictive models identified prior hospitalization [OR:2.23 (CI:1.58-3.14)], norfloxacin prophylaxis [OR:2.26 (CI:1.44-3.55)], prior broad-spectrum antibiotic exposure [OR:1.61 (CI:1.12-2.30)], presence of systemic inflammatory response-SIRS [OR:1.75 (CI: 1.23-2.47)], procalcitonin [OR:4.64 (CI:3.36-6.40)], and HE grade [OR:1.41 (CI:1.04-1.90)], with an area under curve; AUC of 0.891 for infection prediction. For MDRO infection prediction, second infection [OR: 7.19 (CI: 4.11-12.56)], norfloxacin prophylaxis [OR: 2.76 (CI: 1.84-4.13)], CLIF-C OF [OR: 1.10 (CI: 1.01-1.20)], prior broad-spectrum antibiotic exposure [OR: 1.66 (CI: 1.07-2.55)], rifaximin [OR: 040 (0.22-0.74)] multisite [OR: 3.67 (CI: 1.07-12.56)], and polymicrobial infection [OR: 4.55 (CI: 1.45-14.17)] yielded an AUC of 0.779 and 93% specificity. Norfloxacin prophylaxis, multisite infection, mechanical ventilation, prior broad-spectrum antibiotic exposure, and infection as acute precipitant predicted carbapenem-resistant infection (AUC: 0.821). Infections (culture-proven or probable), MDROs, carbapenem/pan-drug resistance, and second infections independently linked with mortality (P < 0.001), adjusted for age, leucocytosis, and organ failures. A model incorporating age [HR:1.02 (CI: 1.01-1.03), infection [HR:1.52 (CI: 1.05-2.20)], prior hospitalization [HR:5.33 (CI: 3.75-7.57)], norfloxacin [HR:1.29 (CI: 1.01-1.65)], multisite infection [HR:1.47 (CI:1.06-2.04)], and chronic liver failure consortium-organ failure score; CLIF-C OF [HR:1.17 (CI: 1.11-1.23)] predicted mortality with C-statistics of 0.782 (P < 0.05). Conclusion High MDRO burden, especially carbapenem-resistant, necessitates urgent control measures in cirrhosis. Site-specific epidemiology and risk models can guide empirical antimicrobial choices in cirrhosis management.
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Affiliation(s)
- Pratibha Garg
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Archana Angrup
- Department of Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Neelam Taneja
- Department of Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Arun Valsan
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Venkata D. Reddy
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jayant Agarwal
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Roma Chaudhary
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Parminder Kaur
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sahaj Rathi
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Samanta A, Sen Sarma M. Fecal microbiota transplantation in the treatment of hepatic encephalopathy: A perspective. World J Hepatol 2024; 16:678-683. [PMID: 38818298 PMCID: PMC11135264 DOI: 10.4254/wjh.v16.i5.678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/06/2024] [Accepted: 04/16/2024] [Indexed: 05/22/2024] Open
Abstract
Due to its complex pathogenesis, treatment of hepatic encephalopathy (HE) continues to be a therapeutic challenge. Of late, gut microbiome has garnered much attention for its role in the pathogenesis of various gastrointestinal and liver diseases and its potential therapeutic use. New evidence suggests that gut microbiota plays a significant role in cerebral homeostasis. Alteration in the gut microbiota has been documented in patients with HE in a number of clinical and experimental studies. Research on gut dysbiosis in patients with HE has opened newer therapeutic avenues in the form of probiotics, prebiotics and the latest fecal microbiota transplantation (FMT). Recent studies have shown that FMT is safe and could be effective in improving outcomes in advanced liver disease patients presenting with HE. However, questions over the appropriate dose, duration and route of administration for best treatment outcome remains unsettled.
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Affiliation(s)
- Arghya Samanta
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
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30
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Redfield R, Latt N, Munoz SJ. Minimal Hepatic Encephalopathy. Clin Liver Dis 2024; 28:237-252. [PMID: 38548436 DOI: 10.1016/j.cld.2024.01.004] [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: 04/02/2024]
Abstract
Minimal hepatic encephalopathy (MHE) is a pervasive frequent complication of cirrhosis of any etiology. The diagnosis of MHE is difficult as the standard neurologic examination is essentially within normal limits. None of the symptoms and signs of overt HE is present in a patient with MHE, such as confusion, disorientation, or asterixis. Progress has been made in diagnostic tools for detection of attention and cognitive deficits at the point of care of MHE. The development of MHE significantly impacts quality of life and activities of daily life in affected patients including driving motor vehicles and machine operation.
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Affiliation(s)
- Rachel Redfield
- Thomas Jefferson Hospital, Division of Gastroenterology, 132 S. 10th Street, Suite 480, Philadelphia, PA 19106, USA
| | - Nyan Latt
- Virtua Health System, Center for Liver Disease and Transplant Program, 63 Kresson Road, Suite 101, Cherry Hill, NJ 08034, USA
| | - Santiago J Munoz
- The Johns Hopkins University School of Medicine and Medical Institutions, Division of Gastroenterology and Hepatology, 600 N. Wolfe Street, Blalock Building, Suite 465, Baltimore, MD 21287, USA.
