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U LK, J D, M R, K S, Sebastian SK, Khatana G, Philip GR. Spontaneous Bacterial Peritonitis: Etiology, Microbiology, and Clinical Outcomes in Cirrhosis Patients. Cureus 2024; 16:e76679. [PMID: 39898135 PMCID: PMC11781897 DOI: 10.7759/cureus.76679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/31/2024] [Indexed: 02/04/2025] Open
Abstract
OBJECTIVE Spontaneous bacterial peritonitis (SBP) is a critical complication in patients with liver cirrhosis, often resulting in high mortality. Understanding the microbiological agents causing SBP and their antibiotic resistance patterns is essential for effective treatment, particularly in tertiary care settings. This prospective observational study aimed to identify the microbial profile of SBP, evaluate antibiotic sensitivity, and assess patient outcomes. METHODOLOGY The study included 100 patients over 18 years old with chronic liver disease and SBP. Data collected included demographics, ascitic fluid analysis, cultures, liver and renal function tests, ultrasonograms, and disease etiology. Scoring systems such as sequential organ failure assessment (SOFA), child-turcotte-pugh (CTP), and model for end-stage liver disease (MELD) were calculated. Patients received standard care, and outcomes (discharge or mortality) were recorded. RESULTS Of the 100 patients with SBP, 91% were men. Most were classified as child-turcotte-pugh Class C (66%), with the remainder as Class B (34%). The leading cause of cirrhosis was alcohol use (72%), followed by metabolic-associated steatotic liver disease (MASLD), hepatitis B virus (HBV), and hepatitis C virus (HCV). Prior antibiotic exposure was noted in 21% of cases. Despite prophylaxis, SBP developed in 19%. Ascitic fluid cultures showed no growth in 56%, but Escherichia coli (16%) and Klebsiella species (8%) were the most common pathogens isolated. Acute-on-chronic liver failure (ACLF) occurred in 19%, with a mortality rate of 89%. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens were identified in 5% and 3% of cases, respectively. CONCLUSION This study identifies Escherichia coli as the most prevalent pathogen in SBP and highlights the impact of comorbidities like diabetes and dyslipidemia on outcomes. High sequential organ failure assessment scores, hepatic encephalopathy, variceal bleeding, renal failure, mechanical ventilation, and alcoholic liver disease significantly increased mortality risk. The emergence of multi-drug-resistant and extensively drug-resistant pathogens underscores the need for vigilant monitoring, early intervention, and customized antibiotic therapies to manage SBP effectively in cirrhotic patients.
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Affiliation(s)
- Lal Krishna U
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Deni J
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Ramu M
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Sandesh K
- Medical Gastroenterology, Government Medical College, Kottayam, IND
| | - Saji K Sebastian
- Gastroenterology and Hepatology, Government Medical College, Kottayam, IND
| | - Gaurav Khatana
- Gastroenterology and Hepatology, Government Medical College, Kottayam, IND
| | - Gino R Philip
- Gastroenterology and Hepatology, Government Medical College, Kottayam, IND
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Xirouchakis E, Kranidioti H, Hadziyanni E, Kourikou A, Reppas C, Vertzoni M, Papadopoulos N, Deutsch M, Papatheodoridis G, Manolakopoulos S. The effect of propranolol on gastrointestinal motility and permeability in patients with cirrhosis and significant portal hypertension. BMC Gastroenterol 2024; 24:420. [PMID: 39574005 PMCID: PMC11580216 DOI: 10.1186/s12876-024-03483-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 10/24/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Patients with cirrhosis and portal hypertension may have alterations in intestinal barrier resulting in increased susceptibility for infections. We investigated the effect of propranolol in gastrointestinal motility, permeability and bacterial overgrowth in cirrhosis. METHODS Patients with cirrhosis and esophageal varices were studied before and after a build-up dose of propranolol according to standard guidelines. Serum TNF-a, IL-6, IL-1b, LPS and bacterial DNA were measured before and during propranolol therapy. Oro-caecal transit time (OCTT) and bacterial overgrowth (BO) have been evaluated with H2 breath testing. Intestinal paracellular (IP), cellular passive non-carrier (ICNC), cellular passive carrier-mediated (ICCM), and gastric permeability (GP) were evaluated by measurement of lactulose, mannitol, D-xylose and sucrose respectively in urine, with high performance liquid chromatography (HPLC). RESULTS 35 patients with cirrhosis and portal hypertension with median age was 59.6 years (range 42-86) were included in the study. Twenty one had viral hepatitis and 25 were classified as having advanced cirrhosis (Child-Pugh B: 14 or C: 11). Median dose of administrated propranolol was 40 mg/day. After 7 days propranolol treatment BO was resolved in 15 out of 16 patients (93.7%, p = 0.0001) and OCTT was reduced significantly from 180 min to 139 min (SD 58.5, difference - 4 1 min, p = 0.0001). Serum IL-6 levels were reduced in 21/35 (60%) patients from 41.1 to 19 pg/ml (p = 0.01), TNF-a in 10/35 (28.5%) patients from 10.7 to 5.6 pg/ml (p = 0.007) and LPS in 20/35 (57%) from 7.1 to 5.2 mg/L (p = 0.1). No bacterial DNA was detected in serum of all patients either baseline or under propranolol treatment. IP was significantly reduced (0.2 to 0.16, p = 0.04) whereas ICNC (p = 0.9), ICCM (p = 0.4) and GP (p = 0.7) were not affected significantly. Intestinal Permeability (PI) index (Lactulose to Mannitol ratio) was significantly reduced (0.027 to 0.02, p = 0.03). CONCLUSION In patients with cirrhosis and portal hypertension, propranolol use is associated with reduction in BO, increase in intestinal motility and amelioration in intestinal permeability. Moreover IL-6 and LPS levels are being decreased in the majority of patients under propranolol.
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Affiliation(s)
- Elias Xirouchakis
- Gastroenterology-Liver-Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens "Hippocration", National and Kapodistrian University of Athens, Athens, Greece
- Department of Gastroenterology and Hepatology, Athens Medical - P. Faliron Hospital, Athens, Greece
| | - Hariklia Kranidioti
- Gastroenterology-Liver-Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens "Hippocration", National and Kapodistrian University of Athens, Athens, Greece
| | - Emilia Hadziyanni
- Gastroenterology-Liver-Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens "Hippocration", National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasia Kourikou
- Gastroenterology-Liver-Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens "Hippocration", National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Reppas
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Vertzoni
- Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Papadopoulos
- Gastroenterology-Liver-Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens "Hippocration", National and Kapodistrian University of Athens, Athens, Greece
| | - Melanie Deutsch
- Gastroenterology-Liver-Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens "Hippocration", National and Kapodistrian University of Athens, Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology National, Kapodistrian University of Athens Laiko General Hospital, Athens, Greece
| | - Spilios Manolakopoulos
- Gastroenterology-Liver-Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens "Hippocration", National and Kapodistrian University of Athens, Athens, Greece.
