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Patel JJ, Barash M. The Gut in Critical Illness. Curr Gastroenterol Rep 2025; 27:11. [PMID: 39792234 DOI: 10.1007/s11894-024-00954-4] [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] [Accepted: 10/30/2024] [Indexed: 01/12/2025]
Abstract
PURPOSE OF REVIEW The purpose of this narrative review is to describe the mechanisms for gut dysfunction during critical illness, outline hypotheses of gut-derived inflammation, and identify nutrition and non-nutritional therapies that have direct and indirect effects on preserving both epithelial barrier function and gut microbiota during critical illness. RECENT FINDINGS Clinical and animal model studies have demonstrated that critical illness pathophysiology and interventions breach epithelial barrier function and convert a normally commensal gut microbiome into a pathobiome. As a result, the gut has been postulated to be the "motor" of critical illness and numerous hypotheses have been put forward to explain how it contributes to systemic inflammation and drives multiple organ failure. Strategies to ameliorate gut dysfunction have focused on maintaining gut barrier function and promoting gut microbiota commensalism. The trajectory of critical illness may be closely related to gut epithelial barrier function, the gut microbiome and interventions that may contribute towards a deleterious pathobiome with immune dysregulation.
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Affiliation(s)
- Jayshil J Patel
- Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Wisconsin, 8701 West Watertown Plank Road, 8th Floor: HUB for Collaborative Medicine, Milwaukee, WI, 53226, USA.
| | - Mark Barash
- Division of Pulmonary, Critical Care, and Sleep Medicine, Medical College of Wisconsin, 8701 West Watertown Plank Road, 8th Floor: HUB for Collaborative Medicine, Milwaukee, WI, 53226, USA
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Schnabl B, Damman CJ, Carr RM. Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations. J Clin Invest 2025; 135:e186423. [PMID: 40166938 PMCID: PMC11957707 DOI: 10.1172/jci186423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.
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Affiliation(s)
- Bernd Schnabl
- Department of Medicine, Division of Gastroenterology, UCSD, San Diego, California, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
| | - Christopher J. Damman
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington, USA
| | - Rotonya M. Carr
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington, USA
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Bloom PP, Bassis CM, Crossette E, Silber JL, Norman JM, Young VB, Lok AS. Safety and efficacy of a defined bacterial consortium, VE303, to treat HE. Hepatol Commun 2025; 9:e0650. [PMID: 39969428 PMCID: PMC11841841 DOI: 10.1097/hc9.0000000000000650] [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: 10/24/2024] [Accepted: 12/24/2024] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Novel therapies are needed to treat HE, and microbiome modulation is a promising target. VE303 is a defined consortium of 8 purified, clonal bacterial strains, known to produce metabolites that may be beneficial in HE. We evaluated the safety and efficacy of VE303 to treat HE. METHODS We performed a single-center, randomized, placebo-controlled trial of VE303 in adult patients with a history of overt HE (NCT04899115). Eligible patients were taking lactulose and rifaximin, had no recent systemic antibiotics, and had MELD ≤20. All patients received 5 days of oral vancomycin followed by randomization to 14 days of VE303 or placebo (2:1). The primary endpoints were incidence of serious adverse events and change in psychometric HE score (PHES) from baseline to 4 weeks after treatment. Stool samples underwent metagenomic sequencing and metabolite quantification. RESULTS Eighteen patients completed the trial, 56% men, with a mean age of 59 years and a mean MELD of 11. Patients who received VE303 had a mean change in PHES of +1.5 versus -1.0 in those who received a placebo (p=0.20). Two of the 12 patients who received VE303 had at least 1 serious adverse event (all overt HE hospitalizations), compared with 0/6 patients who received a placebo. In the patients who received VE303, 2 of 8 strains engrafted in >50% of patients. Both VE303 strain engraftment and increased stool butyrate production had a trend toward improved PHES. CONCLUSIONS VE303 was well tolerated in patients with cirrhosis and a history of overt HE, leading to the engraftment of certain VE303 strains and a higher percentage of patients with improved PHES.
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Affiliation(s)
- Patricia P. Bloom
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Christine M. Bassis
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | | | - Vincent B. Young
- Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan, USA
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA
| | - Anna S.F. Lok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
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Gallego JJ, Ballester MP, Fiorillo A, Casanova-Ferrer F, López-Gramaje A, Urios A, Arenas YM, Ríos MP, Durbán L, Megías J, San-Miguel T, Benlloch S, Lluch P, Jalan R, Montoliu C. Ammonia and beyond - biomarkers of hepatic encephalopathy. Metab Brain Dis 2025; 40:100. [PMID: 39812958 PMCID: PMC11735499 DOI: 10.1007/s11011-024-01512-7] [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: 07/22/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025]
Abstract
Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with liver cirrhosis, leading to neurotoxic effects and hepatic encephalopathy (HE). HE manifestations can range from mild, subclinical disturbances in cognition, or minimal HE (mHE) to gross disorientation and coma, a condition referred to as overt HE. Many blood-based biomarkers reflecting these neurotoxic effects of ammonia and liver disease can be measured in the blood allowing the development of new biomarkers to diagnose cirrhosis patients at risk of developing HE. The effect of ammonia on the brain is modulated by severity of systemic inflammation, and both hyperammonemia and inflammation can induce oxidative stress, which may mediate the neurological alterations associated to HE. This review aims to provide the latest evidence on biomarkers of HE beyond ammonia. We present different approaches to predict overt HE based on the combination of blood ammonia with some analytical and clinical parameters. Magnetic resonance analysis of brain images could also provide sensitive diagnostic biomarkers based on neuroimaging parameters. Some reports suggest that markers of systemic inflammation, oxidative stress, and central nervous system-derived components, may serve as additional biomarkers of HE. The involvement of extracellular vesicles and microbiota in the pathophysiology of mHE and HE has recently acquired importance and it would be interesting to explore their usefulness as early biomarkers of the disease. It is important to have a biomarker or a combination of them for early diagnosis of mHE to improve its treatment and prevent progression to overt HE.
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Affiliation(s)
- Juan-José Gallego
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ballester
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Alessandra Fiorillo
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Franc Casanova-Ferrer
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | | | - Amparo Urios
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Yaiza María Arenas
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ríos
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Lucía Durbán
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Javier Megías
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Teresa San-Miguel
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Salvador Benlloch
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
- CIBERehd. Instituto de Salud Carlos III, Madrid, 28029, Spain
- Universidad Cardenal Herrera-CEU Universities, Valencia, 46115, Spain
| | - Paloma Lluch
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, 08021, Spain.
| | - Carmina Montoliu
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain.
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain.
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Shah MK, Zhu A, Uppuluri A, Henry RK, Zarbin MA, Bhagat N. Risk factors for endogenous endophthalmitis in infectious endocarditis patients. Eye (Lond) 2025; 39:125-132. [PMID: 39402169 PMCID: PMC11733160 DOI: 10.1038/s41433-024-03390-w] [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: 07/05/2023] [Revised: 08/26/2024] [Accepted: 10/04/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES The purpose of this study was to identify demographic variables and systemic comorbidities that may increase risk of endogenous endophthalmitis (EE) development in patients with infective endocarditis (IE). SUBJECTS/METHODS A retrospective database study was conducted using the 2002-2014 National Inpatient Sample (NIS). Patients with IE and EE were identified using ICD-9-CM codes. Descriptive chi-square and logistic regression analysis identified risk factors for EE in IE patients. RESULTS Of 769,472 inpatients with a diagnosis of IE, 2248 had a diagnosis of EE. Women comprised 39.7% of IE patients without EE and 42.6% of those with EE (p = 0.005). The majority of IE cases with EE were in those 21-64-year-old (58.5%) age cohort and 67.4% of cases were Whites. Multivariate analysis revealed IE patients in the 21-64 (OR, 3.660) and 65+ age group (OR, 2.852) had increased risk of developing EE compared to the 0-20-year-old group. Hispanic (OR, 1.377) and Asian/Pacific Islander (OR, 1.620) patients had increased risk compared to White patients. Diabetes with (OR, 2.043) and without (OR, 1.433) chronic complications, alcohol use disorder (AUD; OR, 1.795), and cirrhosis (OR, 1.452) conferred an increased risk of developing EE, whereas, congestive heart failure (CHF; OR, 0.716), arrhythmia (OR, 0.678), and having a cardiac device (OR, 0.336) decreased risk of EE in IE subjects. CONCLUSION Older age (21+ years) and Hispanic and Asian/Pacific Islander background were associated with increased risk of developing EE in IE patients. Diabetes with and without chronic complications, AUD, or cirrhosis also conferred a 1.5-2 times increased risk. CHF, arrhythmia, or having a cardiac device were associated with decreased risk.
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Affiliation(s)
- Megh K Shah
- Institute of Ophthalmology & Visual Science, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Aretha Zhu
- Institute of Ophthalmology & Visual Science, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Aditya Uppuluri
- Institute of Ophthalmology & Visual Science, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Roger K Henry
- Institute of Ophthalmology & Visual Science, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Marco A Zarbin
- Institute of Ophthalmology & Visual Science, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA
| | - Neelakshi Bhagat
- Institute of Ophthalmology & Visual Science, Rutgers New Jersey Medical School, Newark, NJ, 07103, USA.
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U LK, J D, M R, K S, Sebastian SK, Khatana G, Philip GR. Spontaneous Bacterial Peritonitis: Etiology, Microbiology, and Clinical Outcomes in Cirrhosis Patients. Cureus 2024; 16:e76679. [PMID: 39898135 PMCID: PMC11781897 DOI: 10.7759/cureus.76679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2024] [Indexed: 02/04/2025] Open
Abstract
OBJECTIVE Spontaneous bacterial peritonitis (SBP) is a critical complication in patients with liver cirrhosis, often resulting in high mortality. Understanding the microbiological agents causing SBP and their antibiotic resistance patterns is essential for effective treatment, particularly in tertiary care settings. This prospective observational study aimed to identify the microbial profile of SBP, evaluate antibiotic sensitivity, and assess patient outcomes. METHODOLOGY The study included 100 patients over 18 years old with chronic liver disease and SBP. Data collected included demographics, ascitic fluid analysis, cultures, liver and renal function tests, ultrasonograms, and disease etiology. Scoring systems such as sequential organ failure assessment (SOFA), child-turcotte-pugh (CTP), and model for end-stage liver disease (MELD) were calculated. Patients received standard care, and outcomes (discharge or mortality) were recorded. RESULTS Of the 100 patients with SBP, 91% were men. Most were classified as child-turcotte-pugh Class C (66%), with the remainder as Class B (34%). The leading cause of cirrhosis was alcohol use (72%), followed by metabolic-associated steatotic liver disease (MASLD), hepatitis B virus (HBV), and hepatitis C virus (HCV). Prior antibiotic exposure was noted in 21% of cases. Despite prophylaxis, SBP developed in 19%. Ascitic fluid cultures showed no growth in 56%, but Escherichia coli (16%) and Klebsiella species (8%) were the most common pathogens isolated. Acute-on-chronic liver failure (ACLF) occurred in 19%, with a mortality rate of 89%. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens were identified in 5% and 3% of cases, respectively. CONCLUSION This study identifies Escherichia coli as the most prevalent pathogen in SBP and highlights the impact of comorbidities like diabetes and dyslipidemia on outcomes. High sequential organ failure assessment scores, hepatic encephalopathy, variceal bleeding, renal failure, mechanical ventilation, and alcoholic liver disease significantly increased mortality risk. The emergence of multi-drug-resistant and extensively drug-resistant pathogens underscores the need for vigilant monitoring, early intervention, and customized antibiotic therapies to manage SBP effectively in cirrhotic patients.