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31
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Nie MT, Wang PQ, Shi PM, Hong XL, Zhang X, Xiang B, Zhang M, Xie WF. Rifaximin treatment shapes a unique metagenome-metabolism network in patients with decompensated cirrhosis. J Gastroenterol Hepatol 2024; 39:762-771. [PMID: 38233085 DOI: 10.1111/jgh.16484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/04/2023] [Accepted: 12/20/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND Patients with decompensated cirrhosis face poor prognosis and increased mortality risk. Rifaximin, a non-absorbable antibiotic, has been shown to have beneficial effects in preventing complications and improving survival in these patients. However, the underlying mechanisms of rifaximin's effects remain unclear. METHODS We obtained fecal samples from decompensated cirrhotic patients undergoing rifaximin treatment and controls, both at baseline and after 6 months of treatment. Shotgun metagenome sequencing profiled the gut microbiome, and untargeted metabolomics analyzed fecal metabolites. Linear discriminant and partial least squares discrimination analyses were used to identify differing species and metabolites between rifaximin-treated patients and controls. RESULTS Forty-two patients were enrolled and divided into two groups (26 patients in the rifaximin group and 16 patients in the control group). The gut microbiome's beta diversity changed in the rifaximin group but remained unaffected in the control group. We observed 44 species with reduced abundance in the rifaximin group, including Streptococcus_salivarius, Streptococcus_vestibularis, Haemophilus_parainfluenzae, etc. compared to only four in the control group. Additionally, six species were enriched in the rifaximin group, including Eubacterium_sp._CAG:248, Prevotella_sp._CAG:604, etc., and 14 in the control group. Furthermore, rifaximin modulated different microbial functions compared to the control. Seventeen microbiome-related metabolites were altered due to rifaximin, while six were altered in the control group. CONCLUSION Our study revealed distinct microbiome-metabolite networks regulated by rifaximin intervention in patients with decompensated cirrhosis. These findings suggest that targeting these specific metabolites or related bacteria might be a potential therapeutic strategy for decompensated cirrhosis.
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Affiliation(s)
- Mei-Tong Nie
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Pei-Qin Wang
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Pei-Mei Shi
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xia-Lu Hong
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xin Zhang
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Baoyu Xiang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Menghui Zhang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Fen Xie
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
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Gao T, Wang S, Zhu Z, Lin L, Luo Y, Lu M, Liao W. Components from Curcuma longa (Turmeric) Against Hepatobiliary Diseases Based on Gut-Liver Axis: Pharmacotherapeutic Properties and Potential Clinical Applications. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2024; 52:387-415. [PMID: 38490808 DOI: 10.1142/s0192415x24500162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/17/2024]
Abstract
Turmeric is widely used worldwide, and there are many examples of its use in treating hepatobiliary diseases. The gut-liver axis is a bidirectional relationship between gut microorganisms and the liver that is closely related to the pathogenesis of hepatobiliary diseases. This review systematically summarizes the components of turmeric. It links the studies on turmeric affecting gut microorganisms to its effects on liver and biliary diseases to explain the potential mechanism of turmeric's regulation of the gut-liver axis. Besides, ethnopharmacology, phytochemicals, and clinical adverse events associated with turmeric have been researched. Furthermore, turmeric is a safe agent with good clinical efficacy and without apparent toxicity at a certain amount. By summarizing the influence of turmeric on the liver by regulating the gut-liver axis, especially the gut microbiota, it provides a preclinical basis for using turmeric as a safe and effective therapeutic agent for the prevention and treatment of hepatobiliary diseases based on the gut-liver axis. However, more efforts should be made to exploit its clinical application further.
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Affiliation(s)
- Tianhui Gao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Shuyi Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Zongping Zhu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Liting Lin
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Yirong Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
| | - Meigui Lu
- Huachiew TCM Hospital, Bangkok 10100, Thailand
| | - Wan Liao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy/ School of Modern Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
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Zhu X, Zhou Z, Pan X. Research reviews and prospects of gut microbiota in liver cirrhosis: a bibliometric analysis (2001-2023). Front Microbiol 2024; 15:1342356. [PMID: 38550860 PMCID: PMC10972893 DOI: 10.3389/fmicb.2024.1342356] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/15/2024] [Indexed: 06/20/2024] Open
Abstract
INTRODUCTION The gut-liver axis has emerged as a focal point in chronic liver disorders, prompting more research into the role of the gut microbiota in liver cirrhosis. In individuals with liver cirrhosis, changes in the structure and function of the gut microbiota are closely tied to clinical prognosis. However, there is a scarcity of bibliometric evaluations conducted in this particular field. METHODS This study is aiming to conduct a complete analysis of the knowledge structure and centers pertaining to gut microbiota in liver cirrhosis using bibliometric methods. Publications on gut microbiota and liver cirrhosis from 2001 to 2023 are sourced from the Web of Science Core Collection. For the bibliometric analysis, we employ VOSviewer, CiteSpace, and the R package "bibliometrix". RESULTS Our study encompasses a comprehensive collection of 3109 articles originating from 96 countries, with notable contributions from leading nations such as the United States and China. The quantity of publications concerning the gut microbiota of liver cirrhosis rises annually. The University of California San Diego, Virginia Commonwealth University, Zhejiang University are the primary research institutions. World Journal of Gastroenterology publishes the most papers in this field, while hepatology is the most frequently co-cited journal. These publications come from a total of 15,965 authors, and the most prolific authors are Bajaj Jasmohan S., Schnabl Bernd and Gillevet Patrick M., while the most co-cited authors are Bajaj Jasmohan S., Younossi Zobair M., and Reiner Wiest. In addition, "dysbiosis", "gut microbiota", "intestinal barrier", "fecal microbiota transplantation", and "complement-system" are the primary keywords of research trends in recent years. DISCUSSION This study offering a comprehensive insight into the research dynamics surrounding gut microbiota in patients with liver cirrhosis. It delineates the current research frontiers and hotspots, serving as a valuable guide for scholars.