- Department of Gastroenterology National, Kapodistrian University of Athens Laiko General Hospital, Athens, Greece.
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Nautiyal N, Maheshwari D, Kumar D, Rao EP, Tripathi DM, Kumar S, Diwakar S, Bhardwaj M, Mohanty S, Baligar P, Kumari A, Bihari C, Biswas S, Sarin SK, Kumar A. Rejuvenating bone marrow hematopoietic reserve prevents regeneration failure and hepatic decompensation in animal model of cirrhosis. Front Immunol 2024; 15:1439510. [PMID: 39188716 PMCID: PMC11345600 DOI: 10.3389/fimmu.2024.1439510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/24/2024] [Indexed: 08/28/2024] Open
Abstract
Background and aim Bone marrow stem cells (BM-SCs) and their progeny play a central role in tissue repair and regeneration. In patients with chronic liver failure, bone marrow (BM) reserve is severally compromised and they showed marked defects in the resolution of injury and infection, leading to liver failure and the onset of decompensation. Whether BM failure is the cause or consequence of liver failure during cirrhosis is not known. In this study, we aimed to determine the underlying relationship between BM failure and regeneration failure in cirrhosis. Methodology C57Bl/6(J) mice were used to develop chronic liver injury through intra-peritoneal administration of carbon tetrachloride (CCl4) for 15 weeks (0.1-0.5 ml/kg). Animals were sacrificed to study the transition of cirrhosis and BM defects. To restore the BM-SC reserve; healthy BM cells were infused via intra-BM infusion and assessed for changes in liver injury, regeneration, and BM-SC reserve. Results Using a CCl4-induced animal - model of cirrhosis, we showed the loss of BM-SCs reserve occurred before regeneration failure and the onset of non-acute decompensation. Intra-BM infusion of healthy BM cells induced the repopulation of native hematopoietic stem cells (HSCs) in cirrhotic BM. Restoring BM-HSCs reserve augments liver macrophage-mediated clearance of infection and inflammation dampens neutrophil-mediated inflammation, accelerates fibrosis regression, enhances hepatocyte proliferation, and delays the onset of non-acute decompensation. Conclusion These findings suggest that loss of BM-HSCs reserve underlies the compromised innate immune function of the liver, drives regeneration failure, and the onset of non-acute decompensation. We further provide the proof-of-concept that rejuvenating BM-HSC reserve can serve as a potential therapeutic approach for preventing regeneration failure and transition to decompensated cirrhosis.
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Affiliation(s)
- Nidhi Nautiyal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India
| | - Deepanshu Maheshwari
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dhananjay Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - E. Pranshu Rao
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Dinesh Mani Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sandeep Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sunidhi Diwakar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manisha Bhardwaj
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Prakash Baligar
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India
| | - Anupama Kumari
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India
| | - S. K. Sarin
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Anupam Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Han J, Wei FL, Wu HX, Guo LY, Guo S, Han Y, Sun YN, Hou W, Hu ZJ. Clinical evaluation of droplet digital pcr for suspected ascites infection in patients with liver cirrhosis. Hepatol Int 2024; 18:1249-1260. [PMID: 38683274 DOI: 10.1007/s12072-024-10669-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/01/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND Droplet digital PCR (ddPCR) is increasingly used in diagnosing clinical pathogens, but its effectiveness in cirrhosis patients with suspected ascites infection remains uncertain. METHODS The diagnostic performance of ddPCR was assessed in 305 ascites samples, utilizing culture and clinical composite standards. The quantitative value and potential clinical impact of ddPCR were further analyzed in patients with spontaneous bacterial peritonitis. RESULTS With culture standards, ddPCR demonstrated a sensitivity of 86.5% and specificity of 83.2% for bacterial or fungal detection. After adjustment of clinical composite criteria, specificity increased to 96.4%. Better diagnostic performance for all types of targeted pathogens, particularly fungi, was observed with ddPCR compared to culture, and more polymicrobial infections were detected (30.4% versus 5.7%, p < 0.001). Pathogen loads detected by ddPCR correlated with white blood cell count in ascites and blood, as well as polymorphonuclear cell (PMN) count in ascites, reflecting infection status rapidly. A positive clinical impact of 55.8% (43/77) was observed for ddPCR, which was more significant among patients with PMN count ≤ 250/mm3 in terms of medication adjustment and new diagnosis. ddPCR results for fungal detection were confirmed by clinical symptoms and other microbiological tests, which could guide antifungal therapy and reduce the risk of short-term mortality. CONCLUSIONS ddPCR, with appropriate panel design, has advantages in pathogen detection and clinical management of ascites infection, especially for patients with fungal and polymicrobial infections. Patients with atypical spontaneous bacterial peritonitis benefited more from ddPCR.
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Affiliation(s)
- Jie Han
- Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing Institute of Hepatology, Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
| | - Fei-Li Wei
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing Institute of Hepatology, Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
| | - Hao-Xin Wu
- Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
| | - Lu-Yao Guo
- Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
| | - Shan Guo
- Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing Institute of Hepatology, Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
| | - Ying Han
- Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
| | - Ya-Nan Sun
- Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China
| | - Wei Hou
- Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China.
| | - Zhong-Jie Hu
- Beijing You'An Hospital, Capital Medical University, No. 8 You An Men Wai Street, Fengtai District, Beijing, 100069, China.
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Balazs I, Stadlbauer V. Circulating neutrophil anti-pathogen dysfunction in cirrhosis. JHEP Rep 2023; 5:100871. [PMID: 37822786 PMCID: PMC10562928 DOI: 10.1016/j.jhepr.2023.100871] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/16/2023] [Accepted: 07/22/2023] [Indexed: 10/13/2023] Open
Abstract
Neutrophils are the largest population of leucocytes and are among the first cells of the innate immune system to fight against intruding pathogens. In patients with cirrhosis, neutrophils exhibit altered functionality, including changes in phagocytic ability, bacterial killing, chemotaxis, degranulation, reactive oxygen species production and NET (neutrophil extracellular trap) formation. This results in their inability to mount an adequate antibacterial response and protect the individual from infection. Prognosis and survival in patients with cirrhosis are greatly influenced by the development of infectious complications. Multidrug-resistant bacterial infections in patients with cirrhosis are currently a growing problem worldwide; therefore, alternative methods for the prevention and treatment of bacterial infections in cirrhosis are urgently needed. The prevention and treatment of neutrophil dysfunction could be a potential way to protect patients from bacterial infections. However, the reasons for changes in neutrophil function in cirrhosis are still not completely understood, which limits the development of efficient therapeutic strategies. Both cellular and serum factors have been proposed to contribute to the functional impairment of neutrophils. Herein, we review the current knowledge on features and proposed causes of neutrophil dysfunction in cirrhosis, with a focus on current knowledge gaps and limitations, as well as opportunities for future investigations in this field.
