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Karbannek H, Reichert MC, Greinert R, Zipprich A, Lammert F, Ripoll C. Exploring the Relationship Between NOD2 Risk Variants and First Decompensation Events in Cirrhotic Patients With Varices. Liver Int 2025; 45:e16143. [PMID: 39469976 PMCID: PMC11891376 DOI: 10.1111/liv.16143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/05/2024] [Accepted: 10/09/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND AND AIMS NOD2 mutations are associated with impaired gut mucosal barrier function. According to the systemic inflammation hypothesis, bacterial translocation is central in the development of decompensation. The aim was to evaluate whether the presence of NOD2 variants is associated with the development of first decompensation. METHOD Secondary analysis of prospectively collected consecutive patients with compensated cirrhosis, who were screened between 2014 and 2018. Patients with and without NOD2 variants were compared and stratified analysis according to the presence of varices was performed. RESULTS 360 patients [239 (66%) men, median age 61 (53-69) years, 70 (19%) with NOD2 variants, 90 (25%) with varices] were followed for a median of 9 (4-16) months. Similar baseline characteristics were observed across NOD2 status groups, except for beta-blocker use (45% vs. 32% amongst variant carriers vs. non-carriers, p = 0.05). During follow-up, 34 patients (12%) developed their first decompensation, with no differences according to NOD2 status [HR 1.75 (95% CI 0.84-3.67)]. On multivariate analysis, only MELD remained an independent predictor of decompensation. Amongst patients with varices (n = 90), 18 (24.4%) carried a NOD2 variants, with a higher incidence of first decompensation [HR 3.00 (95% CI 1.08-8.32)], primarily due to ascites [HR 3.32 (95% CI 1.07-10.32)]. In this subgroup, MELD [HR 1.18 (95% CI 1.06-1.32)] and NOD2 variants [HR 2.91 (95% CI 0.95-8.89)] were determined to be independent predictors of decompensation. CONCLUSIONS The presence of NOD2 risk variants leads to a greater incidence of first decompensation only in compensated patients with varices.
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Affiliation(s)
- Henrik Karbannek
- Department of Internal Medicine IVJena University HospitalJenaGermany
| | - Matthias C. Reichert
- Department of Medicine II, Saarland University Medical CenterSaarland UniversityHomburgGermany
| | - Robin Greinert
- Department of Internal Medicine IMartin Luther University Halle‐WittenbergHalleGermany
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical CenterSaarland UniversityHomburgGermany
- Health Sciences, Hannover Medical School (MHH)HannoverGermany
| | - Cristina Ripoll
- Department of Internal Medicine IVJena University HospitalJenaGermany
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Li S, Wang Y, Xie Z, Wang Y, Feng Z, Xu J, Yuan B, Zhang Y, Yang G, Wang J, Yuan Y. NLRP3 activation maintains intestinal epithelial barrier and reduces liver injury in alcoholic liver disease mice. Clin Transl Med 2024; 14:e70099. [PMID: 39605303 PMCID: PMC11602754 DOI: 10.1002/ctm2.70099] [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: 09/18/2024] [Revised: 10/27/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Alcoholic liver disease (ALD) patients with bacterial infections usually exhibit high mortality rates. Infections frequently involve bacteria such as Vibrio vulnificus and Enterococcus faecalis. Nevertheless, the mechanisms predisposing ALD patients to bacterial infections and the role of the NLRP3 inflammasome in the intestinal epithelial barrier in ALD remain unclear. METHODS We established ALD mice models of WT, Nlrp3-/- and Gsdmd-/- through chronic alcohol consumption feeding and acute alcohol induction. We compared alterations in gut microbiota, ileitis, and adhesion protein expression, to analyze the role and potential mechanism of NLRP3 in the early onset of ALD. Concurrently, we examined the changes in inflammation and liver damage in the ileum of ALD and healthy mice following foodborne infection with V. vulnificus. RESULTS Compared with the control group, the expression levels of ZO-1, Claudin-1 and E-cadherin were reduced in the ileum of ALD mice, while those of NLRP3, caspase-1(p20), GSDMD-N and IL-1β were elevated. Nlrp3-/- and Gsdmd-/- ALD mice showed an increased gut bacterial load, decreased ileal expression of E-cadherin, more severe ileitis, pronounced liver damage, steatosis and higher plasma levels of FITC-dextran, D-LA and ZO-1 compared with WT mice. Notably, Nlrp3-/- ALD mice exhibited a higher presence of Deferribacterota and Enterobacteriaceae. Furthermore, ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections. CONCLUSIONS This study indicated that NLRP3 activation in the ileum of ALD mice stabilizes the inflammation-related gut microbiota, preserves the intestinal epithelial barrier, and diminishes inflammation and liver injury. Furthermore, the compromised immune defence in ALD mice may contribute to their heightened susceptibility to bacterial pathogens. KEY POINTS Activation of the NLRP3-GSDMD pathway in the ileum of Alcoholic liver disease (ALD) mice. NLRP3 activation maintains homeostasis of gut microbiota and intestinal epithelial barrier in ALD mice. ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections.
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Affiliation(s)
- Shi‐Qing Li
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
- State Key Laboratory of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Ya‐Ru Wang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
- Hainan Medical Products AdministrationHainan Center for Drug InspectionHaikouChina
| | - Zhong‐Liang Xie
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijingChina
| | - Yan Wang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Zi‐Han Feng
- Department of Disease Control and PreventionThe No. 96609 Hospital of Chinese People's Liberation ArmyYinchuanNingxiaChina
| | - Jian‐Hao Xu
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Bing Yuan
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Yi‐Tong Zhang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Guan Yang
- State Key Laboratory of ProteomicsBeijing Proteome Research CenterNational Center for Protein Sciences (Beijing)Beijing Institute of LifeomicsBeijingChina
| | - Jing‐Lin Wang
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
| | - Yuan Yuan
- State Key Laboratory of Pathogen and BiosecurityAcademy of Military Medical Sciences (AMMS)BeijingChina
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Fischer J, La Mura V, Trebicka J. To be or NOD 2 be: The role of NOD2 in predisposing patients with cirrhosis towards infections. Dig Liver Dis 2023; 55:1360-1361. [PMID: 37612213 DOI: 10.1016/j.dld.2023.07.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 07/28/2023] [Accepted: 07/31/2023] [Indexed: 08/25/2023]
Affiliation(s)
- Julia Fischer
- University of Münster, Faculty of Medicine and University of Münster, Department of Internal Medicine B, Albert-Schweitzer-Campus, 48149 Münster, Germany; University of Cologne, Faculty of Medicine and University Hospital of Cologne, Department I of Internal Medicine, Center for Integrated Oncology, D-50931 Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital of Cologne, Center for Molecular Medicine Cologne (CMMC), D-50931 Cologne, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, D-50931 Cologne, Germany
| | - Vincenzo La Mura
- Foundation I.R.C.C.S. Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi and Thrombosis center, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Jonel Trebicka
- University of Münster, Faculty of Medicine and University of Münster, Department of Internal Medicine B, Albert-Schweitzer-Campus, 48149 Münster, Germany; European Foundation for the Study of Chronic Liver Failure - EF Clif, Barcelona 08021, Spain; Department of Medical Gastroenterology and Hepatology, University of Southern Denmark, Odense 5000, Denmark.
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Greinert R, Zipprich A, Casper M, Reichert MC, Lammert F, Ripoll C. Presence of NOD2 mutations is not associated with hepatic or systemic hemodynamic abnormalities of cirrhosis. Dig Liver Dis 2023; 55:1362-1367. [PMID: 37321912 DOI: 10.1016/j.dld.2023.05.016] [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: 02/27/2023] [Revised: 04/25/2023] [Accepted: 05/15/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Patients with cirrhosis who carry NOD2 mutations are susceptible to bacterial infections. The aim was to evaluate the association of NOD2 mutations with hepatic and systemic hemodynamics in cirrhosis. PATIENTS AND METHODS This is a secondary analysis of a prospectively collected database in the context of the screening for the INCA trial (EudraCT 2013-001626-26). This cross-sectional study compared hemodynamic findings according to NOD2 status in 215 patients. Patients were genotyped for NOD2 variants (p.N289S, p.R702W, p.G908R, c.3020insC, rs72796367). Hepatic hemodynamic study and right heart catheterization were performed. RESULTS Patients had a median age of 59 (IQR 53-66) years, and 144 (67%) were men. Most patients (64%) were Child-Pugh stage B. Sixty-six patients (31%) carried a NOD2 mutation, which was slightly more common among Child-Pugh stage C (p = 0.05), without differences in MELD [wild-type: 13 (10-16); NOD2 variants 13 (10-18)]. No differences in hepatic and systemic hemodynamics were observed according to NOD2 status. If excluding patients on prophylactic or therapeutic antibiotics, again no association between hepatic or systemic hemodynamics and NOD2 status could be observed. CONCLUSION NOD2 mutations are not associated with hepatic or systemic hemodynamic abnormalities in patients with decompensated cirrhosis, suggesting that other mechanisms leading to bacterial translocation predominate.
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Affiliation(s)
- Robin Greinert
- Department of Internal Medicine I, Martin-Luther University Halle Wittenberg, Halle, Germany
| | | | - Markus Casper
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany; Health Sciences, Hannover Medical School MHH, Hannover, Germany
| | - Cristina Ripoll
- Internal Medicine IV, Jena University Hospital, Jena, Germany.
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Ripoll C, Greinert R, Reuken P, Reichert MC, Weber SN, Hupfer Y, Staltner R, Meier Clinien M, Lammert F, Bruns T, Zipprich A. Influence of NOD2 risk variants on hepatic encephalopathy and association with inflammation, bacterial translocation and immune activation. Liver Int 2023; 43:1793-1802. [PMID: 37249050 DOI: 10.1111/liv.15627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/21/2023] [Accepted: 05/18/2023] [Indexed: 05/31/2023]
Abstract
BACKGROUND Nucleotide-binding oligomerization domain containing 2 (NOD2) risk variants lead to impaired mucosal barrier function, increased bacterial translocation (BT), and systemic inflammation. AIM To evaluate the association between the presence of NOD2 risk variants, BT, inflammation, and hepatic encephalopathy (HE). PATIENTS AND METHODS This prospective multicenter study included patients with cirrhosis and testing for NOD2 risk variants (p.R702W, p.G908R, c.3020insC, N289S, and c.-958T>C). Patients were evaluated for covert (C) and overt (O) HE. Markers of systemic inflammation (leukocytes, CRP, IL-6, LBP) and immune activation (soluble CD14) as well as bacterial endotoxin (hTRL4 activation) were determined in serum. RESULTS Overall, 172 patients (70% men; median age 60 [IQR 54-66] years; MELD 12 [IQR 9-16]; 72% ascites) were included, of whom 53 (31%) carried a NOD2 risk variant. In this cohort, 11% presented with OHE and 27% and CHE. Presence and severity of HE and surrogates of inflammation, BT, and immune activation did not differ between patients with and without a NOD2 risk variant, also not after adjustment for MELD. HE was associated with increased ammonia and systemic inflammation, as indicated by elevated CRP (w/o HE: 7.2 [2.7-16.7]; with HE 12.6 [4.5-29.7] mg/dL; p < 0.001) and elevated soluble CD14 (w/o HE 2592 [2275-3033]; with HE 2755 [2410-3456] ng/mL; p = 0.025). CONCLUSIONS The presence of NOD2 risk variants in patients with cirrhosis is not associated with HE and has no marked impact on inflammation, BT, or immune activation. In contrast, the presence of HE was linked to ammonia, the acute phase response, and myeloid cell activation.