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Affiliation(s)
- Xiaofei Zhu
- Department of Infectious Diseases, Hangzhou Ninth People’s Hospital, Hangzhou, China
| | - Ziyuan Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaxia Pan
- Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, China
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Jiang X, Xu Y, Fagan A, Patel B, Zhou H, Bajaj JS. Single nuclear RNA sequencing of terminal ileum in patients with cirrhosis demonstrates multi-faceted alterations in the intestinal barrier. Cell Biosci 2024; 14:25. [PMID: 38369527 PMCID: PMC10875857 DOI: 10.1186/s13578-024-01209-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 02/12/2024] [Indexed: 02/20/2024] Open
Abstract
Patients with cirrhosis have intestinal barrier dysfunction but the role of the individual cell types in human small intestine is unclear. We performed single-nuclear RNA sequencing (snRNAseq) in the pinch biopsies of terminal ileum of four age-matched men [56 years, healthy control, compensated, early (ascites and lactulose use) and advanced decompensated cirrhosis (ascites and rifaximin use)]. Cell type proportions, differential gene expressions, cell-type specific pathway analysis using IPA, and cellular crosstalk dynamics were compared. Stem cells, enterocytes and Paneth cells were lowest in advanced decompensation. Immune cells like naive CD4 + T cells were lowest while ITGAE + cells were highest in advanced decompensation patients. MECOM had lowest expression in stem cells in advanced decompensation. Defensin and mucin sulfation gene (PAPSS2) which can stabilize the mucus barrier expression were lowest while IL1, IL6 and TNF-related genes were significantly upregulated in the enterocytes, goblet, and Paneth cells in decompensated subjects. IPA analysis showed higher inflammatory pathways in enterocytes, stem, goblet, and Paneth cells in decompensated patients. Cellular crosstalk analysis showed that desmosome, protease-activated receptors, and cadherin-catenin complex interactions were most perturbed in decompensated patients. In summary, the snRNAseq of the human terminal ileum in 4 subjects (1 control and three cirrhosis) identified multidimensional alteration in the intestinal barrier with lower stem cells and altered gene expression focused on inflammation, mucin sulfation and cell-cell interactions with cirrhosis decompensation.
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Affiliation(s)
- Xixian Jiang
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, 1201 Broad Rock Blvd., Richmond, VA, USA
| | - Ying Xu
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, 1201 Broad Rock Blvd., Richmond, VA, USA
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, 1201 Broad Rock Blvd., Richmond, VA, USA
| | - Bhaumik Patel
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, 1201 Broad Rock Blvd., Richmond, VA, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond VA Medical Center, 1220 East Broad Street, Richmond, VA, 23298, USA.
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, 1201 Broad Rock Blvd., Richmond, VA, USA.
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Bajaj JS, Fagan A, Gavis EA, Mousel T, Gallagher ML, Puri P, Fuchs M, Davis BC, Hylemon PB, Zhou H, Ahluwalia V, Cadrain R, Sikaroodi M, Gillevet PM. The RIVET RCT: Rifamycin SV MMX improves muscle mass, physical function, and ammonia in cirrhosis and minimal encephalopathy. Hepatol Commun 2024; 8:e0384. [PMID: 38315140 PMCID: PMC10843468 DOI: 10.1097/hc9.0000000000000384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 01/02/2024] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) negatively affects the prognosis of cirrhosis, but treatment is not standard. Rifamycin SV MMX (RiVM) is a nonabsorbable rifampin derivative with colonic action. METHODS In a phase 2 placebo-controlled, double-blind randomized clinical trial patients with MHE were randomized to RiVM or placebo for 30 days with a 7-day follow-up. The primary endpoint was a change in stool cirrhosis dysbiosis ratio. Gut-brain (cognition, stool/salivary microbiome, ammonia, brain magnetic resonance spectroscopy), inflammation (stool calprotectin/serum cytokines), patient-reported outcomes (sickness impact profile: total/physical/psychosocial, high = worse), and sarcopenia (handgrip, bioelectric impedance) were secondary. Between/within groups and delta (post-pre) comparisons were performed. RESULTS Thirty patients (15/group) were randomized and completed the study without safety concerns. While cirrhosis dysbiosis ratio was statistically similar on repeated measures ANOVA (95% CI: -0.70 to 3.5), ammonia significantly reduced (95% CI: 4.4-29.6) in RiVM with changes in stool microbial α/β-diversity. MHE status was unchanged but only serial dotting (which tests motor strength) improved in RiVM-assigned patients. Delta physical sickness impact profile (95% CI: 0.33 = 8.5), lean mass (95% CI: -3.3 to -0.9), and handgrip strength (95% CI: -8.1 to -1.0) improved in RiVM versus placebo. Stool short-chain fatty acids (propionate, acetate, and butyrate) increased post-RiVM. Serum, urine, and stool bile acid profile changed to nontoxic bile acids (higher hyocholate/ursodeoxycholate and lower deoxycholate/lithocholate) post-RiVM. Serum IL-1β and stool calprotectin decreased while brain magnetic resonance spectroscopy showed higher glutathione concentrations in RiVM. CONCLUSIONS RiVM is well tolerated in patients with MHE with changes in stool microbial composition and function, ammonia, inflammation, brain oxidative stress, and sarcopenia-related parameters without improvement in cognition. RiVM modulates the gut-brain axis and gut-muscle axis in cirrhosis.
