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Park HJ, Yu D, Hong ST, Lee J, Park SJ, Park MS, Lee H, Kim M, Cheon YH, Lee SG, Sohn DH, Jun JB, Kim S, Lee SI. Bifidobacterium longum RAPO Attenuates Dermal and Pulmonary Fibrosis in a Mouse Model of Systemic Sclerosis through Macrophage Modulation and Growth of Short-Chain Fatty Acid Producers. Immune Netw 2024; 24:e41. [PMID: 39801739 PMCID: PMC11711128 DOI: 10.4110/in.2024.24.e41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/01/2024] [Accepted: 12/02/2024] [Indexed: 01/16/2025] Open
Abstract
Systemic sclerosis (SSc) is a complex autoimmune disease with an unclear etiology and no effective treatments. Recent research has suggested involvement of the microbiome in SSc pathogenesis. This study aimed to identify specific microbial species associated with SSc and explore their therapeutic potential. Serum Abs against 384 intestinal microbial species revealed a significant depletion in Abs against Bifidobacterium longum in patients with SSc compared to healthy controls. In a bleomycin-induced SSc mouse model, oral administration of B. longum strain RAPO attenuated skin and lung fibrosis, accompanied by reduced infiltration of inflammatory monocytes/macrophages and downregulation of pro-inflammatory cytokines and chemoattractant Ccl2 genes in lymph nodes and fibrotic tissues. B. longum RAPO treatment restored fecal microbial diversity and augmented short-chain fatty acid (SCFA)-producing bacteria in the gut, leading to increased fecal butyrate levels and upregulated SCFA receptor Gpr41 in the mesenteric lymph node. In vitro, B. longum RAPO and its culture supernatant suppressed the expressions of pro-inflammatory cytokine genes in macrophages and inhibited myofibroblast differentiation in fibroblasts. These findings highlight the probiotic potential of B. longum RAPO in preventing tissue fibrosis by modulating macrophage activity and promoting the growth of SCFA-producing bacteria, underscoring the therapeutic potential of microbial modulation in SSc.
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Affiliation(s)
- Hee Jin Park
- Division of Rheumatology, Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea
| | - Dakyum Yu
- Division of Rheumatology, Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea
| | - Seong-Tshool Hong
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju 54907, Korea
| | - Juyeon Lee
- Research Center, BIFIDO Co, Ltd., Hongcheon 25117, Korea
| | - Sang-Jun Park
- Research Center, BIFIDO Co, Ltd., Hongcheon 25117, Korea
| | | | - Hanna Lee
- Division of Rheumatology, Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea
| | - Mingyo Kim
- Division of Rheumatology, Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea
| | - Yun-Hong Cheon
- Division of Rheumatology, Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea
| | - Seung-Geun Lee
- Division of Rheumatology, Department of Internal Medicine and Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan 49241, Korea
| | - Dong Hyun Sohn
- Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan 50612, Korea
| | - Jae-Bum Jun
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea
| | - Suhee Kim
- Division of Rheumatology, Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea
| | - Sang-Il Lee
- Division of Rheumatology, Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju 52727, Korea
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Ghozzi M, Mankai A, Mechi F, Ben Chedly Z, Kallala O, Melayah S, Trabelsi A, Ghedira I. High frequency of anti-Saccharomyces cerevisiae antibodies in chronic hepatitis C. Arab J Gastroenterol 2024; 25:378-382. [PMID: 39289081 DOI: 10.1016/j.ajg.2024.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 07/16/2024] [Accepted: 07/26/2024] [Indexed: 09/19/2024]
Abstract
BACKGROUND AND STUDY AIM Chronic hepatitis C (CHC) is a liver disease caused by the hepatitis C virus. Anti-Saccharomyces cerevisiae (S. cerevisiae) antibodies (ASCA) are frequently reported in autoimmune diseases but rarely in viral infections. We aimed to determine the frequency of ASCA in adult patients with CHC. PATIENTS AND METHODS Eighty-eight patients with CHC and 160 healthy blood donors were included in this study. ASCA-IgG and IgA levels were determined using enzyme linked immunosorbent assay. For statistical analysis, we used open EPI version 3 as software. Correlations were determined by Spearman's test using IBM® SPSS® Statistics. RESULTS ASCA (IgG or IgA) were present in 31.8 % of patients and in 3.7 % of controls (p < 10-6). ASCA-IgG and ASCA-IgA were more frequent in patients with CHC than in healthy subjects (23.9 % vs. 3.1 %; p < 10-5 and 9.1 % vs. 0.6 %; p = 0.002, respectively). In patients, mean levels of ASCA-IgG and IgA were significantly higher than in controls (9.95 ± 11.78 U/mL vs. 2.28 ± 2.86 U/mL, p < 10-6 and 5.96 ± 7.69 U/mL vs. 0.56 ± 0.12 U/mL, p < 10-6; respectively). In patients with CHC, the mean level of ASCA-IgG was significantly higher than that of ASCA-IgA (9.95 ± 11.78 U/mL vs. 5.96 ± 7.69 U/mL, p = 0.008). CONCLUSION The frequency of ASCA was significantly higher in patients with CHC than in healthy controls.
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Affiliation(s)
- Mariam Ghozzi
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia; Laboratory of Immunology, Farhat Hached Hospital, Sousse, Tunisia; Research Unit "Epidemiology and Immunogenetics of Viral Infections, LR14SP02", Sahloul University Hospital, Sousse, Tunisia.
| | - Amani Mankai
- High School of Sciences and Techniques of Health, Tunis El Manar University, Tunis, Tunisia; Research Unit "Obesity: Etiopathology and Treatment, UR18ES01", National Institute of Nutrition and Food Technology, Tunis, Tunisia
| | - Fatma Mechi
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Zeineb Ben Chedly
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Ouafa Kallala
- Research Unit "Epidemiology and Immunogenetics of Viral Infections, LR14SP02", Sahloul University Hospital, Sousse, Tunisia; Laboratory of Microbiology, Sahloul University Hospital, Sousse, Tunisia; Department of Microbiology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Sarra Melayah
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia; Laboratory of Immunology, Farhat Hached Hospital, Sousse, Tunisia; LR12SP11, Biochemistry Department, Sahloul University Hospital, Sousse, Tunisia
| | - Abdelhalim Trabelsi
- Research Unit "Epidemiology and Immunogenetics of Viral Infections, LR14SP02", Sahloul University Hospital, Sousse, Tunisia; Laboratory of Microbiology, Sahloul University Hospital, Sousse, Tunisia; Department of Microbiology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia
| | - Ibtissem Ghedira
- Department of Immunology, Faculty of Pharmacy, Monastir University, Monastir, Tunisia; Laboratory of Immunology, Farhat Hached Hospital, Sousse, Tunisia
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Sendid B, Cornu M, Cordier C, Bouckaert J, Colombel JF, Poulain D. From ASCA breakthrough in Crohn's disease and Candida albicans research to thirty years of investigations about their meaning in human health. Autoimmun Rev 2024; 23:103486. [PMID: 38040100 DOI: 10.1016/j.autrev.2023.103486] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 11/23/2023] [Indexed: 12/03/2023]
Abstract
Anti-Saccharomyces cerevisiae antibodies (ASCA) are human antibodies that can be detected using an enzyme-linked immunosorbent assay involving a mannose polymer (mannan) extracted from the cell wall of the yeast S. cerevisiae. The ASCA test was developed in 1993 with the aim of differentiating the serological response in two forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis. The test, which is based on the detection of anti-oligomannosidic antibodies, has been extensively performed worldwide and there have been hundreds of publications on ASCA. The earlier studies concerned the initial diagnostic indications of ASCA and investigations then extended to many human diseases, generally in association with studies on intestinal microorganisms and the interaction of the micro-mycobiome with the immune system. The more information accumulates, the more the mystery of the meaning of ASCA deepens. Many fundamental questions remain unanswered. These questions concern the heterogeneity of ASCA, the mechanisms of their generation and persistence, the existence of self-antigens, and the relationship between ASCA and inflammation and autoimmunity. This review aims to discuss the gray areas concerning the origin of ASCA from an analysis of the literature. Structured around glycobiology and the mannosylated antigens of S. cerevisiae and Candida albicans, this review will address these questions and will try to clarify some lines of thought. The importance of the questions relating to the pathophysiological significance of ASCA goes far beyond IBD, even though these diseases remain the preferred models for their understanding.
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Affiliation(s)
- Boualem Sendid
- INSERM U1285, CNRS UMR 8576, Glycobiology in Fungal Pathogenesis and Clinical Applications, Université de Lille, F-59000 Lille, France; Pôle de Biologie-Pathologie-Génétique, Institut de Microbiologie, Service de Parasitologie-Mycologie, CHU Lille, F-59000 Lille, France.
| | - Marjorie Cornu
- INSERM U1285, CNRS UMR 8576, Glycobiology in Fungal Pathogenesis and Clinical Applications, Université de Lille, F-59000 Lille, France; Pôle de Biologie-Pathologie-Génétique, Institut de Microbiologie, Service de Parasitologie-Mycologie, CHU Lille, F-59000 Lille, France
| | - Camille Cordier
- INSERM U1285, CNRS UMR 8576, Glycobiology in Fungal Pathogenesis and Clinical Applications, Université de Lille, F-59000 Lille, France; Pôle de Biologie-Pathologie-Génétique, Institut de Microbiologie, Service de Parasitologie-Mycologie, CHU Lille, F-59000 Lille, France
| | - Julie Bouckaert
- CNRS UMR 8576, Computational Molecular Systems Biology, Université de Lille, F-59000 Lille, France
| | - Jean Frederic Colombel
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Daniel Poulain
- INSERM U1285, CNRS UMR 8576, Glycobiology in Fungal Pathogenesis and Clinical Applications, Université de Lille, F-59000 Lille, France.