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Affiliation(s)
- Cristina Ripoll
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Robin Greinert
- Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Philipp Reuken
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | | | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Yvonne Hupfer
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Magdalena Meier Clinien
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | | | - Tony Bruns
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
- Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Alexander Zipprich
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
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Association Between Proton Pump Inhibitor Therapy and Spontaneous Bacterial Peritonitis Occurrence in Cirrhotic Patients: A Clinical Review. Curr Med Sci 2022; 42:673-680. [PMID: 35870102 DOI: 10.1007/s11596-022-2607-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 01/20/2022] [Indexed: 11/26/2022]
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Hasa E, Hartmann P, Schnabl B. Liver cirrhosis and immune dysfunction. Int Immunol 2022; 34:455-466. [PMID: 35792761 PMCID: PMC9447994 DOI: 10.1093/intimm/dxac030] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/27/2022] [Indexed: 01/05/2023] Open
Abstract
Cirrhosis is end-stage liver disease resulting from various etiologies and is a common cause of death worldwide. The progression from compensated to decompensated cirrhosis to acute-on-chronic liver failure (ACLF) is due to multiple factors, including continuation of alcohol use or continued exposure to other toxins, an imbalance of the gut microbiota (dysbiosis), increased gut permeability and a disrupted immune response. This disrupted immune response is also named cirrhosis-associated immune dysfunction, which is characterized by worsening systemic inflammation with concomitant immune paralysis, as liver disease deteriorates. This review highlights central immunologic events during the exacerbation of cirrhosis and characterizes the different immune cell populations involved therein.
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Ye C, Li W, Li L, Zhang K. Glucocorticoid Treatment Strategies in Liver Failure. Front Immunol 2022; 13:846091. [PMID: 35371046 PMCID: PMC8965693 DOI: 10.3389/fimmu.2022.846091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
Liver failure is characterized by serious liver decompensation and high mortality. The activation of systemic immune responses and systemic inflammation are widely accepted as the core pathogenesis of liver failure. Glucocorticoids (GCs) are most regularly utilized to suppress excessive inflammatory reactions and immunological responses. GCs have been used in the clinical treatment of liver failure for nearly 60 years. While there has been no unanimity on the feasibility and application of GC treatment in liver failure until recently. The most recent trials have produced conflicting results when it comes to the dose and time for GC therapy of different etiology of liver failure. Our review outlines the issues and options in managing GC treatment in liver failure based on an investigation of the molecular mechanism that GC may give in the treatment.
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Affiliation(s)
- Chao Ye
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wenyuan Li
- Department of Infectious Diseases, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lei Li
- Department of Infectious Diseases, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Kaiguang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Kuchta K, Cameron S. Tradition to Pathogenesis: A Novel Hypothesis for Elucidating the Pathogenesis of Diseases Based on the Traditional Use of Medicinal Plants. Front Pharmacol 2021; 12:705077. [PMID: 34759818 PMCID: PMC8572966 DOI: 10.3389/fphar.2021.705077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/27/2021] [Indexed: 11/13/2022] Open
Abstract
Traditional medicines embody knowledge on medicinal plants that has been accumulated through cultural evolution over millennia. In the latter half of the 20th century, two approaches to medicinal plant research have been established: the "Bench to Bedside" and the "Bedside to Bench" approaches which serve primarily for the development of more efficient therapeutics. Here, we propose a third, novel approach: from "Tradition to Pathogenesis" which aims to understand the pathogenesis of diseases based on the cultural evolution of their respective empirical treatments. We analyse multiple examples of diseases where the acting mechanism of traditional treatments across multiple cultures points to the pathogenesis of the respective disease. E.g., many cultures traditionally treat rheumatism with anti-bacterial botanical drugs, which is at odds with our current understanding that rheumatism is an aseptic inflammation. Furthermore, gastric ailments have traditionally been treated with anti-infectious botanical drugs indicating local infections, as demonstrated by the discovery of Helicobacter pylori as a common cause of gastric ulcer. Understanding traditional treatments can thus help to elucidate the pathogenesis of the disease.
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Affiliation(s)
- Kenny Kuchta
- Forschungsstelle für Fernöstliche Medizin, Department of Vegetation Analysis and Phytodiversity, Albrecht von Haller Institute of Plant Sciences, Georg August University, Göttingen, Germany
| | - Silke Cameron
- Clinic for Gastroenterology and Gastrointestinal Oncology, University Medicine Göttingen, Göttingen, Germany
- Clinic, Hann. Münden, Germany
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Wu X, Luo J, Huang W, Jia B, Luo T. Role of ascitic endocan levels in the diagnosis of spontaneous bacterial peritonitis in decompensated cirrhosis. Biomarkers 2020; 25:360-366. [PMID: 32364003 DOI: 10.1080/1354750x.2020.1764107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Objective: To assess the role of ascitic endocan levels in the diagnosis of spontaneous bacterial peritonitis (SBP) in decompensated cirrhosis.Methods: Ascites samples, as well as demographic and laboratory data, were collected at admission from patients with decompensated cirrhosis. Ascitic endocan, tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured by ELISA. The influencing factors of SBP, the correlation of ascitic endocan with other inflammatory indicators, and the diagnostic value of ascitic endocan for SBP were analyzed.Results: A total of 167 patients were enrolled, 39 with the SBP group and 128 in the non-SBP group. Ascitic endocan, TNF-α, and IL-6 levels were significantly higher in the SBP group than in the non-SBP group (p < 0.001). Multivariate analysis demonstrated that ascitic endocan was an independent risk factor for SBP [OR = 1.006 (95% CI: 1.002-1.011); p < 0.001]. Endocan was positively correlated with ascites polymorphonuclear leukocytes, TNF-α, and IL-6. ROC curve analysis showed that ascitic endocan had an AUC of 0.805 for the diagnosis of SBP (p < 0.001) and had a sensitivity of 82.1% and specificity of 73.4% when the cut-off value was 295.011 pg/ml.Conclusions: Ascitic endocan level is an independent risk factor and a valuable diagnostic indicator for SBP in decompensated cirrhosis.
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Affiliation(s)
- Xianmei Wu
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junli Luo
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenxiang Huang
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bei Jia
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Disease, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tao Luo
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Stengel S, Quickert S, Lutz P, Ibidapo-Obe O, Steube A, Köse-Vogel N, Yarbakht M, Reuken PA, Busch M, Brandt A, Bergheim I, Deshmukh SD, Stallmach A, Bruns T. Peritoneal Level of CD206 Associates With Mortality and an Inflammatory Macrophage Phenotype in Patients With Decompensated Cirrhosis and Spontaneous Bacterial Peritonitis. Gastroenterology 2020; 158:1745-1761. [PMID: 31982413 DOI: 10.1053/j.gastro.2020.01.029] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 01/13/2020] [Accepted: 01/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Peritoneal macrophages (PMs) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PMs and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP). METHODS We isolated PMs from ascites samples of 66 patients with decompensated cirrhosis (19 with SBP) and analyzed them by flow cytometry, quantitative real-time polymerase chain reaction, functional analysis, and RNA microarrays. We used ascites samples of a separate cohort of 111 patients with decompensated cirrhosis (67 with SBP) and quantified the soluble form of the mannose receptor (CD206) and tumor necrosis factor by enzyme-linked immunosorbent assay (test cohort). We performed logistic regression analysis to identify factors associated with 90-day mortality. We validated our findings using data from 71 patients with cirrhosis and SBP. Data from 14 patients undergoing peritoneal dialysis for end-stage renal disease but without cirrhosis were included as controls. RESULTS We used surface levels of CD206 to identify subsets of large PMs (LPM) and small PMs (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPMs vs SPMs from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPMs vs SPMs, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPMs had an inflammatory phenotype, were less susceptible to tolerance induction, and released more tumor necrosis factor than SPMs. LPMs from patients with cirrhosis produced more inflammatory cytokines than LPMs from controls. Activation of PMs by Toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPMs and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPMs in the early phase of SBP, but levels increased after treatment. In the test and validation cohorts, patients with SBP and higher concentrations of soluble CD206 in ascites fluid (>0.53 mg/L) were less likely to survive for 90 days than those with lower levels. CONCLUSIONS Surface level of CD206 can be used to identify mature, resident, inflammatory PMs in patients with cirrhosis. Soluble CD206 is released from activated LPMs and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.
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Affiliation(s)
- Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Stefanie Quickert
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, University of Bonn, Bonn, Germany
| | - Oluwatomi Ibidapo-Obe
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Arndt Steube
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Nilay Köse-Vogel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Melina Yarbakht
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Martin Busch
- Department of Internal Medicine III, Jena University Hospital, Jena, Germany
| | - Annette Brandt
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Sachin D Deshmukh
- The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany; Department of Internal Medicine III, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
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Schaapman JJ, Amoros À, van der Reijden JJ, Laleman W, Zeuzem S, Bañares R, Jalan R, Arroyo V, Clària J, Verspaget HW, Coenraad MJ. Genetic variants of innate immunity receptors are associated with mortality in cirrhotic patients with bacterial infection. Liver Int 2020; 40:646-653. [PMID: 31991025 PMCID: PMC7079071 DOI: 10.1111/liv.14392] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 12/24/2019] [Accepted: 01/23/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis (AD), organ failure(s) and high risk of short-term mortality with bacterial infection frequently as precipitating event. Innate immune pattern recognition receptors and members of the lectin pathway of complement activation are crucial to the innate immune response to pathogens. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of innate immune components are associated with the occurrence of bacterial infections or mortality in patients with cirrhosis hospitalized for AD or ACLF. METHODS Twenty-one innate immunity SNPs with known functional implications were genotyped in 826 AD/ACLF patients included in the CANONIC study. Associations between baseline characteristics of the patients, the occurrence of bacterial infections and survival rate at 90 days of follow-up in relation to the innate immunity genetic variants were analysed. RESULTS The NOD2-G908R genetic variant was associated with mortality (HR 2.25, P = .004) independently of age and MELD Score. This association was also found in a predefined subgroup analysis in patients with bacterial infections (HR 2.78, P < .001) along with MBL_Yx (HR 1.72, P = .008) and MASP2_371 (HR 1.67, P = .012) genetic variants. None of the analysed SNPs were significantly associated with the occurrence of acute bacterial infections or spontaneous bacterial peritonitis in particular. CONCLUSIONS Innate immune system-specific NOD2-G908R, MBL_Yx and MASP2_371 genetic variants were independently associated with increased risk of short-term mortality in AD/ACLF patients with bacterial infection.
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Affiliation(s)
| | - Àlex Amoros
- European Foundation for the study of Chronic Liver FailureBarcelonaSpain
| | | | | | - Stefan Zeuzem
- Universitätsklinikum FrankfurtFrankfurt am MainGermany
| | | | - Rajiv Jalan
- University College LondonRoyal Free HospitalLondonUK
| | - Vicente Arroyo
- European Foundation for the study of Chronic Liver FailureBarcelonaSpain
| | - Joan Clària
- European Foundation for the study of Chronic Liver FailureBarcelonaSpain,Hospital ClínicIDIBAPS and CIBERehdBarcelonaSpain
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Common NOD2 Risk Variants as Major Susceptibility Factors for Bacterial Infections in Compensated Cirrhosis. Clin Transl Gastroenterol 2020; 10:e00002. [PMID: 30702490 PMCID: PMC6369875 DOI: 10.14309/ctg.0000000000000002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Common nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants have been associated with bacterial infections (BIs) in cirrhosis, in particular, spontaneous bacterial peritonitis, and mortality. Our aim was to evaluate the independent association of NOD2 variants with BI according to the decompensation stage.