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Affiliation(s)
- Irina Balazs
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
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Vasudevan D, Ramakrishnan A, Velmurugan G. Exploring the diversity of blood microbiome during liver diseases: Unveiling Novel diagnostic and therapeutic Avenues. Heliyon 2023; 9:e21662. [PMID: 37954280 PMCID: PMC10638009 DOI: 10.1016/j.heliyon.2023.e21662] [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: 06/06/2023] [Revised: 10/07/2023] [Accepted: 10/25/2023] [Indexed: 11/14/2023] Open
Abstract
Liver diseases are a group of major metabolic and immune or inflammation related diseases caused due to various reasons including infection, abnormalities in immune system, genetic defects, and lifestyle habits. However, the cause-effect relationship is not completely understood in liver disease. The role of microbiome, particularly, the role of gut and oral microbiome in liver diseases has been extensively studied in recent years. More interestingly, the presence of blood microbiome and tissue microbiome has been identified in many liver diseases. The translocation of microbes from the gut into the portal circulation has been attributed to be the major reason for the presence of blood microbial components and its clinical implications in liver disorders. Besides microbial translocation, Pathogen associated Molecular Patterns (PAMPs) derived from gut microbiota might also translocate. The presence of blood microbiome in liver disease has been reviewed earlier. However, the role of blood microbiome as a biomarker and therapeutic target in liver diseases has not been analysed earlier. In this review, we confabulate the origin and physiology of blood microbiome and blood microbial components in relation to the progression and pathogenesis of liver disease. In conclusion, we discuss the translational perspectives targeting the blood microbial components in the diagnosis and therapy of liver disease.
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Affiliation(s)
- Dinakaran Vasudevan
- Chemomicrobiomics Laboratory, Department of Biochemistry and Microbiology, KMCH Research Foundation, Coimbatore, 641014, Tamil Nadu, India
- Gut Microbiome Division, SKAN Research Trust, Bengaluru, 560034, Karnataka, India
| | - Arulraj Ramakrishnan
- Chemomicrobiomics Laboratory, Department of Biochemistry and Microbiology, KMCH Research Foundation, Coimbatore, 641014, Tamil Nadu, India
- Liver Unit, Kovai Medical Center and Hospital, Coimbatore, 641014, Tamil Nadu, India
| | - Ganesan Velmurugan
- Chemomicrobiomics Laboratory, Department of Biochemistry and Microbiology, KMCH Research Foundation, Coimbatore, 641014, Tamil Nadu, India
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Sturm L, Hirose M, Stolz L, Schultheiss M, Zoldan K, Reincke M, Huber JP, Kaeser R, Boettler T, Thimme R, Albert E, Busch H, Künstner A, Bettinger D. Proton pump inhibitor treatment aggravates bacterial translocation in patients with advanced cirrhosis and portal hypertension. mBio 2023; 14:e0049223. [PMID: 37623323 PMCID: PMC10653923 DOI: 10.1128/mbio.00492-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/02/2023] [Indexed: 08/26/2023] Open
Abstract
IMPORTANCE Long-term prescription of proton pump inhibitors (PPIs) in patients with cirrhosis is common practice. However, in recent years, several observational studies have reported increased complications and negative prognostic effects of PPI treatment in these patients. Judging the significance of these associations is complicated by the fact that a plausible underlying pathomechanism has not been identified so far. In the present study, we address this important issue by investigating the impact of PPI treatment on subclinical bacterial translocation from the gut into the blood stream in patients with advanced cirrhosis and portal hypertension. Indeed, we report significantly aggravated bacterial translocation in cirrhosis patients receiving PPI treatment. This finding is highly relevant, as bacterial translocation is known to promote the development of complications and impair prognosis in patients with cirrhosis. Hence, the present study could establish a plausible link between PPI treatment and adverse effects in cirrhosis.
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Affiliation(s)
- Lukas Sturm
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Misa Hirose
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Laura Stolz
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Katharina Zoldan
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Marlene Reincke
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Jan Patrick Huber
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Rafael Kaeser
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
- IMM-PACT-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Boettler
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
| | - Elisabeth Albert
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
| | - Hauke Busch
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Axel Künstner
- Luebeck Institute of Experimental Dermatology, University of Luebeck, Luebeck, Germany
- Institute for Cardiogenetics, University of Luebeck, Luebeck, Germany
| | - Dominik Bettinger
- Department of Medicine II, Faculty of Medicine, Medical Center University of Freiburg, Freiburg, Germany
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Adebayo D, Wong F. Pathophysiology of Hepatorenal Syndrome - Acute Kidney Injury. Clin Gastroenterol Hepatol 2023; 21:S1-S10. [PMID: 37625861 DOI: 10.1016/j.cgh.2023.04.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/14/2023] [Accepted: 04/06/2023] [Indexed: 08/27/2023]
Abstract
Hepatorenal syndrome is a complication of liver cirrhosis with ascites that results from the complex interplay of many pathogenetic mechanisms. Advanced cirrhosis is characterized by the development of hemodynamic changes of splanchnic and systemic arterial vasodilatation, with paradoxical renal vasoconstriction and renal hypoperfusion. Cirrhosis is also an inflammatory state. The inflammatory cascade is initiated by a portal hypertension-induced increased translocation of bacteria, bacterial products, and endotoxins from the gut to the splanchnic and then to the systemic circulation. The inflammation, whether sterile or related to infection, is responsible for renal microcirculatory dysfunction, microthrombi formation, renal tubular oxidative stress, and tubular damage. Of course, many of the bacterial products also have vasodilatory properties, potentially exaggerating the state of vasodilatation and worsening the hemodynamic instability in these patients. The presence of cardiac dysfunction, related to cirrhotic cardiomyopathy, with its associated systolic incompetence, can aggravate the mismatch between the circulatory capacitance and the circulation volume, worsening the extent of the effective arterial underfilling, with lower renal perfusion pressure, contributing to renal hypoperfusion and increasing the risk for development of acute kidney injury. The presence of tense ascites can exert an intra-abdominal compartmental syndrome effect on the renal circulation, causing renal congestion and hampering glomerular filtration. Other contributing factors to renal dysfunction include the tubular damaging effects of cholestasis and adrenal dysfunction. Future developments include the use of metabolomics to identify metabolic pathways that can lead to the development of renal dysfunction, with the potential of identifying biomarkers for early diagnosis of renal dysfunction and the development of treatment strategies.