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Affiliation(s)
- Lal Krishna U
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Deni J
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Ramu M
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Sandesh K
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Saji K Sebastian
- Gastroenterology and Hepatology, Government Medical College, Kottayam, IND
| | - Gaurav Khatana
- Gastroenterology and Hepatology, Government Medical College, Kottayam, IND
| | - Gino R Philip
- Gastroenterology and Hepatology, Government Medical College, Kottayam, IND
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Rooney M, Duduskar SN, Ghait M, Reißing J, Stengel S, Reuken PA, Quickert S, Zipprich A, Bauer M, Russo AJ, Rathinam VA, Stallmach A, Rubio I, Bruns T. Type-I interferon shapes peritoneal immunity in cirrhosis and drives caspase-5-mediated progranulin release upon infection. J Hepatol 2024; 81:971-982. [PMID: 38936554 DOI: 10.1016/j.jhep.2024.06.019] [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: 11/11/2023] [Revised: 05/21/2024] [Accepted: 06/17/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND & AIMS Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs). METHODS PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide and IFN, or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP. RESULTS E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced lipopolysaccharide-mediated tumor necrosis factor production without inducing toll-like receptor 4 tolerance. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1β upon bacterial infection. Proteomic screening in mouse macrophages revealed progranulin release as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin D in a type-I IFN- and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP. CONCLUSIONS Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP. IMPACT AND IMPLICATIONS Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.
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Affiliation(s)
- Michael Rooney
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Shivalee N Duduskar
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Mohamed Ghait
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Johanna Reißing
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sven Stengel
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany; Department of Neuropediatrics, Jena University Hospital, 07747 Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Stefanie Quickert
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Alexander Zipprich
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Michael Bauer
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Ashley J Russo
- Department of Immunology, University of Connecticut Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA
| | - Vijay A Rathinam
- Department of Immunology, University of Connecticut Health School of Medicine, 263 Farmington Avenue, Farmington, CT 06030, USA
| | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Ignacio Rubio
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
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Szymanski M, Skiba MM, Piasecka M, Olender A. A rare case of invasive Enterococcus cecorum infection and related diagnostic difficulties. Clin Case Rep 2024; 12:e9386. [PMID: 39210929 PMCID: PMC11358030 DOI: 10.1002/ccr3.9386] [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: 05/23/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Key Clinical Message This report presents a rare case of invasive infection caused by Enterococcus cecorum. There are no specific guidelines regarding antibiotic therapy for this infection. Based on this case, it can be concluded that linezolid demonstrates in vivo activity against Enterococcus cecorum and can be successfully used in therapy. Abstract Enterococcus cecorum is an extremely rare pathogen in humans. Since 1984, when the microorganism was first described, only a dozen cases of invasive infections in humans have been reported in the literature. The diagnostic pathway may involve difficulties in correctly identifying this microorganism. Based on the case described, it can be thought that Enterococcus cecorum is a more challenging bacterium than the much more common Enterococcus faecium or Enterococcus faecalis. The described case underscores the importance of medical vigilance in clinical practice. It seems that due to increasingly advanced techniques in molecular biology, we will more frequently detect pathogens that were previously encountered only sporadically. Since not every center has access to modern and advanced microbiological diagnostic methods, publications that practically combine classical microbiological diagnostic methods with those less accessible but more modern are exceptionally valuable. In the case described, it is also worth noting that classical methods still play a significant and crucial role in conducting microbiological diagnostics. In the era of rapid diagnostic tool development, it is important to emphasize the necessity of combining different methods rather than replacing one with another.
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Affiliation(s)
- Mateusz Szymanski
- Human Anatomy DepartmentMedical UniversityLublinPoland
- Intensive Care UnitStefan Cardinal Wyszyński District Specialist HospitalLublinPoland
| | - Małgorzata M. Skiba
- Intensive Care UnitStefan Cardinal Wyszyński District Specialist HospitalLublinPoland
| | - Małgorzata Piasecka
- Intensive Care UnitStefan Cardinal Wyszyński District Specialist HospitalLublinPoland
| | - Alina Olender
- Chair and Department of Medical MicrobiologyMedical UniversityLublinPoland
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Rusticeanu MA, Zimmer V. Alterations in Intestinal Mucosal Barrier Visualized by Confocal Laser Endomicroscopy in Liver Cirrhosis: A Pilot Trial (AMBIC). Diagnostics (Basel) 2024; 14:1606. [PMID: 39125482 PMCID: PMC11311864 DOI: 10.3390/diagnostics14151606] [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: 06/07/2024] [Revised: 07/15/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Chronic liver disease occurs throughout the world irrespective of region, age, sex, or race, and it is caused by a variety of liver conditions. One of the most frequent infectious complications in liver cirrhosis that severely reduces the median survival is spontaneous bacterial peritonitis. Current guidelines recommend a paracentesis before starting an antibiotic prophylaxis for this complication. METHODS Selective intestinal decontamination significantly lowers the rate of first or recurrent SBP in cirrhotic patients, so in this study we aimed to investigate and quantify the intestinal integrity of patients with liver cirrhosis and correlate a pathologically increased permeability with the incidence of SPB. We included 14 patients who met the inclusion criteria. No patient was excluded. For the CLE investigation, we use probe based confocal laser endomicroscopy techniques from Mauna Kea (Cellvizio), enabling in vivo surface imaging. The images (optical biopsies) were analyzed for functional and structural barrier defects after the procedure using Mauna Kea software (version 1.0.09). RESULTS Because of the small number of included patients and healthy controls, most results are lacking statistical relevance. We found that the CLE investigation showed an increased intestinal permeability in patients with liver cirrhosis, in concordance with previous published data, based on other assessment methods. CONCLUSIONS This study confirms that previously published permeability scores can be applied for patients with liver cirrhosis and is, to our knowledge, the first to investigate the intestinal permeability in vivo in patients with liver cirrhosis. Further data are needed to identify patients at risk and help develop new and less invasive diagnostic criteria for cirrhotic patients who may profit from a prophylactic antibiotic treatment.
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Affiliation(s)
- Monica Alexandrina Rusticeanu
- Department of Gastroenterology, Hospital Asklepios Klinikum Schwalmstadt, Krankenhausstraße 27, 34613 Schwalmstadt, Germany
- Department of Gastroenterology, University Hospital Berne, Freiburgstrasse 18, 3010 Bern, Switzerland
| | - Vincent Zimmer
- Department of Medicine, Hospital Knappschaftsklinikum Saar, In d. Humes 35, 66346 Püttlingen, Germany;
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
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Ramachandran G, Pottakkat B. Probiotics-A Promising Novel Therapeutic Approach in the Management of Chronic Liver Diseases. J Med Food 2024; 27:467-476. [PMID: 38574254 DOI: 10.1089/jmf.2023.k.0129] [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: 04/06/2024] Open
Abstract
An increased incidence of liver diseases has been observed in recent years and is associated with gut dysbiosis, which causes bacterial infection, intestinal permeability, and further leads to disease-related complications. Probiotics, active microbial strains, are gaining more clinical importance due to their beneficial effect in the management of many diseases, including liver diseases. Clinical scenarios show strong evidence that probiotics have efficacy in treating liver diseases due to their ability to improve epithelial barrier function, prevent bacterial translocation, and boost the immune system. Moreover, probiotics survive both bile and gastric acid to reach the gut and exert their health benefit. Evidence shows that probiotics are a promising approach to prevent several complications in clinical practice. Herein, we discuss the recent evidence, challenges, and appropriate use of probiotics in managing advanced liver diseases, which may have an impact on future therapeutic strategies. Furthermore, the superior effect of strain-specific probiotics and their efficacy and safety in managing liver diseases are discussed.
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Affiliation(s)
- Gokulapriya Ramachandran
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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11
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Petakh P, Oksenych V, Kamyshna I, Boisak I, Lyubomirskaya K, Kamyshnyi O. Exploring the complex interplay: gut microbiome, stress, and leptospirosis. Front Microbiol 2024; 15:1345684. [PMID: 38476949 PMCID: PMC10927737 DOI: 10.3389/fmicb.2024.1345684] [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: 11/28/2023] [Accepted: 01/30/2024] [Indexed: 03/14/2024] Open
Abstract
Leptospirosis, a re-emerging zoonotic disease, remains a significant global health concern, especially amid floods and disasters such as the Kakhovka Dam destruction. As is known, the stress that occurs in the conditions of military conflicts among civilian and military personnel significantly affects susceptibility to infectious diseases and possibly even influences their course. This review aims to explore how the gut microbiome and stress mediators (such as catecholamines and corticosteroids) might impact the leptospirosis disease course. The review opens new horizons for research by elucidating the connections between the gut microbiome, stress, and leptospirosis.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, Uzhhorod, Ukraine
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Iryna Boisak
- Department of Childhood Diseases, Uzhhorod National University, Uzhhorod, Ukraine
| | - Katerina Lyubomirskaya
- Department of Obstetrics and Gynecology, Zaporizhzhia State Medical and Pharmaceuticals University, Zaporizhzhia, Ukraine
| | - Oleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
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Poto R, Fusco W, Rinninella E, Cintoni M, Kaitsas F, Raoul P, Caruso C, Mele MC, Varricchi G, Gasbarrini A, Cammarota G, Ianiro G. The Role of Gut Microbiota and Leaky Gut in the Pathogenesis of Food Allergy. Nutrients 2023; 16:92. [PMID: 38201921 PMCID: PMC10780391 DOI: 10.3390/nu16010092] [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: 11/23/2023] [Revised: 12/21/2023] [Accepted: 12/23/2023] [Indexed: 01/12/2024] Open
Abstract
Food allergy (FA) is a growing public health concern, with an increasing prevalence in Western countries. Increasing evidence suggests that the balance of human gut microbiota and the integrity of our intestinal barrier may play roles in the development of FA. Environmental factors, including industrialization and consumption of highly processed food, can contribute to altering the gut microbiota and the intestinal barrier, increasing the susceptibility to allergic sensitization. Compositional and functional alterations to the gut microbiome have also been associated with FA. In addition, increased permeability of the gut barrier allows the translocation of allergenic molecules, triggering Th2 immune responses. Preclinical and clinical studies have highlighted the potential of probiotics, prebiotics, and postbiotics in the prevention and treatment of FA through enhancing gut barrier function and promoting the restoration of healthy gut microbiota. Finally, fecal microbiota transplantation (FMT) is now being explored as a promising therapeutic strategy to prevent FA in both experimental and clinical studies. In this review article, we aim to explore the complex interplay between intestinal permeability and gut microbiota in the development of FA, as well as depict potential therapeutic strategies.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (G.V.)
- 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
| | - William Fusco
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOSD DH Internal Medicine and Digestive Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Emanuele Rinninella
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, Clinical Nutrition Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Marco Cintoni
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, Clinical Nutrition Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Kaitsas
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
| | - Pauline Raoul
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, Clinical Nutrition Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Cristiano Caruso
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOSD DH Internal Medicine and Digestive Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Maria Cristina Mele
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, Clinical Nutrition Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (G.V.)