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14
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Ibidapo-Obe O, Stengel S, Köse-Vogel N, Quickert S, Reuken PA, Busch M, Bauer M, Stallmach A, Bruns T. Mucosal-Associated Invariant T Cells Redistribute to the Peritoneal Cavity During Spontaneous Bacterial Peritonitis and Contribute to Peritoneal Inflammation. Cell Mol Gastroenterol Hepatol 2020; 9:661-677. [PMID: 31954178 PMCID: PMC7160599 DOI: 10.1016/j.jcmgh.2020.01.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 01/06/2020] [Accepted: 01/07/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Mucosal-associated invariant T (MAIT) cells are depleted from blood in patients with advanced liver disease and show features of immune dysfunction. Because circulating MAIT cells differ from organ-resident MAIT cells, we aimed to investigate the frequency, phenotype, and function of peritoneal MAIT cells from patients with cirrhosis and spontaneous bacterial peritonitis (SBP). METHODS MAIT cells in blood and ascitic fluid from patients with cirrhosis were characterized using flow cytometry. Healthy individuals and noncirrhotic patients undergoing peritoneal dialysis served as controls. MAIT cell migration was studied in transwell assays. Cytokine release in response to infected ascitic fluid and bacterial products was assessed in vitro. RESULTS Peritoneal CD3+ CD161hi Vα7.2+ T cells had an inflammatory, tissue retention phenotype, expressing the alpha E integrin, the chemokine receptors CCR5 and CXCR3, and the activation marker CD69 at higher levels than their circulating equivalents. Seventy-seven percent bound to MR1 tetramers loaded with the pyrimidine intermediate 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil. The ratio of peritoneal to blood MAIT cell frequency increased from 1.3 in the absence of SBP to 2.6 at diagnosis and decreased by day 3. MAIT cells migrated toward infected ascitic fluid containing CCL5 and CCL20 and released cytokines in an MR1-restricted fashion. Whereas the depleted circulating MAIT cell pool displayed features of immune exhaustion, peritoneal MAIT cells remained competent producers of inflammatory cytokines in response to bacterial products. Peritoneal MAIT activation correlated with systemic inflammation, suggesting a possible link between peritoneal and systemic immunity. CONCLUSIONS Peritoneal MAIT cells phenotypically and functionally differ from circulating MAIT cells in decompensated cirrhosis and redistribute to the peritoneum during SBP.
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Affiliation(s)
- Oluwatomi Ibidapo-Obe
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Nilay Köse-Vogel
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Stefanie Quickert
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Martin Busch
- Department of Internal Medicine III, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Michael Bauer
- Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany; Department of Anesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany; Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
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Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol 2019; 25:5897-5917. [PMID: 31660028 PMCID: PMC6815800 DOI: 10.3748/wjg.v25.i39.5897] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/15/2019] [Accepted: 09/28/2019] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension (PHT) in advanced chronic liver disease (ACLD) results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition (structural component) and intrahepatic vasoconstriction (functional component). PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding. Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns (PAMPs) that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways. Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability: The intestinal barrier function is affected by impaired microcirculation, neoangiogenesis, and abnormal vascular and mucosal permeability. The close bidirectional relationship between the gut and the liver has been termed “gut-liver axis”. Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function, intestinal barrier integrity, as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects. The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments, however, further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed. In this review, we summarize the clinical impact of PHT on the course of liver disease, discuss the underlying pathophysiological link of PHT to gut-liver axis signaling, and provide insight into molecular mechanisms that may represent novel therapeutic targets.
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Affiliation(s)
- Benedikt Simbrunner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Mattias Mandorfer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
| | - Thomas Reiberger
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
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16
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Facciorusso A, Antonino M, Orsitto E, Sacco R. Primary and secondary prophylaxis of spontaneous bacterial peritonitis: current state of the art. Expert Rev Gastroenterol Hepatol 2019; 13:751-759. [PMID: 31304804 DOI: 10.1080/17474124.2019.1644167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/12/2019] [Indexed: 02/07/2023]
Abstract
Introduction: Spontaneous bacterial peritonitis represents a frequent and severe complication in cirrhotic patients with ascites. In daily practice, the diagnosis of spontaneous bacterial peritonitis might be challenging in the absence of the typical signs and symptoms of infection such as fever or leukocytosis. Areas covered: Aim of this review is to revise the current state of the art on primary and secondary spontaneous bacterial peritonitis. Literature search in Medline/Pubmed was performed. Expert opinion: Historically, gram-negative bacteria were the most frequent etiologic agents of spontaneous bacterial peritonitis, with Escherichia coli and Klebsiella spp. being the most frequently isolated bacteria. However, major changes in this regard occurred over the last few decades with an increasing prevalence of gram-positive, quinolone-resistant, and multidrug-resistant bacteria. In particular, the increasing prevalence of quinolone-resistant bacteria challenged the prominent role of norfloxacin in spontaneous bacterial peritonitis prevention. Given the high mortality rate and the risk of developing the hepatorenal syndrome, prophylaxis of spontaneous bacterial peritonitis is indicated in three high-risk populations: patients with acute gastrointestinal hemorrhage, patients with low total protein content in ascitic fluid and advanced cirrhosis, and patients with a previous history of spontaneous bacterial peritonitis (secondary prophylaxis).
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Affiliation(s)
- Antonio Facciorusso
- a Department of Medical Sciences, Ospedali Riuniti di Foggia , Foggia , Italy
| | - Matteo Antonino
- a Department of Medical Sciences, Ospedali Riuniti di Foggia , Foggia , Italy
| | - Eugenio Orsitto
- b Department of Radiology, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy
| | - Rodolfo Sacco
- a Department of Medical Sciences, Ospedali Riuniti di Foggia , Foggia , Italy
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17
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Outcomes in Patients With Cirrhosis on Primary Compared to Secondary Prophylaxis for Spontaneous Bacterial Peritonitis. Am J Gastroenterol 2019; 114:599-606. [PMID: 30694868 PMCID: PMC6450703 DOI: 10.14309/ajg.0000000000000044] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Antibiotic prophylaxis is recommended for prevention of the first episode of spontaneous bacterial peritonitis (SBP; primary prophylaxis 1°) and subsequent episodes (secondary prophylaxis 2°). We aimed to compare outcomes in cirrhotic inpatients on 1° vs 2° SBP prophylaxis. METHODS Data from North American Consortium for the Study of End-Stage Liver Disease were evaluated for cirrhosis details, reasons for admission/medications, inpatient course recorded, and outcomes over 90 days. Outcomes (intensive care units, acute kidney injury, inpatient/90-day mortality) were compared between the 2 groups after propensity-matching on admission model for end-stage liver disease (MELD) score and serum albumin. RESULTS Among the 2,731 patients enrolled, 305 were on 1° and 187 on 2° SBP prophylaxis. After propensity-matching, 154 patients remained in each group. Patients on 1° prophylaxis were more likely to have admission systemic inflammatory response syndrome (P = 0.02), with higher intensive care unit admissions (31% vs 21%; P = 0.05) and inpatient mortality (19% vs 9%; P = 0.01) than the 2° prophylaxis group. Patients on 2° prophylaxis had higher total (22% vs 10%; P = 0004), readmission (16% vs 9%; P = 0.03), and nosocomial (6% vs 0.5%; P = 0.01) SBP rates with predominant Gram-negative organisms compared to 1° prophylaxis patients. At 90 days, 1° prophylaxis patients had a higher mortality (35% vs 22%; P = 0.02) and acute kidney injury incidence (48% vs 30%; P = 0.04) compared to 2° prophylaxis patients. DISCUSSION In this inpatient cirrhosis study, despite prophylaxis, a high proportion of patients developed SBP, which was associated with mortality. Cirrhotic inpatients on 1° prophylaxis had worse outcomes than those on 2° prophylaxis when propensity-matched for the MELD score and serum albumin during the index admission and 90-day follow-up.
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18
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Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, Krag A, Laleman W, Gines P. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69:406-460. [PMID: 29653741 DOI: 10.1016/j.jhep.2018.03.024] [Citation(s) in RCA: 1759] [Impact Index Per Article: 251.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023]
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Song F, Yi Y, Li C, Hu Y, Wang J, Smith DE, Jiang H. Regulation and biological role of the peptide/histidine transporter SLC15A3 in Toll-like receptor-mediated inflammatory responses in macrophage. Cell Death Dis 2018; 9:770. [PMID: 29991810 PMCID: PMC6039463 DOI: 10.1038/s41419-018-0809-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 05/08/2018] [Accepted: 06/15/2018] [Indexed: 12/23/2022]
Abstract
The peptide/histidine transporter SLC15A3 is responsible for transporting histidine, certain dipeptide and peptidomimetics from inside the lysosome to cytosol. Previous studies have indicated that SLC15A3 transcripts are mainly expressed in the lymphatic system, however, its regulation and biological role in innate immune responses and inflammatory diseases are as yet unknown. In this study, mouse peritoneal macrophages (PMs), mouse bone marrow-derived macrophages (BMDMs), the human acute monocytic leukemia cell line THP-1 and the human lung epithelial carcinoma cell line A549 were used to investigate the regulation and biological role of SLC15A3 in TLR-mediated inflammatory responses. Our results showed that SLC15A3 was upregulated by TLR2, TLR4, TLR7 and TLR9 ligands in macrophages at both the mRNA and protein levels via activation of NF-κB (nuclear factor-kappa-B), MAPK (mitogen-activated protein kinase) and IRF3 (interferon regulatory factor 3). Furthermore, knockdown or overexpression of SLC15A3 influenced the TLR4-triggered expression of proinflammatory cytokines. A reporter gene assay showed that the SLC15A3 promotor contained potential NF-κB binding sites, which were reasonable for regulating SLC15A3 by TLR-activation through NF-κB signaling. Additionally, SLC15A3 expression was increased and positively related to inflammation in mice with bacterial peritonitis. The collective findings suggest that SLC15A3 is regulated by various TLRs, and that it plays an important role in regulating TLR4-mediated inflammatory responses.
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Affiliation(s)
- Feifeng Song
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Yaodong Yi
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Cui Li
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Yongjun Hu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, United States
| | - Jinhai Wang
- The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China
| | - David E Smith
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, United States
| | - Huidi Jiang
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
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20
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Dinya T, Tornai T, Vitalis Z, Tornai I, Balogh B, Tornai D, Antal-Szalmas P, Sumegi A, Andrikovics H, Bors A, Tordai A, Papp M. Functional polymorphisms of innate immunity receptors are not risk factors for the non-SBP type bacterial infections in cirrhosis. Liver Int 2018; 38:1242-1252. [PMID: 29235260 DOI: 10.1111/liv.13664] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 11/28/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Pattern recognition receptors (PRRs) have a key role in the innate host defense. Functional polymorphisms of various PRRs have been established to contribute to an increased susceptibility to spontaneous bacterial peritonitis (SBP). Their role in the development of cirrhosis-associated bacterial infections (BI), beyond SBP or progressive disease course related to pathological bacterial translocation (BT) remains unknown. METHODS Three hundred and forty-nine patients with cirrhosis were genotyped for common NOD2 (R702W, G908R and L1007PfsinsC), TLR2 (-16934T>A), and TLR4 (D299G) variants. Incidence of BIs, decompensating events and liver-related death were assessed in a 5-year follow-up observational study. Pathological BT was assessed based on the presence of antimicrobial antibodies or lipopolysaccharide-binding protein (LBP) level. RESULTS In patients with ascites (n = 88) only NOD2 gene variants were associated with an increased cumulative probability of SBP (76.9% ± 19.9%) compared to wild-type (30.9% ± 6.9%, PLogRank = .047). Individual or combined PRR genetic profiles were associated with the risk of non-SBP type BI. Advanced disease stage (HR [95% CI]: 2.11 [1.38-3.25]) and prior history of a BI episode (HR: 2.42 [1.58-3.72]) were the major clinical risk factors of a subsequent BI. The risk of a non-SBP type BI in patients with advanced disease and a prior BI was even higher (HR: 4.74 [2.68-8.39]). The frequency of antimicrobial antibodies and LBP levels did not differ between various PRR genotypes. Correspondingly, PRR genetic profile was not able to predict the long-term disease course. CONCLUSIONS In cirrhosis, functional polymorphisms of PRRs did not improve the identification of patients with high risk of BI beyond SBP or progressive diseases course.