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Liakina V. Antibiotic resistance in patients with liver cirrhosis: Prevalence and current approach to tackle. World J Clin Cases 2023; 11:7530-7542. [PMID: 38078132 PMCID: PMC10698443 DOI: 10.12998/wjcc.v11.i31.7530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/02/2023] [Accepted: 10/17/2023] [Indexed: 11/06/2023] Open
Abstract
Regardless of etiology, complications with bacterial infection in patients with cirrhosis are reported in the range of 25%-46% according to the most recent data. Due to frequent episodes of bacterial infection and repetitive antibiotic treatment, most often with broad-spectrum gram negative coverage, patients with cirrhosis are at increased risk of encountering multidrug resistant bacteria, and this raises concern. In such patients, extended-spectrum beta-lactamase and AmpC-producing Enterobacterales, methicillin- or vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, carbapenem-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii, all of which are difficult to treat, are the most common. That is why novel approaches to the prophylaxis and treatment of bacterial infections to avoid antibiotic resistance have recently been developed. At the same time, our knowledge of resistance mechanisms is constantly updated. This review summarizes the current situation regarding the burden of antibiotic resistance, including the prevalence and mechanisms of intrinsic and acquired resistance in bacterial species that most frequently cause complications in patients with liver cirrhosis and recent developments on how to deal with multidrug resistant bacteria.
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Affiliation(s)
- Valentina Liakina
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius 01513, Lithuania
- Department of Chemistry and Bioengineering, Faculty of Fundamental Sciences, Vilnius Tech, Vilnius 10223, Lithuania
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Fuster D, Llorente C, Garcia-Calvo X, Bolao F, Zuluaga P, Hernández-Rubio A, Casado-Carbajo J, Leis A, Muga R. Fungal plasma biomarkers in patients admitted for inpatient treatment of alcohol use disorder. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2023; 47:1582-1589. [PMID: 37364901 PMCID: PMC10984271 DOI: 10.1111/acer.15140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 06/28/2023]
Abstract
BACKGROUND Fungal plasma biomarkers have not been studied in patients with unhealthy alcohol use and no apparent end-stage liver disease. METHODS We examined the prevalence of fungal plasma biomarkers, assessed by the presence of anti-Saccharomyces cerevisiae antibodies (ASCA; IgA and IgM), and its disease correlates in patients with alcohol use disorder (AUD). We performed logistic regression analyses to detect the association between clinical and laboratory characteristics and the presence of fungal plasma biomarkers. RESULTS We included 395 patients (75.9% male, median age of 49 years, and median body mass index of 25.6) who drank a median of 150 g of alcohol daily and had a median duration of AUD of 20 years. ASCA IgA and IgG were present in 34.4% and 14.9%, respectively, and 9.9% had both ASCA IgA and ASCA IgG. The presence of ASCA IgA was associated with male sex (p < 0.01); values of serum aspartate transferase (AST) (p = 0.02), gamma-glutamyl transferase (GGT) (p < 0.01), alkaline phosphatase (ALP) (p < 0.01), and bilirubin in the highest quartile (p < 0.01); Fibrosis-4 Index (FIB-4) values suggestive of advanced liver fibrosis (p < 0.01); and values of the macrophage activation factors sCD163 (p < 0.01) and sCD14 (p < 0.01), the cytokine IL-6 (p = 0.01), and lipopolysaccharide-binding protein in the highest quartile (p < 0.01). The presence of ASCA IgG was associated with omeprazole use (p = 0.04); values of AST (p = 0.04) and GGT (p = 0.04) in the highest quartile; FIB-4 values suggestive of advanced liver fibrosis (p < 0.01); and values of sCD163 (p < 0.01) in the highest quartile. The variables associated with the presence of both ASCA IgA and IgG were male sex (p = 0.04) and values of GGT (p = 0.04) and sCD163 in the highest quartile (p < 0.01). CONCLUSIONS In AUD patients, the presence of fungal biomarkers in plasma was common and associated with FIB-4 values suggestive of advanced liver fibrosis and with markers of liver damage, monocyte activation, and microbial translocation, male gender, and omeprazole use. These findings suggest that the presence of plasma anti-Saccharomyces cerevisiae antibodies could be used as a biomarker for an elevated risk of progressive liver disease in patients with AUD.
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Affiliation(s)
- Daniel Fuster
- Department of Internal Medicine. Addiction Unit. Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona (Barcelona), Spain
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Xavier Garcia-Calvo
- Department of Internal Medicine. Addiction Unit. Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona (Barcelona), Spain
| | - Ferran Bolao
- Department of Internal Medicine. Hospital Universitari de Bellvitge. Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat (Barcelona), Spain
| | - Paola Zuluaga
- Department of Internal Medicine. Addiction Unit. Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona (Barcelona), Spain
| | - Anna Hernández-Rubio
- Department of Internal Medicine. Addiction Unit. Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona (Barcelona), Spain
| | - Julia Casado-Carbajo
- Department of Internal Medicine. Addiction Unit. Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona (Barcelona), Spain
| | - Alba Leis
- Department of Biochemistry. Hospital Universitari Germans Trias i Pujol de Badalona. Badalona (Barcelona), Spain
| | - Robert Muga
- Department of Internal Medicine. Addiction Unit. Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona (Barcelona), Spain
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Demir M, Lang S, Hartmann P, Duan Y, Martin A, Miyamoto Y, Bondareva M, Zhang X, Wang Y, Kasper P, Bang C, Roderburg C, Tacke F, Steffen HM, Goeser T, Kruglov A, Eckmann L, Stärkel P, Fouts DE, Schnabl B. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol 2022; 76:788-799. [PMID: 34896404 PMCID: PMC8981795 DOI: 10.1016/j.jhep.2021.11.029] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis. METHODS We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti-Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B. RESULTS The presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C. albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti-C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis. CONCLUSIONS Non-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH. LAY SUMMARY Non-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage.
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Affiliation(s)
- Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Sonja Lang
- University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany,Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Phillipp Hartmann
- Department of Medicine, University of California San Diego, La Jolla, CA, USA,Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Yi Duan
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Anna Martin
- University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Yukiko Miyamoto
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Marina Bondareva
- Belozerskiy Research Institute for Physical and Chemical Biology and Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, 119991, Russia,Chronic Inflammation Lab, German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany
| | - Xinlian Zhang
- Division of Biostatistics and Bioinformatics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA
| | - Yanhan Wang
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Philipp Kasper
- University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Corinna Bang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany
| | - Christoph Roderburg
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany,Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Hans-Michael Steffen
- University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Tobias Goeser
- University of Cologne, Faculty of Medicine, and University Hospital Cologne, Department of Gastroenterology and Hepatology, Cologne, Germany
| | - Andrey Kruglov
- Belozerskiy Research Institute for Physical and Chemical Biology and Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, 119991, Russia,Chronic Inflammation Lab, German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany
| | - Lars Eckmann
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Peter Stärkel
- St. Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | - Derrick E. Fouts
- Department of Genomic Medicine, J. Craig Venter Institute, Rockville, MD, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
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Cheng L, Li L, Liu C, Yan S, Li Y. Meta-analysis of anti- Saccharomyces cerevisiae antibodies as diagnostic markers of Behçet's disease with gastrointestinal involvement. BMJ Open 2020; 10:e033880. [PMID: 33028542 PMCID: PMC7539584 DOI: 10.1136/bmjopen-2019-033880] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE Due to common exposure to yeast in the alcoholic and baking industry, positive rate of anti-Saccharomyces cerevisiae antibodies (ASCA) is reportedly high in patients with Behçet's disease (BD) who have gastrointestinal symptoms (gastrointestinal BD (GIBD)). We performed a meta-analysis to assess the diagnostic value of ASCA in differentiating patients with BD from those with other chronic inflammatory bowel diseases. METHODS The meta-analysis is presented with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology checklist. Relevant studies that investigated ASCA levels in patients with BD were retrieved from PubMed, EMBASE, Web of Science, SCOPUS and the Cochrane Library on 12 July 2019; the search was rerun on 12 February 2020. Stata/SE V.12.0 and Meta-DiSc V.1.4 were used to perform the meta-analysis and sensitivity analysis, disaggregated by isotypes of ASCA. RESULTS Nine studies were included in the meta-analysis. The results revealed a strong association between ASCA and GIBD, especially ASCA-IgG (OR=5.50 (95% CI 2.58 to 11.55), p=0.000) and ASCA-IgG+IgA (OR=5.36 (95% CI 1.40 to 20.45), p=0.014). The positivity rate of ASCA in GIBD was significantly higher than that in ulcerative colitis (UC): IgA (OR=2.13 (95% CI 1.30 to 3.50), p=0.003); IgG+IgA (OR=2.19 (95% CI 1.03 to 4.66), p=0.042); IgG/IgA ((=2.03 (95% CI 1.30 to 3.17), p=0.002). However, the frequency of ASCA-IgG was significantly higher in patients with Crohn's disease than GIBD (OR=0.48 (95% CI 0.28 to 0.83), p=0.009). There was no significant difference in ASCA positivity between BD without gastrointestinal involvement and healthy controls and between GIBD and intestinal tuberculosis (iTB) (p>0.05). CONCLUSION ASCA may play a role in the pathogenesis of gastrointestinal involvement. Negative result of IgG favours the diagnosis of GIBD/BD when differentiated from Crohn's disease. ASCA-IgA showed moderate diagnostic performance in distinguishing GIBD and UC and the diagnostic performance was better in combination with IgG. However, ASCA may not be a useful serologic marker distinguishing GIBD and iTB. PROSPERO REGISTRATION NUMBER CRD42020115245.
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Affiliation(s)
- Linlin Cheng
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Liubing Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Chenxi Liu
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Songxin Yan
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Scarpellini E, Fagoonee S, Rinninella E, Rasetti C, Aquila I, Larussa T, Ricci P, Luzza F, Abenavoli L. Gut Microbiota and Liver Interaction through Immune System Cross-Talk: A Comprehensive Review at the Time of the SARS-CoV-2 Pandemic. J Clin Med 2020; 9:2488. [PMID: 32756323 PMCID: PMC7464500 DOI: 10.3390/jcm9082488] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The gut microbiota is a complex ecosystem containing bacteria, viruses, fungi, yeasts and other single-celled organisms. It is involved in the development and maintenance of both innate and systemic immunity of the body. Emerging evidence has shown its role in liver diseases through the immune system cross-talk. We review herein literature data regarding the triangular interaction between gut microbiota, immune system and liver in health and disease. METHODS We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: gut microbiota, microbiome, gut virome, immunity, gastrointestinal-associated lymphoid tissue (GALT), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), alcoholic liver disease, liver cirrhosis, hepatocellular carcinoma. RESULTS The gut microbiota consists of microorganisms that educate our systemic immunity through GALT and non-GALT interactions. The latter maintain health but are also involved in the pathophysiology and in the outcome of several liver diseases, particularly those with metabolic, toxic or immune-mediated etiology. In this context, gut virome has an emerging role in liver diseases and needs to be further investigated, especially due to the link reported between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and hepatic dysfunctions. CONCLUSIONS Changes in gut microbiota composition and alterations in the immune system response are involved in the pathogenesis of metabolic and immune-mediated liver diseases.