- 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
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOSD DH Internal Medicine and Digestive Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Giovanni Cammarota
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOSD DH Internal Medicine and Digestive Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Gianluca Ianiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy (E.R.); (M.C.); (F.K.); (P.R.); (C.C.); (M.C.M.); (A.G.); (G.C.)
- Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medical and Surgical Sciences, UOSD DH Internal Medicine and Digestive Diseases, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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Jothimani D, Paramasivam R, Manoharan M, Ramachandran H, Muthusamy S, Simon E, Ravichandran J, Rela M. Fecal calprotectin in patients with liver cirrhosis. Indian J Gastroenterol 2023; 42:818-823. [PMID: 37823985 DOI: 10.1007/s12664-023-01450-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 08/10/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND AND OBJECTIVES Sepsis is the most challenging complication in patients with liver cirrhosis. It destabilizes patients leading to worsening of liver dysfunction and increased mortality. Intestinal bacterial dysbiosis, release of endotoxins, increased gut permeability and associated immune dysregulation have been described in cirrhotic patients with septic complications. Calprotectin is a major cytosolic protein secreted by the inflammatory cells and has been widely studied in patients with inflammatory bowel disease. We aimed at evaluating the role of fecal calprotectin (FCAL) in patients with liver cirrhosis. METHODS A prospective, observational study on the utility of FCAL test was conducted in patients with liver cirrhosis. Fifteen milligrams of fecal specimen was collected and analyzed within 48 hours of hospitalization from patients with end-stage liver disease (ESLD), acute-on-chronic liver failure (ACLF) and at the time of outpatient visit for stable cirrhotics. Five healthy volunteers underwent FCAL test as control population. RESULTS The mean FCAL (µg/g) level in healthy control (n = 5), stable cirrhotics (n = 10), ESLD (n = 10) and ACLF (n = 10) patients was 109.2 (95% CI: - 53.39 to 271.79), 143.3 (95% CI: 50.5-236.45), 176.9 (95% CI: 122.93-230.87) and 543.5 (95% CI: 207.09-879.91) (p = 0.005), respectively. Sepsis was identified in 13 (43.3%) patients. Area under the receiver-operating characteristics curve (AUROC) of FCAL was 0.80 (p = 0.005) and FCAL ≥ 200 µg/g (OR = 10.8, p = 0.006) was associated with sepsis. Nine (25.7%) patients expired. FCAL level was significantly higher in dead patients compared to survivors (mean, 493.67 (95% CI: 142.20-845.14) vs. 199.71 (95% CI: 99.84-299.59) μg/g,p = 0.005. CONCLUSIONS FCAL levels are increased in patients with chronic liver disease, with highest level in ACLF. An FCAL level of ≥ 200 µg/g was associated with sepsis and mortality in cirrhotic patients. Larger studies are required to identify the role of FCAL in these patients. Early identification and initiation of anti-microbials may mitigate sepsis and reduce mortality.
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Affiliation(s)
- Dinesh Jothimani
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India.
| | - Ramya Paramasivam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India
| | - Mullaiezhili Manoharan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India
| | - Hemalatha Ramachandran
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India
| | - Subha Muthusamy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India
| | - Evangeline Simon
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India
| | - Jinesh Ravichandran
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, No 7, CLC Works Road, Chrompet, Chennai, 600 044, India
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Sturm L, Hirose M, Stolz L, Schultheiss M, Zoldan K, Reincke M, Huber JP, Kaeser R, Boettler T, Thimme R, Albert E, Busch H, Künstner A, Bettinger D. Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension. mBio 2023; 14:e0049223. [PMID: 37623323 PMCID: PMC10653923 DOI: 10.1128/mbio.00492-23] [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: 02/27/2023] [Accepted: 05/02/2023] [Indexed: 08/26/2023] Open
Abstract
IMPORTANCE Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.
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Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Misa Hirose
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Laura Stolz
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Zoldan
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Rafael Kaeser
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- IMM-PACT-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Elisabeth Albert
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Hauke Busch
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Axel Künstner
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Dominik Bettinger
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
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Georgescu D, Ancusa OE, Azoulay D, Lascu A, Ionita I, Calamar-Popovici D, Ionita M, Rosca CI, Brează GM, Reisz D, Lighezan D. Portal Vein Thrombosis in Patients with Liver Cirrhosis: What Went Wrong? Int J Gen Med 2023; 16:3889-3906. [PMID: 37662503 PMCID: PMC10473422 DOI: 10.2147/ijgm.s413438] [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: 04/26/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023] Open
Abstract
Purpose This study aimed to explore inflammatory biomarkers, stool's functional bacterial groups and their possible link to portal vein thrombosis (PVT) in patients with liver cirrhosis (LC). Materials and Methods An observational study of 300 participants: 200 inhospital cirrhotic patients, who met inclusion criteria, equally assigned into two groups, based on the presence or absence of PVT and 100 healthy controls was carried out. Results The PVT group displayed significant differences related to older age, cigarettes smoking history, emergency admission, higher Child-Pugh score, metabolic related disorders and nonalcoholic fatty liver disease, as well as non-obstructive aspects, with chronic thrombi. The PVT group exhibited significant differences related to biomarkers such as tumor necrosis factor (TNF)-alpha, C-reactive protein (CRP), D-dimers (D-D), as well as gut overall dysbiosis (DB) and alteration of different functional bacterial groups of the gut microbiota. Strong positive correlations were observed between PVT severity, and TNF-alpha, CRP, D-D as well as lipopolysaccharide (LPS) positive bacteria. Esophageal varices, age and abdominal pain were independent predictors for PVT severity as well as CRP, TNF-alpha and D-D. Conclusion Patients with LC and PVT displayed elevation of TNF-alpha, CRP, D-D alterations of the functional gut microbiota, as well as several morphological and clinical particularities. Although the LPS positive gut microbiota was linked to inflammatory biomarkers and PVT severity, it was not proven to be an independent predictor of the PVT severity like CRP, TNF-alpha and D-D.
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Affiliation(s)
- Doina Georgescu
- Center of Advanced Researches in Cardiovascular Diseases and Hemostaseology, Department of Internal Medicine I, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Oana-Elena Ancusa
- Center of Advanced Researches in Cardiovascular Diseases and Hemostaseology, Department of Internal Medicine I, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Daniel Azoulay
- Hepato-Biliary Center, Paul-Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - Ana Lascu
- Department of Functional Sciences, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Ioana Ionita
- Center of Advanced Researches in Cardiovascular Diseases and Hemostaseology, Department of Internal Medicine I, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Despina Calamar-Popovici
- Center of Advanced Researches in Cardiovascular Diseases and Hemostaseology, Department of Internal Medicine I, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Mihai Ionita
- Center of Advanced Researches in Cardiovascular Diseases and Hemostaseology, Department of Internal Medicine I, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Ciprian Ilie Rosca
- Center of Advanced Researches in Cardiovascular Diseases and Hemostaseology, Department of Internal Medicine I, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Gelu-Mihai Brează
- Department IX of Surgery I, Compartment of Hepatic-Biliary-Pancreatic Surgery, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Daniela Reisz
- Department of Neurosciences, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
| | - Daniel Lighezan
- Center of Advanced Researches in Cardiovascular Diseases and Hemostaseology, Department of Internal Medicine I, “V Babes” University of Medicine and Pharmacy, Timisoara, Romania
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Shive CL, Kowal CM, Desotelle AF, Nguyen Y, Carbone S, Kostadinova L, Davitkov P, O’Mara M, Reihs A, Siddiqui H, Wilson BM, Anthony DD. Endotoxemia Associated with Liver Disease Correlates with Systemic Inflammation and T Cell Exhaustion in Hepatitis C Virus Infection. Cells 2023; 12:2034. [PMID: 37626844 PMCID: PMC10453378 DOI: 10.3390/cells12162034] [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: 06/16/2023] [Revised: 07/29/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
Both acute and chronic hepatitis C virus (HCV) infections are characterized by inflammation. HCV and reduced liver blood filtration contribute to inflammation; however, the mechanisms of systemic immune activation and dysfunction as a result of HCV infection are not clear. We measured circulating inflammatory mediators (IL-6, IP10, sCD163, sCD14), indices of endotoxemia (EndoCab, LBP, FABP), and T cell markers of exhaustion and senescence (PD-1, TIGIT, CD57, KLRG-1) in HCV-infected participants, and followed a small cohort after direct-acting anti-viral therapy. IL-6, IP10, Endocab, LBP, and FABP were elevated in HCV participants, as were T cell co-expression of exhaustion and senescence markers. We found positive associations between IL-6, IP10, EndoCab, LBP, and co-expression of T cell markers of exhaustion and senescence. We also found numerous associations between reduced liver function, as measured by plasma albumin levels, and T cell exhaustion/senescence, inflammation, and endotoxemia. We found positive associations between liver stiffness (TE score) and plasma levels of IL-6, IP10, and LBP. Lastly, plasma IP10 and the proportion of CD8 T cells co-expressing PD-1 and CD57 decreased after initiation of direct-acting anti-viral therapy. Although associations do not prove causality, our results support the model that translocation of microbial products, resulting from decreased liver blood filtration, during HCV infection drives chronic inflammation that results in T cell exhaustion/senescence and contributes to systemic immune dysfunction.
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Affiliation(s)
- Carey L. Shive
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
- Pathology Department, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Corinne M. Kowal
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Alexandra F. Desotelle
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Ynez Nguyen
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Sarah Carbone
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Lenche Kostadinova
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Perica Davitkov
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Megan O’Mara
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Alexandra Reihs
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Hinnah Siddiqui
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
| | - Brigid M. Wilson
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Donald D. Anthony
- Cleveland VA Medical Center, Cleveland, OH 44106, USA; (C.M.K.); (A.F.D.); (Y.N.); (S.C.); (L.K.); (P.D.); (M.O.); (A.R.); (H.S.); (B.M.W.); (D.D.A.)
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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17
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Sturm L, Gahm C, Schultheiss M, Reincke M, Huber JP, Boettler T, Thimme R, Bettinger D. Proton pump inhibitor treatment is associated with acute-on-chronic liver failure in patients with advanced cirrhosis. Hepatol Commun 2023; 7:e00178. [PMID: 37347229 PMCID: PMC10289603 DOI: 10.1097/hc9.0000000000000178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/15/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a fatal complication of cirrhosis. Hence, identification of risk factors for ACLF is crucial. Previous studies have linked proton pump inhibitor (PPI) treatment to complications of cirrhosis, however, a possible effect of PPI treatment on the risk of ACLF has not been investigated yet. Therefore, the present study aimed to characterize the impact of PPI treatment on ACLF development. METHODS A total of 642 patients hospitalized due to complications of cirrhosis were retrospectively identified, and PPI treatment during an observation period of 3 years following the hospitalization was reviewed. Subsequently, 74 patients with newly initiated PPI treatment at the time of hospitalization (PPI group) were 1:1 propensity score matched to 74 patients who received no PPI treatment (no-PPI group). Primary end point was the development of ACLF during the observation period, and secondary endpoints were mortality and upper gastrointestinal bleeding. RESULTS PPI and no-PPI groups had comparably severe chronic liver disease at baseline. Nevertheless, the cumulative incidence of ACLF in the presence of death as competing risk was markedly higher in the PPI group compared with the no-PPI group. ACLF-related deaths contributed significantly to a higher 3-year mortality in the PPI group. Uni and multivariable competing risk regression models confirmed that PPI treatment was an independent predictor of ACLF in the study collective (subdistribution HR: 1.892, 95% CI: 1.092-3.281, p = 0.023). The impact of PPI treatment on ACLF development was particularly strong in patients with a model for end-stage liver disease score >12. Upper gastrointestinal bleeding was slightly less frequent in the PPI group. CONCLUSIONS The present results indicate that PPI treatment could be a risk factor for ACLF in patients with advanced cirrhosis.