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Affiliation(s)
- Tamas Dinya
- Faculty of Medicine, Institute of Surgery, University of Debrecen, Debrecen, Hungary
| | - Tamas Tornai
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsuzsanna Vitalis
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Istvan Tornai
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Boglárka Balogh
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - David Tornai
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Peter Antal-Szalmas
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Andrea Sumegi
- Vascular Biology, Thrombosis and Haemostasis Research Group, Hungarian Academy of Sciences, Debrecen, Hungary
| | | | - Andras Bors
- Hungarian National Blood Transfusion Service, Budapest, Hungary
| | - Attila Tordai
- Department of Pathophysiology, Semmelweis University, Budapest, Hungary
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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Ren Y, Liu SF, Nie L, Cai SY, Chen J. Involvement of ayu NOD2 in NF-κB and MAPK signaling pathways: Insights into functional conservation of NOD2 in antibacterial innate immunity. Zool Res 2018; 40:77-88. [PMID: 29872030 PMCID: PMC6378557 DOI: 10.24272/j.issn.2095-8137.2018.066] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nucleotide oligomerization domain 2 (NOD2) is a major cytoplasmic sensor for pathogens and is critical for the clearance of cytosolic bacteria in mammals. However, studies regarding NOD2, especially the initiated signaling pathways, are scarce in teleost species. In this study, we identified a NOD2 molecule (PaNOD2) from ayu (Plecoglossus altivelis). Bioinformatics analysis showed the structure of NOD2 to be highly conserved during vertebrate evolution. Dual-luciferase reporter assays examined the activation of NF-κB signaling and Western blotting analysis detected the phosphorylation of three MAP kinases (p-38, Erk1/2, and JNK1/2). Functional study revealed that, like its mammalian counterparts, PaNOD2 was the receptor of the bacterial cell wall component muramyl dipeptide (MDP), and the leucine-rich repeat motif was responsible for the recognition and binding of PaNOD2 with the ligand. Overexpression of PaNOD2 activated the NF-κB signaling pathway, leading to the upregulation of inflammatory cytokines, including TNF-α and IL-1β in HEK293T cells and ayu head kidney-derived monocytes/macrophages (MO/MΦ). Particularly, we found that PaNOD2 activated the MAPK signaling pathways, as indicated by the increased phosphorylation of p-38, Erk1/2, and JNK1/2, which have not been characterized in any teleost species previously. Our findings proved that the NOD2 molecule and initiated pathways are conserved between mammals and ayu. Therefore, ayu could be used as an animal model to investigate NOD2-based diseases and therapeutic applications.
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Affiliation(s)
- Yi Ren
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo Zhejiang 315211, China
| | - Shui-Fang Liu
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo Zhejiang 315211, China
| | - Li Nie
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo Zhejiang 315211, China; E-mail:
| | - Shi-Yu Cai
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo Zhejiang 315211, China
| | - Jiong Chen
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo Zhejiang 315211, China.,Key Laboratory of Applied Marine Biotechnology of Ministry of Education, Ningbo University, Ningbo Zhejiang 315211, China; E-mail:
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22
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Abstract
Portal hypertension is one cause and a part of a dynamic process triggered by chronic liver disease, mostly induced by alcohol or incorrect nutrition and less often by viral infections and autoimmune or genetic disease. Adequate staging - continuously modified by current knowledge - should guide the prevention and treatment of portal hypertension with defined endpoints. The main goals are interruption of etiology and prevention of complications followed, if necessary, by treatment of these. For the past few decades, shunts, mostly as intrahepatic stent bypass between portal and hepatic vein branches, have played an important role in the prevention of recurrent bleeding and ascites formation, although their impact on survival remains ambiguous. Systemic drugs, such as non-selective beta-blockers, statins, or antibiotics, reduce portal hypertension by decreasing intrahepatic resistance or portal tributary blood flow or by blunting inflammatory stimuli inside and outside the liver. Here, the interactions among the gut, liver, and brain are increasingly examined for new therapeutic options. There is no general panacea. The interruption of initiating factors is key. If not possible or if not possible in a timely manner, combined approaches should receive more attention before considering liver transplantation.
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Affiliation(s)
| | | | - Jonel Trebicka
- Department of Internal Medicine, University of Bonn, Bonn, Germany.,European Foundation for Study of Chronic Liver Failure, Barcelona, Spain
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23
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Alvarado-Tapias E, Guarner-Argente C, Oblitas E, Sánchez E, Vidal S, Román E, Concepción M, Poca M, Gely C, Pavel O, Nieto JC, Juárez C, Guarner C, Soriano G. Toll-like receptor 4 polymorphisms and bacterial infections in patients with cirrhosis and ascites. World J Hepatol 2018; 10:124-133. [PMID: 29399286 PMCID: PMC5787676 DOI: 10.4254/wjh.v10.i1.124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 12/16/2017] [Accepted: 12/29/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. RESULTS We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group (P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group (P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. CONCLUSION Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.
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Affiliation(s)
- Edilmar Alvarado-Tapias
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Carlos Guarner-Argente
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Elida Oblitas
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Elisabet Sánchez
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Silvia Vidal
- Instituto de Salud Carlos III, Institut de Recerca IIB-Sant Pau, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès) 08193, Spain
| | - Eva Román
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Mar Concepción
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Maria Poca
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Cristina Gely
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Oana Pavel
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Juan Camilo Nieto
- Instituto de Salud Carlos III, Institut de Recerca IIB-Sant Pau, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès) 08193, Spain
| | - Cándido Juárez
- Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Carlos Guarner
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
| | - Germán Soriano
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain
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Lutz P, Goeser F, Kaczmarek DJ, Schlabe S, Nischalke HD, Nattermann J, Hoerauf A, Strassburg CP, Spengler U. Relative Ascites Polymorphonuclear Cell Count Indicates Bacterascites and Risk of Spontaneous Bacterial Peritonitis. Dig Dis Sci 2017; 62:2558-2568. [PMID: 28597106 DOI: 10.1007/s10620-017-4637-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 05/26/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Absolute polymorphonuclear (PMN) counts in ascites define spontaneous bacterial peritonitis (SBP), a severe form of bacterial infection in liver cirrhosis. Bacterascites, another form of ascites infection, can progress to SBP or may resolve spontaneously but is not reflected by absolute PMN counts. We investigated whether the relative ascites PMN count (the absolute PMN count divided by the absolute leukocyte count) provides additional information to detect bacterascites or predict SBP. METHODS Hospitalized patients with liver cirrhosis requiring paracentesis were stratified with respect to a diagnosis of bacterascites and SBP with a prospective follow-up for 1 year. Diagnostic power of relative PMN counts in ascites was evaluated by receiver operating characteristics curves. RESULTS At inclusion, we observed 28/269 (10%) and 43/269 (16%) episodes of BA and SBP, respectively. Unlike absolute PMN counts, relative PMN counts in ascites were significantly elevated in bacterascites (p = 0.001). During follow-up, 16 and 30 further episodes of BA and SBP were detected, respectively. Relative PMN counts increased significantly once patients developed BA (p = 0.001). At a threshold of 0.20 for the relative PMN count, sensitivity, specificity, positive and negative predictive values for bacterascites which required antibiotic treatment were 83, 75, 26 and 98%, respectively (p < 0.001). Furthermore, a relative PMN count in ascites ≥0.13 and MELD score >17 was independent factors associated with occurrence of SBP during follow-up. CONCLUSION The relative PMN count is a cheap immunological marker linked to bacterascites and future SBP, which may help to stratify patients according to their risk of infection.
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Affiliation(s)
- Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany. .,German Center for Infection Research, Bonn, Germany.
| | - Felix Goeser
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Dominik J Kaczmarek
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Stefan Schlabe
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Hans Dieter Nischalke
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Achim Hoerauf
- Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
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25
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Jüngst C, Stadlbauer V, Reichert MC, Zimmer V, Weber SN, Ofner-Ziegenfuß L, Voigtländer T, Spindelböck W, Fickert P, Kirchner GI, Lammert F, Lankisch TO, Krawczyk M. NOD2 gene variants confer risk for secondary sclerosing cholangitis in critically ill patients. Sci Rep 2017; 7:7026. [PMID: 28765628 PMCID: PMC5539147 DOI: 10.1038/s41598-017-06268-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 06/08/2017] [Indexed: 12/27/2022] Open
Abstract
Sclerosing cholangitis in critically ill patients (SC-CIP) is a progressive cholestatic disease of unknown aetiology characterized by chronic biliary infections. Hence we hypothesized that common NOD2 (nucleotide-binding oligomerisation domain containing 2) gene variants, known risk factors for Crohn's disease and bacterial translocation in liver cirrhosis, increase the odds of developing SC-CIP. Screening of 4,641 endoscopic retrograde cholangiography procedures identified 17 patients with SC-CIP, who were then genotyped for the three common NOD2 mutations (Cohort 1, discovery cohort). To validate the association, we subsequently tested these NOD2 variants in 29 patients from SC-CIP cohorts of three additional medical centers (Cohort 2, replication cohort). In Cohort 1, the NOD2 variants were present in 5 of 17 SC-CIP patients (29.4%), which is twice the frequency of the general population. These results were replicated in Cohort 2 with 8 patients (27.6%) showing NOD2 mutations. In contrast, polymorphisms of hepatocanalicular transporter genes did not have major impact on SC-CIP risk. This first study on genetic susceptibility in SC-CIP patients shows an extraordinary high frequency of NOD2 variation, pointing to a critical role of inherited impaired anti-bacterial defense in the development of this devastating biliary disease.
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Affiliation(s)
- Christoph Jüngst
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Vanessa Stadlbauer
- Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Vincent Zimmer
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | | | - Torsten Voigtländer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Walter Spindelböck
- Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Gabriele I Kirchner
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Tim O Lankisch
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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26
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Mai M, Stengel S, Al-Herwi E, Peter J, Schmidt C, Rubio I, Stallmach A, Bruns T. Genetic variants of TRAF6 modulate peritoneal immunity and the risk of spontaneous bacterial peritonitis in cirrhosis: A combined prospective-retrospective study. Sci Rep 2017; 7:4914. [PMID: 28687809 PMCID: PMC5501819 DOI: 10.1038/s41598-017-04895-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 05/22/2017] [Indexed: 12/17/2022] Open
Abstract
Alterations of the innate immunity contribute to the development of spontaneous bacterial peritonitis (SBP) in liver cirrhosis. Given its role in immune signaling, antimicrobial function, and macrophage differentiation, we hypothesized that genetic polymorphisms of TRAF6 modulate the risk of SBP. Thus, we determined theTRAF6 haplotype in 432 patients with cirrhosis and ascites using the haplotype-tagging single nucleotide polymorphisms rs331457 and rs5030419. In addition, peritoneal macrophages were immunomagnetically isolated and characterized. Overall, 122 (28%) patients had an episode of SBP. In the combined prospective-retrospective analysis the frequency of SBP differed between the four haplotypes (P = 0.014) and was the highest in 102 patients carrying the rs331457 but not the rs5030419 variant, when compared to other haplotypes (odds ratio 1.95 [1.22-3.12]) or to the wild-type (odds ratio 1.71 [1.04-2.82]). This association was confirmed in multivariate logistic regression (adjusted odds ratio 2.00 [1.24-3.22]) and in prospective sensitivity analysis (hazard ratio 2.09 [1.08-4.07]; P = 0.03). The risk haplotype was associated with lower concentrations of the immune activation marker soluble CD87 in ascitic fluid and with a decreased expression of IL-6 and CXCL8 in isolated peritoneal macrophages. In conclusion, genetic polymorphisms of TRAF6 are associated with decreased peritoneal immune activation and an increased risk of SBP.