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Affiliation(s)
- Emidio Scarpellini
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
- Department of Biomedical Sciences, KU Leuven, Gasthuisberg University Hospital, TARGID, 3000 Leuven, Belgium
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, 10121 Turin, Italy;
| | - Emanuele Rinninella
- Nephrology and Urology Department, Gastroenterology, Endocrinology, Fondazione Policlinico A, Clinical Nutrition Unit, Gemelli IRCCS, 00168 Rome, Italy;
- Institute of Medical Pathology, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Carlo Rasetti
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
| | - Isabella Aquila
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Tiziana Larussa
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Pietrantonio Ricci
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Francesco Luzza
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
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9
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Abstract
STUDY DESIGN A retrospective study of 36 liver cirrhosis patients presenting with spondylodiscitis. OBJECTIVES The aim of this study was to analyze the characteristics of spondylodiscitis in the presence of liver cirrhosis and furthermore, to evaluate the outcome of surgery in this specific group of patients. SUMMARY OF BACKGROUND DATA The incidence of haematogenous spondylodiscitis is increasing. The coexistence of liver cirrhosis makes the course of the disease more aggressive. METHODS A total of 36 liver cirrhosis patients presented with haematogenous spondylodiscitis. The onset of infection, clinical course and outcomes of management were reviewed retrospectively. RESULTS The associated comorbidities were cardiac in 17 patients, diabetes in 19, renal insufficiency in 16, and another focus for infection in nine cases. Neurological deficits were found in 24 patients (67%) and fever in 15 cases. Nine patients had septic manifestations. The lumbar spine was affected in 25 patients (69%). Noncontiguous spinal infection was found in nine patients (25%) and epidural abscess in 24 individuals. The preoperative C-reactive protein was elevated in all cases. The causative organism was most commonly Staphylococcus aureus (17 patients). A combined anteroposterior approach was necessary in 28 patients and a minimallly invasive surgery was performed in 30 cases. In-hospital mortality was 14% (5 patients). The neurological improvement rate was 82%. The postoperative antibiotic therapy was taken for more than 8 weeks in 22 patients. In 15 patients, a combination of antibiotics was necessary. CONCLUSION Spinal infection in the presence of liver cirrhosis is challenging. The rate epidural abscess formation is relatively high. Early diagnosis remains the main cornerstone in the management and the indication for surgery should be carefully considered. Minimally invasive techniques should be used when possible to minimize complication rate, and higher amounts of intraoperative blood loss should be expected. LEVEL OF EVIDENCE 4.
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10
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Wu J, Wu D, Ma K, Wang T, Shi G, Shao J, Wang C, Yan G. Paeonol ameliorates murine alcohol liver disease via mycobiota-mediated Dectin-1/IL-1β signaling pathway. J Leukoc Biol 2020; 108:199-214. [PMID: 32129526 DOI: 10.1002/jlb.3ma0120-325rr] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 01/25/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is caused by long-term consumption of alcohol and has become an important social and medical problem. Intestinal fungal flora (mycobiota) play an important role in ALD, so we used the mycobiota as an entry point to explore the mechanism of action of Paeonol against ALD. Here, we found that Paeonol is effective against ALD inflammatory lesions and relieves liver fat lesions. Furthermore, we found that after the treatment of Paeonol, the fungal dysbiosis is improved, and the fungal abundance is reduced, and the translocation of β-glucan to the liver and its mediated Dectin-1/IL-1β signaling pathway is blocked. Our study shows that paeonol ameliorated acute ALD-related inflammatory injury to the liver by alleviating intestinal fungal dysbiosis and inhibiting the mycobiota-mediated Dectin-1/IL-1β signaling pathway.
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Affiliation(s)
- Jiadi Wu
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Daqiang Wu
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Herbal Compound Formula in Anhui Province, Hefei, China
| | - Kelong Ma
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Tianming Wang
- Key Laboratory of Chinese Herbal Compound Formula in Anhui Province, Hefei, China
| | - Gaoxiang Shi
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Jing Shao
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Herbal Compound Formula in Anhui Province, Hefei, China
| | - Changzhong Wang
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Herbal Compound Formula in Anhui Province, Hefei, China
| | - Guiming Yan
- Department of Pathogenic Biology and Immunology, College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.,Research Institute of Integrated Traditional Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China.,Key Laboratory of Chinese Herbal Compound Formula in Anhui Province, Hefei, China
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11
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Li XV, Leonardi I, Iliev ID. Gut Mycobiota in Immunity and Inflammatory Disease. Immunity 2019; 50:1365-1379. [PMID: 31216461 DOI: 10.1016/j.immuni.2019.05.023] [Citation(s) in RCA: 166] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/01/2019] [Accepted: 05/29/2019] [Indexed: 02/08/2023]
Abstract
The mammalian intestine is colonized by a wealth of microorganisms-including bacteria, viruses, protozoa, and fungi-that are all integrated into a functional trans-kingdom community. Characterization of the composition of the fungal community-the mycobiota-has advanced further than the much-needed mechanistic studies. Recent findings have revealed roles for the gut mycobiota in the regulation of host immunity and in the development and progression of human diseases of inflammatory origin. We review these findings here while placing them in the context of the current understanding of the pathways and cellular networks that induce local and systemic immune responses to fungi in the gastrointestinal tract. We discuss gaps in knowledge and argue for the importance of considering bacteria-fungal interactions as we aim to define the roles of mycobiota in immune homeostasis and immune-associated pathologies.
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Affiliation(s)
- Xin V Li
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Irina Leonardi
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Iliyan D Iliev
- Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
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12
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Zhao J, Shi J, Qu M, Zhao X, Wang H, Huang M, Liu Z, Li Z, He Q, Zhang S, Zhang Z. Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis. Front Immunol 2019; 10:1915. [PMID: 31456809 PMCID: PMC6700335 DOI: 10.3389/fimmu.2019.01915] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 07/29/2019] [Indexed: 12/15/2022] Open
Abstract
Objectives: Liver cirrhosis (LC) is usually accompanied by cirrhosis associated immune dysfunction (CAID), including reduced naïve T cells and memory B cells. However, little is known regarding on follicular helper T (Tfh) cell compartments in cirrhotic patients, especially in the secondary lymphoid organs such as spleen. This study characterizes splenic Tfh cells and explores its association with humoral immunity and disease progression in cirrhotic patients. Methods: Using flow cytometry and histological staining, we analyzed the frequency and cytokine production of splenic Tfh cells from LC patients and healthy controls (HCs). Co-culture experiments of sorted Tfh and B cells were performed for functional analysis in vitro. The correlations between Tfh cells and disease progression markers as well as B cell subset perturbations were also examined. Results: PD-1highICOS+CXCR5+ Tfh cells were preferentially enriched in the spleen of cirrhotic patients, where they expressed higher levels of CXCR3 and produced more interleukin (IL)-21. Histologically, more splenic Tfh cells occupied the B cell follicular structure in LC patients where they shaped more active germinal centers (GCs) than those in HC spleens. In vitro, splenic Tfh cells in cirrhotic patients robustly induce plasma cell differentiation through IL-21 dependent manner. Finally, increased Tfh cell frequency is positively correlated with the plasma cells and disease severity in LC patients. Conclusions: We conclude that hyperactive Tfh cells contribute to dysregulated humoral immunity in patients with liver cirrhosis.
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Affiliation(s)
- Juanjuan Zhao
- The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China.,Institute for Hepatology, Shenzhen Third People's Hospital, Shenzhen, China.,Research Center for Clinical & Translational Medicine, Fifth Medical Center for General Hospital of PLA, Beijing, China
| | - Jijing Shi
- The Central Laboratory, The First People's Hospital of Zhengzhou, Zhengzhou, China
| | - Mengmeng Qu
- Research Center for Clinical & Translational Medicine, Fifth Medical Center for General Hospital of PLA, Beijing, China
| | - Xin Zhao
- The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China.,Department of Surgery, Fifth Medical Center for General Hospital of PLA, Beijing, China
| | - Hongbo Wang
- Department for Liver Transplantation, Fifth Medical Center for General Hospital of PLA, Beijing, China
| | - Man Huang
- The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China.,Institute for Hepatology, Shenzhen Third People's Hospital, Shenzhen, China
| | - Zhenwen Liu
- Department for Liver Transplantation, Fifth Medical Center for General Hospital of PLA, Beijing, China
| | - Zhiwei Li
- The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China.,Department for Liver Transplantation, Shenzhen Third People's Hospital, Shenzhen, China
| | - Qing He
- The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China.,Institute for Hepatology, Shenzhen Third People's Hospital, Shenzhen, China
| | - Shuye Zhang
- Shanghai Public Health Clinical Center and Institute of Biomedical Sciences, Fudan University, Shanghai, China
| | - Zheng Zhang
- The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China.,Institute for Hepatology, Shenzhen Third People's Hospital, Shenzhen, China.,Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.,Key Laboratory of Immunology, School of Basic Medical Sciences, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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13
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IgG Antibodies to GlcNAc β and Asialo-GM2 (GA2) Glycans as Potential Markers of Liver Damage in Chronic Hepatitis C and the Efficacy of Antiviral Treatment. DISEASE MARKERS 2018; 2018:4639805. [PMID: 30627223 PMCID: PMC6304914 DOI: 10.1155/2018/4639805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/24/2018] [Accepted: 09/09/2018] [Indexed: 12/14/2022]
Abstract
Total serum IgG level is a surrogate marker of hepatitis C (HC) severity. Antibodies (Abs) to microbial glycans could be markers of HC severity caused by the translocation of microbial products. The level of anti-glycan (AG) Abs was analysed in serum samples of patients (n = 128) with chronic HC in ELISA using fourteen synthetic glycans present in microbes and adhesins to evaluate the association of Abs with clinical parameters and the efficacy of antiviral treatment. The anti-GlcNAcβ IgG level was significantly higher in patients with fibrosis (P = 0.021) and severe portal inflammation (P < 0.001) regardless of other clinical parameters. The ROC curve analysis showed sensitivity of 0.59, specificity of 0.84, and AUC of 0.71 in discriminating F0 from F1–4 (HCV genotype-1b-infected patients). The level of anti-GA2 Abs before Peg-IFN/RBV treatment was significantly higher in nonsustained viral response (non-SVR) to treatment than in SVR (P = 0.033). ROC analysis showed sensitivity of 0.62, specificity of 0.70, and AUC of 64. Correlations of AG Abs to clinical parameters were found. The quantification of anti-GlcNAcβ Abs deserves attention in assessment of the hepatic damage while anti-GA2 Abs may be a sign of immune response related to the antiviral treatment.