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Affiliation(s)
- Danielle Adebayo
- Department of Gastroenterology, Royal Berkshire National Health Service Foundation Trust, Reading, United Kingdom
| | - Florence Wong
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Chen B, Song Y, Yang X, Yang J, Hao F. Bacterial DNA promoting inflammation via the Sgk1/Nedd4L/Syk pathway in mast cells contributes to antihistamine-nonresponsive CSU. J Leukoc Biol 2023; 113:461-470. [PMID: 36857592 DOI: 10.1093/jleuko/qiad025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/31/2022] [Accepted: 01/31/2023] [Indexed: 03/03/2023] Open
Abstract
Inflammation centered on non-IgE-mediated mast cell activation characterizes chronic spontaneous urticaria resistant to nonsedating H1-antihistamines. We recently uncovered a strong positive association between inflammation and the fecal Escherichia. To further explore the actions of bacterial DNA derived from Escherichia on mast cells, intestinal permeability of patients with chronic spontaneous urticaria with or without nonsedating H1-antihistamine resistance and healthy controls were determined, and LAD2 cells with knockdown of Syk, Nedd4L, or Sgk1 or with incubation of inhibitors GS9973, GSK650394, and MG132 were posttreated with btDNA. We found that (i) serum intestinal permeability indices and bacterial DNA markedly increased in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance compared with those without (all P < 0.001), and bacterial DNA positively correlated with the degree of inflammation; (ii) IL-6 and TNF-α levels were time- and dose-dependently upregulated in bacterial DNA-stimulated LAD2 cells, which relied on unmethylated CpG in bacterial DNA and Toll-like receptor 9 protein in cells; (iii) Syk knockdown or inhibition of Syk Tyr525/526 phosphorylation blocked bacterial DNA-initiated cytokine production; (iv) Nedd4L interacted with Tyr525/526-phosphorylated Syk, and inhibition of Nedd4L Ser448 phosphorylation induced by bacterial DNA-activated Sgk1 was mandatory for bacterial DNA's proinflammatory property; and (v) Sgk1 suppression showed an inhibitory effect on bacterial DNA-induced inflammation by ensuring Nedd4L-mediated ubiquitination of Tyr525/526-phosphorylated Syk. Collectively, we identified previously unknown contributory roles of bacterial translocation and serum bacterial DNA on the inflammation phenotype in patients with chronic spontaneous urticaria with nonsedating H1-antihistamine resistance and further uncovered a vital negative regulatory role for the Sgk1/Nedd4L/Syk pathway in bacterial DNA-induced inflammation in LAD2 cells.
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Affiliation(s)
- Bangtao Chen
- Department of Dermatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, No.165, Xincheng Road, Wanzhou District, Chongqing 400030, China
| | - Yao Song
- Department of Pediatrics, The Third Affiliated Hospital of Chongqing Medical University, No.1, Shuanghu Road, Yubei District, Chongqing 401120, China
- Department of Dermatology, The Third Affiliated Hospital of Chongqing Medical University, No.1, Shuanghu Road, Yubei District, Chongqing 401120, China
| | - Xiongbo Yang
- Department of Dermatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, No.165, Xincheng Road, Wanzhou District, Chongqing 400030, China
| | - Jing Yang
- Department of Dermatology, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, No.165, Xincheng Road, Wanzhou District, Chongqing 400030, China
| | - Fei Hao
- Department of Pediatrics, The Third Affiliated Hospital of Chongqing Medical University, No.1, Shuanghu Road, Yubei District, Chongqing 401120, China
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10
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Shahbazi A, Sepehrinezhad A, Vahdani E, Jamali R, Ghasempour M, Massoudian S, Sahab Negah S, Larsen FS. Gut Dysbiosis and Blood-Brain Barrier Alteration in Hepatic Encephalopathy: From Gut to Brain. Biomedicines 2023; 11:1272. [PMID: 37238943 PMCID: PMC10215854 DOI: 10.3390/biomedicines11051272] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/20/2023] [Accepted: 03/28/2023] [Indexed: 05/28/2023] Open
Abstract
A common neuropsychiatric complication of advanced liver disease, hepatic encephalopathy (HE), impacts the quality of life and length of hospital stays. There is new evidence that gut microbiota plays a significant role in brain development and cerebral homeostasis. Microbiota metabolites are providing a new avenue of therapeutic options for several neurological-related disorders. For instance, the gut microbiota composition and blood-brain barrier (BBB) integrity are altered in HE in a variety of clinical and experimental studies. Furthermore, probiotics, prebiotics, antibiotics, and fecal microbiota transplantation have been shown to positively affect BBB integrity in disease models that are potentially extendable to HE by targeting gut microbiota. However, the mechanisms that underlie microbiota dysbiosis and its effects on the BBB are still unclear in HE. To this end, the aim of this review was to summarize the clinical and experimental evidence of gut dysbiosis and BBB disruption in HE and a possible mechanism.
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Affiliation(s)
- Ali Shahbazi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran; (A.S.); (S.M.)
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran;
| | - Ali Sepehrinezhad
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran; (A.S.); (S.M.)
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran;
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Edris Vahdani
- Department of Microbiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 4815733971, Iran;
| | - Raika Jamali
- Research Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran 1417653761, Iran
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1417653761, Iran
| | - Monireh Ghasempour
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran;
| | - Shirin Massoudian
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran; (A.S.); (S.M.)
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 9815733169, Iran
| | - Fin Stolze Larsen
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Inge Lehmanns Vej 5, 2100 Copenhagen, Denmark
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11
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Preventing Bacterial Translocation in Patients with Leaky Gut Syndrome: Nutrition and Pharmacological Treatment Options. Int J Mol Sci 2022; 23:ijms23063204. [PMID: 35328624 PMCID: PMC8949204 DOI: 10.3390/ijms23063204] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/14/2022] [Accepted: 03/14/2022] [Indexed: 12/11/2022] Open
Abstract
Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation.
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12
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Wang Y, Dan K, Xue X, Yang X, Feng X, Yang Q, Yang J, Chen B. Translocating lipopolysaccharide correlates with the severity of enterovirus A71-induced HFMD by promoting pro-inflammation and viral IRES activity. Gut Pathog 2021; 13:69. [PMID: 34809671 PMCID: PMC8607650 DOI: 10.1186/s13099-021-00465-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/09/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The increase of inflammation-inducing enterobacteria was recently observed in severe hand, foot, and mouth disease (HFMD) caused by Enterovirus A71 (EV-A71). This study aimed to verify the occurrence of bacterial translocation (BT) and further explore the contributory role of BT to severity of EV-A71-mediated HFMD cases. METHODS Serum specimens from 65 mild and 65 severe EV-A71-associated HFMD cases and 65 healthy children were collected. EV-A71 VP1 in serum, inflammatory mediators including C-reactive protein, IL-1β, IL-6, interferon-γ and tumor necrosis factor-α, BT related biomarkers including Claudin-3, intestinal fatty acid binding protein, lipopolysaccharide (LPS), soluble CD14 (sCD14) and endotoxin core antibody were measured by ELISA. Bacterial DNA (BactDNA) fragments were quantified by quantified PCR (qPCR). Rhabdomyosarcoma (RD) or SH-SY5Y cells, infected with LPS-pre-incubated EV-A71 or transfected with plasmid containing viral 2Apro or mRNA containing viral internal ribosomal entry site (IRES), were post-treated with or without LPS in vitro. EV-A71 RNA and viral or cellular proteins were determined by qPCR and western blot, respectively. RESULTS Compared to mild HFMD patients, remarkably higher inflammatory mediators as well as BT-related biomarkers except BactDNA were observed in severe HFMD cases (all P < 0.05). In severe HFMD group, circulating concentrations of LPS and sCD14 showed statistical correlations with inflammation indices (all P < 0.05), serum levels of EV-A71 VP1 were found to be positively correlated with serum LPS (r = 0.341, P = 0.005) and serum sCD14 (r = 0.458, P < 0.001). In vitro, EV-A71 attachment and internalization were only slightly promoted by LPS pre-incubation; however, EV-A71 proliferation and viral 2Apro-mediated IRES activity were significantly accelerated by LPS post-treatment. CONCLUSIONS Our results collectively indicate that gut-derived translocating LPS contributes to the severity of EV-A71-induced HFMD by driving inflammatory response and viral proliferation via viral 2Apro-mediated IRES.
