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Kumar R, Kumar A, Kumar S. Sepsis in liver failure patients: Diagnostic challenges and recent advancements. World J Crit Care Med 2025; 14:101587. [DOI: 10.5492/wjccm.v14.i2.101587] [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: 09/19/2024] [Revised: 01/19/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
Acute liver failure (ALF) and acute-on-chronic LF (ACLF) are prevalent hepatic emergencies characterized by an increased susceptibility to bacterial infections (BI), despite significant systemic inflammation. Literature indicates that 30%–80% of ALF patients and 55%–81% of ACLF patients develop BI, attributed to immunological dysregulation. Bacterial sepsis in these patients is associated with adverse clinical outcomes, including prolonged hospitalization and increased mortality. Early detection of bacterial sepsis is critical; however, distinguishing between sterile systemic inflammation and sepsis poses a significant challenge due to the overlapping clinical presentations of LF and sepsis. Conventional sepsis biomarkers, such as procalcitonin and C-reactive protein, have shown limited utility in LF patients due to inconsistent results. In contrast, novel biomarkers like presepsin and sTREM-1 have demonstrated promising discriminatory performance in this population, pending further validation. Moreover, emerging research highlights the potential of machine learning-based approaches to enhance sepsis detection and characterization. Although preliminary findings are encouraging, further studies are necessary to validate these results across diverse patient cohorts, including those with LF. This article provides a comprehensive review of the magnitude, impact, and diagnostic challenges associated with BI in LF patients, focusing on novel advancements in early sepsis detection and characterization.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Abhishek Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Sudhir Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
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Aehling NF, Hagenunger A, Krohn S, Zeller K, Jäger K, Herber A, Engelmann C, Berg T. Use of Bacterial DNA Concentration in Ascites as a Marker for Spontaneous Bacterial Peritonitis. J Clin Exp Hepatol 2024; 14:101434. [PMID: 38962151 PMCID: PMC11217685 DOI: 10.1016/j.jceh.2024.101434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 04/19/2024] [Indexed: 07/05/2024] Open
Abstract
Background and aims Spontaneous bacterial peritonitis (SBP) is a common and serious complication in patients with decompensated cirrhosis. Precise quantification of bacterial DNA (bactDNA) and the related inflammatory response might add further information on the course of disease. The aim of the study was to evaluate the association between bactDNA, cytokine levels and clinical outcome. Methods Ascites and serum samples of 98 patients with decompensated liver cirrhosis (42 with SBP and 56 without SBP) as well as serum samples of 21 healthy controls were collected. BactDNA in ascites and serum was detected and quantified by 16S rRNA PCR. Concentrations of IL-1β, TNF-α, IL-6, IL-8 and IL-10 were measured by a LEGENDplexTM multi-analyte flow assay. Clinical data were collected and analyzed retrospectively. Results BactDNA was detected more frequently in ascites of patients with SBP (n = 24/42; 57.1%) than in ascites of patients without SBP (n = 5/56; 8.9%; P < 0.001). Additionally, IL-6 levels in both ascites and serum were significantly higher in patients with SBP (ascites P < 0.001, serum P = 0.036). The quantity of bactDNA in ascites was strongly correlated with polymorphonuclear neutrophil count in ascites (r = 0.755; P < 0.001) as well as ascites IL-6 levels (r = 0.399; P < 0.001). Receiver operating characteristic (ROC) curve analysis to diagnose SBP provided an AUC of 0.764 (95% CI: 0.661-0.867) for serum IL-6 levels, an AUC of 0.810 (95% CI: 0.714-0.905) for ascites IL-6 levels, and an AUC of 0.755 (95% CI: 0.651-0.858) for bactDNA levels in ascites. Conclusions The correlation between the amount of bactDNA and IL-6 confirms the pathophysiological relevance of bactDNA and IL-6 as potential biomarkers for the diagnosis of SBP.
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Affiliation(s)
- Niklas F. Aehling
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Germany
- Department of Gastroenterology, Universitaetsklinikum Augsburg, Augsburg, Bayern, Germany
| | - Arno Hagenunger
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Germany
| | - Sandra Krohn
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Germany
| | - Katharina Zeller
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Germany
| | - Kathrin Jäger
- IZKF-FACS-Core Unit, Leipzig University, Leipzig, Germany
| | - Adam Herber
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Germany
| | - Cornelius Engelmann
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Germany
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité - Universitaetsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Germany
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Koliarakis I, Lagkouvardos I, Vogiatzoglou K, Tsamandouras I, Intze E, Messaritakis I, Souglakos J, Tsiaoussis J. Circulating Bacterial DNA in Colorectal Cancer Patients: The Potential Role of Fusobacterium nucleatum. Int J Mol Sci 2024; 25:9025. [PMID: 39201711 PMCID: PMC11354820 DOI: 10.3390/ijms25169025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/03/2024] Open
Abstract
Intestinal dysbiosis is a major contributor to colorectal cancer (CRC) development, leading to bacterial translocation into the bloodstream. This study aimed to evaluate the presence of circulated bacterial DNA (cbDNA) in CRC patients (n = 75) and healthy individuals (n = 25). DNA extracted from peripheral blood was analyzed using PCR, with specific primers targeting 16S rRNA, Escherichia coli (E. coli), and Fusobacterium nucleatum (F. nucleatum). High 16S rRNA and E. coli detections were observed in all patients and controls. Only the detection of F. nucleatum was significantly higher in metastatic non-excised CRC, compared to controls (p < 0.001), non-metastatic excised CRC (p = 0.023), and metastatic excised CRC (p = 0.023). This effect was mainly attributed to the presence of the primary tumor (p = 0.006) but not the presence of distant metastases (p = 0.217). The association of cbDNA with other clinical parameters or co-morbidities was also evaluated, revealing a higher detection of E. coli in CRC patients with diabetes (p = 0.004). These results highlighted the importance of bacterial translocation in CRC patients and the potential role of F. nucleatum as an intratumoral oncomicrobe in CRC.
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Affiliation(s)
- Ioannis Koliarakis
- Department of Anatomy, School of Medicine, University of Crete, 70013 Heraklion, Greece;
| | - Ilias Lagkouvardos
- Department of Clinical Microbiology, School of Medicine, University of Crete, 70013 Heraklion, Greece; (I.L.); (E.I.)
| | - Konstantinos Vogiatzoglou
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (K.V.); (I.M.); (J.S.)
| | - Ioannis Tsamandouras
- Department of Otorhinolaryngology—Head and Neck Surgery, University General Hospital of Heraklion, 71110 Heraklion, Greece;
| | - Evangelia Intze
- Department of Clinical Microbiology, School of Medicine, University of Crete, 70013 Heraklion, Greece; (I.L.); (E.I.)
| | - Ippokratis Messaritakis
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (K.V.); (I.M.); (J.S.)
- Department of Microbiology, German Oncology Center, Yiannoukas Labs LTD, Bioiatriki Group, Limassol 4108, Cyprus
| | - John Souglakos
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (K.V.); (I.M.); (J.S.)
- Department of Medical Oncology, University Hospital of Heraklion, 71110 Heraklion, Greece
| | - John Tsiaoussis
- Department of Anatomy, School of Medicine, University of Crete, 70013 Heraklion, Greece;
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Mogilevski T, Maconi G, Gibson PR. Recent advances in measuring the effects of diet on gastrointestinal physiology: Probing the "leaky gut" and application of real-time ultrasound. JGH Open 2024; 8:e13081. [PMID: 38957479 PMCID: PMC11217769 DOI: 10.1002/jgh3.13081] [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: 01/18/2024] [Revised: 04/01/2024] [Accepted: 04/29/2024] [Indexed: 07/04/2024]
Abstract
There is a large pool of ideas in both mainstream and non-mainstream medicine on how diet can be manipulated in order to treat or prevent illnesses. Despite this, our understanding of how specific changes in diet influence the structure and function of the gastrointestinal tract is limited. This review aims to describe two areas that might provide key information on the integrity and function of the gastrointestinal tract. First, demystifying the "leaky gut syndrome" requires rational application and interpretation of tests of intestinal barrier function. Multiple ways of measuring barrier function have been described, but the inherent difficulties in translation from animal studies to humans have created misinterpretations and misconceptions. The intrinsic nature of intestinal barrier function is dynamic. This is seldom considered in studies of intestinal barrier assessment. To adequately understand the effects of dietary interventions on intestinal barrier function, background barrier function in different regions of the gut and the dynamic responses to stressors (such as psychological stress) should be assessed as a minimum. Second, intestinal ultrasound, which is now established in the assessment and monitoring of inflammatory bowel disease, has hitherto been poorly evaluated in assessing real-time intestinal function and novel aspects of structure in patients with disorders of gut-brain interaction. In conclusion, a more complete functional and structural profile that these investigations enable should permit a greater understanding of the effects of dietary manipulation on the gastrointestinal tract and provide clinically relevant information that, amongst other advantages, might permit opportunities for personalized health care delivery.