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14
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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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15
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Kovacs G, Sipeki N, Suga B, Tornai T, Fechner K, Norman GL, Shums Z, Antal-Szalmas P, Papp M. Significance of serological markers in the disease course of ulcerative colitis in a prospective clinical cohort of patients. PLoS One 2018; 13:e0194166. [PMID: 29590158 PMCID: PMC5874003 DOI: 10.1371/journal.pone.0194166] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 02/13/2018] [Indexed: 12/20/2022] Open
Abstract
Background & aims To determine the prognostic potential of classic and novel serologic antibodies regarding unfavorable disease course in a prospective ulcerative colitis (UC) patient cohort, since few and conflicting data are available in the literature regarding this matter. Methods 187 consecutive patients were studied prospectively (median follow-up: 135 months) from a single referral IBD center in Hungary. Sera were tested for different IgA/IgG type autoantibodies (anti-neutrophil cytoplasmic [ANCA], anti-DNA-bound-lactoferrin [anti-LFS], anti-goblet cell [anti-GAB] and anti-pancreatic [PAB: anti-CUZD1 and anti-GP2)]) by indirect immunofluorescence technique and for anti-microbial (anti-Saccharomyces cerevisiae [ASCA] IgG/IgA and anti-OMP Plus™ IgA) antibodies by enzyme-linked immunosorbent assays. Results A total of 73.6%, 62.4% and 11.2% of UC patients were positive for IgA/IgG type of atypical perinuclear-ANCA, anti-LFS and anti-GAB, respectively. Occurrences of PABs were 9.6%, while ASCA IgA/IgG and anti-OMP IgA were 17.6% and 19.8%, respectively. Antibody status was stable over time. IgA type PABs were more prevalent in patients with primary sclerosing cholangitis (37.5% vs. 4.7% for anti-CUZD1 and 12.5% vs. 0% for anti-GP2, p<0.001 for both). IgA type ASCA and anti-CUZD1 antibodies were associated with higher risk of requirement for long-term immunosuppressant therapy in Kaplan-Meier analysis (pLogRank <0.01 for both). However, in multivariate Cox-regression analysis only ASCA IgA (HR: 2.74, 95%CI: 1.46–5.14, p<0.01) remained independent predictor. UC-related hospitalization due to disease activity was only associated with multiple antibody positivity (for 3 or more; HR 2.03 [95% CI: 1.16–3.56]; p = 0.013). None of the individual antibodies or their combination was associated with the risk of development of extensive disease or colectomy. Conclusion Even with low prevalence rates, present study gives further evidence to the role of certain antibodies as markers for distinct phenotype and disease outcome in UC. Considering the result of the multivariate analysis the novel antibodies investigated do not seem to be associated with poor clinical outcome in UC, only a classic antibody, IgA subtype ASCA remained an independent predictor of long-term immunosuppressive therapy.
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Affiliation(s)
- Gyorgy Kovacs
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Nora Sipeki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Boglarka Suga
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamas Tornai
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Kai Fechner
- Institute of Experimental Immunology, Euroimmun AG, Lübeck, Germany
| | - Gary L. Norman
- Inova Diagnostics, Inc., San Diego, California, United Statesof America
| | - Zakera Shums
- Inova Diagnostics, Inc., San Diego, California, United Statesof America
| | - Peter Antal-Szalmas
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- * E-mail:
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16
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Tornai T, Tornai D, Sipeki N, Tornai I, Alsulaimani R, Fechner K, Roggenbuck D, Norman GL, Veres G, Par G, Par A, Szalay F, Lakatos PL, Antal-Szalmas P, Papp M. Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis. Sci Rep 2018; 8:399. [PMID: 29321484 PMCID: PMC5762861 DOI: 10.1038/s41598-017-18622-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 12/14/2017] [Indexed: 02/08/2023] Open
Abstract
Glycoprotein 2[GP2] is a specific target of pancreatic autoantibodies[PAbs] in Crohn's disease(CD) and is involved in gut innate immunity processes. Our aim was to evaluate the prevalence and prognostic potential of PAbs in primary sclerosing cholangitis(PSC). Sixty-five PSC patients were tested for PAbs by indirect immunofluorescence and compared with healthy (n = 100) and chronic liver disease controls(CLD, n = 488). Additionally, a panel of anti-microbial antibodies and secretory (s)IgA levels were measured, as markers of bacterial translocation and immune dysregulation. PAbs were more frequent in PSC(46.2%) compared to controls(healthy:0% and CLD:4.5%), [P < 0.001, for each]. Occurrence of anti-GP2 antibody was 30.8% (20/65) and was exclusively of IgA isotype. Anti-GP2 IgA positive patients had higher sIgA levels (P = 0.021). With flow-cytometry, 68.4% (13/19) of anti-GP2 IgA antibodies were bound with secretory component, suggesting an active retro-transportation of anti-GP2 from the gut lumen to the mucosa. Anti-GP2 IgA was associated with shorter transplant-free survival [PLogRank < 0.01] during the prospective follow-up (median, IQR: 87 [9-99] months) and remained an independent predictor after adjusting for Mayo risk score(HR: 4.69 [1.05-21.04], P = 0.043). These results highlight the significance of gut-liver interactions in PSC. Anti-GP2 IgA might be a valuable tool for risk stratification in PSC and considered as a potential therapeutic target.
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Affiliation(s)
- 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 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
| | - Rayan Alsulaimani
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Kai Fechner
- Institute of Experimental Immunology, Euroimmun AG, Lübeck, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
- GA Generic Assays GmbH, Dahlewitz, Germany
| | | | - Gabor Veres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Gabriella Par
- 1st Department of Medicine, University of Pecs, Pecs, Hungary
| | - Alajos Par
- 1st Department of Medicine, University of Pecs, Pecs, Hungary
| | - Ferenc Szalay
- 1st Department of Medicine, Semmelweis University, Budapest, 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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17
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Aitbaev KA, Murkamilov IT, Fomin VV. [Liver diseases: The pathogenetic role of the gut microbiome and the potential of treatment for its modulation]. TERAPEVT ARKH 2017; 89:120-128. [PMID: 28914862 DOI: 10.17116/terarkh2017898120-128] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The paper gives an update on the role of the gut microbiome (GM) in the development of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver cirrhosis (LC), and its complications, such as hepatic encephalopathy (HE) and hepatocellular carcinoma (HCC), and discusses the possibilities of its correction with prebiotics, probiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). The pathophysiology of the liver diseases in question demonstrates some common features that are characterized by pathogenic changes in the composition of the gastrointestinal tract microflora, by intestinal barrier impairments, by development of endotoxemia, by increased liver expression of proinflammatory factors, and by development of liver inflammation. In progressive liver disease, the above changes are more pronounced, which contributes to the development of LC, HE, and HCC. GM modulation using prebiotics, probiotics, synbiotics, antibiotics, and FMT diminishes dysbacteriosis, strengthens the intestinal mucosal barrier, reduces endotoxemia and liver damage, and positively affects the clinical manifestations of HE. Further investigations are needed, especially in humans, firstly, to assess a relationship of GM to the development of liver diseases in more detail and, secondly, to obtain evidence indicating the therapeutic efficacy of GM-modulating agents in large-scale, well-designed, randomized, controlled, multicenter studies.
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Affiliation(s)
- K A Aitbaev
- Research Institute of Molecular Biology and Medicine, National Center of Cardiology and Therapy, Ministry of Health of the Kyrgyz Republic, Bishkek, Kyrgyz Republic
| | - I T Murkamilov
- I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyz Republic
| | - V V Fomin
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
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Cai W, Ran Y, Li Y, Wang B, Zhou L. Intestinal microbiome and permeability in patients with autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2017; 31:669-673. [PMID: 29566910 DOI: 10.1016/j.bpg.2017.09.013] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/16/2017] [Indexed: 01/31/2023]
Abstract
Autoimmune hepatitis (AIH) is a severe inflammatory liver disease. The underlying mechanisms remain unclear, but recent studies provided new perspectives on altered intestinal microbiome and permeability in AIH animal models and patients, highlighting gut-liver crosstalk in the pathogenesis of AIH. Transgenic AIH mice carrying HLA-DR3 showed reduced diversity and total load of gut microbiota. Germ-free mice are resistant to concanavalin A-induced liver injury, whereas enterogenouss antigens induce the activation of natural killer T cells participating in concanavalin A-induced liver injury, supporting the close relationship between microbiota and AIH. Moreover, 'molecular mimicry' provides a plausible interpretation of the immune reactions between microorganic antigens and liver autoantigens, for instance, cytochrome P4502D6, the target of cross-reactivity between virus and self. Nevertheless, direct evidence for the intestinal microbiome and permeability in AIH is still limited. The relationship between AIH susceptibilities and an intestinal microbiome shaped by drugs, diets or genes needs further study.
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Affiliation(s)
- Wangfeng Cai
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, PR China
| | - Ying Ran
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, PR China
| | - Yanni Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, PR China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, PR China.
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300052, PR China.
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Paterson MJ, Oh S, Underhill DM. Host-microbe interactions: commensal fungi in the gut. Curr Opin Microbiol 2017; 40:131-137. [PMID: 29175338 PMCID: PMC5733715 DOI: 10.1016/j.mib.2017.11.012] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 11/07/2017] [Accepted: 11/10/2017] [Indexed: 02/07/2023]
Abstract
Fungi are ubiquitous microbes that are common in diverse environments including as commensal organisms on the human body. In addition to its obvious role as a digestive organ, the intestines have been further appreciated as important for the development, maintenance, and instruction of the immune system. The gut harbors many types of microorganisms including bacteria, archaea, fungi, and viruses, and many studies over the past couple of decades have documented an important role for intestinal bacteria in immunological function. Recent studies are now suggesting that intestinal fungi (the gut 'mycobiome') may similarly play important roles in host immunity and inflammation. This review will discuss recent studies that will influence our growing understanding of the role(s) of intestinal fungi in health and disease.