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Affiliation(s)
- Yuya Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
| | - Kena Dan
- Department of Dermatology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
| | - Xiaoling Xue
- Department of Hematology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China
| | - Xiongbo Yang
- Department of Dermatology, Chongqing University Three Gorges Hospital, Chongqing, 404100, China
| | - Xujiao Feng
- Department of Infectious Diseases, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, China
| | - Qingqing Yang
- Department of Infectious Diseases, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046000, China
| | - Jing Yang
- Department of Dermatology, Chongqing University Three Gorges Hospital, Chongqing, 404100, China.
| | - Bangtao Chen
- Department of Dermatology, Chongqing University Three Gorges Hospital, Chongqing, 404100, China.
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13
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Wang C, Zhang T, He L, Fu JY, Deng HX, Xue XL, Chen BT. Bacterial Translocation Associates With Aggression in Schizophrenia Inpatients. Front Syst Neurosci 2021; 15:704069. [PMID: 34658801 PMCID: PMC8511448 DOI: 10.3389/fnsys.2021.704069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 08/19/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: Accumulating evidence indicates that inflammation abnormalities may contribute to aggression behaviors in psychotic patients, however, the possible sources of inflammation remain elusive. We aimed to evaluate the associations among aggression, inflammation, and bacterial translocation (BT) in aggression-affected schizophrenia (ScZ) inpatients with 2 weeks of antipsychotics discontinuation. Methods: Serum specimens collected from 112 aggression and 112 non-aggression individuals with ScZ and 56 healthy adults were used for quantifications of inflammation- or BT-related biomarkers. Aggression severity was assessed by Modified Overt Aggression Scale (MOAS). Results: Proinflammation phenotype dominated and leaky gut-induced BT occurred only in cases with ScZ with a history of aggression, and the MOAS score positively related to levels of C-reactive protein, interleukin (IL)-6, IL-1β, and tumor necrosis factor-α. Furthermore, serum levels of BT-derived lipopolysaccharide (LPS), as well as LPS-responded soluble CD14, were not only positively correlated with levels of above proinflammation mediators but also the total MOAS score and subscore for aggression against objects or others. Conclusion: Our results collectively demonstrate the presence of leaky gut and further correlate BT-derived LPS and soluble CD14 to onset or severity of aggression possibly by driving proinflammation response in inpatients with ScZ, which indicates that BT may be a novel anti-inflammation therapeutic target for aggression prophylaxis.
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Affiliation(s)
- Chong Wang
- Department of Psychiatry, Zhumadian Psychiatric Hospital (The Second People's Hospital of Zhumadian), Zhumadian, China
| | - Teng Zhang
- Department of Psychiatry, Zhumadian Psychiatric Hospital (The Second People's Hospital of Zhumadian), Zhumadian, China
| | - Lei He
- Department of Psychiatry, Zhumadian Psychiatric Hospital (The Second People's Hospital of Zhumadian), Zhumadian, China
| | - Ji-Yong Fu
- Department of Psychiatry, Zhumadian Psychiatric Hospital (The Second People's Hospital of Zhumadian), Zhumadian, China
| | - Hong-Xin Deng
- Department of Psychiatry, Zhumadian Psychiatric Hospital (The Second People's Hospital of Zhumadian), Zhumadian, China
| | - Xiao-Ling Xue
- Department of Hematology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bang-Tao Chen
- Department of Dermatology, Chongqing University Three Gorges Hospital, Chongqing, China
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14
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Nishimura N, Kaji K, Kitagawa K, Sawada Y, Furukawa M, Ozutsumi T, Fujinaga Y, Tsuji Y, Takaya H, Kawaratani H, Moriya K, Namisaki T, Akahane T, Fukui H, Yoshiji H. Intestinal Permeability Is a Mechanical Rheostat in the Pathogenesis of Liver Cirrhosis. Int J Mol Sci 2021; 22:ijms22136921. [PMID: 34203178 PMCID: PMC8267717 DOI: 10.3390/ijms22136921] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Recent studies have suggested that an alteration in the gut microbiota and their products, particularly endotoxins derived from Gram-negative bacteria, may play a major role in the pathogenesis of liver diseases. Gut dysbiosis caused by a high-fat diet and alcohol consumption induces increased intestinal permeability, which means higher translocation of bacteria and their products and components, including endotoxins, the so-called "leaky gut". Clinical studies have found that plasma endotoxin levels are elevated in patients with chronic liver diseases, including alcoholic liver disease and nonalcoholic liver disease. A decrease in commensal nonpathogenic bacteria including Ruminococaceae and Lactobacillus and an overgrowth of pathogenic bacteria such as Bacteroidaceae and Enterobacteriaceae are observed in cirrhotic patients. The decreased diversity of the gut microbiota in cirrhotic patients before liver transplantation is also related to a higher incidence of post-transplant infections and cognitive impairment. The exposure to endotoxins activates macrophages via Toll-like receptor 4 (TLR4), leading to a greater production of proinflammatory cytokines and chemokines including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8, which play key roles in the progression of liver diseases. TLR4 is a major receptor activated by the binding of endotoxins in macrophages, and its downstream signal induces proinflammatory cytokines. The expression of TLR4 is also observed in nonimmune cells in the liver, such as hepatic stellate cells, which play a crucial role in the progression of liver fibrosis that develops into hepatocarcinogenesis, suggesting the importance of the interaction between endotoxemia and TLR4 signaling as a target for preventing liver disease progression. In this review, we summarize the findings for the role of gut-derived endotoxemia underlying the progression of liver pathogenesis.