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Affiliation(s)
- Tamara Mogilevski
- Department of GastroenterologySchool of Translational Medicine, Monash UniversityMelbourneVictoriaAustralia
| | - Giovanni Maconi
- Gastroenterology Unit, Department of Biomedical and Clinical SciencesLuigi Sacco University Hospital University of MilanMilanItaly
| | - Peter R Gibson
- Department of GastroenterologySchool of Translational Medicine, Monash UniversityMelbourneVictoriaAustralia
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Karvellas CJ, Bajaj JS, Kamath PS, Napolitano L, O'Leary JG, Solà E, Subramanian R, Wong F, Asrani SK. AASLD Practice Guidance on Acute-on-chronic liver failure and the management of critically ill patients with cirrhosis. Hepatology 2024; 79:1463-1502. [PMID: 37939273 DOI: 10.1097/hep.0000000000000671] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 11/10/2023]
Affiliation(s)
- Constantine J Karvellas
- Division of Gastroenterology (Liver Unit), Department of Critical Care Medicine, University of Alberta, Edmonton, Canada
| | - Jasmohan S Bajaj
- Virginia Commonwealth University, Central Virginia Veterans Healthcare System, Richmond, Virginia, USA
| | - Patrick S Kamath
- Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | | | - Jacqueline G O'Leary
- Department of Medicine, Dallas Veterans Medical Center, University of Texas Southwestern Medical Center Dallas, Texas, USA
| | - Elsa Solà
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA
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Efremova I, Maslennikov R, Poluektova E, Medvedev O, Kudryavtseva A, Krasnov G, Fedorova M, Romanikhin F, Zharkova M, Zolnikova O, Bagieva G, Ivashkin V. Presepsin as a biomarker of bacterial translocation and an indicator for the prescription of probiotics in cirrhosis. World J Hepatol 2024; 16:822-831. [PMID: 38818295 PMCID: PMC11135270 DOI: 10.4254/wjh.v16.i5.822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/12/2024] [Accepted: 04/12/2024] [Indexed: 05/22/2024] Open
Abstract
BACKGROUND The gut-liver axis and bacterial translocation are important in cirrhosis, but there is no available universal biomarker of cellular bacterial translocation, for which presepsin may be a candidate. AIM To evaluate the relationship of the blood presepsin levels with the state of the gut microbiota in cirrhosis in the absence of obvious infection. METHODS This study included 48 patients with Child-Pugh cirrhosis classes B and C and 15 healthy controls. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of presepsin were measured. A total of 22 patients received a probiotic (Saccharomyces boulardii) for 3 months. RESULTS Presepsin levels were higher in patients with cirrhosis than in healthy individuals [342 (91-2875) vs 120 (102-141) pg/mL; P = 0.048]. Patients with elevated presepsin levels accounted for 56.3% of all included patients. They had lower levels of serum albumin and higher levels of serum total bilirubin and overall severity of cirrhosis as assessed using the Child-Pugh scale. Patients with elevated presepsin levels had an increased abundance of the main taxa responsible for bacterial translocation, namely Bacilli and Proteobacteria (including the main class Gammaproteobacteria and the minor taxa Xanthobacteraceae and Stenotrophomonas), and a low abundance of bacteria from the family Lachnospiraceae (including the minor genus Fusicatenibacter), which produce short-chain fatty acids that have a positive effect on intestinal barrier function. The presepsin level directly correlated with the relative abundance of Bacilli, Proteobacteria, and inversely correlated with the abundance of Lachnospiraceae and Propionibacteriaceae. After 3 months of taking the probiotic, the severity of cirrhosis on the Child-Pugh scale decreased significantly only in the group with elevated presepsin levels [from 9 (8-11) to 7 (6-9); P = 0.004], while there were no significant changes in the group with normal presepsin levels [from 8 (7-8) to 7 (6-8); P = 0.123]. A high level of presepsin before the prescription of the probiotic was an independent predictor of a greater decrease in Child-Pugh scores (P = 0.046), as well as a higher level of the Child-Pugh scale (P = 0.042), but not the C-reactive protein level (P = 0.679) according to multivariate linear regression analysis. CONCLUSION The level of presepsin directly correlates with the abundance in the gut microbiota of the main taxa that are substrates of bacterial translocation in cirrhosis. This biomarker, in the absence of obvious infection, seems important for assessing the state of the gut-liver axis in cirrhosis and deciding on therapy targeted at the gut microbiota in this disease.
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Affiliation(s)
- Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Department of Scientific, Scientific Community for the Promotion of the Clinical Study of the Human Microbiome, Moscow 119435, Russia.
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Department of Scientific, Scientific Community for the Promotion of the Clinical Study of the Human Microbiome, Moscow 119435, Russia
| | - Oleg Medvedev
- Department of Pharmacology, Lomonosov Moscow State University, Moscow 119192, Russia
| | - Anna Kudryavtseva
- Department of Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - George Krasnov
- Department of Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Maria Fedorova
- Department of Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Filipp Romanikhin
- Department of Pharmacology, Lomonosov Moscow State University, Moscow 119192, Russia
| | - Maria Zharkova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Oxana Zolnikova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Gyunay Bagieva
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Department of Scientific, Scientific Community for the Promotion of the Clinical Study of the Human Microbiome, Moscow 119435, Russia
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7
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Juanola A, Ma AT, de Wit K, Gananandan K, Roux O, Zaccherini G, Jiménez C, Tonon M, Solé C, Villaseca C, Uschner FE, Graupera I, Pose E, Moreta MJ, Campion D, Beuers U, Mookerjee RP, Francoz C, Durand F, Vargas V, Piano S, Alonso S, Trebicka J, Laleman W, Asrani SK, Soriano G, Alessandria C, Serra-Burriel M, Morales-Ruiz M, Torres F, Allegretti AS, Krag A, Caraceni P, Watson H, Abraldes JG, Solà E, Kamath PS, Hernaez R, Ginès P. Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis. Gut 2023; 73:156-165. [PMID: 37884354 DOI: 10.1136/gutjnl-2023-329923] [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: 03/22/2023] [Accepted: 09/18/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.
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Affiliation(s)
- Adrià Juanola
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Ann Thu Ma
- Toronto Centre for Liver Disease Francis Family Liver Clinic, Toronto General Hospital, Toronto, Ontario, Canada
| | - Koos de Wit
- Gastroenterology and Hepatology, Amsterdam UMC Location AMC, Amsterdam, The Netherlands
| | - Kohilan Gananandan
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Olivier Roux
- Department of Hepatology, Beaujon Hospital, Clichy, France
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-related Diseases, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
| | - César Jiménez
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
| | - Marta Tonon
- Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Cristina Solé
- Department of Gastroenterology and Hepatology, Consorci Corporació Sanitària Parc Taulí, Sabadell, Spain
| | - Clara Villaseca
- Digestive Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Frank E Uschner
- Department of Internal Medicine B, University of Münster, Munster, Germany
| | - Isabel Graupera
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Elisa Pose
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
| | - Maria José Moreta
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
| | - Daniela Campion
- Division of Gastroenterology and Hepatology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Ulrich Beuers
- Gastroenterology & Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Rajeshawar P Mookerjee
- Institute of Liver and Digestive Health, University College London Medical School, London, UK
| | - Claire Francoz
- Department of Hepatology, Beaujon Hospital, Clichy, France
| | - Francois Durand
- DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, Hôpital Beaujon, AP-HP, Clichy, France
- Université Denis Diderot-Paris 7, Paris, France
| | - Victor Vargas
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
| | - Salvatore Piano
- Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Sonia Alonso
- Digestive Disease Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Munster, Germany
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Wim Laleman
- Division of Liver and Biliopanreatic Disorders, KU Leuven, University of Leuven, Leuven, Belgium
| | - Sumeet K Asrani
- Division of Hepatology, Department of Medicine, Baylor University Medical Center at Dallas, Dallas, Texas, USA
| | - German Soriano
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Miquel Serra-Burriel
- University of Zurich Institute of Epidemiology Biostatistics and Prevention, Zurich, Switzerland
| | - Manuel Morales-Ruiz
- Biochemistry and Molecular Genetics Department-CDB, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Ferran Torres
- Biostatistics and Data Management Core Facility, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Andrew S Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aleksander Krag
- Department of Gastroenterology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Juan G Abraldes
- Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada
| | - Elsa Solà
- Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, California, USA
| | - Patrick S Kamath
- Gastroenterology and Hepatology, Mayo Medical School, Rochester, Minnesota, USA
| | - Ruben Hernaez
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Pere Ginès
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
- Centro de Investigacion Biomedica en Red Enfermedades Hepaticas y Digestivas, Barcelona, Spain
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, Spain
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8
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Maslennikov R, Poluektova E, Zolnikova O, Sedova A, Kurbatova A, Shulpekova Y, Dzhakhaya N, Kardasheva S, Nadinskaia M, Bueverova E, Nechaev V, Karchevskaya A, Ivashkin V. Gut Microbiota and Bacterial Translocation in the Pathogenesis of Liver Fibrosis. Int J Mol Sci 2023; 24:16502. [PMID: 38003692 PMCID: PMC10671141 DOI: 10.3390/ijms242216502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/11/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Cirrhosis is the end result of liver fibrosis in chronic liver diseases. Studying the mechanisms of its development and developing measures to slow down and regress it based on this knowledge seem to be important tasks for medicine. Currently, disorders of the gut-liver axis have great importance in the pathogenesis of cirrhosis. However, gut dysbiosis, which manifests as increased proportions in the gut microbiota of Bacilli and Proteobacteria that are capable of bacterial translocation and a decreased proportion of Clostridia that strengthen the intestinal barrier, occurs even at the pre-cirrhotic stage of chronic liver disease. This leads to the development of bacterial translocation, a process by which those microbes enter the blood of the portal vein and then the liver tissue, where they activate Kupffer cells through Toll-like receptor 4. In response, the Kupffer cells produce profibrogenic cytokines, which activate hepatic stellate cells, stimulating their transformation into myofibroblasts that produce collagen and other elements of the extracellular matrix. Blocking bacterial translocation with antibiotics, probiotics, synbiotics, and other methods could slow down the progression of liver fibrosis. This was shown in a number of animal models but requires further verification in long-term randomized controlled trials with humans.