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Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Program, University of Freiburg, Freiburg, Germany
| | - Chiara Gahm
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Program, University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Dominik Bettinger
- Department of Medicine II, Medical Center University of Freiburg, University of Freiburg, Freiburg, Germany
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18
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Giuli L, Maestri M, Santopaolo F, Pompili M, Ponziani FR. Gut Microbiota and Neuroinflammation in Acute Liver Failure and Chronic Liver Disease. Metabolites 2023; 13:772. [PMID: 37367929 DOI: 10.3390/metabo13060772] [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: 04/06/2023] [Revised: 05/25/2023] [Accepted: 06/10/2023] [Indexed: 06/28/2023] Open
Abstract
Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.
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Affiliation(s)
- Lucia Giuli
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Marta Maestri
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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19
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Zha C, Peng Z, Huang K, Tang K, Wang Q, Zhu L, Che B, Li W, Xu S, Huang T, Yu Y, Zhang W. Potential role of gut microbiota in prostate cancer: immunity, metabolites, pathways of action? Front Oncol 2023; 13:1196217. [PMID: 37265797 PMCID: PMC10231684 DOI: 10.3389/fonc.2023.1196217] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/04/2023] [Indexed: 06/03/2023] Open
Abstract
The gut microbiota helps to reveal the relationship between diseases, but the role of gut microbiota in prostate cancer (PCa) is still unclear. Recent studies have found that the composition and abundance of specific gut microbiota are significantly different between PCa and non-PCa, and the gut microbiota may have common and unique characteristics between different diseases. Intestinal microorganisms are affected by various factors and interact with the host in a variety of ways. In the complex interaction model, the regulation of intestinal microbial metabolites and the host immune system is particularly important, and they play a key role in maintaining the ecological balance of intestinal microorganisms and metabolites. However, specific changes in the composition of intestinal microflora may promote intestinal mucosal immune imbalance, leading to the formation of tumors. Therefore, this review analyzes the immune regulation of intestinal flora and the production of metabolites, as well as their effects and mechanisms on tumors, and briefly summarizes that specific intestinal flora can play an indirect role in PCa through their metabolites, genes, immunity, and pharmacology, and directly participate in the occurrence, development, and treatment of tumors through bacterial and toxin translocation. We also discussed markers of high risk PCa for intestinal microbiota screening and the possibility of probiotic ingestion and fecal microbiota transplantation, in order to provide better treatment options for clinic patients. Finally, after summarizing a number of studies, we found that changes in immunity, metabolites.
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Affiliation(s)
- Cheng Zha
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Zheng Peng
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Kunyuan Huang
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Kaifa Tang
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Urology & Andrology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Qiang Wang
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Lihua Zhu
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Bangwei Che
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Wei Li
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Shenghan Xu
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Tao Huang
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ying Yu
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Wenjun Zhang
- Department of Urology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
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20
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Gou W, Zhang D, Gao L. Qingdu decoction can reduce LPS induced ACLF endotoxemia by regulating microRNA-34c/MAZ/TJs and microRNA-122a/Zonulin/EGFR signal pathway. JOURNAL OF ETHNOPHARMACOLOGY 2023; 302:115922. [PMID: 36414212 DOI: 10.1016/j.jep.2022.115922] [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: 08/25/2022] [Revised: 10/27/2022] [Accepted: 11/07/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qingdu Decoction (QDT) is a traditional Chinese medicine (TCM) that was derived from Xiaochengqi Decoction, a famous decoction documented in the book of Treatise on Exogenous Febrile Disease in the Eastern Han Dynasty. According to our years of clinical application, QDT showed satisfactory efficacy in the treatment of endotoxemia in acute-on-chronic liver failure (ACLF). However, the underlying molecular mechanisms remain largely unknown. AIM OF STUDY In this study, we aimed to systematically evaluate the intervention effect of QDT on endotoxemia in rats and further clarify its potential regulatory mechanism. MATERIALS AND METHODS The rat model of ACLF endotoxemia was induced by TAA and LPS + D-Gal. Then the rats were treated with clinical doses of QDT and lactulose. The rats were divided into four groups: CG, MG, QG and LG. The target microRNA was screened by high-throughput sequencing. The rat weight, liver index, hepatointestinal phenotype, serum biochemical indexes, mast cell activity, and hepatointestinal histopathology were used to evaluate the intervention effect. Western blot analysis was used to detect the expression levels of MAZ and its downstream genes ZO-1 and Occludin, and the expression levels of Zonulin and its downstream gene EGFR in colon. Finally, the expression of the miR-34c, MAZ, ZO-1, Occludin, miR-122a, Zonulin, and EGFR in colon was detected by qRT-PCR to further confirm the mechanism of the miR-34c/MAZ/TJs pathway and the miR-122a/Zonulin/EGFR pathway. RESULTS The rat weight, liver index, liver and colon phenotype, and serum biochemical indexes showed that QDT could significantly reduce liver and intestine injury and inhibit the progress of ACLF and endotoxemia. Toluidine blue staining and cytokine indexes showed that QDT could inhibit the activity of MCs and reduce the release of inflammatory factors. Mechanistically, QDT can inhibit the activity of MCs, activate miR-34c/MAZ/TJs pathway and miR-122a/Zonulin/EGFR pathway in colon, promote the recovery of intestinal barrier homeostasis, reduce and restore the damage of endotoxemia. CONCLUSION Our results suggested that QDT can significantly reduce rat ACLF endotoxemia by regulating the miR-34c/MAZ/TJs pathway and the miR-122a/Zonulin/EGFR pathway in colon.
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Affiliation(s)
- Wenjing Gou
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Di Zhang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Lianyin Gao
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
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21
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Manilla V, Di Tommaso N, Santopaolo F, Gasbarrini A, Ponziani FR. Endotoxemia and Gastrointestinal Cancers: Insight into the Mechanisms Underlying a Dangerous Relationship. Microorganisms 2023; 11:microorganisms11020267. [PMID: 36838231 PMCID: PMC9963870 DOI: 10.3390/microorganisms11020267] [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: 11/11/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Lipopolysaccharide (LPS), also known as endotoxin, is a component of the membrane of gram-negative bacteria and a well-recognized marker of sepsis. In case of disruption of the intestinal barrier, as occurs with unhealthy diets, alcohol consumption, or during chronic diseases, the microbiota residing in the gastrointestinal tract becomes a crucial factor in amplifying the systemic inflammatory response. Indeed, the translocation of LPS into the bloodstream and its interaction with toll-like receptors (TLRs) triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both of which are preceded by a prolonged inflammatory injury; in addition, the risk of recurrence and development of metastasis appears to be associated with endotoxemia. Here, we review the mechanisms that link the promotion and progression of tumorigenesis with endotoxemia, and the possible therapeutic interventions that can be deployed to counteract these events.
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Affiliation(s)
- Vittoria Manilla
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Natalia Di Tommaso
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Correspondence:
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22
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Kim KS, Kwon HM, Kim JH, Yang JW, Jun IG, Song JG, Hwang GS. C-reactive protein-to-albumin ratio is a predictor of 1-year mortality following liver transplantation. Anesth Pain Med (Seoul) 2022; 17:420-428. [PMID: 36317435 PMCID: PMC9663950 DOI: 10.17085/apm.22176] [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: 05/04/2022] [Accepted: 08/22/2022] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Considering the importance of the inflammatory status of recipients on outcomes following liver transplantation (LT), we investigated the association between C-reactive protein-to-albumin ratio (CAR) and one-year mortality following LT and compared it with other parameters reflecting patients' underlying inflammatory status. METHODS A total of 3,614 consecutive adult LT recipients were retrospectively evaluated. Prognostic parameters were analyzed using area under the receiver operating characteristic curve (AUROC) analysis, and subsequent cutoffs were derived. For survival analysis, Cox proportional hazards and Kaplan-Meier analyses were performed. RESULTS The AUROC for CAR to predict one-year mortality after LT was 0.68 (0.65-0.72), which was the highest compared with other inflammatory parameters, with the best cutoff of 0.34. A CAR ≥ 0.34 was associated with a significantly higher one-year mortality rate (13.3% vs. 5.8 %, log-rank P < 0.001) and overall mortality rate (24.5% vs. 12.9%, log-rank P = 0.039). A CAR ≥ 0.34 was an independent predictor of one-year mortality (hazard ratio, 1.40 [1.03-1.90], P = 0.031) and overall mortality (hazard ratio 1.39 [1.13-1.71], P = 0.002) after multivariable adjustment. CONCLUSIONS Preoperative CAR (≥ 0.34) was independently associated with a higher risk of one-year and overall mortality after LT. This may suggest that CAR, a simple and readily available biomarker, maybe a practical index that may assist in the risk stratification of liver transplantation outcomes.
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Affiliation(s)
- Kyoung-Sun Kim
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hye-Mee Kwon
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Corresponding author: Hye-Mee Kwon, Ph.D. Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: 82-2-3010-3868; Fax: 82-2-470-1363;
| | - Jae Hwan Kim
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji-Woong Yang
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Gu Jun
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jun-Gol Song
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gyu-Sam Hwang
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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23
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Spontaneous Bacterial Peritonitis in Decompensated Liver Cirrhosis—A Literature Review. LIVERS 2022. [DOI: 10.3390/livers2030018] [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: 11/16/2022] Open
Abstract
Background: Spontaneous bacterial peritonitis (SBP) is defined as a bacterial infection of the ascitic fluid without a surgically treatable intra-abdominal infection source. SBP is a common, severe complication in cirrhosis patients with ascites, and if left untreated, in-hospital mortality may exceed 90%. However, the incidence of SBP has been lowered to approx. 20% through early diagnosis and antibiotic therapy. Clinical awareness, prompt diagnosis, and immediate treatment are advised when caring for these patients to reduce mortality and morbidity. Aim: To discuss important issues comprising types of SBP, pathogenesis, bacteriology, including the emergence of multidrug-resistant (MDR) microorganisms, prompt diagnosis, risk factors, prognosis, treatment strategies, as well as recurrence prevention through antibiotic prophylaxis until liver transplantation and future trends in treating and preventing SBP in detail. Methods: This article is a literature review and appraisal of guidelines, randomized controlled trials, meta-analyses, and other review articles found on PubMed from between 1977 and 2022. Results: There are three types of SBP. Bacterial translocation from GI tract is the most common source of SBP. Therefore, two thirds of SBP cases were caused by Gram-negative bacilli, of which Escherichia coli is the most frequently isolated pathogen. However, a trend of Gram-positive cocci associated SBP has been demonstrated in recent years, possibly related to more invasive procedures and long-term quinolone prophylaxis. A diagnostic paracentesis should be performed in all patients with cirrhosis and ascites who require emergency room care or hospitalization, who demonstrate or report consistent signs/symptoms in order to confirm evidence of SBP. Distinguishing SBP from secondary bacterial peritonitis is essential because the conditions require different therapeutic strategies. The standard treatment for SBP is prompt broad-spectrum antibiotic administration and should be tailored according to community-acquired SBP, healthcare-associated or nosocomial SBP infections and local resistance profile. Albumin supplementation, especially in patients with renal impairment, is also beneficial. Selective intestinal decontamination is associated with a reduced risk of bacterial infection and mortality in high-risk group. Conclusions: The standard treatment for SBP is prompt broad-spectrum antibiotic administration and should be tailored according to community-acquired SBP, healthcare-associated or nosocomial SBP infections and local resistance profile. Since the one-year overall mortality rates for SBP range from 53.9 to 78%, liver transplantation should be seriously considered for SBP survivors who are good candidates for transplantation. Further development of non-antibiotic strategies based on pathogenic mechanisms are also urgently needed.