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Affiliation(s)
- Marissa J Paterson
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and the Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Seeun Oh
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and the Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - David M Underhill
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and the Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
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20
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Yang AM, Inamine T, Hochrath K, Chen P, Wang L, Llorente C, Bluemel S, Hartmann P, Xu J, Koyama Y, Kisseleva T, Torralba MG, Moncera K, Beeri K, Chen CS, Freese K, Hellerbrand C, Lee SM, Hoffman HM, Mehal WZ, Garcia-Tsao G, Mutlu EA, Keshavarzian A, Brown GD, Ho SB, Bataller R, Stärkel P, Fouts DE, Schnabl B. Intestinal fungi contribute to development of alcoholic liver disease. J Clin Invest 2017; 127:2829-2841. [PMID: 28530644 DOI: 10.1172/jci90562] [Citation(s) in RCA: 353] [Impact Index Per Article: 44.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 03/30/2017] [Indexed: 12/14/2022] Open
Abstract
Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin-like receptor CLEC7A on Kupffer cells and possibly other bone marrow-derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non-alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.
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Affiliation(s)
- An-Ming Yang
- Department of Medicine, UCSD, La Jolla, California, USA.,Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Tatsuo Inamine
- Department of Medicine, UCSD, La Jolla, California, USA.,Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | | | - Peng Chen
- Department of Medicine, UCSD, La Jolla, California, USA
| | - Lirui Wang
- Department of Medicine, UCSD, La Jolla, California, USA.,Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
| | - Cristina Llorente
- Department of Medicine, UCSD, La Jolla, California, USA.,Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
| | - Sena Bluemel
- Department of Medicine, UCSD, La Jolla, California, USA
| | | | - Jun Xu
- Department of Surgery, UCSD, La Jolla, California, USA
| | | | | | | | | | - Karen Beeri
- J. Craig Venter Institute, La Jolla, California, USA
| | - Chien-Sheng Chen
- Institute of Systems Biology and Bioinformatics, National Central University, Taoyuan City, Taiwan
| | - Kim Freese
- Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry (Emil-Fischer Zentrum), Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Serene Ml Lee
- Department of General, Visceral and Transplantation Surgery, Hospital of the LMU Munich, Munich, Germany
| | - Hal M Hoffman
- Department of Medicine, UCSD, La Jolla, California, USA.,Department of Pediatrics, UCSD, La Jolla, California, USA
| | - Wajahat Z Mehal
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.,Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA.,Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Ece A Mutlu
- Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Ali Keshavarzian
- Department of Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Gordon D Brown
- Aberdeen Fungal Group, Medical Research Council Centre for Medical Mycology, University of Aberdeen, Aberdeen, United Kingdom
| | - Samuel B Ho
- Department of Medicine, UCSD, La Jolla, California, USA.,Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
| | - Ramon Bataller
- Liver Center, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Peter Stärkel
- Saint Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
| | | | - Bernd Schnabl
- Department of Medicine, UCSD, La Jolla, California, USA.,Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
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Serologic Anti-GP2 Antibodies Are Associated with Genetic Polymorphisms, Fibrostenosis, and Need for Surgical Resection in Crohn's Disease. Inflamm Bowel Dis 2016; 22:2648-2657. [PMID: 27753692 PMCID: PMC5082182 DOI: 10.1097/mib.0000000000000936] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND The presentation of Crohn's disease (CD) is heterogeneous and often leads to serious complications and need for surgery. We tested serum anti-zymogen granule glycoprotein 2 (GP2) antibodies, including its novel isoform alpha, for association with genetic variants, diagnosis, disease stratification, and prediction of CD courses in a combined cross-sectional and cohort study. METHODS Serum samples of 303 CD, 108 ulcerative colitis, 72 other inflammatory gastrointestinal diseases, and 206 controls without predominant gastrointestinal diseases controls (HC) were tested for the presence of Anti-GP2 and Anti-Saccharomyces cervisiae (ASCA) by enzyme-linked immunosorbent assay. Genetic analysis was performed using the Illumina Immunochip. RESULTS GP2 IgA and IgG had the highest discriminatory capability for CD versus ulcerative colitis and CD versus inflammatory gastrointestinal diseases. We identified an association of GP2 IgA and IgG each with 5 distinct single-nucleotide polymorphisms. Levels of anti-GP2 IgG were moderately associated with ileal disease location. Interestingly, both, anti-GP2 IgA and IgG were exclusively associated with the occurrence of stenosis and need for surgery, independently of disease location, but not with fistulizing CD, early disease onset or disease activity. ASCA IgG and IgA were qualitatively and quantitatively linked to CD, CD complications, and need for surgery. Increased levels of ASCA IgG and IgA and positivity for ASCA IgG, but neither levels nor positivity for GP2 IgG or IgA were predictive of the earlier occurrence of complications or surgery. CONCLUSIONS Anti-GP2 antibodies may aid as a tool for diagnosis and differentiation of CD and could indicate a more complicated CD course.
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Vaikunthanathan T, Safinia N, Lombardi G, Lechler RI. Microbiota, immunity and the liver. Immunol Lett 2016; 171:36-49. [PMID: 26835593 DOI: 10.1016/j.imlet.2016.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 01/24/2016] [Accepted: 01/27/2016] [Indexed: 12/18/2022]
Abstract
The gut harbors a complex community of over 100 trillion microbial cells known to exist in symbiotic harmony with the host influencing human physiology, metabolism, nutrition and immune function. It is now widely accepted that perturbations of this close partnership results in the pathogenesis of several major diseases with increasing evidence highlighting their role outside of the intestinal tract. The intimate proximity and circulatory loop of the liver and the gut has attracted significant attention regarding the role of the microbiota in the development and progression of liver disease. Here we give an overview of the interaction between the microbiota and the immune system and focus on their convincing role in both the propagation and treatment of liver disease.
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Affiliation(s)
- T Vaikunthanathan
- MRC Centre for Transplantation, Division of Transplantation Immunology & Mucosal Biology, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
| | - N Safinia
- MRC Centre for Transplantation, Division of Transplantation Immunology & Mucosal Biology, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
| | - G Lombardi
- MRC Centre for Transplantation, Division of Transplantation Immunology & Mucosal Biology, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
| | - R I Lechler
- MRC Centre for Transplantation, Division of Transplantation Immunology & Mucosal Biology, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
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Gómez-Hurtado I, Such J, Francés R. Microbiome and bacterial translocation in cirrhosis. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 39:687-696. [PMID: 26775042 DOI: 10.1016/j.gastrohep.2015.10.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 10/20/2015] [Accepted: 10/22/2015] [Indexed: 02/06/2023]
Abstract
Qualitative and quantitative changes in gut microbiota play a very important role in cirrhosis. Humans harbour around 100 quintillion gut bacteria, thus representing around 10 times more microbial cells than eukaryotic ones. The gastrointestinal tract is the largest surface area in the body and it is subject to constant exposure to these living microorganisms. The existing symbiosis, proven by the lack of proinflammatory response against commensal bacteria, implies the presence of clearly defined communication lines that contribute to the maintenance of homeostasis of the host. Therefore, alterations of gut flora seem to play a role in the pathogenesis and progress of multiple liver and gastrointestinal diseases. This has made its selective modification into an area of high therapeutic interest. Bacterial translocation is defined as the migration of bacteria or bacterial products from the intestines to the mesenteric lymph nodes. It follows that alteration in gut microbiota have shown importance, at least to some extent, in the pathogenesis of several complications arising from terminal liver disease, such as hepatic encephalopathy, portal hypertension and spontaneous bacterial peritonitis. This review sums up, firstly, how liver disease can alter the common composition of gut microbiota, and secondly, how this alteration contributes to the development of complications in cirrhosis.
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Affiliation(s)
- Isabel Gómez-Hurtado
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España
| | - José Such
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dabi, Emiratos Árabes Unidos
| | - Rubén Francés
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Departamento de Medicina Clínica, Universidad Miguel Hernández, San Juan de Alicante, Alicante, España.
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Jhun JY, Kim HY, Byun JK, Chung BH, Bae SH, Yoon SK, Kim DG, Yang CW, Cho ML, Choi JY. B-cell-associated immune profiles in patients with decompensated cirrhosis. Scand J Gastroenterol 2015; 50:884-91. [PMID: 25861705 DOI: 10.3109/00365521.2014.907335] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Previous observations on immune dysfunction in decompensated cirrhosis have raised the possibility of B-cell impairment. METHODS B-cell subsets in decompensated cirrhotic patients were investigated. Twenty-six decompensated cirrhotic patients and 26 healthy controls were included in this study. The percentages of B-cell subsets, such as mature, memory, immature B cells, and interleukin (IL)-10+-B-cell subpopulations, were measured using fluorescent activated cell sorting. B-cell-associated cytokines (IL-10, IL-21 and IL-4) were determined using an enzyme-linked immunosorbent assay. RESULTS The percentage of total B cells and mature B cells increased in patients with decompensated cirrhosis compared to healthy controls. The proportions of memory B cells were significantly lower in the decompensated cirrhosis group than the control group. However, the frequency of immature B cells and the percentage of IL-10-expressing cells that were CD19+, memory, mature, or immature B cells were not significantly different between the two groups. Serum levels of IL-10, IL-21, and IL-4 were significantly lower in the decompensated cirrhosis group compared to the control group. CONCLUSION These results indicate significant alterations in peripheral blood B-cell subsets in patients with decompensated cirrhosis. Specifically, a profound reduction of memory B cells was observed in spite of an increase in total B-cell populations in decompensated cirrhotic patients. This implies the underlying mechanisms of impaired immune response in these patients.