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Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study of the Human Microbiome”, 119048 Moscow, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study of the Human Microbiome”, 119048 Moscow, Russia
| | - Oxana Zolnikova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Alla Sedova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Anastasia Kurbatova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Yulia Shulpekova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Natyia Dzhakhaya
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Svetlana Kardasheva
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Maria Nadinskaia
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Elena Bueverova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Vladimir Nechaev
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Anna Karchevskaya
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, 119048 Moscow, Russia (A.S.); (N.D.); (M.N.); (E.B.)
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study of the Human Microbiome”, 119048 Moscow, Russia
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9
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Sturm L, Hirose M, Stolz L, Schultheiss M, Zoldan K, Reincke M, Huber JP, Kaeser R, Boettler T, Thimme R, Albert E, Busch H, Künstner A, Bettinger D. Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension. mBio 2023; 14:e0049223. [PMID: 37623323 PMCID: PMC10653923 DOI: 10.1128/mbio.00492-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/02/2023] [Indexed: 08/26/2023] Open
Abstract
IMPORTANCE Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.
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Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Misa Hirose
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Laura Stolz
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Zoldan
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Rafael Kaeser
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- IMM-PACT-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Elisabeth Albert
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Hauke Busch
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Axel Künstner
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Dominik Bettinger
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
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10
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Maslennikov R, Alieva A, Poluektova E, Zharikov Y, Suslov A, Letyagina Y, Vasileva E, Levshina A, Kozlov E, Ivashkin V. Sarcopenia in cirrhosis: Prospects for therapy targeted to gut microbiota. World J Gastroenterol 2023; 29:4236-4251. [PMID: 37545638 PMCID: PMC10401661 DOI: 10.3748/wjg.v29.i27.4236] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/25/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023] Open
Abstract
Decreased muscle mass and function, also known as sarcopenia, is common in patients with cirrhosis and is associated with a poor prognosis. Although the pathogenesis of this disorder has not been fully elucidated, a disordered gut-muscle axis probably plays an important role. Decreased barrier function of the gut and liver, gut dysbiosis, and small intestinal bacterial overgrowth (SIBO) can lead to increased blood levels of ammonia, lipopolysaccharides, pro-inflammatory mediators, and myostatin. These factors have complex negative effects on muscle mass and function. Drug interventions that target the gut microbiota (long-term use of rifaximin, lactulose, lactitol, or probiotics) positively affect most links of the compromised gut-muscle axis in patients with cirrhosis by decreasing the levels of hyperammonemia, bacterial translocation, and systemic inflammation and correcting gut dysbiosis and SIBO. However, although these drugs are promising, they have not yet been investigated in randomized controlled trials specifically for the treatment and prevention of sarcopenia in patients with cirrhosis. No data exist on the effects of fecal transplantation on most links of gut-muscle axis in cirrhosis; however, the results of animal experimental studies are promising.
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Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Scientific Community for Human Microbiome Research, Moscow 119435, Russia
| | - Aliya Alieva
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Scientific Community for Human Microbiome Research, Moscow 119435, Russia
| | - Yury Zharikov
- Department of Human Anatomy and Histology, Sechenov University, Moscow 119435, Russia
| | - Andrey Suslov
- Department of Human Anatomy and Histology, Sechenov University, Moscow 119435, Russia
| | - Yana Letyagina
- Department of Human Anatomy and Histology, Sechenov University, Moscow 119435, Russia
| | - Ekaterina Vasileva
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Anna Levshina
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- Laboratory of Immunopathology, Department of Clinical Immunology and Allergy, Sechenov University, Moscow 119991, Russia
| | - Evgenii Kozlov
- Laboratory of Immunopathology, Department of Clinical Immunology and Allergy, Sechenov University, Moscow 119991, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Scientific Community for Human Microbiome Research, Moscow 119435, Russia
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11
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Ouyang J, Yan J, Zhou X, Isnard S, Harypursat V, Cui H, Routy JP, Chen Y. Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV. Front Immunol 2023; 14:1173956. [PMID: 37153621 PMCID: PMC10160480 DOI: 10.3389/fimmu.2023.1173956] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.
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Affiliation(s)
- Jing Ouyang
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jiangyu Yan
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network, Canadian Institutes for Health Research, Vancouver, BC, Canada
| | - Vijay Harypursat
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
| | - Yaokai Chen
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
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12
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Wu HX, Hou W, Zhang W, Wang Z, Guo S, Chen DX, Li Z, Wei F, Hu Z. Clinical evaluation of bacterial DNA using an improved droplet digital PCR for spontaneous bacterial peritonitis diagnosis. Front Cell Infect Microbiol 2022; 12:876495. [PMID: 36061877 PMCID: PMC9433567 DOI: 10.3389/fcimb.2022.876495] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Objective Bacterial DNA (bactDNA) detection can be used to quickly identify pathogenic bacteria and has been studied on ascitic fluid. We aimed to retrospectively analyze the diagnostic value and applicational prospect of the bactDNA load in spontaneous bacterial peritonitis (SBP). Method We extracted viable bactDNA from ascitic samples of 250 patients with decompensated cirrhosis collected from October 2019 to April 2021 and detected the bactDNA by droplet digital polymerase chain reaction (ddPCR). We used ascitic samples of a baseline cohort of 191 patients to establish diagnostic thresholds for SBP and analyze the patients' diagnostic performance based on ascites polymorphonuclear (PMN) and clinical manifestation. We performed bactDNA quantification analysis on 13 patients with a PMN less than 250 cells/mm3 but with clinical symptoms. The dynamic changes of the bactDNA load from eight patients (before, during, and after SBP) were analyzed. Results After the removal of free DNA, the bactDNA detected by ddPCR was generally decreased (1.75 vs. 1.5 log copies/µl, P < 0.001). Compared with the traditional culture and PMN count in the SBP diagnosis, the bactDNA showed that the ddPCR sensitivity was 80.5%, specificity was 95.3%, positive predictive value was 82.5%, and negative predictive value was 94.7%, based on clinical composite criteria. In patients with a PMN less than 250 cells/mm3, the bactDNA load of 13 patients with symptoms was significantly higher than those without symptoms (2.7 vs. 1.7 log copies/µl, P < 0.001). The bactDNA in eight patients had SBP that decreased by 1.6 log copies/µl after 48 h of antibiotic treatment and by 1.0 log copies/µl after 3 days of continued treatment. Conclusion BactDNA detection can be used to further enhance the diagnostic efficiency of SBP. Therefore, the application of ddPCR assay not only can be used to discriminate and quantify bacteria but also can be used in the clinical assessment for antibiotics treatment.