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24
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Beyoğlu D, Idle JR. The gut microbiota - a vehicle for the prevention and treatment of hepatocellular carcinoma. Biochem Pharmacol 2022; 204:115225. [PMID: 35998677 DOI: 10.1016/j.bcp.2022.115225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) arises principally against a background of cirrhosis and these two diseases are responsible globally for over 2 million deaths a year. There are few treatment options for liver cirrhosis and HCC, so it is vital to arrest these pathologies early in their development. To do so, we propose dietary and therapeutic solutions that involve the gut microbiota and its consequences. Integrated dietary, environmental and intrinsic signals result in a bidirectional connection between the liver and the gut with its microbiota, known as the gut-liver axis. Numerous lifestyle factors can result in dysbiosis with a change in the functional composition and metabolic activity of the microbiota. A panoply of metabolites can be produced by the microbiota, including ethanol, secondary bile acids, trimethylamine, indole, quinolone, phenazine and their derivatives and the quorum sensor acyl homoserine lactones that may contribute to HCC but have yet to be fully investigated. Gram-negative bacteria can activate the pattern recognition receptor toll-like receptor 4 (TLR4) in the liver leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, which can contribute to HCC initiation and progression. The goal in preventing HCC should be to ensure a healthy gut microbiota using probiotic supplements containing beneficial bacteria and prebiotic plant fibers such as oligosaccharides that stimulate their growth. The clinical development of TLR4 antagonists is urgently needed to counteract the pathological effects of dysbiosis on the liver and other organs. Further nutrigenomic studies are required to understand better how the diet influences the gut microbiota and its adverse effects on the liver.
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Affiliation(s)
- Diren Beyoğlu
- Arthur G. Zupko Institute for Systems Pharmacology and Pharmacogenomics, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York 11201, USA
| | - Jeffrey R Idle
- Arthur G. Zupko Institute for Systems Pharmacology and Pharmacogenomics, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York 11201, USA.
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25
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Santopaolo F, Coppola G, Giuli L, Gasbarrini A, Ponziani FR. Influence of Gut–Liver Axis on Portal Hypertension in Advanced Chronic Liver Disease: The Gut Microbiome as a New Protagonist in Therapeutic Management. MICROBIOLOGY RESEARCH 2022; 13:539-555. [DOI: 10.3390/microbiolres13030038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Clinically significant portal hypertension is associated with most complications of advanced chronic liver disease (ACLD), including variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. Gut dysbiosis is a hallmark of ACLD with portal hypertension and consists of the overgrowth of potentially pathogenic bacteria and a decrease in autochthonous bacteria; additionally, congestion makes the intestinal barrier more permeable to bacteria and their products, which contributes to the development of complications through inflammatory mechanisms. This review summarizes current knowledge on the role of the gut–liver axis in the pathogenesis of portal hypertension, with a focus on therapies targeting portal hypertension and the gut microbiota. The modulation of the gut microbiota on several levels represents a major challenge in the upcoming years; in-depth characterization of the molecular and microbiological mechanisms linking the gut–liver axis to portal hypertension in a bidirectional relationship could pave the way to the identification of new therapeutic targets for innovative therapies in the management of ACLD.
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Affiliation(s)
- Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Lucia Giuli
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Abstract
The World Health Organization describes antimicrobial resistance as one of the biggest threats to global health, food security, and development with indiscriminate use of antimicrobials globally driving the emergence of multidrug-resistant bacteria, resistant to 60% of antimicrobials in some countries. Infections with multidrug-resistant organisms (MDROs) have increased in recent decades in patients with cirrhosis, who are frequently prescribed antibiotics, regularly undergo invasive procedures such as large volume paracentesis, and have recurrent hospitalizations, posing a particular risk in this already immunocompromised cohort of patients. In this review, we explore mechanisms underlying this vulnerability to MDRO infection; the effect of bacterial infections on disease course in cirrhosis; prevalence of MDROs in patients with cirrhosis; outcomes following MDRO infection; fungal infections; antibiotics and their efficacy; and management of MDRO infections in terms of detection, antimicrobial and nonantimicrobial treatments, prophylaxis, antibiotic stewardship, the gut microbiome, and technological interventions.
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Affiliation(s)
- Charles E Gallaher
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Debbie L Shawcross
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom.,Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
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27
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Kronsten VT, Woodhouse CA, Zamalloa A, Lim TY, Edwards LA, Martinez-Llordella M, Sanchez-Fueyo A, Shawcross DL. Exaggerated inflammatory response to bacterial products in decompensated cirrhotic patients is orchestrated by interferons IL-6 and IL-8. Am J Physiol Gastrointest Liver Physiol 2022; 322:G489-G499. [PMID: 35195033 PMCID: PMC8993594 DOI: 10.1152/ajpgi.00012.2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cirrhosis-associated immune dysfunction (CAID) contributes to disease progression and organ failure development. We interrogated immune system function in nonseptic compensated and decompensated cirrhotic patients using the TruCulture whole blood stimulation system, a novel technique that allows a more accurate representation than traditional methods, such as peripheral blood mononuclear cell culture, of the immune response in vivo. Thirty cirrhotics (21 decompensated and 9 compensated) and seven healthy controls (HCs) were recruited. Whole blood was drawn directly into three TruCulture tubes [unstimulated to preloaded with heat-killed Escherichia coli 0111:B4 (HKEB) or lipopolysaccharide (LPS)] and incubated in dry heat blocks at 37°C for 24 h. Cytokine analysis of the supernatant was performed by multiplex assay. Cirrhotic patients exhibited a robust proinflammatory response to HKEB compared with HCs, with increased production of interferon-γ-induced protein 10 (IP-10) and IFN-λ1, and to LPS, with increased production of IFN-λ1. Decompensated patients demonstrated an augmented immune response compared with compensated patients, orchestrated by an increase in type I, II, and III interferons, and higher levels of IL-1β, IL-6, and IL-8 post-LPS stimulation. IL-1β, TNF-α, and IP-10 post-HKEB stimulation and IP-10 post-LPS stimulation negatively correlated with biochemical markers of liver disease severity and liver disease severity scores. Cirrhotic patients exposed to bacterial products exhibit an exaggerated inflammatory response orchestrated by IFNs, IL-6, and IL-8. Poststimulation levels of a number of proinflammatory cytokines negatively correlate with markers of liver disease severity raising the possibility that the switch to an immunodeficient phenotype in CAID may commence earlier in the course of advanced liver disease. NEW & NOTEWORTHY Decompensated cirrhotic patients, compared with compensated patients, exhibit a greater exaggerated inflammatory response to bacterial products orchestrated by interferons, IL-6, and IL-8. Postbacterial product stimulation levels of a number of pro-inflammatory cytokines negatively correlate with liver disease severity biomarkers and liver disease severity scores raising the possibility that the switch to an immunodeficient phenotype in cirrhosis-associated immune dysfunction may commence earlier in the course of advanced liver disease.
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Affiliation(s)
- Victoria T. Kronsten
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Charlotte A. Woodhouse
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Ane Zamalloa
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Tiong Yeng Lim
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Lindsey A. Edwards
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Marc Martinez-Llordella
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Debbie L. Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
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Mu S, Xiang H, Wang Y, Wei W, Long X, Han Y, Kuang Z, Yang Y, Xu F, Xue M, Dong Z, Tong C, Zheng H, Song Z. The pathogens of secondary infection in septic patients share a similar genotype to those that predominate in the gut. Crit Care 2022; 26:68. [PMID: 35331299 PMCID: PMC8944137 DOI: 10.1186/s13054-022-03943-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/07/2022] [Indexed: 01/05/2023] Open
Abstract
Background Secondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection. Methods In this prospective, observational case–control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks. Results The abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice. Conclusion Our study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-022-03943-z.
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Affiliation(s)
- Sucheng Mu
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Hao Xiang
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yuezhu Wang
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, 2140 Xietu Road, Shanghai, China.,Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Institute for Biomedical and Pharmaceutical Technologies, 250 Bibo Road, Shanghai, China
| | - Wei Wei
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Xiangyu Long
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yi Han
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhongshu Kuang
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Yilin Yang
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Feixiang Xu
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Mingming Xue
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhimin Dong
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Chaoyang Tong
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Huajun Zheng
- NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, 2140 Xietu Road, Shanghai, China.
| | - Zhenju Song
- Department of Emergency Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. .,Shanghai Key Laboratory of Lung Inflammation and Injury, 180 Fenglin Road, Shanghai, China. .,Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai, China.
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Triantos C, Kalafateli M, Assimakopoulos SF, Karaivazoglou K, Mantaka A, Aggeletopoulou I, Spantidea PI, Tsiaoussis G, Rodi M, Kranidioti H, Goukos D, Manolakopoulos S, Gogos C, Samonakis DN, Daikos GL, Mouzaki A, Thomopoulos K. Endotoxin Translocation and Gut Barrier Dysfunction Are Related to Variceal Bleeding in Patients With Liver Cirrhosis. Front Med (Lausanne) 2022; 9:836306. [PMID: 35308545 PMCID: PMC8929724 DOI: 10.3389/fmed.2022.836306] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/10/2022] [Indexed: 12/15/2022] Open
Abstract
Background Bacterial infections are associated with the risk of variceal bleeding through complex pathophysiologic pathways. Objectives The primary objective of the present case-control study was to investigate the role of bacterial translocation and intestinal barrier dysfunction in the pathogenesis of variceal bleeding. A secondary objective was to determine independent predictors of key outcomes in variceal bleeding, including bleeding-related mortality. Methods Eighty-four (n = 84) consecutive patients participated in the study, 41 patients with acute variceal bleeding and 43 patients with stable cirrhosis, and were followed up for 6 weeks. Peripheral blood samples were collected at patient admission and before any therapeutic intervention. Results Child-Pugh (CP) score (OR: 1.868; p = 0.044), IgM anti-endotoxin antibody levels (OR: 0.954; p = 0.016) and TGF-β levels (OR: 0.377; p = 0.026) were found to be significant predictors of variceal bleeding. Regression analysis revealed that albumin (OR: 0.0311; p = 0.023), CRP (OR: 3.234; p = 0.034) and FABP2 levels (OR:1.000, p = 0.040), CP score (OR: 2.504; p = 0.016), CP creatinine score (OR: 2.366; p = 0.008), end-stage liver disease model (MELD), Na (OR: 1.283; p = 0.033), portal vein thrombosis (OR: 0.075; p = 0.008), hepatocellular carcinoma (OR: 0.060; p = 0.003) and encephalopathy (OR: 0.179; p = 0.045) were significantly associated with 6-week mortality. Conclusions Bacterial translocation and gut barrier impairment are directly related to the risk of variceal bleeding. Microbiota-modulating interventions and anti-endotoxin agents may be promising strategies to prevent variceal bleeding.