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Affiliation(s)
- Joo Yeon Jhun
- Conversant Research Consortium in Immunologic Disease, College of Medicine, The Catholic University of Korea , Seoul , Korea
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Salamati S, Martins C, Kulseng B. Baker's yeast (Saccharomyces cerevisiae) antigen in obese and normal weight subjects. Clin Obes 2015; 5:42-7. [PMID: 25611585 DOI: 10.1111/cob.12079] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 08/21/2014] [Accepted: 09/16/2014] [Indexed: 01/04/2023]
Abstract
Baker's yeast (Saccharomyces cerevisiae) and its cell wall components have been used as one of the alternatives to antibiotic growth promoters in the feed industry. Antibodies to cell wall mannan of this yeast (ASCA) have been traditionally used in the study of Crohn's disease (CD). We applied ASCA in relation to obesity. This study aims (i) to determine the concentration of ASCA (immunoglobulin A [IgA] and immunoglobulin G [IgG]) in obese compared with normal weight individuals and (ii) to determine if there is a correlation between ASCA concentrations, obesity indices and C-reactive protein. Forty obese individuals (body mass index [BMI] > 35 kg m(-2) ) and 18 healthy (BMI < 25 kg m(-2) ) volunteers participated in this case-control study. Binding activity of serum IgA and IgG to the cell wall mannan of S. cerevisiae was measured by enzyme-linked immunosorbent assay. More than one-third of the obese individual (35%) showed elevated titres of ASCA compared with the control group (5%). This antibody was positively associated with weight (P = 0.01), BMI (P = 0.02) and waist circumference (P = 0.02), but not with C-reactive protein. It seems that ASCA are not only specific for CD but are also associated with obesity. S. cerevisiae or a related antigen may play a role in the matrix of this complex condition.
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Affiliation(s)
- S Salamati
- Center for Obesity, Department of Surgery, St. Olav Hospital - Trondheim University Hospital, Trondheim, Norway
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Kevans D, Waterman M, Milgrom R, Xu W, Van Assche G, Silverberg M. Serological markers associated with disease behavior and response to anti-tumor necrosis factor therapy in ulcerative colitis. J Gastroenterol Hepatol 2015; 30:64-70. [PMID: 25041458 DOI: 10.1111/jgh.12661] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Information is limited on the relationship between serological markers and disease behavior and anti-tumor necrosis factor-α (anti-TNF) therapy response in ulcerative colitis (UC). This study aimed to determine the association between serological markers and unfavorable UC behavior defined as need for colectomy or UC-related hospitalization. The association between serological markers and requirement for and outcome of anti-TNF therapy was also evaluated. METHODS Two hundred thirty patients were studied. Requirement for colectomy, UC-related hospitalization, and anti-TNF therapy were documented. Response to anti-TNF therapy at 1 year and rates of therapy discontinuation were recorded. Titers of perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs), anti-Saccharomyces cerevisiae antibody (ASCA), and antibody to Escherichia Coli outer membrane porin (anti-OmpC) were determined. Antibody reference ranges were used to dichotomize subjects into seropositive and seronegative groups. Where multiple tests were performed, P-values were Bonferroni corrected (pcorr). RESULTS Extensive colitis was associated with requirement for colectomy and UC-related hospitalization, HR 7.7 (95% confidence interval [CI] 1.9-32.2) pcorr = 0.03 and HR 2.7 (95% CI 1.5-4.6), pcorr = 0.006, respectively. No serological variable was associated with unfavorable UC behavior. Anti-OmpC positivity was associated with a lack of response to anti-TNF therapy at 1 year (odds ratio 0.14 [95% CI 0.03-0.60], pcorr = 0.04) and increased likelihood of therapy discontinuation (HR 2.2 [95% CI 1.1-4.7], P = 0.03). CONCLUSION Extensive colitis is associated with unfavorable disease course in UC. Anti-OmpC holds promise as a biomarker of anti-TNF therapy response in UC; however, prospective studies are required before it can be incorporated into routine clinical practice.
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Affiliation(s)
- David Kevans
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
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Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61:1385-96. [PMID: 25135860 DOI: 10.1016/j.jhep.2014.08.010] [Citation(s) in RCA: 837] [Impact Index Per Article: 76.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 07/27/2014] [Accepted: 08/09/2014] [Indexed: 02/06/2023]
Abstract
The term cirrhosis-associated immune dysfunction refers to the main syndromic abnormalities of immune function, immunodeficiency and systemic inflammation that are present in cirrhosis. The course of advanced cirrhosis, regardless of its aetiology, is complicated by cirrhosis-associated immune dysfunction and this constitutes the pathophysiological hallmark of an increased susceptibility to bacterial infection, distinctive of the disease. Cirrhosis impairs the homeostatic role of the liver in the systemic immune response. Damage to the reticulo-endothelial system compromises the immune surveillance function of the organ and the reduced hepatic synthesis of proteins, involved in innate immunity and pattern recognition, hinders the bactericidal ability of phagocytic cells. Systemic inflammation, in form of activated circulating immune cells and increased serum levels of pro-inflammatory cytokines, is the result of persistent episodic activation of circulating immune cells from damage-associated molecular patterns, released from necrotic liver cells and, as cirrhosis progresses, from pathogen-associated molecular patterns, released from the leaky gut. Cirrhosis-associated immune dysfunction phenotypes switch from predominantly "pro-inflammatory" to predominantly "immunodeficient" in patients with stable ascitic cirrhosis and in patients with severely decompensated cirrhosis and extra-hepatic organ failure (e.g. acute-on-chronic liver failure), respectively. These cirrhosis-associated immune dysfunction phenotypes represent the extremes of a spectrum of reversible dynamic events that take place during the course of cirrhosis. Systemic inflammation can affect the functions of tissue somatic cells and modify the clinical manifestation of cirrhosis. The best characterized example is the contribution of systemic inflammation to the haemodynamic derangement of cirrhosis, which correlates negatively with prognosis.
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Affiliation(s)
- Agustín Albillos
- Department of Medicine, Universidad de Alcalá, Madrid, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Service of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
| | - Margaret Lario
- Department of Medicine, Universidad de Alcalá, Madrid, Spain
| | - Melchor Álvarez-Mon
- Department of Medicine, Universidad de Alcalá, Madrid, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Service of Immune Diseases and Oncology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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Hung TH, Chou CL, Fang TC. Impact of renal dysfunction in cirrhotic patients with bacterial infections other than spontaneous bacterial peritonitis. Hepatol Res 2014; 44:863-70. [PMID: 23809358 DOI: 10.1111/hepr.12190] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 06/10/2013] [Accepted: 06/24/2013] [Indexed: 02/08/2023]
Abstract
AIM The impact of renal dysfunction has not been well evaluated among cirrhotic patients having bacterial infections other than spontaneous bacterial peritonitis (SBP). We aimed to examine the impact of renal function impairment (RFI) among cirrhotic patients with non-SBP bacterial infections. METHODS Data of 7134 cirrhotic patients with non-SBP bacterial infections extracted from the Taiwan National Health Insurance Database, derived from the Taiwan National Health Insurance Program, in 2004 were analyzed. RESULTS A total of 579 (8.1%) patients had renal dysfunction. Of these, 223 patients had acute renal failure (ARF), and 141 had end-stage renal disease (ESRD) requiring hemodialysis before admission. The overall 30-day, 1-year and 3-year mortalities were 15.8%, 39.3% and 54.5%, respectively. Compared with the non-RFI group, the adjusted hazard ratios (HR) of 30-day mortality for RFI, ARF and ESRD were 3.20 (P < 0.001), 4.81 (P < 0.001) and 1.59 (P = 0.015); the adjusted HR of 1-year mortality for RFI, ARF and ESRD were 2.68 (P < 0.001), 3.50 (P < 0.001) and 1.84 (P < 0.001), and adjusted HR of 3-year mortality for RFI, ARF and ESRD were 2.34 (P < 0.001), 2.97 (P < 0.001) and 1.76 (P < 0.001). The adjusted HR of 30-day, 1-year and 3-year mortalities for the ARF group were 2.98 (P < 0.001), 1.74 (P < 0.001) and 1.58 (P = 0.001) compared with the ESRD group, respectively. CONCLUSION This population-based cohort study shows that RFI, especially ARF, is an independent poor prognostic factor in cirrhotic patients with non-SBP bacterial infections.
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Affiliation(s)
- Tsung-Hsing Hung
- Division of Gastroenterology, Department of Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi; School of Medicine, Tzu Chi University
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Abstract
Microbes are present in large numbers in each human being, in particularly in the gastrointestinal (GI) tract, and have long been believed to have some beneficial effects for their hosts. Till recently, however, we lacked tools for studying these organisms. Rapid technological advances in recent years have markedly improved our understanding of their role both in health and disease. Recent literature suggests that organisms in the GI tract, referred to collectively as gut microbiota, play an indispensable role in the maintenance of host's homeostasis. Alterations in the gut microbiota, that is in the nature and relative density of various constituent bacterial species, appear to have a role in pathogenesis and progression of several GI and hepatic diseases. This has also opened the vista for tinkering with gut flora in an attempt to treat or prevent such diseases. In this review, we have tried to summarize information on normal gut microbiota, laboratory techniques and animal models used to study it, and the role of its perturbations in some of the common hepatic disorders, such as non-alcoholic fatty liver disease (including obesity), non-alcoholic steatohepatitis, alcoholic liver disease, and liver cirrhosis and its complications.
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Affiliation(s)
- Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Kovács M, Müller KE, Papp M, Lakatos PL, Csöndes M, Veres G. New serological markers in pediatric patients with inflammatory bowel disease. World J Gastroenterol 2014; 20:4873-4882. [PMID: 24803798 PMCID: PMC4009518 DOI: 10.3748/wjg.v20.i17.4873] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/16/2014] [Accepted: 03/06/2014] [Indexed: 02/07/2023] Open
Abstract
The spectrum of serological markers associated with inflammatory bowel disease (IBD) is rapidly growing. Due to frequently delayed or missed diagnoses, the application of non-invasive diagnostic tests for IBD, as well as differentiation between ulcerative colitis (UC) and Crohn's disease (CD), would be useful in the pediatric population. In addition, the combination of pancreatic autoantibodies and antibodies against Saccharomyces cerevisiae antibodies/perinuclear cytoplasmic antibody (pANCA) improved the sensitivity of serological markers in pediatric patients with CD and UC. Some studies suggested that age-associated differences in the patterns of antibodies may be present, particularly in the youngest children. In CD, most patients develop stricturing or perforating complications, and a significant number of patients undergo surgery during the disease course. Based on recent knowledge, serum antibodies are qualitatively and quantitatively associated with complicated CD behavior and CD-related surgery. Pediatric UC is characterized by extensive colitis and a high rate of colectomy. In patients with UC, high levels of anti-CBir1 and pANCA are associated with the development of pouchitis after ileal pouch-anal anastomosis. Thus, serologic markers for IBD can be applied to stratify IBD patients into more homogeneous subgroups with respect to disease progression. In conclusion, identification of patients at an increased risk of rapid disease progression is of great interest, as the application of early and more aggressive pharmaceutical intervention could have the potential to alter the natural history of IBD, and reduce complications and hospitalizations.