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Affiliation(s)
- Hao-Xin Wu
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Wei Hou
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Wei Zhang
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zheng Wang
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Shan Guo
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - De-Xi Chen
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhen Li
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Feili Wei
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongjie Hu
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
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13
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Abstract
In patients with cirrhosis and chronic liver disease, acute-on-chronic liver failure is emerging as a major cause of mortality. These guidelines indicate the preferred approach to the management of patients with acute-on-chronic liver failure and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.
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14
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Reißing J, Lutz P, Frissen M, Ibidapo-Obe O, Reuken PA, Wirtz TH, Stengel S, Quickert S, Rooney M, Große K, Zimmermann HW, Trautwein C, Stallmach A, Bruns T. Immunomodulatory receptor VSIG4 is released during spontaneous bacterial peritonitis and predicts short-term mortality. JHEP Rep 2022; 4:100391. [PMID: 34917912 PMCID: PMC8666561 DOI: 10.1016/j.jhepr.2021.100391] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 10/01/2021] [Accepted: 10/20/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND & AIMS V-set Ig-domain-containing 4 (VSIG4) is an immunomodulatory macrophage complement receptor modulating innate and adaptive immunity and affecting the resolution of bacterial infections. Given its expression on peritoneal macrophages (PMs), we hypothesised a prognostic role of peritoneal VSIG4 concentrations in patients with spontaneous bacterial peritonitis (SBP). METHODS We isolated PMs from patients with cirrhosis and analysed VSIG4 expression and release by flow cytometry, quantitative real-time PCR, ELISA, and confocal microscopy. We measured soluble VSIG4 concentrations in ascites from 120 patients with SBP and 40 patients without SBP and investigated the association of soluble VSIG4 in ascites with 90-day survival after SBP using Kaplan-Meier statistics, Cox regression, and competing-risks regression analysis. RESULTS VSIG4 expression was high on resting, large PMs, which co-expressed CD206, CD163, and tyrosine-protein kinase Mer (MERTK). VSIG4 gene expression in PMs decreased in patients with SBP and normalised after resolution. During SBP, VSIG4hi PMs were depleted (25% vs. 57%; p <0.001) and soluble VSIG4 in ascites were higher in patients with SBP than in patients without (0.73 vs. 0.35 μg/ml; p <0.0001). PM activation by Toll-like receptor (TLR) agonists or infection with live bacteria in vitro resulted in a loss of surface VSIG4 and the release of soluble VSIG4. Mechanistically, shedding of VSIG4 from PMs was protease-dependent and susceptible to microtubule transport inhibition. Soluble VSIG4 in ascites exceeded serum concentrations and correlated with serum creatinine, model for end-stage liver disease score and C-reactive protein during SBP. Concentrations of 1.0206 μg/ml or higher indicated increased 90-day mortality (hazard ratio 1.70; 95% CI 1.01-2.86; p = 0.046). CONCLUSIONS VSIG4 is released from activated PMs into ascites during SBP. Higher peritoneal VSIG4 levels indicate patients with organ failure and poor prognosis. LAY SUMMARY Patients with liver cirrhosis who develop ascites have an increased risk of infection and mortality. Our study shows that in patients with infected ascites, the complement receptor VSIG4 is released by resident macrophages into the abdominal fluid where it can be measured. Patients with elevated levels of this protein in ascites are at high risk of dying within 90 days.
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Key Words
- AF, ascitic fluid
- BSA, bovine serum albumin
- Bacterial infection
- Biomarker
- C3, complement component 3
- CCR2, C-C chemokine receptor type 2
- EEA1, early endosome antigen 1
- FCS, foetal calf serum
- FMO, fluorescence minus one
- HLA-DR, human leucocyte antigen-DR isotype
- IMC, isotype-matched control
- INR, international normalised ratio
- LAMP2, lysosome-associated membrane protein 2
- LPS, lipopolysaccharide
- MACS, magnet-activated cell sorting
- MELD, model for end-stage liver disease
- MERTK, tyrosine-protein kinase Mer
- MFI, median fluorescence intensity
- MMP, matrix metalloproteinase
- MOI, multiplicity of infection
- MPLA, monophosphoryl lipid A
- PAMP, pathogen-associated molecular pattern
- PD-L1, programmed cell death 1 ligand 1
- PFA, paraformaldehyde
- PM, peritoneal macrophage
- Prognostic factor
- Risk of death
- SBP, spontaneous bacterial peritonitis
- TAPI-2, tumour necrosis factor protease inhibitor 2
- TLR, Toll-like receptor
- TNF, tumour necrosis factor
- VSIG4, V-set Ig-domain-containing 4
- qRT-PCR, quantitative real-time PCR
- sVSIG4, soluble V-set Ig-domain-containing 4
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Affiliation(s)
- Johanna Reißing
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- German Center for Infection Research, University of Bonn, Bonn, Germany
| | - Mick Frissen
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Oluwatomi Ibidapo-Obe
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Philipp A. Reuken
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Theresa H. Wirtz
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Stefanie Quickert
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Michael Rooney
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Karsten Große
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Henning W. Zimmermann
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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15
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Mani I, Vrioni G, Hadziyannis E, Alexopoulos T, Vasilieva L, Tsiriga A, Tsiamis C, Tsakris A, Dourakis SP, Alexopoulou A. Bacterial DNA is a prognostic factor for mortality in patients who recover from spontaneous bacterial peritonitis. Ann Gastroenterol 2021; 34:852-861. [PMID: 34815652 PMCID: PMC8596224 DOI: 10.20524/aog.2021.0665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 05/26/2021] [Indexed: 11/13/2022] Open
Abstract
Background Spontaneous bacterial peritonitis (SBP) is associated with a high mortality. The aim was to investigate whether bacterial deoxyribonucleic acid (bactDNA) could offer an accurate identification of pathogens and to explore its prognostic role during and early after an SBP episode. Methods Consecutive patients with SBP (SBP-group) and patients with decompensated cirrhosis without SBP/bacterascites (control-group) were enrolled. Standard culture methodology was used to isolate and identify pathogens from blood and ascitic fluid (AF). The SeptiFast test was used to identify bactDNA directly from AF. Results Fifty-five patients, median age 60 (interquartile range [IQR] 53-74), model-for-end-stage liver disease (MELD) score 18 (IQR 13-29), with SBP were prospectively included. AF cultures were positive in 52.7% (17.2% drug-resistant bacteria) and bactDNA in 29.1% (58.2% combined sensitivity). BactDNA results were 84.6% concordant with AF cultures. Three patients had positive bactDNA in the culture-negative SBP-group. BactDNA was negative in all 36 of the control group (100% specificity). In multivariate analysis for 7-day survival, factors adversely affecting outcome were MELD (P=0.049) and C-reactive protein (P=0.012). After patients who died during the first week post-admission were excluded, patients with positive bactDNA had a poor prognosis compared to those with a negative test (log-rank P=0.005). Variables independently associated with 30-day mortality were neutrophil-to-lymphocyte ratio (P=0.011) and positive bactDNA (P=0.020). Conclusions No evidence was found for the usefulness of bactDNA to improve bacterial identification during an SBP episode. However, bactDNA was a predictor of 30-day mortality in the subset of patients who recovered from the infection episode.