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Affiliation(s)
- Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Maria Kalafateli
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Katerina Karaivazoglou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Aikaterini Mantaka
- Department of Gastroenterology, University Hospital of Heraklion, Heraklion, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece.,Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Panagiota I Spantidea
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Georgios Tsiaoussis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Maria Rodi
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Hariklia Kranidioti
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | - Dimitrios Goukos
- Department of Propedeutic Medicine, Laiko General Hospital, Athens, Greece
| | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | - Charalambos Gogos
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Georgios L Daikos
- Department of Propedeutic Medicine, Laiko General Hospital, Athens, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
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Preventing Bacterial Translocation in Patients with Leaky Gut Syndrome: Nutrition and Pharmacological Treatment Options. Int J Mol Sci 2022; 23:ijms23063204. [PMID: 35328624 PMCID: PMC8949204 DOI: 10.3390/ijms23063204] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/14/2022] [Accepted: 03/14/2022] [Indexed: 12/11/2022] Open
Abstract
Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation.
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Kronsten VT, Tranah TH, Pariante C, Shawcross DL. Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J Hepatol 2022; 76:665-680. [PMID: 34800610 DOI: 10.1016/j.jhep.2021.11.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/13/2021] [Accepted: 11/08/2021] [Indexed: 02/08/2023]
Abstract
Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.
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Affiliation(s)
- Victoria T Kronsten
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
| | - Thomas H Tranah
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Carmine Pariante
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, UK
| | - Debbie L Shawcross
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK
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Chan YC, Chen CL, Wang CC, Lin CC, Yong CC, Chiu KW, Wu KL. Extremity risk factors of sepsis for gastrointestinal endoscopy in patients with liver cirrhosis. BMC Gastroenterol 2022; 22:54. [PMID: 35139804 PMCID: PMC8826657 DOI: 10.1186/s12876-022-02124-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 01/27/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Liver cirrhosis is a well-known risk factor of sepsis after emergent gastrointestinal (GI) endoscopy. Elective GI endoscopy before living donor liver transplantation (LDLT), however, may also carry the septic risk among these patients. METHODS This retrospective study reviewed the medical records of 642 cirrhotic recipients who underwent GI endoscopy from 2008 to 2016. We analyzed the incidence and risk factors of post-endoscopy sepsis during 2008-2012 (experience cohort). Our protocol changed after 2013 (validation cohort) to include antibiotic prophylaxis. RESULTS In experience cohort, 36 cases (10.5%) of the 342 LDLT candidates experienced sepsis within 48 h after endoscopy. The sepsis rate was significantly higher in patients with hepatic decompensation than patients without (22.2% vs. 9.6% vs. 2.6% in Child C/B/A groups respectively; ×2 = 20.97, P < 0.001). Using multivariate logistic regression analysis, the factors related to post-endoscopy sepsis were the Child score (OR 1.46; 95% CI 1.24-1.71), Child classes B and C (OR 3.80 and 14.13; 95% CI 1.04-13.95 and 3.97-50.23, respectively), hepatic hydrothorax (OR 4.85; 95% CI 1.37-17.20), and use of antibiotic prophylaxis (OR 0.08; 95% CI 0.01-0.64). In validation cohort, antibiotics were given routinely, and all cases of hepatic hydrothorax (n = 10) were drained. Consequently, 4 (1.3%) episodes of sepsis occurred among 300 LDLT candidates, and the incidence was significantly lower than before (1.3% vs. 10.5%, P < 0.001). CONCLUSIONS Patients with decompensated cirrhosis and hepatic hydrothorax have higher risk of sepsis following endoscopy. In advanced cirrhotic patients, antibiotic prophylaxis and drainage of hydrothorax may be required to prevent sepsis before elective GI endoscopy.
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Affiliation(s)
- Yi-Chia Chan
- Liver Transplantation Center, and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, 83303, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center, and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, 83303, Kaohsiung, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Center, and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, 83303, Kaohsiung, Taiwan
| | - Chih-Che Lin
- Liver Transplantation Center, and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, 83303, Kaohsiung, Taiwan.
| | - Chee-Chien Yong
- Liver Transplantation Center, and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, 83303, Kaohsiung, Taiwan
| | - King-Wah Chiu
- Liver Transplantation Center, and Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Keng-Liang Wu
- Liver Transplantation Center, and Department of Internal Medicine, Division of Hepato-Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Portincasa P, Bonfrate L, Khalil M, Angelis MD, Calabrese FM, D’Amato M, Wang DQH, Di Ciaula A. Intestinal Barrier and Permeability in Health, Obesity and NAFLD. Biomedicines 2021; 10:83. [PMID: 35052763 PMCID: PMC8773010 DOI: 10.3390/biomedicines10010083] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/20/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
The largest surface of the human body exposed to the external environment is the gut. At this level, the intestinal barrier includes luminal microbes, the mucin layer, gastrointestinal motility and secretion, enterocytes, immune cells, gut vascular barrier, and liver barrier. A healthy intestinal barrier is characterized by the selective permeability of nutrients, metabolites, water, and bacterial products, and processes are governed by cellular, neural, immune, and hormonal factors. Disrupted gut permeability (leaky gut syndrome) can represent a predisposing or aggravating condition in obesity and the metabolically associated liver steatosis (nonalcoholic fatty liver disease, NAFLD). In what follows, we describe the morphological-functional features of the intestinal barrier, the role of major modifiers of the intestinal barrier, and discuss the recent evidence pointing to the key role of intestinal permeability in obesity/NAFLD.
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Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Maria De Angelis
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Francesco Maria Calabrese
- Department of Soil, Plant and Food Sciences, University of Bari Aldo Moro, Via Amendola 165/a, 70126 Bari, Italy; (M.D.A.); (F.M.C.)
| | - Mauro D’Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE-BRTA, 48160 Derio, Spain;
- Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (L.B.); (M.K.); (A.D.C.)
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Araki R, Iwanaga K, Ueda K, Isaka M. Intestinal Complication With Myxomatous Mitral Valve Diseases in Chihuahuas. Front Vet Sci 2021; 8:777579. [PMID: 34888377 PMCID: PMC8649761 DOI: 10.3389/fvets.2021.777579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/28/2021] [Indexed: 11/25/2022] Open
Abstract
The effects of cardiac disease on the intestine have been reported in humans but not in dogs. We investigated the effects of myxomatous mitral valve disease (MMVD), which is capable of causing congestion and tissue hypoperfusion, on the intestine in Chihuahuas, a breed frequently encountered in clinical practice as the preferred breed for MMVD. In this study, 69 Chihuahuas were divided into four groups based on echocardiography and chest radiography: 19 healthy Chihuahuas (H) and 50 Chihuahuas with MMVD classified according to the ACVIM consensus (stage B1, B2, C/D). In all the cases, serum intestinal fatty acid-binding protein (I-FABP) and D/L-lactate concentrations, markers of intestinal mucosal injury, were measured. I-FABP was significantly higher in stage C/D Chihuahuas than in other groups (p < 0.05), and stage B2 was significantly higher than H (p < 0.05). D-lactate was significantly increased in stages B2 and C/D compared to H and stage B1 (p < 0.05). L-lactate was significantly higher in stage C/D Chihuahuas than in any other group (p < 0.05), and stage B2 was significantly higher than that in H and stage B1 (p < 0.05). Intestinal mucosal injury risk was significantly higher in Chihuahuas with heart failure due to MMVD, suggesting that the risk could increase with worsening heart disease. This is the first study to investigate the intestinal complications of MMVD, and further investigations a needed in the future.
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Affiliation(s)
- R Araki
- Yokohama Yamate Dog & Cat Medical Center, Yokohama, Japan.,Tokyo Veterinary Cardiology Center, Fukazawa, Japan.,Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
| | - K Iwanaga
- Tokyo Veterinary Cardiology Center, Fukazawa, Japan
| | - Kazunori Ueda
- Yokohama Yamate Dog & Cat Medical Center, Yokohama, Japan
| | - M Isaka
- Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan
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Hypoglycemia is an early, independent predictor of bacteremia and in-hospital death in patients with cirrhosis. Eur J Gastroenterol Hepatol 2021; 33:e693-e699. [PMID: 34074985 PMCID: PMC8669667 DOI: 10.1097/meg.0000000000002218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS Bacteremia is a common cause of death in patients with cirrhosis and early antimicrobial therapy can be life-saving. Severe liver disease impairs glucose metabolism such that hypoglycemia may be a presenting sign of infection in patients with cirrhosis. We explored this association using granular retrospective data. METHODS We conducted a case-control analysis from 1 January 2008 to 31 December 17 in the University of Pennsylvania Health System. We identified the first blood culture results from all cirrhosis hospitalizations and obtained detailed vital sign and laboratory data in the 24-72 h prior to culture results. We used multivariable logistic regression to develop models predicting blood culture positivity and in-hospital mortality. We repeated these analyses restricted to normothermic individuals. Restricted cubic splines were used to model nonlinearity in the glucose variable. RESULTS We identified 1274 cirrhosis admissions with blood culture results (52.7% positive). In adjusted models, minimum glucose 24-72 h prior to blood culture result date was a significant predictor of blood culture positivity. In particular, glucose levels below 100 mg/dL significantly increased the probability of subsequent positive blood culture (e.g. odds ratio 1.89 for 50 mg/dL vs. 100 mg/dL, P = 0.004). This relationship persisted when restricting the cohort to normothermic individuals. Glucose levels <100 mg/dL in patients with bacteremia were also positively associated with in-hospital mortality. CONCLUSIONS Early hypoglycemia is predictive of subsequently documented bacteremia and in-hospital mortality in patients with cirrhosis, even among normothermic individuals. In patients without other overt signs of infection, low glucose values may serve as an additional data point to justify early antibiosis.
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Systemic inflammation as a risk factor for portal vein thrombosis in cirrhosis: a prospective longitudinal study. Eur J Gastroenterol Hepatol 2021; 33:e108-e113. [PMID: 33208682 DOI: 10.1097/meg.0000000000001982] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS Various risk factors for portal vein thrombosis (PVT) development in patients with cirrhosis have been identified, but the role of systemic inflammatory reaction is unknown. The study aims to assess the association between markers of systemic inflammation and PVT in cirrhosis. METHODS Between January 2014 and October 2015, 107 outpatients with cirrhosis and no PVT were recruited, and followed till February 2017. White blood cell count, serum concentrations of high-sensitive C-reactive protein, ferritin, tumor necrosis factor-alpha and interleukin-6 (IL-6) were evaluated at baseline and every 3 or 6 months till PVT diagnosis or end of follow-up. RESULTS Median age, model for end-stage liver disease (MELD) score and follow-up period of the studied population was 55 years (IQR 46-62 years), 9.6 points (IQR 7.5-12 points) and 19 months (12-24 months), respectively. PVT developed in 10.3% of the patients. Lymphocyte count below 1.2 ´ 109/L [hazard ratio, 6.04; 95% confidence interval (CI), 1.29-28.2; P = 0.022], IL-6 above 5.5 pg/mL (hazard ratio, 5.64; 95% CI, 1.21-26.33; P = 0.028) and neutrophil-to-lymphocyte ratio (hazard ratio, 1.46; 95% CI, 1.04-2.04; P = 0.028) were associated with a higher risk of PVT development. IL-6 and lymphopenia remained associated with subsequent PVT development after adjustment for nonselective beta-blockers, spleen size, portosystemic collaterals, oesophageal varices (grade ≥2) and ascites, but also with alcohol as the cause for cirrhosis and MELD ≥13. CONCLUSION In patients with cirrhosis, markers of systemic inflammation IL-6 and lymphopenia are predictive of PVT independently of markers of portal hypertension. These results draw our attention on a factor so far overlooked in the pathogenesis of PVT.