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Funderburg NT, Stubblefield Park SR, Sung HC, Hardy G, Clagett B, Ignatz-Hoover J, Harding CV, Fu P, Katz JA, Lederman MM, Levine AD. Circulating CD4(+) and CD8(+) T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation. Immunology 2013; 140:87-97. [PMID: 23600521 DOI: 10.1111/imm.12114] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2012] [Revised: 03/19/2013] [Accepted: 04/11/2013] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohn's disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4(+) and CD8(+) T lymphocytes in cycle (Ki67(+) ) are increased in patients with IBD compared with these proportions in controls. CD8(+) T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-γ levels were elevated in resting and polyclonally activated CD4(+) and CD8(+) T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4(+) and CD8(+) T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.
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Affiliation(s)
- Nicholas T Funderburg
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4952, USA
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Trivedi PJ, Adams DH. Mucosal immunity in liver autoimmunity: A comprehensive review. J Autoimmun 2013; 46:97-111. [DOI: 10.1016/j.jaut.2013.06.013] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 06/19/2013] [Indexed: 12/14/2022]
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Papp M, Sipeki N, Vitalis Z, Tornai T, Altorjay I, Tornai I, Udvardy M, Fechner K, Jacobsen S, Teegen B, Sumegi A, Veres G, Lakatos PL, Kappelmayer J, Antal-Szalmas P. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J Hepatol 2013; 59:457-466. [PMID: 23639483 DOI: 10.1016/j.jhep.2013.04.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 04/12/2013] [Accepted: 04/16/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Anti-neutrophil cytoplasmic antibodies (ANCA) are a non-uniform family of antibodies recognizing diverse components of neutrophil granulocytes. ANCA formation might be induced by protracted bacterial infections or probably reflect an abnormal immune response to commensal microorganisms. Bacterial infections are common complications in cirrhosis with high incidence of episodes caused by enteric organisms, therefore, we sought to study the presence and clinical importance of ANCA in cirrhosis. METHODS Sera of 385 patients with cirrhosis of different etiologies were assayed for ANCA of IgG, IgA, IgA1, IgA2, and secretory IgA subtypes by indirect immunofluorescence and ELISAs. The control group comprised 202 patients with chronic liver diseases without cirrhosis and 100 healthy subjects. In cirrhosis, a 2-year follow-up, observational study was conducted to assess a possible association between the presence of ANCA and clinically significant bacterial infections. RESULTS Prevalence of ANCA IgA was significantly higher in cirrhosis (52.2%) compared to chronic liver diseases (18.6%) or healthy controls (0%, p<0.001 for both). ANCA IgA subtyping assays revealed marked increase in the proportion of IgA2 subtype (46% of total ANCA IgA) and presence of the secretory component concurrently. Presence of ANCA IgA was associated with disease-specific clinical characteristics (Child-Pugh stage and presence of ascites, p<0.001). During a 2-year follow-up period, risk of infections was higher among patients with ANCA IgA compared to those without (41.8% vs. 23.4%, p<0.001). ANCA IgA positivity was associated with a shorter time to the first infectious complication (pLogRank <0.001) in Kaplan-Meier analysis and was identified as an independent predictor in multivariate Cox-regression analysis (HR:1.74, 95% CI: 1.18-2.56, p=0.006). CONCLUSIONS Presence of IgA type ANCA is common in cirrhosis. Involvement of gut mucosal immune system is in center of their formation and probably reflects sustained exposure to bacterial constituents.
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Affiliation(s)
- Maria Papp
- 2nd Department of Medicine, Division of Gastroenterology, University of Debrecen, Debrecen, Hungary.
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Lamontagne A, Long RE, Comunale MA, Hafner J, Rodemich-Betesh L, Wang M, Marrero J, Di Bisceglie AM, Block T, Mehta A. Altered functionality of anti-bacterial antibodies in patients with chronic hepatitis C virus infection. PLoS One 2013; 8:e64992. [PMID: 23750224 PMCID: PMC3672197 DOI: 10.1371/journal.pone.0064992] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Accepted: 04/19/2013] [Indexed: 02/07/2023] Open
Abstract
Background Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease. Methods The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined. Results Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure. Conclusions Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease.
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Affiliation(s)
- Anne Lamontagne
- Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, United States of America
- * E-mail: (AL); (AM)
| | - Ronald E. Long
- Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, United States of America
| | - Mary Ann Comunale
- Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, United States of America
| | - Julie Hafner
- Immunotope Inc., Doylestown, Pennsylvania, United States of America
| | - Lucy Rodemich-Betesh
- Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, United States of America
| | - Mengjun Wang
- Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, United States of America
| | - Jorge Marrero
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Adrian M. Di Bisceglie
- Department of Internal Medicine and Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, Missouri, United States of America
| | - Timothy Block
- Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, United States of America
| | - Anand Mehta
- Drexel University College of Medicine, and Department of Microbiology and Immunology and Drexel Institute for Biotechnology and Virology, Doylestown, Pennsylvania, United States of America
- * E-mail: (AL); (AM)
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Reiberger T, Ferlitsch A, Payer BA, Mandorfer M, Heinisch BB, Hayden H, Lammert F, Trauner M, Peck-Radosavljevic M, Vogelsang H. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol 2013; 58:911-21. [PMID: 23262249 DOI: 10.1016/j.jhep.2012.12.011] [Citation(s) in RCA: 251] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2012] [Revised: 12/04/2012] [Accepted: 12/05/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS We evaluated the gastrointestinal permeability and bacterial translocation in cirrhotic patients with portal hypertension (PHT) prior to and after non-selective betablocker (NSBB) treatment. METHODS Hepatic venous pressure gradient (HVPG) was measured prior to and under NSBB treatment. Gastroduodenal and intestinal permeability was assessed by the sucrose-lactulose-mannitol (SLM) test. Anti-gliadin and anti-endomysial antibodies were measured. Levels of LPS-binding protein (LBP) and interleukin-6 (IL-6) were quantified by ELISA, and NOD2 and toll-like receptor 2 (TLR2) polymorphisms were genotyped. RESULTS Fifty cirrhotics were included (72% male, 18% ascites, 60% alcoholic etiology). Abnormal gastroduodenal and intestinal permeability was found in 72% and 59% of patients, respectively. Patients with severe portal hypertension (HVPG ≥20 mm Hg; n=35) had increased markers of gastroduodenal/intestinal permeability (urine sucrose levels p=0.049; sucrose/mannitol ratios p=0.007; intestinal permeability indices p=0.002), and bacterial translocation (LBP p=0.002; IL-6 p=0.025) than patients with HVPG <20 mm Hg. A substantial portion of patients showed elevated levels of anti-gliadin antibodies (IgA: 60%, IgG: 34%) whereas no anti-endomysial antibodies were detected. A significant correlation of portal pressure (i.e., HVPG) with all markers of gastroduodenal/intestinal permeability and with LBP and IL-6 levels was observed. NOD2 and TLR2 risk variants were associated with abnormal intestinal permeability and elevated markers of bacterial translocation. At follow-up HVPG measurements under NSBB, we found an amelioration of gastroduodenal/intestinal permeability and a decrease of bacterial translocation (LBP - 16% p=0.018; IL-6 - 41% p<0.0001) levels, which was not limited to hemodynamic responders. Abnormal SLM test results and higher LBP/IL-6 levels were associated with a higher risk of variceal bleeding during follow-up but not with mortality. CONCLUSIONS Abnormal gastroduodenal/intestinal permeability, anti-gliadin antibodies, and bacterial translocation are common findings in cirrhotic patients and are correlated with the degree of portal hypertension. NSBB treatment ameliorates gastroduodenal/intestinal permeability and reduces bacterial translocation partially independent of their hemodynamic effects on portal pressure, which may contribute to a reduced risk of variceal bleeding.
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Affiliation(s)
- Thomas Reiberger
- Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Austria.
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Hartmann P, Chen WC, Schnabl B. The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease. Front Physiol 2012; 3:402. [PMID: 23087650 PMCID: PMC3468817 DOI: 10.3389/fphys.2012.00402] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2012] [Accepted: 09/24/2012] [Indexed: 01/18/2023] Open
Abstract
Alcoholic liver disease (ALD) encompasses hepatic steatosis, which may progress to alcoholic hepatitis, fibrosis, and cirrhosis. It remains a leading cause of morbidity and mortality in the US and worldwide. The severity of liver disease correlates with plasma levels of bacterial products in patients, and experimental ALD depends on the level of gut derived bacterial products in rodents. Since intestinal decontamination and deficiency of bacterial product receptors or their downstream signaling molecules protect from alcohol-induced liver disease, bacterial translocation (BT), qualitative, and quantitative changes of the enteric microbiome are considered as being of fundamental importance in the pathogenesis of ALD. Recent enhancements in diagnostic technologies provide a better insight into these shifts. This review highlights vital events in ALD such as BT, the importance of Toll-like receptor (TLR) signaling, intestinal bacterial overgrowth (IBO), and changes in the intestinal microbiome. Furthermore, a treatment trial section of patients reviews possible future options of therapy for ALD modifying the enteric microbiome.
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Affiliation(s)
- Phillipp Hartmann
- Department of Medicine, University of California San DiegoLa Jolla, CA, USA
| | - Wei-Chung Chen
- Department of Medicine, The Methodist Hospital, Weill Cornell CollegeHouston, TX, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San DiegoLa Jolla, CA, USA
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Wu X, Wu YF, Mao CL, Wu ZM. Changes in intestinal microflora in patients with hepatic cirrhosis. Shijie Huaren Xiaohua Zazhi 2012; 20:2491-2495. [DOI: 10.11569/wcjd.v20.i26.2491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [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
AIM: To compare the differences in the numbers of Bifidobacterium, Bacteroides, Eubacterium rectale-Clostridium, Escherichia coli, Enterococcus, Clostridium difficile in stool samples between patients with hepatic cirrhosis and controls to understand the changes in intestinal flora in patients with hepatic cirrhosis.