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Affiliation(s)
- Martina Mai
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Eihab Al-Herwi
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Jack Peter
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Caroline Schmidt
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Ignacio Rubio
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany.,Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Andreas Stallmach
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Tony Bruns
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany. .,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany.
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27
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Foldi I, Tornai T, Tornai D, Sipeki N, Vitalis Z, Tornai I, Dinya T, Antal-Szalmas P, Papp M. Lectin-complement pathway molecules are decreased in patients with cirrhosis and constitute the risk of bacterial infections. Liver Int 2017; 37:1023-1031. [PMID: 28109038 DOI: 10.1111/liv.13368] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 01/12/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Lectin pathway molecules of the complement system are synthesized by hepatocytes and have pivotal role in innate host defence against infectious organisms. Ficolins (FCNs) act as soluble pattern recognition molecules, while mannan-binding lectin serine proteases(MASPs) do as effector molecules in elimination of pathogens. We aimed to study the significance of low level of these molecules in the development of cirrhosis-associated bacterial infections, which has not been elucidated so far. METHODS Sera of 266 stable outpatients with cirrhosis and 160 healthy subjects were assayed for a panel of lectin molecules (FCN-2, FCN-3 and MASP-2) by ELISA. In cirrhosis, a 5-year follow-up observational study was conducted to assess a possible association between lectin levels and development of clinically significant bacterial infections(CSI). RESULTS FCN-2, FCN-3 and MASP-2 levels were significantly lower in cirrhosis compared to healthy subjects and decreased according to disease severity (P<.001 for all molecules). In Kaplan-Meier analysis, development of CSI was associated with low level of FCN-2 (<427 ng/mL, pLogRank=0.047) and FCN-3 (<4857 ng/mL, pLogRank=0.029), but not with MASP-2 deficiency (<100 ng/mL, pLogRank=0.306). Combined FCN deficiency was associated with increased risk of development of bacterial infections in a step-wise manner. Patients with low level of both FCNs had higher cumulative probability of CSI (63.8%) compared to those with low level of one or normal FCN (52.7% and 45.7%, pLogRank=0.016). Neither FCN serum profile, nor MASP-2 deficiency were associated with infection-related mortality. CONCLUSIONS Low level of FCNs associated with hepatic insufficiency might be considered as an additional constituent of cirrhosis-associated immune dysfunction.
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Affiliation(s)
- Ildiko Foldi
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamas Tornai
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - David Tornai
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Nora Sipeki
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsuzsanna Vitalis
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Istvan Tornai
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamas Dinya
- Institute of Surgery, Faculty of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Peter Antal-Szalmas
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Maria Papp
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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28
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Török HP, Bellon V, Konrad A, Lacher M, Tonenchi L, Siebeck M, Brand S, De Toni EN. Functional Toll-Like Receptor (TLR)2 polymorphisms in the susceptibility to inflammatory bowel disease. PLoS One 2017; 12:e0175180. [PMID: 28388655 PMCID: PMC5384663 DOI: 10.1371/journal.pone.0175180] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 03/21/2017] [Indexed: 01/17/2023] Open
Abstract
Background The recent genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) suggest significant genetic overlap with complex mycobacterial diseases like tuberculosis or leprosy. TLR variants have previously been linked to susceptibility for mycobacterial diseases. Here we investigated the contribution to IBD risk of two TLR2 polymorphisms, the low-prevalence variant Arg753Gln and the GTn microsatellite repeat polymorphism in intron 2. We studied association with disease, possible correlations with phenotype and gene-gene interactions. Methodology/Principal findings We conducted a large study in 843 patients with Crohn’s disease, 426 patients with ulcerative colitis and 805 healthy, unrelated controls, all of European origin. Overall, the frequency for carriers of shorter GTn repeats in intron 2 of the TLR2 gene, which have previously been associated with low TLR2 expression and high IL-10 production, was slightly elevated in Crohn’s disease and ulcerative colitis compared to healthy controls (16.0% resp. 16.7% vs. 12.8%). The highest frequency of short GTn carriers was noted among IBD patients on anti TNF-alpha therapy. However, none of these differences was significant in the multivariate analysis. The Arg753Gln polymorphism showed no association with any clinical subtype of IBD, including extensive colitis, for which such an association was previously described. We found no association with specific phenotypic disease subgroups. Also, epistasis analysis revealed no significant interactions between the two TLR2 variants and confirmed IBD susceptibility genes. Conclusions The two functional relevant polymorphisms in TLR2, the GTn microsatellite repeat polymorphism in intron 2 and the Arg753Gln variant do not seem to play a role in the susceptibility to Crohn’s disease or ulcerative colitis.
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Affiliation(s)
- Helga Paula Török
- Department of Medicine II, Ludwig-Maximilians-University, Munich, Germany
- * E-mail:
| | - Victor Bellon
- MINES ParisTech, PSL-Research University, CBIO-Centre for Computational Biology, Fontainebleau, France
- Institut Curie, Paris,France
- INSERM U900, Paris, France
| | - Astrid Konrad
- Department of Medicine II, Ludwig-Maximilians-University, Munich, Germany
| | - Martin Lacher
- Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
| | - Laurian Tonenchi
- Department of General, Visceral, Vascular and Transplantation Surgery, Ludwig-Maximilians-University, Munich, Germany
| | - Matthias Siebeck
- Department of General, Visceral, Vascular and Transplantation Surgery, Ludwig-Maximilians-University, Munich, Germany
| | - Stephan Brand
- Department of Medicine II, Ludwig-Maximilians-University, Munich, Germany
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29
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Noor MT, Manoria P. Immune Dysfunction in Cirrhosis. J Clin Transl Hepatol 2017; 5:50-58. [PMID: 28507927 PMCID: PMC5411357 DOI: 10.14218/jcth.2016.00056] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 01/20/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis due to any etiology disrupts the homeostatic role of liver in the body. Cirrhosis-associated immune dysfunction leads to alterations in both innate and acquired immunity, due to defects in the local immunity of liver as well as in systemic immunity. Cirrhosis-associated immune dysfunction is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, and is responsible for 30% mortality. It also plays an important role in acute as well as chronic decompensation. Immune paralysis can accompany it, which is characterized by increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines. There is also presence of increased gut permeability, reduced gut motility and altered gut flora, all of which leads to increased bacterial translocation. This increased bacterial translocation and consequent endotoxemia leads to increased blood stream bacterial infections that cause systemic inflammatory response syndrome, sepsis, multiorgan failure and death. The gut microbiota of cirrhotic patients has more pathogenic microbes than that of non-cirrhotic individuals, and this disturbs the homeostasis and favors gut translocation. Prompt diagnosis and treatment of such infections are necessary for better survival. We have reviewed the various mechanisms of immune dysfunction and its consequences in cirrhosis. Recognizing the exact pathophysiology of immune dysfunction will help treating clinicians in avoiding its complications in their patients and can lead to newer therapeutic interventions and reducing the morbidity and mortality rates.
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Affiliation(s)
- Mohd Talha Noor
- Department of Gastroenterology, Sri Aurobindo Medical College and Post Graduate Institute, Indore, India
- *Correspondence to: Mohd Talha Noor, Department of Gastroenterology, Sri Aurobindo Medical College and Post Graduate Institute, Indore 453 111, India. Tel: +91-7314231751, +91-8305421496, Fax: +91-7314231012, E-mail: ,
| | - Piyush Manoria
- Department of Gastroenterology, Sri Aurobindo Medical College and Post Graduate Institute, Indore, India
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30
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MicroRNA-155 is upregulated in ascites in patients with spontaneous bacterial peritonitis. Sci Rep 2017; 7:40556. [PMID: 28074870 PMCID: PMC5225438 DOI: 10.1038/srep40556] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Accepted: 12/08/2016] [Indexed: 02/08/2023] Open
Abstract
MircoRNA’s (miR) have been recognised as important modulators of gene expression and potential biomarkers. However, they have been rarely investigated in bio fluids apart from blood. We investigated the association of miR-125b and miR-155 with complications of cirrhosis. Ascites was prospectively collected from patients with cirrhosis undergoing paracentesis at our department. miR’s were determined in the supernatant using qPCR and normalized by SV-40. Clinical parameters were assessed at paracentesis and during follow-up. 76 specimens from 72 patients were analysed. MiR’s were not associated to age, sex or aetiology of cirrhosis. MiR-125b levels differed between patients with low and high MELD score, and miR-125b levels showed an inverse correlation to serum creatinine (r2 = −0.23; p = 0.05). MiR-155 was elevated in patients with spontaneous bacterial peritonitis (SBP) (n = 10; p = 0.04). MiR-155 levels differed between patients with and without 30-day survival (p = 0.02). No association of ascites levels of investigated miR’s to size of varices, episodes of gastrointestinal bleeding or hepatorenal syndrome was observed. While miR-125b levels in ascites seem to be associated with liver and renal dysfunction, miR-155 might be implicated in local immune response in SBP.
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Abstract
Sepsis and septic shock are characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a central role during sepsis, and is essential to the regulation of immune defence during systemic infections by mechanisms such as bacterial clearance, acute-phase protein or cytokine production and metabolic adaptation to inflammation. However, the liver is also a target for sepsis-related injury, including hypoxic hepatitis due to ischaemia and shock, cholestasis due to altered bile metabolism, hepatocellular injury due to drug toxicity or overwhelming inflammation, as well as distinct pathologies such as secondary sclerosing cholangitis in critically ill patients. Hence, hepatic dysfunction substantially impairs the prognosis of sepsis and serves as a powerful independent predictor of mortality in the intensive care unit. Sepsis is particularly problematic in patients with liver cirrhosis (who experience increased bacterial translocation from the gut and impaired microbial defence) as it can trigger acute-on-chronic liver failure - a syndrome with high short-term mortality. Here, we review the importance of the liver as a guardian, modifier and target of sepsis, the factors that contribute to sepsis in patients with liver cirrhosis and new therapeutic strategies.
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32
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Aguirre Valadez JM, Rivera-Espinosa L, Méndez-Guerrero O, Chávez-Pacheco JL, García Juárez I, Torre A. Intestinal permeability in a patient with liver cirrhosis. Ther Clin Risk Manag 2016; 12:1729-1748. [PMID: 27920543 PMCID: PMC5125722 DOI: 10.2147/tcrm.s115902] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a worldwide public health problem, and patients with this disease are at high risk of developing complications, bacterial translocation from the intestinal lumen to the mesenteric nodes, and systemic circulation, resulting in the development of severe complications related to high mortality rate. The intestinal barrier is a structure with a physical and biochemical activity to maintain balance between the external environment, including bacteria and their products, and the internal environment. Patients with liver cirrhosis develop a series of alterations in different components of the intestinal barrier directly associated with the severity of liver disease that finally increased intestinal permeability. A "leaky gut" is an effect produced by damaged intestinal barrier; alterations in the function of tight junction proteins are related to bacterial translocation and their products. Instead, increasing serum proinflammatory cytokines and hemodynamics modification, which results in the appearance of complications of liver cirrhosis such as hepatic encephalopathy, variceal hemorrhage, bacterial spontaneous peritonitis, and hepatorenal syndrome. The intestinal microbiota plays a fundamental role in maintaining the proper function of the intestinal barrier; bacterial overgrowth and dysbiosis are two phenomena often present in people with liver cirrhosis favoring bacterial translocation. Increased intestinal permeability has an important role in the genesis of these complications, and treating it could be the base for prevention and partial treatment of these complications.