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Affiliation(s)
- Jasmohan S. Bajaj
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Andrew Fagan
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Edith A. Gavis
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Travis Mousel
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Mary L. Gallagher
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Puneet Puri
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Michael Fuchs
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Brian C. Davis
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
| | - Vishwadeep Ahluwalia
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, Virginia, USA
- Center for Advanced Brain Imaging, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Robert Cadrain
- Collaborative Advanced Research Imaging Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Masoumeh Sikaroodi
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Patrick M. Gillevet
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
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Rodrigues SG, van der Merwe S, Krag A, Wiest R. Gut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases. Semin Immunol 2024; 71:101859. [PMID: 38219459 DOI: 10.1016/j.smim.2023.101859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/11/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Schalk van der Merwe
- Department of Gastroenterology and Hepatology, University hospital Gasthuisberg, University of Leuven, Belgium
| | - Aleksander Krag
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark, University of Southern Denmark, Odense, Denmark
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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Casanova-Ferrer F, Gallego JJ, Fiorillo A, Urios A, Ríos MP, León JL, Ballester MP, Escudero-García D, Kosenko E, Belloch V, Montoliu C. Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity. J Transl Med 2024; 22:49. [PMID: 38217008 PMCID: PMC10787503 DOI: 10.1186/s12967-023-04844-7] [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: 07/14/2023] [Accepted: 12/29/2023] [Indexed: 01/14/2024] Open
Abstract
BACKGROUND Rifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well. METHODS Twenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed. RESULTS After rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers. CONCLUSIONS There was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.
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Affiliation(s)
- Franc Casanova-Ferrer
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Juan-José Gallego
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Alessandra Fiorillo
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - Amparo Urios
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain
| | - María-Pilar Ríos
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova de Valencia, Valencia, Spain
| | - José Luis León
- Universitats Neurorradiology Unit, Ascires Biomedical Group, Valencia, Spain
| | - María-Pilar Ballester
- Servicio de Medicina Digestiva, Hospital Clinico Universitario de Valencia, Valencia, Spain
| | - Desamparados Escudero-García
- Servicio de Medicina Digestiva, Hospital Clinico Universitario de Valencia, Valencia, Spain
- Departamento de Medicina, University of Valencia, Valencia, Spain
| | - Elena Kosenko
- Institute of Theoretical and Experimental Biophysics of Russian Academy of Sciences, Pushchino, Russia
| | - Vicente Belloch
- Universitats Neurorradiology Unit, Ascires Biomedical Group, Valencia, Spain
| | - Carmina Montoliu
- Fundacion de Investigación Hospital Clinico Universitario de Valencia-INCLIVA, Valencia, Spain.
- Department of Pathology, Faculty of Medicine, University of Valencia, Av Blasco Ibáñez, 15, 46010, Valencia, Spain.
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Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
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Khaledi M, Poureslamfar B, Alsaab HO, Tafaghodi S, Hjazi A, Singh R, Alawadi AH, Alsaalamy A, Qasim QA, Sameni F. The role of gut microbiota in human metabolism and inflammatory diseases: a focus on elderly individuals. ANN MICROBIOL 2024; 74:1. [DOI: 10.1186/s13213-023-01744-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2025] Open
Abstract
Abstract
Background
The gut microbiota plays a crucial role in regulating the host’s immune responses during aging, which was characterized by a different abundance of bacteria in several age groups.
Main body
Gut microbiota dysbiosis is associated with aging, antibiotic exposure, underlying diseases, infections, hormonal variations, circadian rhythm, and malnutrition, either singularly or in combination. The appropriate use of prebiotics and probiotics may be able to prevent or reduce this disruption.
Conclusion
The current review focuses on the gut microbiota composition across the life cycle, factors affecting gut microbiota changes with aging, and interventions to modulate gut microbiota.
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Bajaj JS, O'Leary JG, Jakab SS, Fagan A, Sikaroodi M, Gillevet PM. Gut microbiome profiles to exclude the diagnosis of hepatic encephalopathy in patients with cirrhosis. Gut Microbes 2024; 16:2392880. [PMID: 39189586 PMCID: PMC11352695 DOI: 10.1080/19490976.2024.2392880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/15/2024] [Accepted: 08/12/2024] [Indexed: 08/28/2024] Open
Abstract
Patients with cirrhosis who have cognitive complaints are presumed to have hepatic encephalopathy (HE), which leads to unwarranted medications while ignoring the underlying disease process causing these complaints. Since neuropsychological testing, the current gold standard for HE diagnosis, is not readily available, an orderable test is needed. We aimed to develop and validate a rapid gut microbiota test to exclude HE and determine stakeholder input on this approach. Stool was collected from two cohorts: a two-center training cohort (n = 305, on/not on HE-related therapy) and a multicenter validation cohort (n = 30, on HE treatment). Stool microbiota was analyzed rapidly using nanopore analysis. Stakeholder (patients and clinicians) needs assessment was evaluated using semi-quantitative questionnaires. In the training cohort, machine learning using neural network identified a 20-species signature that differentiated HE vs no-HE with 84% specificity compared to the gold standard neuropsychological testing. This high specificity persisted regardless of whether patients were on HE-related therapy or not. In the validation cohort, application of this profile led to reevaluation of the HE diagnosis and treatment in > 40% of the patients. This approach was acceptable to patients (Veterans in the validation cohort) and clinician (n = 40 nationwide) stakeholders. We conclude that a machine learning stool signature based on 20 microbial species developed in a training set and validated in a separate multicenter prospective cohort differentiated those with vs. without HE, identified patients misdiagnosed with HE, and was acceptable to patients and clinician stakeholders.