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Affiliation(s)
- Iliana Mani
- 2 Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece (Iliana Mani, Emilia Hadziyannis, Theodoros Alexopoulos, Larisa Vasilieva, Athanasia Tsiriga, Spyros P. Dourakis, Alexandra Alexopoulou)
| | - Georgia Vrioni
- Department of Microbiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece (Georgia Vrioni, Constantinos Tsiamis, Athanasios Tsakris)
| | - Emilia Hadziyannis
- 2 Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece (Iliana Mani, Emilia Hadziyannis, Theodoros Alexopoulos, Larisa Vasilieva, Athanasia Tsiriga, Spyros P. Dourakis, Alexandra Alexopoulou)
| | - Theodoros Alexopoulos
- 2 Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece (Iliana Mani, Emilia Hadziyannis, Theodoros Alexopoulos, Larisa Vasilieva, Athanasia Tsiriga, Spyros P. Dourakis, Alexandra Alexopoulou)
| | - Larisa Vasilieva
- 2 Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece (Iliana Mani, Emilia Hadziyannis, Theodoros Alexopoulos, Larisa Vasilieva, Athanasia Tsiriga, Spyros P. Dourakis, Alexandra Alexopoulou)
| | - Athanasia Tsiriga
- 2 Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece (Iliana Mani, Emilia Hadziyannis, Theodoros Alexopoulos, Larisa Vasilieva, Athanasia Tsiriga, Spyros P. Dourakis, Alexandra Alexopoulou)
| | - Constantinos Tsiamis
- Department of Microbiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece (Georgia Vrioni, Constantinos Tsiamis, Athanasios Tsakris)
| | - Athanasios Tsakris
- Department of Microbiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece (Georgia Vrioni, Constantinos Tsiamis, Athanasios Tsakris)
| | - Spyros P Dourakis
- 2 Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece (Iliana Mani, Emilia Hadziyannis, Theodoros Alexopoulos, Larisa Vasilieva, Athanasia Tsiriga, Spyros P. Dourakis, Alexandra Alexopoulou)
| | - Alexandra Alexopoulou
- 2 Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece (Iliana Mani, Emilia Hadziyannis, Theodoros Alexopoulos, Larisa Vasilieva, Athanasia Tsiriga, Spyros P. Dourakis, Alexandra Alexopoulou)
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16
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Maslennikov R, Ivashkin V, Efremova I, Poluektova E, Shirokova E. Gut-liver axis in cirrhosis: Are hemodynamic changes a missing link? World J Clin Cases 2021; 9:9320-9332. [PMID: 34877269 PMCID: PMC8610853 DOI: 10.12998/wjcc.v9.i31.9320] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/05/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Recent evidence suggests that the condition of the gut and its microbiota greatly influence the course of liver disease, especially cirrhosis. This introduces the concept of the gut–liver axis, which can be imagined as a chain connected by several links. Gut dysbiosis, small intestinal bacterial overgrowth, and intestinal barrier alteration lead to bacterial translocation, resulting in systemic inflammation. Systemic inflammation further causes vasodilation, arterial hypotension, and hyperdynamic circulation, leading to the aggravation of portal hypertension, which contributes to the development of complications of cirrhosis, resulting in a poorer prognosis. The majority of the data underlying this model were obtained initially from animal experiments, and most of these correlations were further reproduced in studies including patients with cirrhosis. However, despite the published data on the relationship of the disorders of the gut microbiota with the complications of cirrhosis and the proposed pathogenetic role of hemodynamic disorders in their development, the direct relations between gut dysbiosis and hemodynamic changes in this disease are poorly studied. They remain a missing link in the gut–liver axis and a challenge for future research.
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Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Interregional Public Organization "Scientific Community for the Promotion of the Clinical Study of the Human Microbiome", Moscow 119435, Russia
- Department of Internal Medicine, Consultative and Diagnostic Center of the Moscow City Health Department, Moscow 107564, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Interregional Public Organization "Scientific Community for the Promotion of the Clinical Study of the Human Microbiome", Moscow 119435, Russia
| | - Elena Shirokova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
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Detection of Circulating Tumor Cells and Microbial DNA Fragments in Stage III Colorectal Cancer Patients under Three versus Six Months of Adjuvant Treatment. Cancers (Basel) 2021; 13:cancers13143552. [PMID: 34298766 PMCID: PMC8305584 DOI: 10.3390/cancers13143552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Oxaliplatin-fluoropyrimidine combination therapy is the gold standard treatment for patients with stage III colorectal cancer (CRC); however, treatment duration is now under re-evaluation. The aim of the study was the evaluation of the non-inferiority of three over six months treatment with FOLFOX or CAPOX, in stage III CRC patients. Peripheral blood samples from 121 patients were collected, at three time points during treatment and evaluated for circulating tumor cells (CTCs) and microbial DNA detection (16S rRNA, Escherichia coli, Bacteroides fragilis, Candida albicans). Of all patients, 41.3% and 58.7% were treated with FOLFOX and CAPOX, respectively. CTCs were significantly decreased and increased after three and six months of treatment, respectively. CAPOX tends to reduce the CTCs after 3 months, whereas there is a statistically significant increase of CTCs in patients under FOLFOX after 6 months. A significant correlation was demonstrated between microbial DNA detection and both CTCs detection at baseline and CTCs increase between baseline and three months of treatment. To conclude, the current study provides additional evidence of non-inferiority of three over 6 months of treatment, mainly in patients under CAPOX.
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Reichert MC, Schneider C, Greinert R, Casper M, Grünhage F, Wienke A, Zipprich A, Lammert F, Ripoll C. Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis. Liver Int 2021; 41:1370-1378. [PMID: 33641234 DOI: 10.1111/liv.14842] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 01/12/2021] [Accepted: 02/22/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis. METHODS We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. RESULTS About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. CONCLUSIONS In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.
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Affiliation(s)
- Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Christina Schneider
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Robin Greinert
- Department of Medicine I, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Markus Casper
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Grünhage
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Andreas Wienke
- Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Alexander Zipprich
- Department of Medicine I, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany.,Department of Internal Medicine IV, Friedrich-Schiller-University Jena, Jena, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.,Hannover Medical School, Hannover, Germany
| | - Cristina Ripoll
- Department of Medicine I, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
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Stengel S, Quickert S, Lutz P, Ibidapo-Obe O, Steube A, Köse-Vogel N, Yarbakht M, Reuken PA, Busch M, Brandt A, Bergheim I, Deshmukh SD, Stallmach A, Bruns T. Peritoneal Level of CD206 Associates With Mortality and an Inflammatory Macrophage Phenotype in Patients With Decompensated Cirrhosis and Spontaneous Bacterial Peritonitis. Gastroenterology 2020; 158:1745-1761. [PMID: 31982413 DOI: 10.1053/j.gastro.2020.01.029] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 01/13/2020] [Accepted: 01/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Peritoneal macrophages (PMs) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PMs and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP). METHODS We isolated PMs from ascites samples of 66 patients with decompensated cirrhosis (19 with SBP) and analyzed them by flow cytometry, quantitative real-time polymerase chain reaction, functional analysis, and RNA microarrays. We used ascites samples of a separate cohort of 111 patients with decompensated cirrhosis (67 with SBP) and quantified the soluble form of the mannose receptor (CD206) and tumor necrosis factor by enzyme-linked immunosorbent assay (test cohort). We performed logistic regression analysis to identify factors associated with 90-day mortality. We validated our findings using data from 71 patients with cirrhosis and SBP. Data from 14 patients undergoing peritoneal dialysis for end-stage renal disease but without cirrhosis were included as controls. RESULTS We used surface levels of CD206 to identify subsets of large PMs (LPM) and small PMs (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPMs vs SPMs from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPMs vs SPMs, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPMs had an inflammatory phenotype, were less susceptible to tolerance induction, and released more tumor necrosis factor than SPMs. LPMs from patients with cirrhosis produced more inflammatory cytokines than LPMs from controls. Activation of PMs by Toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPMs and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPMs in the early phase of SBP, but levels increased after treatment. In the test and validation cohorts, patients with SBP and higher concentrations of soluble CD206 in ascites fluid (>0.53 mg/L) were less likely to survive for 90 days than those with lower levels. CONCLUSIONS Surface level of CD206 can be used to identify mature, resident, inflammatory PMs in patients with cirrhosis. Soluble CD206 is released from activated LPMs and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.
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Affiliation(s)
- Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Stefanie Quickert
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, University of Bonn, Bonn, Germany
| | - Oluwatomi Ibidapo-Obe
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Arndt Steube
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Nilay Köse-Vogel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Melina Yarbakht
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Martin Busch
- Department of Internal Medicine III, Jena University Hospital, Jena, Germany
| | - Annette Brandt
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Sachin D Deshmukh
- The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany; Department of Internal Medicine III, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
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Bruns T, Stallmach A. Gastrointestinale Mikrobiota bei Leberzirrhose: pathophysiologische Veränderungen und therapeutische Interventionen. DER GASTROENTEROLOGE 2020; 15:194-200. [DOI: 10.1007/s11377-020-00436-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Messaritakis I, Vogiatzoglou K, Tsantaki K, Ntretaki A, Sfakianaki M, Koulouridi A, Tsiaoussis J, Mavroudis D, Souglakos J. The Prognostic Value of the Detection of Microbial Translocation in the Blood of Colorectal Cancer Patients. Cancers (Basel) 2020; 12:E1058. [PMID: 32344707 PMCID: PMC7226464 DOI: 10.3390/cancers12041058] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023] Open
Abstract
Dysbiosis has been associated with various diseases and is of major health importance. Dysbiosis leads to microbial translocation, which is the passage of microorganisms, their fragments, or their metabolites from the intestinal lumen into the blood circulation and other sites. The aim of the study was to determine whether microbial translocation occurs in stage II/III-IV colorectal cancer (CRC) patients. The aim was also to evaluate the usefulness of blood PCR for diagnosis of such translocation and correlate the presence of toll-like receptor/vitamin D receptor (TLR/VDR) gene polymorphisms with microbial DNA fragments detected in the blood of CRC patients. Three hundred and ninety-seven CRC patients enrolled in the study. Peripheral blood DNA was analyzed using PCR for the amplification of genomic DNA encoding 16S rRNA, the β-galactosidase gene of Escherichia coli, glutamine synthase gene of Bacteroides fragilis, and 5.8S rRNA of Candida albicans. Significantly higher rates of all microbial fragments, but E. coli, detected were observed in the CRC patients (p < 0.001); such detection of all four microbial fragments was also significantly associated with the metastatic disease (p < 0.001), leading to shorter survival rates (p < 0.001). Tumor location in the right colon also significantly correlated with shorter survival (p = 0.016). Individuals with homozygous mutant alleles of TLR/VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. The detection of microbial DNA fragments in CRC patients highlighted the role of these microbes in cancer development, progression, and patients' survival.