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Affiliation(s)
| | | | - Osvely Méndez-Guerrero
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición”Salvador Zubirán
| | | | - Ignacio García Juárez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición”Salvador Zubirán
| | - Aldo Torre
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición”Salvador Zubirán
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TLR4/CD14 Variants-Related Serologic and Immunologic Dys-Regulations Predict Severe Sepsis in Febrile De-Compensated Cirrhotic Patients. PLoS One 2016; 11:e0166458. [PMID: 27861595 PMCID: PMC5115743 DOI: 10.1371/journal.pone.0166458] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 10/30/2016] [Indexed: 12/14/2022] Open
Abstract
Genetic variants and dysfunctional monocyte had been reported to be associated with infection susceptibility in advanced cirrhotic patients. This study aims to explore genetic predictive markers and relevant immune dysfunction that contributed to severe sepsis in febrile acute de-compensated cirrhotic patents. Polymorphism analysis of candidate genes was undergone in 108 febrile acute de-compensated cirrhotic patients and 121 healthy volunteers. Various plasma inflammatory/regulatory cytokines, proportion of classical (CD 16-, phagocytic) and non-classical (CD16+, inflammatory) monocytes, lipopolysaccharide (LPS)-stimulated toll-like receptor 4 (TLR4) and intracellular/extracellular cytokines on cultured non-classical monocytes, mCD14/HLA-DR expression and phagocytosis of classical monocytes were measured. For TLR4+896A/G variant allele carriers with severe sepsis, high plasma endotoxin/IL-10 inhibits HLA-DR expression and impaired phagocytosis were noted in their classical monocyte. In the same group, increased non-classical monocyte subset, enhanced LPS-stimulated TLR4 expression and TNFα/nitrite production, and systemic inflammation [high plasma soluble CD14 (sCD14) and total nitric oxide (NOx) levels] were noted. For CD14-159C/T variant allele carriers with severe sepsis, persist endotoxemia inhibited mCD14/HLA-DR expression and impaired phagocytosis of their classical monocyte. In the same group, increased non-classical monocyte subset up-regulated TLR4-NFκB-iNOS and p38MAPK pathway, stimulated TNFα/nitrite production and elicited systemic inflammation. In febrile acute de-compensated cirrhotic patients, TLR4+896A/G and CD14-159C/T polymorphisms-related non-classical and classical monocytes dysfunction resulted in increased severe sepsis risk. Malnutrition, high plasma endotoxin and sCD14 levels, single TLR4+896A/G or CD14-159C/T variant allele carriers and double variant allele carriers are significant predictive factors for the development of severe sepsis among them.
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34
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Caro E, Francés R, Zapater P, Pascual S, Bellot P, Such J. Grade of soluble inflammatory response is mainly affected by circulating bacterial DNA concentrations in cirrhosis. Liver Int 2016; 36:1473-80. [PMID: 26991936 DOI: 10.1111/liv.13118] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 03/08/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Patients with decompensated cirrhosis show a marked innate immune response that shows a wide variability. The reasons for this fact have not been previously evaluated. This investigation was undertaken to study factors influencing the immune response intensity in both serum and ascitic fluid in patients with cirrhosis and ascites with presence of bactDNA. METHODS 77 patients with cirrhosis and presence of bactDNA fragments in blood and ascitic fluid were included. Identification of bactDNA was evaluated by 16SrRNA gene PCR followed by nucleotide sequencing and by species-specific PCR. Concentration of amplified bacterial-DNA, bacteria identification, LPS, TNF-alpha, IFN-gamma, Interleukin 12 and nitric oxide in serum and ascitic fluid were evaluated as factors related to intensity of the immune response. RESULTS Serum and AF levels of bactDNA, TNF-α, IFN-γ and nitric oxide concentration were higher in patients with presence of bactDNA from gram negative bacteria. Serum TNF-α levels showed a significant correlation with concentrations of bactDNA (r = 0.88; P = 0.001) and LPS (r = 0.28; P = 0.016). Serum nitric oxide levels were also significantly correlated with concentrations of bactDNA (r = 0.761; P = 0.001) but not with LPS levels. Levels of INF-γ and IL-12 were not significantly correlated with either bactDNA nor LPS levels. Plasmatic concentration of bactDNA was the most accurately correlated factor with the inflammatory response (ancova model included only levels of bactDNA (r(2) = 0.87, P = 0.047 for TNF-α; r(2) = 0.45, P = 0.03 for NOx). CONCLUSIONS Bacterial-DNA concentration is the most influencing variable associated with serum TNF-α and nitric oxide response.
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Affiliation(s)
- Elena Caro
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain
| | - Rubén Francés
- Departamento de Medicina Clínica, Universidad Miguel Hernández, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Unidad de Farmacología Clínica, Hospital General Universitario de Alicante y Universidad Miguel Hernández, Alicante, Spain
| | - Sonia Pascual
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Pablo Bellot
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - José Such
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE, Lerner School of medicine, Case Western Reserve University, Cleveland, OH, US.
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Cervoni JP, Amorós À, Bañares R, Luis Montero J, Soriano G, Weil D, Moreau R, Pavesi M, Thévenot T, Di Martino V. Prognostic value of C-reactive protein in cirrhosis: external validation from the CANONIC cohort. Eur J Gastroenterol Hepatol 2016; 28:1028-1034. [PMID: 27271159 DOI: 10.1097/meg.0000000000000676] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIMS The variations in C-reactive protein (CRP) levels have been reported to have prognostic significance in decompensated cirrhotic patients. We aimed to provide an external validation of a prognostic model combining model for end-stage liver disease (MELD) and 'sustained high CRP levels' as main variables and to optimize the model to the context of liver transplantation by focusing on 3-month mortality with no consideration of severe chronic extrahepatic diseases. PATIENTS AND METHODS Data from cirrhotic patients enrolled in the CANONIC study were collected. Multivariate analyses used the competing risk model. The prognostic performance [area under receiver operating characteristic curve (AUROC)] of the model incorporating CRP variations within 15 days was compared with that of the MELD score alone. RESULTS 583 decompensated cirrhotic patients with Child-Pugh more than B7 and serial CRP measures available were included. Of these, 111 patients had baseline CRP at least 29 mg/l and 60 still had CRP at least 29 mg/l at day 15±6 (group A). Multivariate analysis (competing risk) identified three predictors of 3-month mortality: high MELD score [hazard ratio (HR)=1.14; 95% confidence intervals (CI): 1.11-1.17, P<0.001], age (HR=1.04; 95% CI: 1.02-1.06, P<0.001), and group A (HR=1.69; 95% CI: 1.01-2.81, P=0.046). The performance of the three variables taken together for predicting 3-month mortality was 0.796 (AUROC), which was significantly higher than that of the MELD score (AUROC=0.769; P=0.019). CONCLUSION In Child-Pugh higher than B7 cirrhotic patients with decompensation, prognostic models incorporating variations in CRP within 15 days and age predict 3-month mortality better than the MELD score alone. Such models would improve the ranking of candidates for liver transplantation by differentiating the severe patients with persistent systemic inflammation and intermediate MELD scores.
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Affiliation(s)
- Jean-Paul Cervoni
- aDepartment of Hepatology, University Hospital of Besançon bUniversity of Franche Comte, Besançon cDepartment of Hepatology, University Hospital Beaujon, Clichy, France dLiver and Transplant Unit, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Facultad de Medicina, CIBEREHD, Madrid eDepartment of Hepatology, University Hospital Reina Sofía, Córdoba fData Management Center, CLIF Consortium gDepartment of Gastroenterology, University Hospital Santa Creu i Sant Pau, Barcelona, Spain
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Bruns T, Reuken PA, Stengel S, Gerber L, Appenrodt B, Schade JH, Lammert F, Zeuzem S, Stallmach A. The prognostic significance of bacterial DNA in patients with decompensated cirrhosis and suspected infection. Liver Int 2016; 36:1133-42. [PMID: 26901072 DOI: 10.1111/liv.13095] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 02/11/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Circulating and peritoneal fragments of microbial DNA (bactDNA) are evidence for bacterial translocation in decompensated cirrhosis and may serve as a rational approach for antibiotic therapy when infection is suspected. METHODS Prospective multicenter study to investigate whether identification of bactDNA from blood or ascitic fluid (AF) by multiplex polymerase chain reaction (PCR) is associated with increased 90-day mortality in 218 patients with cirrhosis and signs of infection. RESULTS BactDNA in either compartment was detected in 134 (61%) patients, comprising 54 with bactDNA in blood and AF, 48 with AF bactDNA only, and 32 with blood bactDNA only. BactDNA was associated with spontaneous bacterial peritonitis and blood stream infections (SBP/BSI), acute-on-chronic liver failure (ACLF), encephalopathy and markers of inflammation. The prevalence of bactDNA in patients with proven SBP/BSI (36/49; 73%) was similar to that in patients with sterile ACLF (37/52; 71%). Actuarial 90-day survival was 56 ± 5% in the absence of bactDNA in both compartments and did not differ if bactDNA was detected in blood only (63 ± 9%), AF only (63 ± 7%), or in blood and AF (52 ± 7%). Predictors of 90-day mortality were SBP (HR = 3.10; 95% CI: 1.90-5.06), BSI (HR = 4.94; 95% CI: 2.71-9.02), and ACLF (HR = 2.20; 95% CI: 1.44-3.35). The detection of resistance genes in blood or AF in the absence of SBP/BSI (n = 11) was associated with poor 1-year survival (HR = 2.35; 95% CI: 1.03-5.35). CONCLUSIONS BactDNA in sterile body fluids did not indicate increased mortality in cirrhotic patients with suspected infection. Using multiplex PCR for risk stratification cannot be recommended in these patients.
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Affiliation(s)
- Tony Bruns
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Philipp A Reuken
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Ludmila Gerber
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Beate Appenrodt
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Johannes H Schade
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Frank Lammert
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Andreas Stallmach
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
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Bruns T, Reuken PA, Stengel S, Gerber L, Appenrodt B, Schade JH, Lammert F, Zeuzem S, Stallmach A. NOD2 Risk Variants and Pathological Bacterial Translocation in Decompensated Cirrhosis. Dig Dis Sci 2016; 61:2142-4. [PMID: 27052012 DOI: 10.1007/s10620-016-4151-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 03/29/2016] [Indexed: 01/05/2023]
Affiliation(s)
- Tony Bruns
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. .,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany.
| | - Philipp A Reuken
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Ludmila Gerber
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Beate Appenrodt
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Johannes H Schade
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Frank Lammert
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Andreas Stallmach
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
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Harputluoglu MMM, Dertli R, Otlu B, Demirel U, Yener O, Bilgic Y, Erdogan MA, Atayan Y, Cagin YF. Nucleotide-Binding Oligomerization Domain-Containing Protein 2 Variants in Patients with Spontaneous Bacterial Peritonitis. Dig Dis Sci 2016; 61:1545-52. [PMID: 26725065 DOI: 10.1007/s10620-015-4024-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 12/20/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND The occurrence of spontaneous bacterial peritonitis (SBP) is significantly increased in carriers of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants, suggesting that local immune alterations might be implicated in bacterial translocation (BT). AIMS We aimed to assess the role of the NOD2 gene in conferring susceptibility to SBP. We also sought to determine whether levels of serum interleukin-6 (IL-6), lipopolysaccharide-binding protein, and soluble TNF-α receptor, along with the presence of bacterial DNA (bactDNA) in ascitic fluid, are appropriate markers for BT in patients with liver cirrhosis and SBP. METHODS A cohort of 171 patients was divided into two groups: patients with SBP (n = 82) and those without SBP (n = 89). The presence of the most common NOD2 variants (p.R702W, p.G908R, and c.3020insC) was determined in these patients. RESULTS We detected the p.G908R variant in four patients (4.9 %) of the SBP group. No significant difference was observed between the SBP and non-SBP groups for NOD2 risk variants. The frequency of bactDNA in ascitic fluid was higher for patients with NOD2 variants than for patients without variants (p = 0.021). Serum IL-6 levels in the SBP group were higher than those in the non-SBP group. CONCLUSIONS The frequent detection of bactDNA in ascites of patients with the p.G908R variant suggests there is a strong association between NOD2 risk variants and BT in SBP patients. In addition, increased serum IL-6 levels and bactDNA in ascitic fluid could be considered surrogate markers for BT in patients with cirrhosis.