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15
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Non-alcoholic fatty liver disease is associated with bacterial translocation and a higher inflammation response in psoriatic patients. Sci Rep 2021; 11:8593. [PMID: 33883616 PMCID: PMC8060289 DOI: 10.1038/s41598-021-88043-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 04/06/2021] [Indexed: 02/08/2023] Open
Abstract
Psoriasis and non-alcoholic fatty liver disease (NAFLD) are both inflammatory diseases. The study objective was to estimate the risk of NAFLD, non-alcoholic steatohepatitis, and liver fibrosis (by liver stiffness and liver biopsy) in patients with psoriasis and to determine the epidemiological, clinical, immunological (TNF-α, IL-2, IL-6, IL-12, IL-17, IL-23, and TGF-β) characteristics, and bacterial translocation. Of the 215 psoriatic patients included, 91 presented NAFLD (prevalence: 42.3%). Compared to patients with psoriasis alone, those with NAFLD were significantly more likely to have metabolic syndrome, diabetes, dyslipidemia, body mass index ≥ 30 kg/m2, homeostatic model assessment of insulin resistance ≥ 2.15, and greater psoriasis area severity index. NAFLD patients also had significantly higher levels of TNF-α (p = 0.002) and TGF-β (p = 0.007) and a higher prevalence of bacterial translocation (29.7% vs. 13.7%; p = 0.004). Liver stiffness measurement was over 7.8 kPa in 17.2% (15/87) of NAFLD patients; 13 of these underwent liver biopsy, and 5.7% (5/87) had liver fibrosis, while 1.1% (1/87) had advanced fibrosis or non-alcoholic steatohepatitis. In conclusion the prevalence of NAFLD in patients with psoriasis is high and associated with a higher prevalence of metabolic syndrome features, bacterial translocation and a higher pro-inflammatory state. It is worth mentioning that liver fibrosis and non-alcoholic steatohepatitis are not frequent in this population of patients.
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Abstract
Cirrhosis is the fifth leading cause of death in adults. Advanced cirrhosis can cause significant portal hypertension (PH), which is responsible for many of the complications observed in patients with cirrhosis, such as varices. If portal pressure exceeds a certain threshold, the patient is at risk of developing life-threatening bleeding from varices. Variceal bleeding has a high incidence among patients with liver cirrhosis and carries a high risk of mortality and morbidity. The management of variceal bleeding is complex, often requiring a multidisciplinary approach involving pharmacological, endoscopic, and radiologic interventions. In terms of management, three stages can be considered: primary prophylaxis, active bleeding, and secondary prophylaxis. The main goal of primary and secondary prophylaxis is to prevent variceal bleeding. However, active variceal bleeding is a medical emergency that requires swift intervention to stop the bleeding and achieve durable hemostasis. We describe the pathophysiology of cirrhosis and PH to contextualize the formation of gastric and esophageal varices. We also discuss the currently available treatments and compare how they fare in each stage of clinical management, with a special focus on drugs that can prevent bleeding or assist in achieving hemostasis.
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17
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Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol 2021; 18:167-180. [PMID: 33257833 DOI: 10.1038/s41575-020-00376-3] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 12/12/2022]
Abstract
The human gut microbiome has emerged as a major player in human health and disease. The liver, as the first organ to encounter microbial products that cross the gut epithelial barrier, is affected by the gut microbiome in many ways. Thus, the gut microbiome might play a major part in the development of liver diseases. The common end stage of liver disease is decompensated cirrhosis and the further development towards acute-on-chronic liver failure (ACLF). These conditions have high short-term mortality. There is evidence that translocation of components of the gut microbiota, facilitated by different pathogenic mechanisms such as increased gut epithelial permeability and portal hypertension, is an important driver of decompensation by induction of systemic inflammation, and thereby also ACLF. Elucidating the role of the gut microbiome in the aetiology of decompensated cirrhosis and ACLF deserves further investigation and improvement; and might be the basis for development of diagnostic and therapeutic strategies. In this Review, we focus on the possible pathogenic, diagnostic and therapeutic role of the gut microbiome in decompensation of cirrhosis and progression to ACLF.
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Affiliation(s)
- Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, Frankfurt, Germany. .,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain. .,Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. .,Institute for Bioengineering of Catalonia, Barcelona, Spain.
| | - Peer Bork
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Manimozhiyan Arumugam
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. .,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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18
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Yin XR, Liu P, Xu X, Xia Y, Huang KZ, Wang QD, Lai MM, Yu QG, Zheng XQ. Elevated plasma phage load as a marker for intestinal permeability in leukemic patients. Med Microbiol Immunol 2020; 209:693-703. [PMID: 32995957 DOI: 10.1007/s00430-020-00694-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Accepted: 09/18/2020] [Indexed: 01/16/2023]
Abstract
Microbial translocation (MT) and altered gut microbiota have been described in acute leukemic patients and contribute to immune activation and inflammation. However, phage translocation has not been investigated in leukemia patients yet. We recruited 44 leukemic patients and 52 healthy adults and quantified the levels of 3 phages in peripheral blood, which were the most positive phages screened from fecal samples. The content of 16S rRNA in plasma was detected by qPCR to assess the intestinal mucosa of these patients. Spearman's rank correlation was used to analyze the relationship between phage load and the relevant clinical data. We found the most prevalent phages in fecal samples were λ phage, Wphi phage, and P22 phage, and λ phage had the highest detection rate in plasma (68%). Phage content was affected by chemotherapy and course of disease and correlated with the levels of CRP (r = 0.43, p = 0.003), sCD14 (r = 0.37, p = 0.014), and sCD163 (r = 0.44, p = 0.003). Our data indicate that plasma phage load is a promising marker for gut barrier damage and that gut phage translocation correlates with monocyte/macrophage activation and systemic inflammatory response in leukemic patients.
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Affiliation(s)
- Xue-Rui Yin
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Ping Liu
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.,Qilu Children's Hospital of Shandong University, Jinan, 250000, China
| | - Xi Xu
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Ying Xia
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Kai-Zhao Huang
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Qiong-Dan Wang
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.,The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Mei-Mei Lai
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Qi-Gui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Xiao-Qun Zheng
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China. .,School of Laboratory Medicine and Life Sciences, The Key Laboratory of Laboratory Medicine, Ministry of Education of China, Wenzhou Medical University, University Town, Room 327, Tongren Building, Chashan, Wenzhou, 325000, Zhejiang, China.