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Affiliation(s)
- Ippokratis Messaritakis
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
| | - Konstantinos Vogiatzoglou
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
| | - Konstantina Tsantaki
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
| | - Agapi Ntretaki
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
| | - Maria Sfakianaki
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
| | - Asimina Koulouridi
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
| | - John Tsiaoussis
- Laboratory of Anatomy, Medical School, University of Crete, 70013 Heraklion, Crete, Greece;
| | - Dimitrios Mavroudis
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
- Department of Medical Oncology, University General Hospital of Heraklion, 70013 Heraklion, Crete, Greece
| | - John Souglakos
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Crete, Greece; (K.V.); (K.T.); (A.N.); (M.S.); (A.K.); (D.M.); (J.S.)
- Department of Medical Oncology, University General Hospital of Heraklion, 70013 Heraklion, Crete, Greece
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Ibidapo-Obe O, Stengel S, Köse-Vogel N, Quickert S, Reuken PA, Busch M, Bauer M, Stallmach A, Bruns T. Mucosal-Associated Invariant T Cells Redistribute to the Peritoneal Cavity During Spontaneous Bacterial Peritonitis and Contribute to Peritoneal Inflammation. Cell Mol Gastroenterol Hepatol 2020; 9:661-677. [PMID: 31954178 PMCID: PMC7160599 DOI: 10.1016/j.jcmgh.2020.01.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 01/06/2020] [Accepted: 01/07/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Mucosal-associated invariant T (MAIT) cells are depleted from blood in patients with advanced liver disease and show features of immune dysfunction. Because circulating MAIT cells differ from organ-resident MAIT cells, we aimed to investigate the frequency, phenotype, and function of peritoneal MAIT cells from patients with cirrhosis and spontaneous bacterial peritonitis (SBP). METHODS MAIT cells in blood and ascitic fluid from patients with cirrhosis were characterized using flow cytometry. Healthy individuals and noncirrhotic patients undergoing peritoneal dialysis served as controls. MAIT cell migration was studied in transwell assays. Cytokine release in response to infected ascitic fluid and bacterial products was assessed in vitro. RESULTS Peritoneal CD3+ CD161hi Vα7.2+ T cells had an inflammatory, tissue retention phenotype, expressing the alpha E integrin, the chemokine receptors CCR5 and CXCR3, and the activation marker CD69 at higher levels than their circulating equivalents. Seventy-seven percent bound to MR1 tetramers loaded with the pyrimidine intermediate 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil. The ratio of peritoneal to blood MAIT cell frequency increased from 1.3 in the absence of SBP to 2.6 at diagnosis and decreased by day 3. MAIT cells migrated toward infected ascitic fluid containing CCL5 and CCL20 and released cytokines in an MR1-restricted fashion. Whereas the depleted circulating MAIT cell pool displayed features of immune exhaustion, peritoneal MAIT cells remained competent producers of inflammatory cytokines in response to bacterial products. Peritoneal MAIT activation correlated with systemic inflammation, suggesting a possible link between peritoneal and systemic immunity. CONCLUSIONS Peritoneal MAIT cells phenotypically and functionally differ from circulating MAIT cells in decompensated cirrhosis and redistribute to the peritoneum during SBP.
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Affiliation(s)
- Oluwatomi Ibidapo-Obe
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Nilay Köse-Vogel
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Stefanie Quickert
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Martin Busch
- Department of Internal Medicine III, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Michael Bauer
- Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany; Department of Anesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany; Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
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Fukui H. Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far? Diseases 2019; 7:diseases7040058. [PMID: 31726747 PMCID: PMC6956030 DOI: 10.3390/diseases7040058] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 10/29/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Accumulating evidence supports that gut dysbiosis may relate to various liver diseases. Alcoholics with high intestinal permeability had a decrease in the abundance of Ruminnococcus. Intestinal dysmotility, increased gastric pH, and altered immune responses in addition to environmental and genetic factors are likely to cause alcohol-associated gut microbial changes. Alcohol-induced dysbiosis may be associated with gut barrier dysfunction, as microbiota and their products modulate barrier function by affecting epithelial pro-inflammatory responses and mucosal repair functions. High levels of plasma endotoxin are detected in alcoholics, in moderate fatty liver to advanced cirrhosis. Decreased abundance of Faecalibacterium prausnitzii, an anti-inflammatory commensal, stimulating IL-10 secretion and inhibiting IL-12 and interferon-γ expression. Proteobacteria, Enterobacteriaceae, and Escherichia were reported to be increased in NAFLD (nonalcoholic fatty liver disease) patients. Increased abundance of fecal Escherichia to elevated blood alcohol levels in these patients and gut microbiota enriched in alcohol-producing bacteria produce more alcohol (alcohol hypothesis). Some undetermined pathological sequences related to gut dysbiosis may facilitate energy-producing and proinflammatory conditions for the progression of NAFLD. A shortage of autochthonous non-pathogenic bacteria and an overgrowth of potentially pathogenic bacteria are common findings in cirrhotic patients. The ratio of the amounts of beneficial autochthonous taxa (Lachnospiraceae + Ruminococaceae + Veillonellaceae + Clostridiales Incertae Sedis XIV) to those of potentially pathogenic taxa (Enterobacteriaceae + Bacteroidaceae) was low in those with early death and organ failure. Cirrhotic patients with decreased microbial diversity before liver transplantation were more likely to develop post-transplant infections and cognitive impairment related to residual dysbiosis. Patients with PSC had marked reduction of bacterial diversity. Enterococcus and Lactobacillus were increased in PSC patients (without liver cirrhosis.) Treatment-naive PBC patients were associated with altered composition and function of gut microbiota, as well as a lower level of diversity. As serum anti-gp210 antibody has been considered as an index of disease progression, relatively lower species richness and lower abundance of Faecalibacterium spp. in gp210-positive patients are interesting. The dysbiosis-induced altered bacterial metabolites such as a hepatocarcinogenesis promotor DCA, together with a leaky gut and bacterial translocation. Gut protective Akkermansia and butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early hepatocellular carcinoma (HCC) patients.
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Affiliation(s)
- Hiroshi Fukui
- Department of Gastroenterology, Nara Medical University, Kashihara 634-8522, Japan
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Zhang Y, Zhao R, Shi D, Sun S, Ren H, Zhao H, Wu W, Jin L, Sheng J, Shi Y. Characterization of the circulating microbiome in acute-on-chronic liver failure associated with hepatitis B. Liver Int 2019; 39:1207-1216. [PMID: 30864226 DOI: 10.1111/liv.14097] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 03/05/2019] [Accepted: 03/06/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Patients with hepatitis B-related acute-on-chronic liver failure (HB-ACLF) may have an increased circulating microbial burden. This study aimed to assess circulating microbial load and composition and to explore the association between the circulating microbiome and both systemic inflammation (SI) and clinical outcome in HB-ACLF. METHODS Plasma from 50 HB-ACLF patients, 23 healthy controls and 25 patients with compensated liver cirrhosis (C-LC) was analysed for chemokines/cytokines and bacterial DNA and further analysed by 16S rDNApyrosequencing. Linear discriminant analysis effect size (LEfSe) and inferred metagenomics analyses were performed. RESULTS The circulating bacterial DNA was significantly increased in HB-ACLF patients compared to that in the control groups. The overall microbial diversity was significantly decreased in HB-ACLF patients. HB-ACLF patients were enriched with Moraxellaceae, Sulfurovum, Comamonas and Burkholderiaceae but were depleted in Actinobacteria, Deinococcus-Thermus, Alphaproteobacteria, Xanthomonadaceae and Enterobacteriaceae compared to controls. Network analysis revealed a direct positive correlation between Burkholderiaceae and chemokine IP-10 in HB-ACLF patients. The relative abundance of Prevotellaceae independently predicted 28-day mortality. Inferred functional metagenomics predicted an enrichment of bacteria with genes related to methane, alanine, aspartate, glutamate, pyrimidine, purine and energy metabolism. CONCLUSIONS HB-ACLF patients display increased circulating microbial burden, altered microbiome composition and a shift in microbiome functionality. The alteration in circulating microbiota is associated with SI and clinical outcome in HB-ACLF.