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Affiliation(s)
| | - Ramazan Dertli
- Department of Internal Medicine, Medical Faculty, Inonu University, Malatya, Turkey
| | - Baris Otlu
- Department of Microbiology, Medical Faculty, Inonu University, Malatya, Turkey
| | - Ulvi Demirel
- Department of Gastroenterology, Medical Faculty, Firat University, Elazig, Turkey
| | - Ozkan Yener
- Department of Microbiology, Medical Faculty, Inonu University, Malatya, Turkey
| | - Yilmaz Bilgic
- Department of Gastroenterology, Medical Faculty, Inonu University, Malatya, Turkey
| | - Mehmet Ali Erdogan
- Department of Gastroenterology, Medical Faculty, Inonu University, Malatya, Turkey
| | - Yahya Atayan
- Department of Gastroenterology, Medical Faculty, Inonu University, Malatya, Turkey
| | - Yasir Furkan Cagin
- Department of Gastroenterology, Medical Faculty, Inonu University, Malatya, Turkey
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39
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Schäffler H, Kaschitzki A, Alberts C, Bodammer P, Bannert K, Köller T, Warnke P, Kreikemeyer B, Lamprecht G. Alterations in the mucosa-associated bacterial composition in Crohn's disease: a pilot study. Int J Colorectal Dis 2016; 31:961-971. [PMID: 26951181 DOI: 10.1007/s00384-016-2548-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/25/2016] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Changes in the intestinal bacterial composition seem to play a major role in the pathogenesis and in the clinical course of inflammatory bowel diseases (IBD), which consist of Crohn's disease (CD), and ulcerative colitis (UC). Mutations in the NOD2 gene are the most important genetic risk factors for the development of CD. In this study, the association between mucosal biopsies and the mucosa-associated bacterial composition from CD and UC patients regarding their genetic risk factors (mutations in the NOD2 gene), their endoscopic activity, and their medical therapy (TNF-α blocking therapy) was examined. MATERIAL AND METHODS Seventy biopsies from routine colonoscopies from 33 IBD patients (26 CD and 7 UC) were obtained. Disease activity and clinical characteristics were assessed. Seven different bacterial strains (Bacteroides fragilis, Escherichia coli, Prevotella melaninogenica, Clostridium coccoides, Clostridium difficile, Bifidobacterium bifidum, and Faecalibacterium prausnitzii) were quantified using real-time PCR. NOD2 genotyping from patients with CD was performed. RESULTS Five of the 24 patients were positive for at least one mutation in the NOD2 gene. The bacterial composition was different in CD compared to UC, in macroscopic healthy compared to macroscopic inflamed biopsies, in NOD2 mutated compared to NOD2 wildtype patients, and in patients receiving TNF-α blocking therapy compared to patients without this treatment. CONCLUSION This study further characterizes the mucosa-associated bacteria in IBD patients. Different clinical situations lead to an altered mucosa-associated bacterial composition. The analyzed bacteria could be promising targets for cost-effective surveillance or therapies in IBD patients.
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Affiliation(s)
- Holger Schäffler
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany.
| | - Annika Kaschitzki
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Christian Alberts
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Peggy Bodammer
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Karen Bannert
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
| | - Thomas Köller
- Institute of Medical Microbiology, Virology and Hygiene, University Hospital Rostock, Rostock, Germany
| | - Philipp Warnke
- Institute of Medical Microbiology, Virology and Hygiene, University Hospital Rostock, Rostock, Germany
| | - Bernd Kreikemeyer
- Institute of Medical Microbiology, Virology and Hygiene, University Hospital Rostock, Rostock, Germany
| | - Georg Lamprecht
- Division of Gastroenterology and Endocrinology, Department of Medicine II, University Medical Center Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany
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Rieder F, Bettenworth D, Imai J, Inagaki Y. Intestinal Fibrosis and Liver Fibrosis: Consequences of Chronic Inflammation or Independent Pathophysiology? Inflamm Intest Dis 2016; 1:41-49. [PMID: 29922656 DOI: 10.1159/000445135] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
Background Intestinal fibrosis and liver fibrosis represent a significant burden for our patients and health-care systems. Despite the severe clinical problem and the observation that fibrosis is reversible, no specific antifibrotic therapies exist. Summary In this review, using an 'East-West' scientific collaboration, we summarize the current knowledge on principal mechanisms shared by intestinal fibrosis and liver fibrosis. We furthermore discuss inflammation as the cause of fibrogenesis in both entities, depict unique features of intestinal and hepatic fibrosis, and provide a future outlook on the development of antifibrotic therapies. Key Messages A collaborative effort in the field of fibrosis, covering multiple organ systems, will have the highest chance of leading to the development of a successful antifibrotic intervention.
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Affiliation(s)
- Florian Rieder
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland, Ohio, USA.,Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | | | - Jin Imai
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.,Department of Gastroenterology, Tokai University School of Medicine, Isehara, Japan
| | - Yutaka Inagaki
- Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.,Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
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Lutz P, Krämer B, Kaczmarek DJ, Hübner MP, Langhans B, Appenrodt B, Lammert F, Nattermann J, Hoerauf A, Strassburg CP, Spengler U, Nischalke HD. A variant in the nuclear dot protein 52kDa gene increases the risk for spontaneous bacterial peritonitis in patients with alcoholic liver cirrhosis. Dig Liver Dis 2016; 48:62-8. [PMID: 26493630 DOI: 10.1016/j.dld.2015.09.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 08/18/2015] [Accepted: 09/20/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Spontaneous bacterial peritonitis is frequently a fatal infection in patients with liver cirrhosis. We investigated if nuclear dot protein 52kDa (NDP52), a negative regulator of toll-like receptor (TLR) signalling and autophagy adaptor protein, might be involved. METHODS Two cohorts comprising 152 (derivation cohort) and 198 patients (validation cohort) with decompensated liver cirrhosis and 168 healthy controls were genotyped for the rs2303015 polymorphism in the NDP52 gene and prospectively followed-up for spontaneous bacterial peritonitis. RESULTS Overall, 57 (38%) patients in the derivation cohort and 77 (39%) in the validation cohort had spontaneous bacterial peritonitis. Cirrhosis was due to alcohol abuse in 57% of the derivation and 66% of the validation cohort. In patients with alcoholic cirrhosis, patients with spontaneous bacterial peritonitis had an increased frequency of the NDP52 rs2303015 minor variant in the derivation (p=0.04) and in the validation cohort (p=0.01). Multivariate analysis confirmed this minor variant (odds ratio 4.7, p=0.002) and the TLR2 -16934 TT variant (odds ratio 2.5, p=0.008) as risk factors for spontaneous bacterial peritonitis. In addition, presence of the NDP52 minor variant affected survival negatively. CONCLUSION Presence of the NDP52 rs2303015 minor variant increases the risk for spontaneous bacterial peritonitis in patients with alcoholic cirrhosis.
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Affiliation(s)
- Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany.
| | - Benjamin Krämer
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Dominik J Kaczmarek
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Marc P Hübner
- Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Bettina Langhans
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Beate Appenrodt
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Achim Hoerauf
- Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
| | - Hans Dieter Nischalke
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany
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Bajaj JS, Betrapally NS, Hylemon PB, Thacker LR, Daita K, Kang DJ, White MB, Unser AB, Fagan A, Gavis EA, Sikaroodi M, Dalmet S, Heuman DM, Gillevet PM. Gut Microbiota Alterations can predict Hospitalizations in Cirrhosis Independent of Diabetes Mellitus. Sci Rep 2015; 5:18559. [PMID: 26692421 PMCID: PMC4686976 DOI: 10.1038/srep18559] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 11/20/2015] [Indexed: 02/08/2023] Open
Abstract
Diabetes (DM) is prevalent in cirrhosis and may modulate the risk of hospitalization through gut dysbiosis. We aimed to define the role of gut microbiota on 90-day hospitalizations and of concomitant DM on microbiota. Cirrhotic outpatients with/without DM underwent stool and sigmoid mucosal microbial analysis and were followed for 90 days. Microbial composition was compared between those with/without DM, and those who were hospitalized/not. Regression/ROC analyses for hospitalizations were performed using clinical and microbial features. 278 cirrhotics [39% hepatic encephalopathy (HE), 31%DM] underwent stool while 72 underwent mucosal analyses. Ultimately, 94 were hospitalized and they had higher MELD, proton pump inhibitor (PPI) use and HE without difference in DM. Stool/mucosal microbiota were significantly altered in those who were hospitalized (UNIFRAC p< = 1.0e-02). Specifically, lower stool Bacteroidaceae, Clostridiales XIV, Lachnospiraceae, Ruminococcacae and higher Enterococcaceae and Enterobacteriaceae were seen in hospitalized patients. Concomitant DM impacted microbiota UNIFRAC (stool, p = 0.003, mucosa,p = 0.04) with higher stool Bacteroidaceae and lower Ruminococcaeae. Stool Bacteroidaceaeae and Clostridiales XIV predicted 90-day hospitalizations independent of clinical predictors (MELD, HE, PPI). Stool and colonic mucosal microbiome are altered in cirrhotics who get hospitalized with independent prediction using stool Bacteroidaceae and Clostridiales XIV. Concomitant DM distinctly impacts gut microbiota without affecting hospitalizations.
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Affiliation(s)
- Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, McGuire VA Hospital, Richmond, USA
| | - Naga S Betrapally
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Phillip B Hylemon
- Department of Microbiology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Leroy R Thacker
- Department of Biostatistics, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Kalyani Daita
- Division of Gastroenterology, Hepatology and Nutritiony, George Mason University, Manassas, Virginia, USA
| | - Dae Joong Kang
- Division of Gastroenterology, Hepatology and Nutritiony, George Mason University, Manassas, Virginia, USA
| | - Melanie B White
- Division of Gastroenterology, Hepatology and Nutritiony, George Mason University, Manassas, Virginia, USA
| | - Ariel B Unser
- Division of Gastroenterology, Hepatology and Nutritiony, George Mason University, Manassas, Virginia, USA
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology and Nutritiony, George Mason University, Manassas, Virginia, USA
| | - Edith A Gavis
- Division of Gastroenterology, Hepatology and Nutritiony, George Mason University, Manassas, Virginia, USA
| | - Masoumeh Sikaroodi
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Swati Dalmet
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
| | - Douglas M Heuman
- Division of Gastroenterology, Hepatology and Nutritiony, George Mason University, Manassas, Virginia, USA
| | - Patrick M Gillevet
- Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA
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Zapater P, González-Navajas JM, Such J, Francés R. Immunomodulating effects of antibiotics used in the prophylaxis of bacterial infections in advanced cirrhosis. World J Gastroenterol 2015; 21:11493-11501. [PMID: 26556982 PMCID: PMC4631956 DOI: 10.3748/wjg.v21.i41.11493] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 05/29/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
The use of norfloxacin either as primary or secondary prophylaxis of bacterial infections in advanced cirrhosis has improved patient’s survival. This may be explained not only due to a significant decrease in the number of infections, but also because of a direct immunomodulatory effect. Selective intestinal decontamination with norfloxacin reduces translocation of either viable bacteria or bacteria-driven products from the intestinal lumen. In addition, norfloxacin directly modulates the systemic inflammatory response. The pro-inflammatory cytokine profile secreted by neutrophils from these patients shows a close, significant, and inverse correlation with serum norfloxacin levels. Similar effects have been described with other quinolones in different clinical conditions. Although the underlying mechanisms are not well defined for most of the antibiotics, the pathways triggered for norfloxacin to induce such immunomodulatory effects involve the down-regulation of pro-inflammatory inducible nitric oxide synthase, cyclooxygenase-2, and NF-κB and the up-regulation of heme-oxygenase 1 and IL-10 expression. The knowledge of these immunomodulatory effects, additional to their bactericidal role, improves our comprehension of the interaction between antibiotics and the cellular host response and offer new possibilities for the development of new therapeutic strategies to manage and prevent bacterial infections in cirrhosis.