METHODS: Stool samples collected from 29 patients with hepatic cirrhosis who were treated at the First People's Hospital of Zunyi during the period between March to December 2010 and 13 healthy volunteers were used in this study. The samples were fixed, smeared on slides, and analyzed by fluorescent in situ hybridization (FISH) and laser scanning confocal microscopy (LSCM). The t-test and rank correlation test were used for statistical analysis.
RESULTS: The numbers of Bifidobacterium, Bacteroides, Eubacterium rectale-Clostridium, Escherichia coli, Enterococcus, and Clostridium difficile were significantly lower in patients with hepatic cirrhosis than in controls (Z = -4.006, -4.34, -4.399, -4.174, -3.558, -3.95; all P < 0.01). The proportions of all 6 kinds of bacteria were changed. The numbers of obligate anaerobes such as Bifidobacteria and Bacteroides were reduced, while those of E. coli, Eubacterium rectale-Clostridium, Enterococcus, and ClostriDium difficile were increased (all P < 0.05). The numbers and portions of bacteria had no significant correlation with etiology and severity of hepatic cirrhosis (Child-Pugh classification).
CONCLUSION: The numbers and proportions of six kinds of bacteria changed in patients with hepatic cirrhosis. Changes in intestinal microflora have no significant correlation with etiology and Child-Pugh classification.
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Clinical significance and prevalence of anti-Saccharomyces cerevisiae antibody in Chinese patients with primary biliary cirrhosis. Clin Exp Med 2012; 13:245-50. [DOI: 10.1007/s10238-012-0207-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 08/13/2012] [Indexed: 01/28/2023]
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Ilan Y. Leaky gut and the liver: A role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol 2012; 18:2609-18. [PMID: 22690069 PMCID: PMC3369997 DOI: 10.3748/wjg.v18.i21.2609] [Citation(s) in RCA: 135] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2011] [Revised: 01/31/2012] [Accepted: 04/21/2012] [Indexed: 02/06/2023] Open
Abstract
Gut flora and bacterial translocation (BT) play important roles in the pathogenesis of chronic liver disease, including cirrhosis and its complications. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen predispose patients to bacterial infections, major complications and also play a role in the pathogenesis of chronic liver disorders. Levels of bacterial lipopolysaccharide, a component of gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver disease. Impaired gut epithelial integrity due to alterations in tight junction proteins may be the pathological mechanism underlying bacterial translocation. Preclinical and clinical studies over the last decade have suggested a role for BT in the pathogenesis of nonalcoholic steatohepatitis (NASH). Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of NASH and its complications. A better understanding of the cell-specific recognition and intracellular signaling events involved in sensing gut-derived microbes will help in the development of means to achieve an optimal balance in the gut-liver axis and ameliorate liver diseases. These may suggest new targets for potential therapeutic interventions for the treatment of NASH. Here, we review some of the mechanisms connecting BT and NASH and potential therapeutic developments.
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Sellin JH, Shah RR. The promise and pitfalls of serologic testing in inflammatory bowel disease. Gastroenterol Clin North Am 2012; 41:463-82. [PMID: 22500529 DOI: 10.1016/j.gtc.2012.01.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
The role of IBD serologies is still evolving. However, as that evolution progresses, it will continue to provide important insights into the etiology of IBD and help define individualized treatment strategies for patients. The presence of multiple IBD antimicrobial antibodies and increased reactivity form a useful heuristic model to understand the evolution of CD. The role of ANCAs and autoantibodies in pathogenesis of UC is an area that requires further investigation. Although IBD serologies exhibit considerable diagnostic accuracy, it is unclear whether they will supplant simpler and more direct evaluations in making an initial diagnosis of UC or Crohn (Table 3). The utility of panels of IBD serologies to stratify and predict the course of CD has been an arena of fertile investigation. Developing individual treatment strategies based on the probability of developing complicated aggressive disease would be a significant advance in medical management of CD. However, if major clinical decisions are to be made based on these serologies, we will need more prospective critical studies from the time of diagnosis to define their clinical applicability and to demonstrate a true difference in outcomes.
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Affiliation(s)
- Joseph H Sellin
- Division of Gastroenterology, Baylor College of Medicine, 1709 Dryden, Houston, TX 77030, USA.
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Yan AW, Schnabl B. Bacterial translocation and changes in the intestinal microbiome associated with alcoholic liver disease. World J Hepatol 2012; 4:110-8. [PMID: 22567183 PMCID: PMC3345535 DOI: 10.4254/wjh.v4.i4.110] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 11/13/2011] [Accepted: 04/24/2012] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease progresses through several stages of tissue damage, from simple steatosis to alcoholic hepatitis, fibrosis, or cirrhosis. Alcohol also affects the intestine, increases intestinal permeability and changes the bacterial microflora. Liver disease severity correlates with levels of systemic bacterial products in patients, and experimental alcoholic liver disease is dependent on gut derived bacterial products in mice. Supporting evidence for the importance of bacterial translocation comes from animal studies demonstrating that intestinal decontamination is associated with decreased liver fibrogenesis. In addition, mice with a gene mutation or deletion encoding receptors for either bacterial products or signaling molecules downstream from these receptors, are resistant to alcohol-induced liver disease. Despite this strong association, the exact molecular mechanism of bacterial translocation and of how changes in the intestinal microbiome contribute to liver disease progression remains largely unknown. In this review we will summarize evidence for bacterial translocation and enteric microbial changes in response to alcoholic liver injury and chronic alcoholic liver disease. We will further describe consequences of intestinal dysbiosis on host biology. We finally discuss how therapeutic interventions may modify the gastrointestinal microflora and prevent or reduce alcoholic liver disease progression.
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Affiliation(s)
- Arthur W Yan
- Arthur W Yan, Division of Gastroenterology, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, United States
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Papp M, Vitalis Z, Altorjay I, Tornai I, Udvardy M, Harsfalvi J, Vida A, Kappelmayer J, Lakatos PL, Antal-Szalmas P. Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infections. Liver Int 2012; 32:603-611. [PMID: 22145664 DOI: 10.1111/j.1478-3231.2011.02689.x] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 10/26/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND Bacterial infections are common cause of morbidity and mortality in patients with cirrhosis. The early diagnosis of these infections is rather difficult. AIMS To assess the accuracy of acute phase proteins in the identification of bacterial infections. METHODS Concentration of C-reactive protein (CRP), procalcitonin (PCT), lipopolysaccharide-binding protein (LBP), sCD14 and antimicrobial antibodies were measured in serum of 368 well-characterized patients with cirrhosis of whom 139 had documented infection. Clinical data was gathered by reviewing the patients' medical charts. RESULTS Serum levels of CRP, PCT and LBP were significantly higher in patients with clinically overt infections. Among the markers, CRP - using a 10 mg/L cut-off value- proved to be the most accurate in identifying patients with infection (AUC: 0.93). The accuracy of CRP, however, decreased in advanced stage of the disease, most probably because of the significantly elevated CRP levels in non-infected patients. Combination of CRP and PCT increased the sensitivity and negative predictive value, compared with CRP on its own, by 10 and 5% respectively. During a 3-month follow-up period in patients without overt infections, Kaplan-Meier and proportional Cox-regression analyses showed that a CRP value of >10 mg/L (P = 0.035) was independently associated with a shorter duration to progress to clinically significant bacterial infections. There was no correlation between acute phase protein levels and antimicrobial seroreactivity. CONCLUSIONS C-reactive protein on its own is a sensitive screening test for the presence of bacterial infections in cirrhosis and is also a useful marker to predict the likelihood of clinically significant bacterial infections in patients without overt infections.
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Affiliation(s)
- Maria Papp
- 2nd Department of Medicine, Division of Gastroenterology, University of Debrecen, Debrecen, Hungary.
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Doi H, Iyer TK, Carpenter E, Li H, Chang KM, Vonderheide RH, Kaplan DE. Dysfunctional B-cell activation in cirrhosis resulting from hepatitis C infection associated with disappearance of CD27-positive B-cell population. Hepatology 2012; 55:709-19. [PMID: 21932384 PMCID: PMC3245804 DOI: 10.1002/hep.24689] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Accepted: 09/09/2011] [Indexed: 12/12/2022]
Abstract
UNLABELLED Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma (HCC). Both advanced solid tumors and HCV have previously been associated with memory B-cell dysfunction. In this study, we sought to dissect the effect of viral infection, cirrhosis, and liver cancer on memory B-cell frequency and function in the spectrum of HCV disease. Peripheral blood from healthy donors, HCV-infected patients with F1-F2 liver fibrosis, HCV-infected patients with cirrhosis, patients with HCV-related HCC, and non-HCV-infected cirrhotics were assessed for B-cell phenotype by flow cytometry. Isolated B cells were stimulated with anti-cluster of differentiation (CD)40 antibodies and Toll-like receptor (TLR)9 agonist for assessment of costimulation marker expression, cytokine production, immunoglobulin (Ig) production, and CD4(+) T-cell allostimulatory capacity. CD27(+) memory B cells and, more specifically, CD27(+) IgM(+) B cells were markedly less frequent in cirrhotic patients independent of HCV infection. Circulating B cells in cirrhotics were hyporesponsive to CD40/TLR9 activation, as characterized by CD70 up-regulation, tumor necrosis factor beta secretion, IgG production, and T-cell allostimulation. Last, blockade of TLR4 and TLR9 signaling abrogated the activation of healthy donor B cells by cirrhotic plasma, suggesting a role for bacterial translocation in driving B-cell changes in cirrhosis. CONCLUSION Profound abnormalities in B-cell phenotype and function occur in cirrhosis independent of HCV infection. These B-cell defects may explain, in part, the vaccine hyporesponsiveness and susceptibility to bacterial infection in this population.
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Affiliation(s)
- Hiroyoshi Doi
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - Tara K. Iyer
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | | | - Hong Li
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | - Kyong-Mi Chang
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| | | | - David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
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