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Affiliation(s)
- Jasmohan S Bajaj
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, VA, USA
| | - Jacqueline G O'Leary
- Department of Medicine, North Texas VA Medical Center and UT Southwestern Medical Center, Dallas, TX, USA
| | - Sofia S Jakab
- Department of Medicine, West Haven VA Medical Center and Yale University School of Medicine, West Haven, CT, USA
| | - Andrew Fagan
- Department of Medicine, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, VA, USA
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DuPont HL. The potential for development of clinically relevant microbial resistance to rifaximin-α: a narrative review. Clin Microbiol Rev 2023; 36:e0003923. [PMID: 37971270 PMCID: PMC10732030 DOI: 10.1128/cmr.00039-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023] Open
Abstract
Rifaximin-α is a gut-targeted antibiotic indicated for numerous gastrointestinal and liver diseases. Its multifaceted mechanism of action goes beyond direct antimicrobial effects, including alterations in bacterial virulence, cytoprotective effects on host epithelial cells, improvement of impaired intestinal permeability, and reduction of proinflammatory cytokine expression via activation of the pregnane X receptor. Rifaximin-α is virtually non-absorbed, with low systemic drug levels contributing to its excellent safety profile. While there are high concentrations of drug in the colon, low water solubility leads to low colonic drug bioavailability, protecting the gut microbiome. Rifaximin-α appears to be more active in the bile-rich small bowel. Its important biologic effects are largely at sub-inhibitory concentration. Although in vitro testing of clinical isolates from rifaximin recipients has revealed rifaximin-resistant strains in some studies, the risk of emergent rifaximin-α resistance appears to be lower than for many other antibiotics. Rifaximin-α has been used for many years for traveler's diarrhea with no apparent increase in resistance levels in causative pathogens. Further, rifaximin-α retains its efficacy after long-term and recurrent usage in chronic gastrointestinal disorders. There are numerous reasons why the risk of microbial resistance to rifaximin-α may be lower than that for other agents, including low intestinal bioavailability in the aqueous colon, the mechanisms of action of rifaximin-α not requiring inhibitory concentrations of drug, and the low risk of cross transmission of rifaximin-α resistance between bacterial species. Reported emergence of vancomycin-resistant Enterococcus in liver-disease patients maintained on rifaximin needs to be actively studied. Further studies are required to assess the possible correlation between in vitro resistance and rifaximin-α efficacy.
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Affiliation(s)
- Herbert L. DuPont
- School of Public Health and McGovern Medical School, Baylor College of Medicine, Kelsey Research Foundation, University of Texas Health Science Center Houston, Houston, Texas, USA
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Ilie OD, Duta R, Nita IB, Dobrin I, Gurzu IL, Girleanu I, Huiban L, Muzica C, Ciobica A, Popescu R, Cianga P, Stanciu C, Cimpoesu D, Trifan A. A Comprehensive Overview of the Past, Current, and Future Randomized Controlled Trials in Hepatic Encephalopathy. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2143. [PMID: 38138246 PMCID: PMC10744451 DOI: 10.3390/medicina59122143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/01/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023]
Abstract
Background: Hepatic encephalopathy (HE) caused by cirrhosis has severe consequences on an individual's lifespan, leading to long-term liver complications and potentially life-threatening outcomes. Despite recent interest in this condition, the effectiveness of secondary prophylaxis involving rixafimin, lactulose, or L-ornithine L-aspartate (LOLA) may be hindered by the unique microbial profiles each patient possesses. Methods: Thus, in this manuscript, we aimed to search, identify, and gather all randomized controlled trials (RCTs) published between 2000-2023 (November) in four major academic databases such as PubMed, ISI Web of Science, Scopus, and ScienceDirect by using a controlled terminology and web strings that reunite six main keywords. We complementarily retrieved data on the ongoing RCTs. Results: Regardless of the relatively high number of results displayed (n = 75), 46.66% (n = 35) were initially deemed eligible after the first evaluation phase after removing duplicates, n = 40 (53.34%). At the second assessment stage, we eliminated 11.42% (n = 4) studies, of which n = 22 finally met the eligibility criteria to be included in the main body of the manuscript. In terms of RCTs, otherwise found in distinct stages of development, n = 3 target FMT and n = 1 probiotics. Conclusions: Although we benefit from the necessary information and technology to design novel strategies for microbiota, only probiotics and synbiotics have been extensively studied in the last decade compared to FMT.