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Hall RA, Hillebrandt S, Lammert F. Exploring multiple quantitative trait loci models of hepatic fibrosis in a mouse intercross. Mamm Genome 2015; 27:70-80. [PMID: 26547557 DOI: 10.1007/s00335-015-9609-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 10/08/2015] [Indexed: 12/31/2022]
Abstract
Most common diseases are attributed to multiple genetic variants, and the feasibility of identifying inherited risk factors is often restricted to the identification of alleles with high or intermediate effect sizes. In our previous studies, we identified single loci associated with hepatic fibrosis (Hfib1-Hfib4). Recent advances in analysis tools allowed us to model loci interactions for liver fibrosis. We analysed 322 F2 progeny from an intercross of the fibrosis-susceptible strain BALB/cJ and the resistant strain FVB/NJ. The mice were challenged with carbon tetrachloride (CCl4) for 6 weeks to induce chronic hepatic injury and fibrosis. Fibrosis progression was quantified by determining histological fibrosis stages and hepatic collagen contents. Phenotypic data were correlated to genome-wide markers to identify quantitative trait loci (QTL). Thirteen susceptibility loci were identified by single and composite interval mapping, and were included in the subsequent multiple QTL model (MQM) testing. Models provided evidence for susceptibility loci with strongest association to collagen contents (chromosomes 1, 2, 8 and 13) or fibrosis stages (chromosomes 1, 2, 12 and 14). These loci contained the known fibrosis risk genes Hc, Fasl and Foxa2 and were incorporated in a fibrosis network. Interestingly the hepatic fibrosis locus on chromosome 1 (Hfib5) connects both phenotype networks, strengthening its role as a potential modifier locus. Including multiple QTL mapping to association studies adds valuable information on gene-gene interactions in experimental crosses and human cohorts. This study presents an initial step towards a refined understanding of profibrogenic gene networks.
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Affiliation(s)
- Rabea A Hall
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421, Homburg, Germany
| | - Sonja Hillebrandt
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421, Homburg, Germany.
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Clinical and pathophysiological consequences of alterations in the microbiome in cirrhosis. Am J Gastroenterol 2015; 110:1399-410; quiz 1411. [PMID: 26416191 DOI: 10.1038/ajg.2015.313] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 08/04/2015] [Indexed: 02/06/2023]
Abstract
Cirrhosis is a major cause of mortality worldwide. Exponential rises in prevalence have been observed secondary to increases in obesity and alcohol consumption. Multiple lines of evidence implicate gut-derived bacteria and bacterial ligands as a central driver of pathogenesis. Recent developments in culture-independent techniques have facilitated a more accurate description of microbiome composition in cirrhosis and led to the description of measures of dysbiosis shown to be associated with disease. More importantly, metagenomic studies are adding to an understanding of the functional contribution of the microbiota and may prove to be a more clinically relevant biomarker than phylogenetic studies. Much like other dysbiotic states such as inflammatory bowel disease, the microbiota in cirrhosis is characterized by a low microbial and genetic diversity. Therapeutic strategies to diminish this process are currently limited to selective intestinal decontamination with antibiotics. This review summarizes the available data and develops a framework for the use of current and future treatment strategies to diminish the consequences of dysbiosis in cirrhosis. Interventional strategies to bind bacterial products in the gut lumen and blood, and modulate the magnitude of host sensing mechanisms remain an unmet clinical need. A greater understanding of the host-microbiota interaction in cirrhosis is of key importance to inform future interventional strategies to diminish the currently escalating burden of the disease.
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Nousbaum JB. [Spontaneous bacterial peritonitis in patients with cirrhosis]. Presse Med 2015; 44:1235-42. [PMID: 26358667 DOI: 10.1016/j.lpm.2015.07.017] [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: 06/30/2015] [Accepted: 07/09/2015] [Indexed: 11/19/2022] Open
Abstract
Spontaneous bacterial peritonitis (SBP) is a severe complication occurring in patients with cirrhosis, and is associated with high mortality. Liver transplantation should be considered after a first episode of SBP. Gram-negative bacilli are the major cause of SBP, however there is an increasing trend of Gram-positive cocci related SBP. Management includes empirical antibiotic treatment and albumin infusion. The choice of antibiotics depends on the site of acquisition (community-acquired vs nosocomial or health-care associated infection) and local resistance profile, due to the emergence of drug-resistant bacteria. Secondary prophylaxis is recommended after resolution of SBP and reduces recurrence and mortality. Primary prophylaxis in patients with low protein ascites (<15 g/L) should be restricted to patients with severe cirrhosis awaiting for liver transplantation.
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Affiliation(s)
- Jean-Baptiste Nousbaum
- CHU La Cavale-Blanche, service d'hépato-gastroentérologie, boulevard Tanguy-Prigent, 29609 Brest cedex, France.
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Tsiaoussis GI, Assimakopoulos SF, Tsamandas AC, Triantos CK, Thomopoulos KC. Intestinal barrier dysfunction in cirrhosis: Current concepts in pathophysiology and clinical implications. World J Hepatol 2015; 7:2058-2068. [PMID: 26301048 PMCID: PMC4539399 DOI: 10.4254/wjh.v7.i17.2058] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 06/22/2015] [Accepted: 06/30/2015] [Indexed: 02/06/2023] Open
Abstract
The intestinal lumen is a host place for a wide range of microbiota and sets a unique interplay between local immune system, inflammatory cells and intestinal epithelium, forming a physical barrier against microbial invaders and toxins. Bacterial translocation is the migration of viable or nonviable microorganisms or their pathogen-associated molecular patterns, such as lipopolysaccharide, from the gut lumen to the mesenteric lymph nodes, systemic circulation and other normally sterile extraintestinal sites. A series of studies have shown that translocation of bacteria and their products across the intestinal barrier is a commonplace in patients with liver disease. The deterioration of intestinal barrier integrity and the consulting increased intestinal permeability in cirrhotic patients play a pivotal pathophysiological role in the development of severe complications as high rate of infections, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, variceal bleeding, progression of liver injury and hepatocellular carcinoma. Nevertheless, the exact cellular and molecular mechanisms implicated in the phenomenon of microbial translocation in liver cirrhosis have not been fully elucidated yet.
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Affiliation(s)
- Georgios I Tsiaoussis
- Georgios I Tsiaoussis, Christos K Triantos, Konstantinos C Thomopoulos, Department of Gastroenterology and Hepatology, University Hospital of Patras, CP 26504 Patras, Greece
| | - Stelios F Assimakopoulos
- Georgios I Tsiaoussis, Christos K Triantos, Konstantinos C Thomopoulos, Department of Gastroenterology and Hepatology, University Hospital of Patras, CP 26504 Patras, Greece
| | - Athanassios C Tsamandas
- Georgios I Tsiaoussis, Christos K Triantos, Konstantinos C Thomopoulos, Department of Gastroenterology and Hepatology, University Hospital of Patras, CP 26504 Patras, Greece
| | - Christos K Triantos
- Georgios I Tsiaoussis, Christos K Triantos, Konstantinos C Thomopoulos, Department of Gastroenterology and Hepatology, University Hospital of Patras, CP 26504 Patras, Greece
| | - Konstantinos C Thomopoulos
- Georgios I Tsiaoussis, Christos K Triantos, Konstantinos C Thomopoulos, Department of Gastroenterology and Hepatology, University Hospital of Patras, CP 26504 Patras, Greece
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Li Y, Han T. Mechanisms of susceptibility to bacterial infections in cirrhotic patients. Shijie Huaren Xiaohua Zazhi 2015; 23:3560-3566. [DOI: 10.11569/wcjd.v23.i22.3560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Bacterial infections are very common in cirrhotic patients, and the incidence is 4-5 times higher than that in the general population. The mechanisms of susceptibility to bacterial infections in cirrhotic patients include intestinal bacterial overgrowth, bacterial translocation, increased number of potentially pathogenic bacteria accompanied by reduced number of beneficial bacteria; small bowel motility disturbances and delayed gut transit, increased intestinal permeability; genetic predisposition to bacterial infections; immunodeficiency accompanied by persistent activation of the immune cells with production of pro-inflammatory cytokines. In this paper, we will discuss the mechanisms of susceptibility to bacterial infections in cirrhotic patients.
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Abstract
Patients with cirrhosis are prone to developing bacterial infections. Moreover, bacterial infection is the most common identifiable trigger of acute-on-chronic liver failure (ACLF), which is characterized by organ failures and a high risk of death. There is evidence of an excessive immune response of the host as a major mechanism leading to the development of organ failures in patients with cirrhosis. However, a role for direct tissue damage caused by bacterial toxins and virulence factors cannot be excluded. Failed tolerance mechanisms may also contribute to organ failures, although the involved mechanisms are unclear. A proportion of patients with infection-related ACLF have a prolonged stay in the intensive care unit. These patients have immune suppression, increased risk of superinfection and poor outcome. Immune suppression might be a consequence of the first infection episode that has led patients to be admitted to hospital.
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Affiliation(s)
- Richard Moreau
- Inserm, U1149, Centre de Recherche sur l'Inflammation (CRI), Université Paris Diderot-Paris 7, Paris, France
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Dever JB, Sheikh MY. Review article: spontaneous bacterial peritonitis--bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther 2015; 41:1116-31. [PMID: 25819304 DOI: 10.1111/apt.13172] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Revised: 02/02/2015] [Accepted: 03/03/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with cirrhosis and ascites. AIM To review the known and changing bacteriology, risk factors, ascitic fluid interpretation, steps in performing paracentesis, treatment, prophylaxis and evolving perspectives related to SBP. METHODS Information was obtained from reviewing medical literature accessible on PubMed Central. The search term 'spontaneous bacterial peritonitis' was cross-referenced with 'bacteria', 'risk factors', 'ascites', 'paracentesis', 'ascitic fluid analysis', 'diagnosis', 'treatment', 'antibiotics', 'prophylaxis', 'liver transplantation' and 'nutrition'. RESULTS Gram-positive cocci (GPC) such as Staphylococcus, Enterococcus as well as multi-resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Health care-associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta-adrenergic antagonist therapies are strongly associated with SBP in at-risk individuals. CONCLUSIONS Third-generation, broad-spectrum cephalosporins remain a good initial choice for SBP treatment. Levofloxacin is an acceptable alternative for patients not receiving long-term flouroquinolone prophylaxis or for those with a penicillin allergy. For uncomplicated SBP, early oral switch therapy is reasonable. Alternative antibiotics such as pipercillin-tazobactam should be considered for patients with nosocomial SBP or for patients who fail to improve on traditional antibiotic regimens. Selective albumin supplementation remains an important adjunct in SBP treatment. Withholding acid suppressive medication deserves strong consideration, and discontinuing beta-adrenergic antagonist therapy in patients with end-stage liver disease and resistant ascites is standard care. Liver transplant evaluation should be undertaken for patients who develop SBP barring contraindications.
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Affiliation(s)
- J B Dever
- Department of Gastroenterology, VA San Diego Healthcare System, San Diego, CA, USA
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