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Influence of Probiotics Administration Before Liver Resection in Patients with Liver Disease: A Randomized Controlled Trial. World J Surg 2021; 46:656-665. [PMID: 34837121 DOI: 10.1007/s00268-021-06388-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND By inhibiting the growth of pathogenic bacteria and modulating the local intestinal immune system, probiotics may reduce bacterial translocation and systemic endotoxaemia, factors partially responsible for post-operative complications following liver resection for hepatocellular carcinoma in patients with cirrhosis. METHODS Patients with resectable hepatocellular carcinoma developed in the setting of chronic liver disease were prospectively divided into two equal-sized groups: one receiving probiotic treatment 14 days prior to surgery and the other receiving placebo. The primary endpoint was the level of circulating endotoxins after hepatectomy. Secondary endpoints were systemic inflammation (inflammatory cytokine levels), post-operative liver function and overall post-operative complication rate. RESULTS From May 2013 to December 2018, 64 patients were randomized, and 54 patients were included in the analysis, 27 in each arm. No significant change in endotoxin levels was observed over time in either group (P = 0.299). No difference between the groups in terms of post-operative liver function and overall complication rates was observed. The only differences observed were significant increases in the levels of TNFalpha (P = 0.019) and interleukin 1-b (P = 0.028) in the probiotic group in the post-operative period. CONCLUSION Contrary to the modest data reported in the literature, the administration of probiotics before minor liver resection for hepatocellular carcinoma developed in the setting of compensated chronic liver disease does not seem to have an impact on circulating endotoxin levels or post-operative complication rates. TRIAL REGISTRATION Trial registration: NCT02021253.
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Kronborg TM, Ytting H, Hobolth L, Møller S, Kimer N. Novel Anti-inflammatory Treatments in Cirrhosis. A Literature-Based Study. Front Med (Lausanne) 2021; 8:718896. [PMID: 34631742 PMCID: PMC8495012 DOI: 10.3389/fmed.2021.718896] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
Liver cirrhosis is a disease characterised by multiple complications and a poor prognosis. The prevalence is increasing worldwide. Chronic inflammation is ongoing in liver cirrhosis. No cure for the inflammation is available, and the current treatment of liver cirrhosis is only symptomatic. However, several different medical agents have been suggested as potential healing drugs. The majority are tested in rodents, but few human trials are effectuated. This review focuses on medical agents described in the literature with supposed alleviating and curing effects on liver cirrhosis. Twelve anti-inflammatory, five antioxidative, and three drugs with effects on gut microflora and the LPS pathway were found. Two drugs not categorised by the three former categories were found in addition. In total, 42 rodent studies and seven human trials were found. Promising effects of celecoxib, aspirin, curcumin, kahweol, pentoxifylline, diosmin, statins, emricasan, and silymarin were found in cirrhotic rodent models. Few indices of effects of etanercept, glycyrrhizin arginine salt, and mitoquinone were found. Faecal microbiota transplantation is in increasing searchlight with a supposed potential to alleviate cirrhosis. However, human trials are in demand to verify the findings in this review.
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Affiliation(s)
- Thit Mynster Kronborg
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Henriette Ytting
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Lise Hobolth
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine 260, Center for Functional and Diagnostic Imaging and Research, Amager-Hvidovre Hospital, Hvidovre, Denmark.,Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark.,Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Hsu H, Seah V, Marriott D, Moore J. Enterococcus cecorum infective endocarditis in a patient with chronic myeloid leukemia and cirrhosis. Pathology 2021; 54:495-497. [PMID: 34565605 DOI: 10.1016/j.pathol.2021.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/28/2021] [Accepted: 07/03/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Hannah Hsu
- Haematology Department, St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia.
| | - Vincent Seah
- Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia
| | - Deborah Marriott
- Department of Infectious Diseases and Clinical Microbiology, St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia
| | - John Moore
- Haematology Department, St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia
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Abstract
Antifibrotic therapies for the treatment of liver fibrosis represent an unconquered area of drug development. The significant involvement of the gut microbiota as a driving force in a multitude of liver disease, be it pathogenesis or fibrotic progression, suggest that targeting the gut–liver axis, relevant signaling pathways, and/or manipulation of the gut’s commensal microbial composition and its metabolites may offer opportunities for biomarker discovery, novel therapies and personalized medicine development. Here, we review potential links between bacterial translocation and deficits of host-microbiome compartmentalization and liver fibrosis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies, translated from our current knowledge of the gut–liver axis, targeted at restoring intestinal eubiosis, ameliorating hepatic fibrosis and rising portal hypertension that characterize and define the course of decompensated cirrhosis.
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Liu W, Luo X, Tang J, Mo Q, Zhong H, Zhang H, Feng F. A bridge for short-chain fatty acids to affect inflammatory bowel disease, type 1 diabetes, and non-alcoholic fatty liver disease positively: by changing gut barrier. Eur J Nutr 2021; 60:2317-2330. [PMID: 33180143 DOI: 10.1007/s00394-020-02431-w] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE In previous studies, short-chain fatty acids (SCFAs) have been found to regulate gut microbiota and change gut barrier status, and the potential positive effects of SCFAs on inflammatory bowel disease (IBD), type 1 diabetes mellitus (T1D), and non-alcoholic fatty liver disease (NAFLD) have also been found, but the role of SCFAs in these three diseases is not clear. This review aims to summarize existing evidence on the effects of SCFAs on IBD, T1D, and NHFLD, and correlates them with gut barrier and gut microbiota (gut microbiota barrier). METHODS A literature search in PubMed, Web of Science, Springer, and Wiley Online Library up to October 2020 was conducted for all relevant studies published. RESULTS This is a retrospective review of 150 applied research articles or reviews. The destruction of gut barrier may promote the development of IBD, T1D, and NAFLD. SCFAs seem to maintain the gut barrier by promoting the growth of intestinal epithelial cells, strengthening the intestinal tight connection, and regulating the activities of gut microbiota and immune cells, which might result possible beneficial effects on the above three diseases at a certain dose. CONCLUSIONS Influencing gut barrier health may be a bridge for SCFAs (especially butyrate) to have positive effects on IBD, T1D, and NAFLD. It is expected that this article can provide new ideas for the subsequent research on the treatment of diseases by SCFAs and help SCFAs be better applied to precise and personalized treatment.
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Affiliation(s)
- Wangxin Liu
- College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, No. 866, Yuhangtang Road, Hangzhou, 310058, China
| | - Xianliang Luo
- College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, No. 866, Yuhangtang Road, Hangzhou, 310058, China
| | - Jun Tang
- College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, No. 866, Yuhangtang Road, Hangzhou, 310058, China
| | - Qiufen Mo
- College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, No. 866, Yuhangtang Road, Hangzhou, 310058, China
| | - Hao Zhong
- College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, No. 866, Yuhangtang Road, Hangzhou, 310058, China
| | - Hui Zhang
- College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, No. 866, Yuhangtang Road, Hangzhou, 310058, China
| | - Fengqin Feng
- College of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, National Engineering Laboratory of Intelligent Food Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of Ministry of Agriculture and Rural Affairs, Key Laboratory for Agro-Products Nutritional Evaluation of Ministry of Agriculture, Zhejiang University, No. 866, Yuhangtang Road, Hangzhou, 310058, China.
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Edwards LA, Goldenberg SD, Shawcross DL. Meeting the Challenge of Antimicrobial Resistance in Cirrhosis: The Invisible Threat That Lies Within. Gastroenterology 2021; 161:413-415. [PMID: 34048780 DOI: 10.1053/j.gastro.2021.05.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 05/21/2021] [Indexed: 12/18/2022]
Affiliation(s)
- Lindsey A Edwards
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College, London, UK
| | - Simon D Goldenberg
- Centre for Clinical Infection and Diagnostics Research, King's College London and, Department of Microbiology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Debbie L Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London and, Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.
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Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol 2021; 75 Suppl 1:S67-S81. [PMID: 34039493 PMCID: PMC8973011 DOI: 10.1016/j.jhep.2020.11.013] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Cirrhosis - the common end-stage of chronic liver disease - is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.
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Affiliation(s)
- Jonel Trebicka
- Translational Hepatology, Internal Medicine I, Goethe University Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
| | - Jane Macnaughtan
- Institute for Liver and Digestive Health, Royal Free Campus, University College London, United Kingdom
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Debbie L Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Denmark Hill Campus, London, United Kingdom
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, VA, USA
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Bai Q, Guo HX, Su CY, Han QF, Wang T, Tang W. Serum Sphingosine-1-phosphate level and peritonitis in peritoneal dialysis patients. Ren Fail 2021; 42:829-835. [PMID: 32787649 PMCID: PMC7472472 DOI: 10.1080/0886022x.2020.1805763] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
BACKGROUND Given the important role of Sphingosine-1-phosphate (S1P) in maintaining the hemostasis in intestinal barrier function and regulation of inflammation and immune, we hypothesize that S1P might be a biomarker to predict peritonitis in peritoneal dialysis (PD) patients. METHODS In this case-control study, 78 stable, continuous ambulatory peritoneal dialysis patients were enrolled and followed for the episode of PD associated peritonitis. Patients were divided into two groups by whether or not they had peritonitis during follow-up: non-peritonitis (n = 65) and peritonitis (n = 13) group. S1P was analyzed by enzyme-linked immunosorbent assay. Logistic regression analysis was used to assess factors associated with peritonitis. The variables identified by univariable regression models (p < 0.1) were further selected into the multivariable logistic regression model to determine whether they could independently affect peritonitis. RESULTS Patients with peritonitis had a lower level of S1P than that of patients without peritonitis (1.3 ng/mL IQ 0.8, 3.6 ng/mL vs. 2.8 ng/mL IQ 1.5, 5.4 ng/mL, p = 0.018). The peritonitis group had lower serum albumin, lower blood leukocyte, lower hemoglobin and lower platelet count as compared to the non-peritonitis group. Logistic regression analysis showed that S1P (OR = 0.381, 95% CI = 0.171-0.848, p = 0.018), blood leukocyte count (OR = 0.438, 95% CI = 0.207-0.925, p = 0.030), and serum albumin (OR = 0.732, 95% CI = 0.556-0.962, p = 0.025) were independent factors associated with peritonitis in the present PD population. CONCLUSION Our study showed that S1P was an independent determinant of subsequent peritonitis in PD patients. S1P might serve as a biomarker to predict peritonitis in PD patients.