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Affiliation(s)
- Ovidiu-Dumitru Ilie
- Gastroenterology Group, CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
| | - Raluca Duta
- Gastroenterology Group, CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
| | - Ilinca-Bianca Nita
- Department of Medicine III, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
| | - Irina Dobrin
- Department of Medicine III, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
- Institute of Psychiatry “Socola”, Bucium Street No. 36, 700282 Iasi, Romania
| | - Irina-Luciana Gurzu
- Department of Preventive Medicine and Interdisciplinarity, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” County Emergency Clinical Hospital, Independence Avenue No. 1, 700111 Iasi, Romania
| | - Laura Huiban
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” County Emergency Clinical Hospital, Independence Avenue No. 1, 700111 Iasi, Romania
| | - Cristina Muzica
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” County Emergency Clinical Hospital, Independence Avenue No. 1, 700111 Iasi, Romania
| | - Alin Ciobica
- Department of Biology, Faculty of Biology, “Alexandru Ioan Cuza” University, Carol I Avenue No. 20A, 700505 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue No. 8, 700506 Iasi, Romania
- Academy of Romanian Scientists, Splaiul Independentei No. 54, Sector 5, 050094 Bucharest, Romania
- Preclinical Department, “Apollonia” University, Păcurari Street No. 11, 700511 Iasi, Romania
| | - Roxana Popescu
- Department of Medical Genetics, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
- Department of Medical Genetics, “Saint Mary” Emergency Children’s Hospital, Vasile Lupu Street No. 62, 700309 Iasi, Romania
| | - Petru Cianga
- Department of Immunology, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
| | - Carol Stanciu
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue No. 8, 700506 Iasi, Romania
| | - Diana Cimpoesu
- Gastroenterology Group, CENEMED Platform for Interdisciplinary Research, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
- Department of Emergency Medicine, “St. Spiridon” County Emergency Clinical Hospital, Independence Avenue No. 1, 700111 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy “Grigore T. Popa”, University Street No. 16, 700115 Iasi, Romania
- Institute of Gastroenterology and Hepatology, “St. Spiridon” County Emergency Clinical Hospital, Independence Avenue No. 1, 700111 Iasi, Romania
- Centre of Biomedical Research, Romanian Academy, Carol I Avenue No. 8, 700506 Iasi, Romania
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Liakina V. Antibiotic resistance in patients with liver cirrhosis: Prevalence and current approach to tackle. World J Clin Cases 2023; 11:7530-7542. [PMID: 38078132 PMCID: PMC10698443 DOI: 10.12998/wjcc.v11.i31.7530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/02/2023] [Accepted: 10/17/2023] [Indexed: 11/06/2023] Open
Abstract
Regardless of etiology, complications with bacterial infection in patients with cirrhosis are reported in the range of 25%-46% according to the most recent data. Due to frequent episodes of bacterial infection and repetitive antibiotic treatment, most often with broad-spectrum gram negative coverage, patients with cirrhosis are at increased risk of encountering multidrug resistant bacteria, and this raises concern. In such patients, extended-spectrum beta-lactamase and AmpC-producing Enterobacterales, methicillin- or vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, carbapenem-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii, all of which are difficult to treat, are the most common. That is why novel approaches to the prophylaxis and treatment of bacterial infections to avoid antibiotic resistance have recently been developed. At the same time, our knowledge of resistance mechanisms is constantly updated. This review summarizes the current situation regarding the burden of antibiotic resistance, including the prevalence and mechanisms of intrinsic and acquired resistance in bacterial species that most frequently cause complications in patients with liver cirrhosis and recent developments on how to deal with multidrug resistant bacteria.
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Affiliation(s)
- Valentina Liakina
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, Vilnius Tech, Vilnius 10223, Lithuania
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Saeidinejad M, Elshabrawi A, Sriphoosanaphan S, Andreola F, Mehta G, Agarwal B, Jalan R. Novel Therapeutic Approaches in Treatment of Acute-on-Chronic Liver Failure. Semin Liver Dis 2023; 43:429-445. [PMID: 38101419 PMCID: PMC10723941 DOI: 10.1055/s-0043-1776773] [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] [Indexed: 12/17/2023]
Abstract
Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.
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Affiliation(s)
- MohammadMahdi Saeidinejad
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Ahmed Elshabrawi
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Endemic Hepatology and Gastroenterology Department, Mansoura University, Mansoura, Egypt
| | - Supachaya Sriphoosanaphan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok
| | - Fausto Andreola
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Gautam Mehta
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Banwari Agarwal
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Royal Free Hospital, London, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Hepatology Department, Royal Free Hospital, London, United Kingdom
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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Baumert LS, Shih A, Chung RT. Management of liver disease and portal hypertension in common variable immunodeficiency (CVID). JHEP Rep 2023; 5:100882. [PMID: 37869072 PMCID: PMC10585302 DOI: 10.1016/j.jhepr.2023.100882] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/30/2023] [Accepted: 07/22/2023] [Indexed: 10/24/2023] Open
Abstract
Patients with common variable immunodeficiency (CVID) frequently develop liver disease and associated complications, which represent an increasingly prevalent unmet medical need. The main hepatic manifestation of CVID is nodular regenerative hyperplasia (NRH), resulting in non-cirrhotic portal hypertension (NCPH). Liver disease is often underdiagnosed, leading to poor outcomes and decreased survival. The increasing numbers of patients with CVID who are diagnosed late with progressive liver disease underscores the importance of appropriate clinical management and treatment of liver complications. At the same time, specific guidelines for the clinical management of CVID-related liver disease are still lacking. Here, we review the epidemiology of CVID-related liver disease, reveal new insights into NRH and NCPH biology and highlight recently uncovered opportunities for NCPH diagnostics in CVID. Finally, we focus on current management of liver disease, portal hypertension and its complications - the key challenge in patients with CVID. Specifically, we review recent data regarding the role of transjugular intrahepatic portosystemic shunt and liver transplantation in clinical management. The role for anticoagulants and immunosuppressants targeting the pathogenesis of NRH will also be discussed. We propose an updated algorithm for the diagnostic work-up and treatment of NCPH in CVID. Finally, we consider future needs and therapeutic opportunities for CVID-related liver disease.