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Affiliation(s)
- Yi Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China
| | - Ruihong Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shanshan Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haotang Ren
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hong Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Linfeng Jin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jifang Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, Krag A, Laleman W, Gines P. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69:406-460. [PMID: 29653741 DOI: 10.1016/j.jhep.2018.03.024] [Citation(s) in RCA: 1722] [Impact Index Per Article: 246.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023]
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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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Low circulating chemerin levels correlate with hepatic dysfunction and increased mortality in decompensated liver cirrhosis. Sci Rep 2018; 8:9242. [PMID: 29915268 PMCID: PMC6006249 DOI: 10.1038/s41598-018-27543-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 05/30/2018] [Indexed: 12/23/2022] Open
Abstract
Nutritional status, infections, inflammation and extrahepatic organ dysfunction are critical factors for the progression of chronic liver disease. Chemerin is an immune-metabolically and chemotactically active adipokine and we hypothesized that it is associated with disease severity and prognosis in patients with advanced decompensated cirrhosis. Therefore, we measured serum concentrations of chemerin in a prospectively characterized cohort of 80 patients with decompensated cirrhosis and ascites and assessed the associations with markers of disease severity and short-term outcome at 28 days. In a subset of patients (n = 40), ascitic fluid chemerin was determined. Advanced liver disease was associated with decreased serum but not ascitic chemerin levels. Serum chemerin correlated with markers of hepatic function (total bilirubin, albumin, INR) and inversely correlated with indicators of portal hypertension (platelet count, gastrointestinal bleeding) but not with extrahepatic organ failure and systemic inflammation. Patients presenting with acute-on-chronic liver failure or infection did not exhibit altered serum or ascitic fluid chemerin concentrations. However, serum chemerin levels below 87 ng/ml predicted an increased risk for mortality or liver transplantation within 28 days independently of MELD and infections. We conclude that low serum chemerin is an independent adverse prognostic factor in patients with advanced decompensated cirrhosis.
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28
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The first episode of spontaneous bacterial peritonitis is a threat event in children with end-stage liver disease. Eur J Gastroenterol Hepatol 2018; 30:323-327. [PMID: 29303884 DOI: 10.1097/meg.0000000000001046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Studies on native liver survival (NLS) after the first episode of spontaneous bacterial peritonitis (SBP) are rare. Our objective was to evaluate NLS in children up to 1 year after SBP. METHODS A historical cohort study of 18 children followed after the first episode of SBP was conducted. NLS, in-hospital mortality, causes of death, and rate of multidrug-resistant organisms were reported. RESULTS Biliary atresia was the most prevalent diagnosis (72.2%); all were Child-Pugh C, and the median age was 1.0 year. The probability of NLS was 77.8, 27.8, and 11.1% at 1, 3 and 6 months, respectively. At 9 months, no child had the native liver. In-hospital mortality was 38.9%, and the main causes of death were septic shock and acute-on-chronic liver failure. Escherichia coli was the predominant organism cultured. Multidrug-resistant organisms were not detected. The cumulative probability of NLS was 77.8% at 1 month, 27.8% at 3 months, and 11.1% at 6 months. At 9-month follow-up, none of children had their native liver. Ascites PMN count cell more than 1000 cells/mm, positive ascites culture, and prolonged international normalized ratio reached a significant value as predictive factors of NLS and were selected for multivariate analysis. We did not identify independent predictors of survival. CONCLUSION Development of SBP was a late event in children and had a high effect on NLS.
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29
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Serum metabolic signatures in patients with overt hepatic encephalopathy. J Hepatol 2017; 67:1114-1115. [PMID: 28690175 DOI: 10.1016/j.jhep.2017.06.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 04/27/2017] [Accepted: 06/01/2017] [Indexed: 12/04/2022]
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30
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Weiss N, Colsch B, Fenaille F, Junot C, Thabut D. Reply to: "Serum metabolic signatures in patients with overt hepatic encephalopathy": Metabolic signature for severe cirrhosis with inflammation or hepatic encephalopathy: Do we really face two different entities? J Hepatol 2017; 67:1115-1116. [PMID: 28688802 DOI: 10.1016/j.jhep.2017.06.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 06/30/2017] [Indexed: 12/04/2022]
Affiliation(s)
- Nicolas Weiss
- Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Paris, France; Unité de réanimation neurologique, Fédération de neurologie 1, pôle des maladies du système nerveux, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Assistance Publique - Hôpitaux de Paris et Institut de neurosciences translationnelles IHU-A-ICM, Paris, France
| | - Benoit Colsch
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, 91191 Gif-sur-Yvette cedex, France
| | - François Fenaille
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, 91191 Gif-sur-Yvette cedex, France
| | - Christophe Junot
- CEA, iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, Laboratoire d'Etude du Métabolisme des Médicaments, MetaboHUB-Paris, 91191 Gif-sur-Yvette cedex, France
| | - Dominique Thabut
- Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Paris, France; Unité de Soins Intensifs d'Hépato-gastroentérologie, Groupement Hospitalier Pitié-Salpêtrière-Charles Foix, Assistance Publique - Hôpitaux de Paris et Université Pierre et Marie Curie Paris 6, Paris, France.
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31
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Lutz P, Goeser F, Kaczmarek DJ, Schlabe S, Nischalke HD, Nattermann J, Hoerauf A, Strassburg CP, Spengler U. Relative Ascites Polymorphonuclear Cell Count Indicates Bacterascites and Risk of Spontaneous Bacterial Peritonitis. Dig Dis Sci 2017; 62:2558-2568. [PMID: 28597106 DOI: 10.1007/s10620-017-4637-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 05/26/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Absolute polymorphonuclear (PMN) counts in ascites define spontaneous bacterial peritonitis (SBP), a severe form of bacterial infection in liver cirrhosis. Bacterascites, another form of ascites infection, can progress to SBP or may resolve spontaneously but is not reflected by absolute PMN counts. We investigated whether the relative ascites PMN count (the absolute PMN count divided by the absolute leukocyte count) provides additional information to detect bacterascites or predict SBP. METHODS Hospitalized patients with liver cirrhosis requiring paracentesis were stratified with respect to a diagnosis of bacterascites and SBP with a prospective follow-up for 1 year. Diagnostic power of relative PMN counts in ascites was evaluated by receiver operating characteristics curves. RESULTS At inclusion, we observed 28/269 (10%) and 43/269 (16%) episodes of BA and SBP, respectively. Unlike absolute PMN counts, relative PMN counts in ascites were significantly elevated in bacterascites (p = 0.001). During follow-up, 16 and 30 further episodes of BA and SBP were detected, respectively. Relative PMN counts increased significantly once patients developed BA (p = 0.001). At a threshold of 0.20 for the relative PMN count, sensitivity, specificity, positive and negative predictive values for bacterascites which required antibiotic treatment were 83, 75, 26 and 98%, respectively (p < 0.001). Furthermore, a relative PMN count in ascites ≥0.13 and MELD score >17 was independent factors associated with occurrence of SBP during follow-up. CONCLUSION The relative PMN count is a cheap immunological marker linked to bacterascites and future SBP, which may help to stratify patients according to their risk of infection.
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Affiliation(s)
- Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany. .,German Center for Infection Research, Bonn, Germany.
| | - Felix Goeser
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Dominik J Kaczmarek
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Stefan Schlabe
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Hans Dieter Nischalke
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Achim Hoerauf
- Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Sigmund-Freud-Straße 25, 53105, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.,German Center for Infection Research, Bonn, Germany
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32
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Alexopoulou A, Agiasotelli D, Vasilieva LE, Dourakis SP. Bacterial translocation markers in liver cirrhosis. Ann Gastroenterol 2017; 30:486-497. [PMID: 28845103 PMCID: PMC5566768 DOI: 10.20524/aog.2017.0178] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 06/19/2017] [Indexed: 12/12/2022] Open
Abstract
Bacterial translocation (BT) is an important mechanism in the development of infection in liver cirrhosis. The migration and colonization of bacteria and/or bacterial products from the bowel to mesenteric lymph nodes is a controlled process in healthy persons. Increased intestinal permeability, bacterial overgrowth and defect of gut-associated lymphatic tissue promote impaired BT in cirrhotics. We reviewed the reports on markers used for the evaluation of BT published between 1987 and 2016. We focused on the clinical consequences of BT in cirrhosis, as indicated by the values of the BT markers. Patients with cirrhosis are reported to have elevated levels of surrogate markers associated with BT compared with controls. The most widely used BT parameters are C-reactive protein, procalcitonin, bacterial DNA, endotoxin or lipopolysaccharide, lipopolysaccharide binding protein, calprotectin, and bactericidal/permeability increasing protein. High levels of these factors in serum and/or ascitic fluid in humans may be associated with advanced liver disease, hemodynamic instability, high levels of proinflammatory cytokines, susceptibility to the development of severe or recurrent infections, acute-on-chronic liver failure, hepatic encephalopathy, hepatorenal syndrome and poor prognosis during follow up. In conclusion, high levels of BT markers are associated with a high inflammatory response, increased complications of liver cirrhosis and occasionally high fatality rates.