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Affiliation(s)
- Qiong Bai
- Department of Nephrology, Peking University Third Hospital, Beijing, China
| | - Hong-Xia Guo
- Department of Nephrology, Peking University Third Hospital, Beijing, China
| | - Chun-Yan Su
- Department of Nephrology, Peking University Third Hospital, Beijing, China
| | - Qing-Feng Han
- Department of Nephrology, Peking University Third Hospital, Beijing, China
| | - Tao Wang
- Department of Nephrology, Peking University Third Hospital, Beijing, China
| | - Wen Tang
- Department of Nephrology, Peking University Third Hospital, Beijing, China
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Abstract
Biliary atresia (BA) is a fibro-obliterative condition of the biliary tree, presenting in infancy. The bilioenteric conduit formed at Kasai portoenterostomy (KPE), achieves restoration of bile flow in approximately 60% of infants. Even if the operation is successful, cirrhosis and its associated complications are, however, common. BA remains the leading cause for liver transplantation (LT) in children. Antibiotic, choleretic, and steroid therapy post-KPE have not convincingly reduced LT rates. Advances in molecular technology have enabled characterisation of the encoded genes of the gut microbiota (gut microbiome). The gut microbiome plays an important role in host metabolism, nutrition, and immune function, with alterations in its diversity and/or composition, known as dysbiosis, being described in disease states, including liver disease. Liver-gut microbiome exploration in adulthood largely focuses on nonalcoholic liver disease, cirrhosis (mainly alcohol- or viral-based aetiology) and cholestatic liver diseases (eg, primary sclerosing cholangitis), with microbial signatures correlating to disease severity. Investigation of the gut microbiota in BA had been limited to culture-based methodology, but molecular studies are emerging, and although in their infancy, highlight a potential pathogenic role for Enterobacteriaceae and Streptococcus, and a potential beneficial role for Bifidobacteria. Bacterial translocation, and the production of gut microbiome-derived metabolites, are key host-microbiome-mechanistic pathways in liver disease pathogenesis. Microbiome-targeted therapeutics for liver disease are in development, with faecal microbiota transplantation showing promise in cirrhosis. Could the gut microbiome be a novel modifiable risk factor in BA, reducing the need for LT?
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Lee DU, Fan GH, Hastie DJ, Prakasam VN, Addonizio EA, Ahern RR, Seog KJ, Karagozian R. The Clinical Impact of Cirrhosis on the Hospital Outcomes of Patients Admitted With Influenza Infection: Propensity Score Matched Analysis of 2011-2017 US Hospital Data. J Clin Exp Hepatol 2021; 11:531-543. [PMID: 34511813 PMCID: PMC8414330 DOI: 10.1016/j.jceh.2021.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVES Patients with cirrhosis have liver-related immune dysfunction that potentially predisposes the patients to increased influenza infection risk. Our study evaluates this cross-sectional relationship using a national registry of hospital patients. METHODS This study included the 2011-2017 National Inpatient Sample database. From this, respiratory influenza cases were isolated and stratified using the presence of cirrhosis into a cirrhosis-present study cohort and cirrhosis-absent controls; propensity score matching method was used to match the controls to the study cohort (cirrhosis-present) using a 1:1 matching ratio. The endpoints included mortality, length of stay, hospitalization costs, and influenza-related complications. RESULTS Following the match, there were 2,040 with cirrhosis and matched 2,040 without cirrhosis admitted with respiratory influenza infection. Compared to the controls, cirrhosis patients had higher in-hospital mortality (7.79 vs 3.43% p < 0.001, OR 2.38 95% CI 1.78-3.17), longer length of stay (7.25 vs 6.52 d p < 0.001), higher hospitalization costs ($70,009 vs $65,035 p < 0.001), and were more likely be discharged to a skilled nursing facility and home healthcare (vs routine home discharges). In terms of influenza-related complications, the cirrhosis cohort had higher rates of sepsis (29.8 vs 22% p < 0.001, OR 1.51 95% CI 1.31-1.74). In the multivariate regression analysis, cirrhosis was associated with higher mortality (p < 0.001, aOR 2.31 95% CI 1.59-3.35) and length of stay (p = 0.018, aOR 1.03 95% CI 1.01-1.06). In subgroup analysis of patients with decompensated (n = 597) versus compensated cirrhosis (n = 1443), those with decompensated cirrhosis had higher rates of in-hospital mortality (12.7 vs 5.75% p < 0.001, OR 2.39 95% CI 1.72-3.32), length of stay (8.85 vs 6.59 d p < 0.001), and hospitalization costs ($92,858 vs $60,556 p < 0.001). In the multivariate analysis, decompensated cirrhosis was associated with increased mortality (p < 0.001, aOR 2.86 95% CI 1.90-4.32). CONCLUSION This study shows the presence of cirrhosis to result in higher hospital mortality and postinfluenza complications in patients with influenza infection.
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Key Words
- AHRQ, agency for healthcare research and quality
- DRG, diagnosis-related group
- HCUP, healthcare cost and utilization project
- ICD-10, international classification of diseases, tenth edition
- ICD-9, international classification of diseases, ninth edition
- NIS, nationwide inpatient sample
- SBP, spontaneous bacterial peritonitis
- SID, state inpatient database
- VIF, variation inflation factor
- ascites
- common cold
- flu
- influenza-related complications
- portal hypertension
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Affiliation(s)
- David U. Lee
- Address for correspondence: David Uihwan Lee MD, Liver Center, Division of Gastroenterology, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA. T: 617-636-4168, F: 617-636-9292.
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Scott RA, Williams HG, Hoad CL, Alyami A, Ortori CA, Grove JI, Marciani L, Moran GW, Spiller RC, Menys A, Aithal GP, Gowland PA. MR Measures of Small Bowel Wall
T2
Are Associated With Increased Permeability. J Magn Reson Imaging 2020; 53:1422-1431. [DOI: 10.1002/jmri.27463] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Affiliation(s)
- Robert A. Scott
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Nottingham Digestive Diseases Centre University of Nottingham Nottingham UK
| | - Hannah G. Williams
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy University of Nottingham Nottingham UK
| | - Caroline L. Hoad
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy University of Nottingham Nottingham UK
| | - Ali Alyami
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
| | - Catherine A. Ortori
- Centre for Analytical Bioscience, School of Pharmacy University of Nottingham Nottingham UK
| | - Jane I. Grove
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Nottingham Digestive Diseases Centre University of Nottingham Nottingham UK
| | - Luca Marciani
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Nottingham Digestive Diseases Centre University of Nottingham Nottingham UK
| | - Gordon W. Moran
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Nottingham Digestive Diseases Centre University of Nottingham Nottingham UK
| | - Robin C. Spiller
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Nottingham Digestive Diseases Centre University of Nottingham Nottingham UK
| | | | - Guruprasad P. Aithal
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Nottingham Digestive Diseases Centre University of Nottingham Nottingham UK
| | - Penny A. Gowland
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK
- Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy University of Nottingham Nottingham UK
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Zhang Q, Ma C, Duan Y, Heinrich B, Rosato U, Diggs LP, Ma L, Roy S, Fu Q, Brown ZJ, Wabitsch S, Thovarai V, Fu J, Feng D, Ruf B, Cui LL, Subramanyam V, Frank KM, Wang S, Kleiner DE, Ritz T, Rupp C, Gao B, Longerich T, Kroemer A, Wang XW, Ruchirawat M, Korangy F, Schnabl B, Trinchieri G, Greten TF. Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma. Cancer Discov 2020; 11:1248-1267. [PMID: 33323397 DOI: 10.1158/2159-8290.cd-20-0304] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 10/14/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2+ PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer. SIGNIFICANCE: MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis.See related commentary by Chagani and Kwong, p. 1014.This article is highlighted in the In This Issue feature, p. 995.
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Affiliation(s)
- Qianfei Zhang
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Chi Ma
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Yi Duan
- Department of Medicine, University of California, San Diego, La Jolla, California.,Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Umberto Rosato
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Laurence P Diggs
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Lichun Ma
- Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Soumen Roy
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Qiong Fu
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Zachary J Brown
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Simon Wabitsch
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Vishal Thovarai
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Jianyang Fu
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Linda L Cui
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Varun Subramanyam
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Karen M Frank
- Microbiology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland
| | - Sophie Wang
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | | | - Thomas Ritz
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Rupp
- Department of Gastroenterology, University Hospital of Heidelberg, Heidelberg, Germany
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, District of Columbia
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.,NCI-CCR Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Mathuros Ruchirawat
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, Thailand.,Center of Excellence on Environmental Health and Toxicology, Office of the Higher Education Commission, Ministry of Education, Bangkok, Thailand
| | - Firouzeh Korangy
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, California.,Department of Medicine, VA San Diego Healthcare System, San Diego, California
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. .,NCI-CCR Liver Cancer Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
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49
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Javed I, Cui X, Wang X, Mortimer M, Andrikopoulos N, Li Y, Davis TP, Zhao Y, Ke PC, Chen C. Implications of the Human Gut-Brain and Gut-Cancer Axes for Future Nanomedicine. ACS NANO 2020; 14:14391-14416. [PMID: 33138351 DOI: 10.1021/acsnano.0c07258] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Recent clinical and pathological evidence have implicated the gut microbiota as a nexus for modulating the homeostasis of the human body, impacting conditions from cancer and dementia to obesity and social behavior. The connections between microbiota and human diseases offer numerous opportunities in medicine, most of which have limited or no therapeutic solutions available. In light of this paradigm-setting trend in science, this review aims to provide a comprehensive and timely summary of the mechanistic pathways governing the gut microbiota and their implications for nanomedicines targeting cancer and neurodegenerative diseases. Specifically, we discuss in parallel the beneficial and pathogenic relationship of the gut microbiota along the gut-brain and gut-cancer axes, elaborate on the impact of dysbiosis and the gastrointestinal corona on the efficacy of nanomedicines, and highlight a molecular mimicry that manipulates the universal cross-β backbone of bacterial amyloid to accelerate neurological disorders. This review further offers a forward-looking section on the rational design of cancer and dementia nanomedicines exploiting the gut-brain and gut-cancer axes.
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Affiliation(s)
- Ibrahim Javed
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia
| | - Xuejing Cui
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
| | - Xiaoyu Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
| | - Monika Mortimer
- Institute of Environmental and Health Sciences, College of Quality and Safety Engineering, China Jiliang University, Hangzhou, Zhejiang 310018, China
| | - Nikolaos Andrikopoulos
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia
| | - Yuhuan Li
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia
- Zhongshan Hospital, Fudan University, 111 Yixueyuan Rd, Xuhui District, Shanghai 200032, China
| | - Thomas P Davis
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia
| | - Yuliang Zhao
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
| | - Pu Chun Ke
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia
- Zhongshan Hospital, Fudan University, 111 Yixueyuan Rd, Xuhui District, Shanghai 200032, China
| | - Chunying Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China
- GBA Research Innovation Institute for Nanotechnology, Guangdong 510700, China
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50
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Skinner C, Thompson AJ, Thursz MR, Marchesi JR, Vergis N. Intestinal permeability and bacterial translocation in patients with liver disease, focusing on alcoholic aetiology: methods of assessment and therapeutic intervention. Therap Adv Gastroenterol 2020; 13:1756284820942616. [PMID: 33149761 PMCID: PMC7580143 DOI: 10.1177/1756284820942616] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/25/2020] [Indexed: 02/04/2023] Open
Abstract
Increased bacterial translocation (BT) across the gut barrier due to greater intestinal permeability (IP) is seen across a range of conditions, including alcohol-related liver disease (ArLD). The phenomenon of BT may contribute to both the pathogenesis and the development of complications in ArLD. There are a number of methods available to assess IP and in this review we look at their various advantages and limitations. The knowledge around BT and IP in ArLD is also reviewed, as well as the therapeutic strategies currently in use and in development.
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Affiliation(s)
- Charlotte Skinner
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
| | - Alex J. Thompson
- Department of Surgery & Cancer, St. Mary’s Hospital Campus, Imperial College London, London, UK
| | - Mark R. Thursz
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
| | - Julian R. Marchesi
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
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