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Affiliation(s)
- Lukas S. Baumert
- Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Faculty of Medicine, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Angela Shih
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Raymond T. Chung
- Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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46
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Bakulin IG, Ivanova KN, Eremina EY, Marchenko NV. Comparative Analysis of the Efficacy of Different Regimens of 12 Months Rifaximin-Alfa Therapy in Patients with Liver Cirrhosis and Minimal Hepatic Encephalopathy. Diagnostics (Basel) 2023; 13:3239. [PMID: 37892060 PMCID: PMC10606376 DOI: 10.3390/diagnostics13203239] [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: 08/17/2023] [Revised: 09/16/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
It is a matter of current interest which rifaximin-α regimens in patients with liver cirrhosis and minimal hepatic encephalopathy are the most efficient. STUDY OBJECTIVE to evaluate the effect of various rifaximin-α regimens for 12 months on clinical and laboratory parameters and quality of life in patients with liver cirrhosis and minimal hepatic encephalopathy. METHODS It was a multicenter, prospective, open-label, observational study that included 288 patients with liver cirrhosis and minimal hepatic encephalopathy of both sexes over the age of 18 years, who were prescribed a 12-month course of treatment with rifaximin-α in accordance with the product label. Statistical analysis was performed in the population of patients who completed all visits according to the protocol (n = 258). Retrospectively, the patients were divided into two subgroups: subgroup 1 (continuous course)-patients who received the study drug for a year and the number of days of administration was 360 days (n = 41); subgroup 2 (cyclic course)-patients who received the study drug during the year for less than 360 days (n = 217). At each of the 4 visits, the quality of life was assessed using the CLDQ questionnaire, the time to perform the number connection test, the severity of symptoms associated with hepatic encephalopathy, and laboratory parameters. RESULTS During the 12-month observation period, an increase in the total score on the CLDQ quality of life questionnaire in patients with chronic liver diseases was revealed, which indicates an improvement in the quality of life of patients receiving rifaximin-α therapy. When patients were divided into subgroups depending on the duration of therapy, some benefits of continuous rifaximin-α therapy were noted in the more pronounced dynamics of decrease in the time to perform the number connection test, and in decreased severity of the following symptoms associated with hepatic encephalopathy: impaired concentration and memory, cognitive impairment, and decreased performance. Laboratory findings showed positive dynamics in both subgroups. CONCLUSION A continuous rifaximin-α regimen in patients with liver cirrhosis and minimal hepatic encephalopathy for 12 months was superior to cyclic use with a more pronounced effect on the quality of life of patients and on the symptoms associated with hepatic encephalopathy.
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Affiliation(s)
- Igor G. Bakulin
- Department of Propaedeutics of Internal Medicine, Gastroenterology and Dietetics Named after S.M. Ryss «Mechnikov North-Western State Medical University» of the Ministry of Health of Russia, 191015 St. Petersburg, Russia
| | - Kristina N. Ivanova
- Department of Propaedeutics of Internal Medicine, Gastroenterology and Dietetics Named after S.M. Ryss «Mechnikov North-Western State Medical University» of the Ministry of Health of Russia, 191015 St. Petersburg, Russia
| | - Elena Y. Eremina
- Department of Propaedeutics of Internal Diseases, Federal State Budgetary Educational Institution of Higher Education «National Research Mordovian State University Named after. N.P. Ogarev», 430005 Saransk, Russia
| | - Natalya V. Marchenko
- Clinical and Educational Center, Gastroenterology and Hepatology, St. Petersburg State University, 199034 St. Petersburg, Russia
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Poto R, Laniro G, de Paulis A, Spadaro G, Marone G, Gasbarrini A, Varricchi G. Is there a role for microbiome-based approach in common variable immunodeficiency? Clin Exp Med 2023; 23:1981-1998. [PMID: 36737487 PMCID: PMC9897624 DOI: 10.1007/s10238-023-01006-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023]
Abstract
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by low levels of serum immunoglobulins and increased susceptibility to infections, autoimmune disorders and cancer. CVID embraces a plethora of heterogeneous manifestations linked to complex immune dysregulation. While CVID is thought to be due to genetic defects, the exact cause of this immune disorder is unknown in the large majority of cases. Compelling evidences support a linkage between the gut microbiome and the CVID pathogenesis, therefore a potential for microbiome-based treatments to be a therapeutic pathway for this disorder. Here we discuss the potential of treating CVID patients by developing a gut microbiome-based personalized approach, including diet, prebiotics, probiotics, postbiotics and fecal microbiota transplantation. We also highlight the need for a better understanding of microbiota-host interactions in CVID patients to prime the development of improved preventive strategies and specific therapeutic targets.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
- Department of Oncology and Molecular Medicine, Istituto Superiore Di Sanità (ISS), Rome, Italy
| | - Gianluca Laniro
- Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of Rome, Rome, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
| | - Giuseppe Spadaro
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy
| | - Antonio Gasbarrini
- Digestive Disease Center, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
- Department of Translational Medicine and Surgery, Catholic University of Rome, Rome, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131, Naples, Italy.
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131, Naples, Italy.
- World Allergy Organization (WAO), Center of Excellence, 80131, Naples, Italy.
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131, Naples, Italy.
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Fiorillo A, Gallego JJ, Casanova-Ferrer F, Urios A, Ballester MP, San Miguel T, Megías J, Kosenko E, Tosca J, Rios MP, Escudero-García D, Montoliu C. Neurofilament Light Chain Protein in Plasma and Extracellular Vesicles Is Associated with Minimal Hepatic Encephalopathy and Responses to Rifaximin Treatment in Cirrhotic Patients. Int J Mol Sci 2023; 24:14727. [PMID: 37834174 PMCID: PMC10572420 DOI: 10.3390/ijms241914727] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/19/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Neurofilament light chain protein (NfL) levels reflect neuronal damage in several neurological diseases and have been proposed as a possible biomarker. Plasma extracellular vesicles (EVs) could play an important role as mediators of the inflammatory changes associated with inducing minimal hepatic encephalopathy (MHE) in cirrhotic patients. This study investigated the association of NfL levels in plasma and EVs with the presence of MHE in cirrhotic patients, and with responses to rifaximin treatment. The NfL levels in plasma and EVs were assessed in 71 patients with liver cirrhosis (40 with MHE and 31 without MHE) and 26 controls. A total of 31 patients with MHE received rifaximin treatment. We examined changes in NfL levels in plasma and EVs before and after 6 months of rifaximin treatment. The NfL measures were correlated with cognitive alterations and plasma inflammatory cytokines. MHE patients showed increased plasma levels of NfL, which were reverted after rifaximin treatment in patients who responded to treatment. The NfL content in EVs also showed a reversal pattern in MHE patients treated with rifaximin. In multivariable analyses, NfL levels were independently associated with the presence of MHE. We also showed that patients with high levels of both ammonia and fractalkine had significantly higher NfL levels than patients with low levels of least one of these parameters. Rifaximin treatment in MHE patients showed promising results in improving axonal damage, suggesting that rifaximin may have therapeutic benefits against disease progression in MHE.