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Affiliation(s)
- Alexandra Alexopoulou
- 2 Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "Hippokration" Hospital, Athens, Greece
| | - Danai Agiasotelli
- 2 Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "Hippokration" Hospital, Athens, Greece
| | - Larisa E Vasilieva
- 2 Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "Hippokration" Hospital, Athens, Greece
| | - Spyros P Dourakis
- 2 Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, "Hippokration" Hospital, Athens, Greece
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33
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Vergis N, Atkinson SR, Knapp S, Maurice J, Allison M, Austin A, Forrest EH, Masson S, McCune A, Patch D, Richardson P, Gleeson D, Ryder SD, Wright M, Thursz MR. In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA. Gastroenterology 2017; 152:1068-1077.e4. [PMID: 28043903 PMCID: PMC6381387 DOI: 10.1053/j.gastro.2016.12.019] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/16/2016] [Accepted: 12/03/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Infections are common in patients with severe alcoholic hepatitis (SAH), but little information is available on how to predict their development or their effects on patients. Prednisolone is advocated for treatment of SAH, but can increase susceptibility to infection. We compared the effects of infection on clinical outcomes of patients treated with and without prednisolone, and identified risk factors for development of infection in SAH. METHODS We analyzed data from 1092 patients enrolled in a double-blind placebo-controlled trial to evaluate the efficacy of treatment with prednisolone (40 mg daily) or pentoxifylline (400 mg 3 times each day) in patients with SAH. The 2 × 2 factorial design led to 547 patients receiving prednisolone; 546 were treated with pentoxifylline. The trial was conducted in the United Kingdom from January 2011 through February 2014. Data on development of infection were collected at evaluations performed at screening, baseline, weekly during admission, on discharge, and after 90 days. Patients were diagnosed with infection based on published clinical and microbiologic criteria. Risk factors for development of infection and effects on 90-day mortality were evaluated separately in patients treated with prednisolone (n = 547) and patients not treated with prednisolone (n = 545) using logistic regression. Pretreatment blood levels of bacterial DNA (bDNA) were measured in 731 patients. RESULTS Of the 1092 patients in the study, 135 had an infection at baseline, 251 developed infections during treatment, and 89 patients developed an infection after treatment. There was no association between pentoxifylline therapy and the risk of serious infection (P = .084), infection during treatment (P = .20), or infection after treatment (P = .27). Infections classified as serious were more frequent in patients treated with prednisolone (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.27-2.92; P = .002). There was no association between prednisolone therapy and infection during treatment (OR, 1.04; 95% CI, 0.78-1.37; P = .80). However, a higher proportion (10%) of patients receiving prednisolone developed an infection after treatment than of patients not given prednisolone (6%) (OR, 1.70; 95% CI, 1.07-2.69; P = .024). Development of infection was associated with increased 90-day mortality in patients with SAH treated with prednisolone, independent of model for end-stage liver disease or Lille score (OR, 2.46; 95% CI, 1.41-4.30; P = .002). High circulating bDNA predicted infection that developed within 7 days of prednisolone therapy, independent of Model for End-Stage Liver Disease and white blood cell count (OR, 4.68; 95% CI, 1.80-12.17; P = .001). In patients who did not receive prednisolone, infection was not independently associated with 90-day mortality (OR, 0.94; 95% CI, 0.54-1.62; P = .82) or levels of bDNA (OR, 0.83; 95% CI, 0.39-1.75; P = .62). CONCLUSIONS Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125.
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Affiliation(s)
| | - Stephen R. Atkinson
- Imperial College, London, United Kingdom,Reprint requests Address requests for reprints to: Stephen Atkinson, PhD, St Mary’s Hospital, Imperial College, London, W2 1NY, UK. fax: +4420 7724 9369.
| | | | | | | | | | | | - Steven Masson
- Freeman Hospital, The Newcastle Upon Tyne Hospitals, National Health Service Foundation Trust, Newcastle Upon Tyne, United Kingdom
| | - Anne McCune
- Bristol Royal Infirmary, Bristol, United Kingdom
| | | | - Paul Richardson
- Royal Liverpool University National Health Service Trust, Liverpool, United Kingdom
| | - Dermot Gleeson
- Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom
| | - Stephen D. Ryder
- NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals National Health Service Trust and The University of Nottingham, Nottingham, United Kingdom
| | - Mark Wright
- Southampton University Hospital, Southampton, United Kingdom
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34
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Bruns T, Nuraldeen R, Mai M, Stengel S, Zimmermann HW, Yagmur E, Trautwein C, Stallmach A, Strnad P. Low serum transferrin correlates with acute-on-chronic organ failure and indicates short-term mortality in decompensated cirrhosis. Liver Int 2017; 37:232-241. [PMID: 27473364 DOI: 10.1111/liv.13211] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Accepted: 07/23/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Iron represents an essential, but potentially harmful micronutrient, whose regulation has been associated with poor outcome in liver disease. Its homeostasis is tightly linked to oxidative stress, bacterial infections and systemic inflammation. To study the prognostic short-term significance of iron parameters in a cohort study of patients with decompensation of cirrhosis at risk of acute-on-chronic liver failure (ACLF). METHODS Ferritin, transferrin, iron, transferrin saturation (TSAT) and hepcidin were determined in sera from 292 German patients hospitalized for decompensation of cirrhosis with ascites, of which 78 (27%) had ACLF. Short-term mortality was prospectively assessed 30 and 90 days after inclusion. RESULTS Transferrin concentrations were significantly lower, whereas ferritin and TSAT were higher in patients with ACLF compared to patients without ACLF (P≤.006). Transferrin, TSAT and ferritin differentially correlated with the severity of organ failure, active alcoholism and surrogates of systemic inflammation and macrophage activation. As compared with survivors, 30-day non-survivors displayed lower serum transferrin (P=.0003) and higher TSAT (P=.003), whereas 90-day non-survivors presented with higher ferritin (P=.03) and lower transferrin (P=.02). Lower transferrin (continuous or dichotomized at 87 mg/dL) and consecutively higher TSAT (continuous or dichotomized >41%) indicated increased mortality within 30 days and remained significant after adjustment for organ failure and inflammation in multivariate regression models and across subgroups of patients. CONCLUSION Among the investigated indicators of iron metabolism, serum transferrin concentration was the best indicator of organ failure and an independent predictor of short-term mortality at 30 days.
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Affiliation(s)
- Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany.,The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena, Germany
| | - Renwar Nuraldeen
- Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany
| | - Martina Mai
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany.,The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | - Henning W Zimmermann
- Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany
| | - Eray Yagmur
- Laboratory Diagnostics Center, University Hospital Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany.,The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.,Interdisciplinary Center for Clinical Research (IZKF), University Hospital Aachen, Aachen, Germany
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35
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Albillos A, Martínez J. Prognostic value of bacterial infection in acute and chronic liver failure. Liver Int 2016; 36:1090-2. [PMID: 27403767 DOI: 10.1111/liv.13141] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 04/06/2016] [Indexed: 12/24/2022]
Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Martínez
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
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36
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Bruns T, Reuken PA, Stengel S, Gerber L, Appenrodt B, Schade JH, Lammert F, Zeuzem S, Stallmach A. NOD2 Risk Variants and Pathological Bacterial Translocation in Decompensated Cirrhosis. Dig Dis Sci 2016; 61:2142-4. [PMID: 27052012 DOI: 10.1007/s10620-016-4151-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 03/29/2016] [Indexed: 01/05/2023]
Affiliation(s)
- Tony Bruns
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany. .,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany.
| | - Philipp A Reuken
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Sven Stengel
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Ludmila Gerber
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Beate Appenrodt
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Johannes H Schade
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
| | - Frank Lammert
- Department of Internal Medicine II, Saarland University Hospital, Homburg, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, Frankfurt University Hospital, Frankfurt, Germany
| | - Andreas Stallmach
- The Integrated Research and Treatment Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.,Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany
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