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19
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Almenara S, Lozano B, Gimenez P, Herrera I, Miralles C, Bellot P, Rodríguez M, Francés R, Gonzalez-Navajas JM, Pascual S, Zapater P. Functionality of beta-adrenergic receptors in patients with cirrhosis treated chronically with non-selective beta-blockers. Hepatol Int 2020; 14:858-868. [DOI: 10.1007/s12072-020-10083-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 08/17/2020] [Indexed: 12/25/2022]
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Gut Microbiota and Liver Interaction through Immune System Cross-Talk: A Comprehensive Review at the Time of the SARS-CoV-2 Pandemic. J Clin Med 2020; 9:jcm9082488. [PMID: 32756323 PMCID: PMC7464500 DOI: 10.3390/jcm9082488] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
Background and aims: The gut microbiota is a complex ecosystem containing bacteria, viruses, fungi, yeasts and other single-celled organisms. It is involved in the development and maintenance of both innate and systemic immunity of the body. Emerging evidence has shown its role in liver diseases through the immune system cross-talk. We review herein literature data regarding the triangular interaction between gut microbiota, immune system and liver in health and disease. Methods: We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: gut microbiota, microbiome, gut virome, immunity, gastrointestinal-associated lymphoid tissue (GALT), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), alcoholic liver disease, liver cirrhosis, hepatocellular carcinoma. Results: The gut microbiota consists of microorganisms that educate our systemic immunity through GALT and non-GALT interactions. The latter maintain health but are also involved in the pathophysiology and in the outcome of several liver diseases, particularly those with metabolic, toxic or immune-mediated etiology. In this context, gut virome has an emerging role in liver diseases and needs to be further investigated, especially due to the link reported between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and hepatic dysfunctions. Conclusions: Changes in gut microbiota composition and alterations in the immune system response are involved in the pathogenesis of metabolic and immune-mediated liver diseases.
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Abstract
BACKGROUND AND AIMS Recurrence of spontaneous bacterial peritonitis (SBP) is still a matter of debate. We conducted this study to evaluate the probable factors that predict the recurrence of SBP in patients who recovered from the first episode of SBP and the long-term outcomes of SBP recurrence. METHODS One hundred twenty-four patients diagnosed with liver cirrhosis, SBP and did not receive secondary prophylaxis either with norfloxacin or other antibiotics were included in this prospective cohort pilot study. Clinical, biochemical and ascitic fluid analysis parameters were evaluated. Ascitic fluid interferon-γ-induced protein (IP-10), calprotectin, interleukin-6 and tumor necrosis factor-α were measured by ELISA. RESULTS Of these, 76 patients survived with an in-hospital mortality rate of 38.7%. The survivors were classified into two groups according to recurrence and nonrecurrence of SBP and survival time, clinical parameters and cause of death were investigated. Thirty-one participants had one or more attacks of SBP, with a recurrence rate of 40.8% within one-year follow-up. Before discharge, multivariate analysis showed that ascitic IP-10 (≥1220 pg/ml), ascitic calprotectin (≥550 ng/ml), serum albumin (≤2.5 g/dl), nonuse of prophylactic β-blockers and use of proton-pump inhibitors (PPIs) were the independent variables in predicting recurrent SBP. Sepsis-related organ failure was the most common etiology of mortality in the recurrent SBP group within 3 and 6 months. CONCLUSION Increased ascitic calprotectin and IP-10, hypoalbuminemia, nonuse of prophylactic β-blockers and use of PPI were independently associated with increased SBP recurrence rate. Sepsis-related organ failure was the most common etiology of mortality.
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Park J, Kim BW, Choi HJ, Hong SH, Park CS, Choi JH, Chae MS. Risk stratification for early bacteremia after living donor liver transplantation: a retrospective observational cohort study. BMC Surg 2020; 20:2. [PMID: 32160890 PMCID: PMC7066734 DOI: 10.1186/s12893-019-0658-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/27/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND This study investigated perioperative clinical risk factors for early post-transplant bacteremia in patients undergoing living donor liver transplantation (LDLT). Additionally, postoperative outcomes were compared between patients with and without early post-transplant bacteremia. METHODS Clinical data of 610 adult patients who underwent elective LDLT between January 2009 and December 2018 at Seoul St. Mary's Hospital were retrospectively collected. The exclusion criteria included overt signs of infection within 1 month before surgery. A total of 596 adult patients were enrolled in this study. Based on the occurrence of a systemic bacterial infection after surgery, patients were classified into non-infected and infected groups. RESULTS The incidence of bacteremia at 1 month after LDLT was 9.7% (57 patients) and Enterococcus faecium (31.6%) was the most commonly cultured bacterium in the blood samples. Univariate analysis showed that preoperative psoas muscle index (PMI), model for end-stage disease score, utility of continuous renal replacement therapy (CRRT), ascites, C-reactive protein to albumin ratio, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio, and sodium level, as well as intraoperative post-reperfusion syndrome, mean central venous pressure, requirement for packed red blood cells and fresh frozen plasma, hourly fluid infusion and urine output, and short-term postoperative early allograft dysfunction (EAD) were associated with the risk of early post-transplant bacteremia. Multivariate analysis revealed that PMI, the CRRT requirement, the NLR, and EAD were independently associated with the risk of early post-transplant bacteremia (area under the curve: 0.707; 95% confidence interval: 0.667-0.745; p < 0.001). The overall survival rate was better in the non-infected patient group. Among patients with bacteremia, anti-bacterial treatment was unable to resolve infection in 34 patients, resulting in an increased risk of patient mortality. Among the factors included in the model, EAD was significantly correlated with non-resolving infection. CONCLUSIONS We propose a prognostic model to identify patients at high risk for a bloodstream bacterial infection; furthermore, our findings support the notion that skeletal muscle depletion, CRRT requirement, systemic inflammatory response, and delayed liver graft function are associated with a pathogenic vulnerability in cirrhotic patients who undergo LDLT.