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Affiliation(s)
- Alessandra Fiorillo
- Fundación de Investigación, Hospital Clínico Universitario de Valencia-INCLIVA, 46010 Valencia, Spain; (A.F.); (J.J.G.); (F.C.-F.); (A.U.)
| | - Juan José Gallego
- Fundación de Investigación, Hospital Clínico Universitario de Valencia-INCLIVA, 46010 Valencia, Spain; (A.F.); (J.J.G.); (F.C.-F.); (A.U.)
| | - Franc Casanova-Ferrer
- Fundación de Investigación, Hospital Clínico Universitario de Valencia-INCLIVA, 46010 Valencia, Spain; (A.F.); (J.J.G.); (F.C.-F.); (A.U.)
| | - Amparo Urios
- Fundación de Investigación, Hospital Clínico Universitario de Valencia-INCLIVA, 46010 Valencia, Spain; (A.F.); (J.J.G.); (F.C.-F.); (A.U.)
| | - María-Pilar Ballester
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain; (M.-P.B.); (J.T.); (D.E.-G.)
| | - Teresa San Miguel
- Departamento de Patología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain; (T.S.M.); (J.M.)
| | - Javier Megías
- Departamento de Patología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain; (T.S.M.); (J.M.)
| | - Elena Kosenko
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia;
| | - Joan Tosca
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain; (M.-P.B.); (J.T.); (D.E.-G.)
| | - Maria-Pilar Rios
- Servicio de Digestivo, Hospital Arnau de Vilanova, 46015 Valencia, Spain;
| | - Desamparados Escudero-García
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, 46010 Valencia, Spain; (M.-P.B.); (J.T.); (D.E.-G.)
- Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Carmina Montoliu
- Fundación de Investigación, Hospital Clínico Universitario de Valencia-INCLIVA, 46010 Valencia, Spain; (A.F.); (J.J.G.); (F.C.-F.); (A.U.)
- Departamento de Patología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain; (T.S.M.); (J.M.)
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Widjaja F, Rietjens IMCM. From-Toilet-to-Freezer: A Review on Requirements for an Automatic Protocol to Collect and Store Human Fecal Samples for Research Purposes. Biomedicines 2023; 11:2658. [PMID: 37893032 PMCID: PMC10603957 DOI: 10.3390/biomedicines11102658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 10/29/2023] Open
Abstract
The composition, viability and metabolic functionality of intestinal microbiota play an important role in human health and disease. Studies on intestinal microbiota are often based on fecal samples, because these can be sampled in a non-invasive way, although procedures for sampling, processing and storage vary. This review presents factors to consider when developing an automated protocol for sampling, processing and storing fecal samples: donor inclusion criteria, urine-feces separation in smart toilets, homogenization, aliquoting, usage or type of buffer to dissolve and store fecal material, temperature and time for processing and storage and quality control. The lack of standardization and low-throughput of state-of-the-art fecal collection procedures promote a more automated protocol. Based on this review, an automated protocol is proposed. Fecal samples should be collected and immediately processed under anaerobic conditions at either room temperature (RT) for a maximum of 4 h or at 4 °C for no more than 24 h. Upon homogenization, preferably in the absence of added solvent to allow addition of a buffer of choice at a later stage, aliquots obtained should be stored at either -20 °C for up to a few months or -80 °C for a longer period-up to 2 years. Protocols for quality control should characterize microbial composition and viability as well as metabolic functionality.
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Affiliation(s)
- Frances Widjaja
- Division of Toxicology, Wageningen University & Research, 6708 WE Wageningen, The Netherlands;
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Stojic J, Kukla M, Grgurevic I. The Intestinal Microbiota in the Development of Chronic Liver Disease: Current Status. Diagnostics (Basel) 2023; 13:2960. [PMID: 37761327 PMCID: PMC10528663 DOI: 10.3390/diagnostics13182960] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic liver disease (CLD) is a significant global health burden, leading to millions of deaths annually. The gut-liver axis plays a pivotal role in this context, allowing the transport of gut-derived products directly to the liver, as well as biological compounds from the liver to the intestine. The gut microbiota plays a significant role in maintaining the health of the digestive system. A change in gut microbiome composition as seen in dysbiosis is associated with immune dysregulation, altered energy and gut hormone regulation, and increased intestinal permeability, contributing to inflammatory mechanisms and damage to the liver, irrespective of the underlying etiology of CLD. The aim of this review is to present the current knowledge about the composition of the intestinal microbiome in healthy individuals and those with CLD, including the factors that affect this composition, the impact of the altered microbiome on the liver, and the mechanisms by which it occurs. Furthermore, this review analyzes the effects of gut microbiome modulation on the course of CLD, by using pharmacotherapy, nutrition, fecal microbiota transplantation, supplements, and probiotics. This review opens avenues for the translation of knowledge about gut-liver interplay into clinical practice as an additional tool to fight CLD and its complications.
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Affiliation(s)
- Josip Stojic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
| | - Michał Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagellonian University Medical College, 31-688 Kraków, Poland;
- Department of Endoscopy, University Hospital, 30-688 Kraków, Poland
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
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