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Affiliation(s)
- Jaesik Park
- Department of Anesthesiology and Pain medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Bae Wook Kim
- Department of Anesthesiology and Pain medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang Hyun Hong
- Department of Anesthesiology and Pain medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Chul Soo Park
- Department of Anesthesiology and Pain medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Jong Ho Choi
- Department of Anesthesiology and Pain medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Min Suk Chae
- Department of Anesthesiology and Pain medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
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Zhang Y, Lou JW, Kang A, Zhang Q, Zhou SK, Bao BH, Cao YD, Yao WF, Tang YP, Zhang L. Kansuiphorin C and Kansuinin A ameliorate malignant ascites by modulating gut microbiota and related metabolic functions. JOURNAL OF ETHNOPHARMACOLOGY 2020; 249:112423. [PMID: 31765764 DOI: 10.1016/j.jep.2019.112423] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 11/10/2019] [Accepted: 11/21/2019] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Euphorbia kansui is a toxic Chinese herbal medicine and exhibits promising treatment to the malignant ascites (MA) in its traditional use. Ingenane-type and jastrophane-type diterpenes are demonstrated to be responsible for the toxicity and efficacy of kansui. Two representative compounds, kansuiphorin C (KPC) and kansuinin A (KA) in each type were proved to effectively reduce the ascites. The biological and toxicological effects are closely associated with the gastrointestinal tract, but the possible mechanism and related metabolic functions of KPC and KA treating MA through modulating the gut microbiota remain unclear. AIM OF THE STUDY To investigate the possible mechanism and related metabolism of KPC and KA ameliorating malignant ascites through modulating gut microbiota. MATERIALS AND METHODS MA rats and normal rats were divided into different groups and administrated with KPC, KA, and positive drug, respectively. 16S rDNA gene sequencing and metagenomes analysis combined with the quantification of short-chain fatty acids of feces were performed to reflect the modulation of gut microbiota. Then, the metabolites of KPC and KA in rat feces under the normal and pathological circumstances were detected by ultra-fast liquid chromatography coupled with MS/MS detector (UFLC-MS/MS) to explore the in-vivo bacterial biotransformation. RESULTS KPC and KA were modulatory compounds for gut microbiota. The richness of Lactobacillus and the decreased abundance of Helicobacter involved in the carbohydrate metabolism and amino acid metabolism could be responsible for their prohibitory effects on malignant ascites. KPC exhibited stronger modulation of gut microbiota through making the abundance of Helicobacter about 3.5 times lower than KA. Besides, in-vivo microbial biotransformation of KPC and KA contained oxidation, hydrolysis, dehydration, and methylation to form metabolites of lower polarity. Besides, at the dosage of 10 mg kg-1, the toxicity of both compounds had weaker influences on the gut microbiota of normal rats. CONCLUSION KPC and KA could ameliorate malignant ascites by modulating gut microbiota mainly containing the increase of Lactobacillus and the decrease of Helicobacter and related carbohydrate and amino acid metabolism, providing a basis for their promising clinical usage.
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Affiliation(s)
- Yi Zhang
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - Jian-Wei Lou
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - An Kang
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - Qiao Zhang
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - Shi-Kang Zhou
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - Bei-Hua Bao
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - Yu-Dan Cao
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - Wei-Feng Yao
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China
| | - Yu-Ping Tang
- Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, Shaanxi University of Chinese Medicine, Xi'an, 712046, Shaanxi Province, PR China
| | - Li Zhang
- Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine and Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, No.138, Xianlin Road, Qixia District, Nanjing, 210023, PR China.
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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: 84] [Impact Index Per Article: 14.0] [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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Tsien C, Antonova L, Such J, Garcia-Martinez I, Wong F. Impact of Bacterial Translocation on Sarcopenia in Patients with Decompensated Cirrhosis. Nutrients 2019; 11:nu11102379. [PMID: 31590379 PMCID: PMC6836001 DOI: 10.3390/nu11102379] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 12/14/2022] Open
Abstract
Advanced liver disease is associated with a persistent inflammatory state, derived from abnormal bacterial translocation from the gut, which may contribute to the development of sarcopenia in cirrhosis. We aim to document the association of chronic inflammation and bacterial translocation with the presence of sarcopenia in cirrhosis. We prospectively followed cirrhotic patients aged 18-70 years with medically refractory ascites at a single tertiary care center in Toronto, Canada. The baseline data included patient demographic variables, the presence of bacterial DNA in serum/ascitic fluid, systemic inflammatory response syndrome (SIRS) status, and nutritional assessment. Thirty-one patients were enrolled, 18 (58.1%) were sarcopenic, 9 (29%) had bacterial DNA in serum and ascites fluid. The mean MELD score was 11.5 ± 4.0 (6-23). Sarcopenic and non-sarcopenic patients did not differ significantly in their baseline MELD scores, caloric intake, resting energy expenditure, the incidence of bacterial translocation, or SIRS. While sarcopenia was not linked to increased hospital admissions or death, it was strongly associated with increased episodes of acute kidney injury (3 vs. 0, p = 0.05). This pilot study did not demonstrate an association between sarcopenia and SIRS or bacterial translocation. These results should be confirmed in future larger studies, encompassing a greater number of chronic inflammation events and quantifying levels of bacterial DNA.
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Affiliation(s)
- Cynthia Tsien
- Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
- Department of Medicine, the Ottawa Hospital, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
| | - Lilia Antonova
- Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
| | - Jose Such
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE.
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA.
| | - Irma Garcia-Martinez
- CIBERehd Hospital general Universitario de Alicante, 03010 Alicante, Spain.
- Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Florence Wong
- Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, ON M5G 2C4, Canada.
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Hispán P, Murcia O, Gonzalez-Villanueva I, Francés R, Giménez P, Riquelme J, Betlloch I, Pascual JC. Identification of bacterial DNA in the peripheral blood of patients with active hidradenitis suppurativa. Arch Dermatol Res 2019; 312:159-163. [DOI: 10.1007/s00403-019-01965-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/23/2019] [Accepted: 06/15/2019] [Indexed: 12/22/2022]
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Portilla I, Reus S, León R, van-der Hofstadt C, Sánchez J, López N, Boix V, Merino E, Portilla J. Neurocognitive Impairment in Well-Controlled HIV-Infected Patients: A Cross-Sectional Study. AIDS Res Hum Retroviruses 2019; 35:634-641. [PMID: 30880401 DOI: 10.1089/aid.2018.0279] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The reported prevalence of HIV-associated neurocognitive disorders in HIV people depends on the population studied and the methodology used. We analyze the prevalence of neurocognitive impairment (NCI) and associated factors in patients on successful antiretroviral therapy (ART), without comorbidities. Cross-sectional observational study in HIV subjects, ≥18 years old, on stable ART, and HIV viral load of <50 copies/mL. Patients with medical or psychiatric comorbidities and substance abuse were excluded. NCI was diagnosed using Frascati criteria, examining seven neurocognitive domains (NDs). We analyzed the association between NCI and HIV-related clinical variables, carotid intima-media thickness, bacterial translocation, and plasma inflammatory biomarkers [soluble CD14, interleukin-6 (IL-6), and tumor necrosis factor-α]. The prevalence of NCI was calculated with a 95% confidence interval (CI). We fitted a logistic regression model to assess the strength of the associations. Eighty-four patients were included with an observed NCI prevalence of 29.8% (95% CI: 21.0-40.2): 19% had asymptomatic NCI, 8.3% had mild neurocognitive disorder, and 2.4% had HIV-associated dementia. Delayed recall was the most commonly affected ND (27.4%). People diagnosed at least 10 years ago (odds ratio [OR]: 6.5, 95% CI: 1.6-21.7) and those with IL-6 levels above 1.8 pg/mL (OR: 6.0, 95% CI: 1.1-31.3) showed higher odds of NCI in adjusted analyses. Participants with carotid plaques had lower scores for delayed recall: -0.9 ± 1.1 versus -0.2 ± 1.1 (p = .04). Prevalence of NCI is high in otherwise healthy adults with HIV-infection. In this population, more than 10 years since HIV diagnosis and high IL-6 levels are associated with NCI. Delayed recall ND is worse in patients with subclinical atherosclerosis.
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Affiliation(s)
- Irene Portilla
- Department of Infectious Diseases, General University Hospital of Alicante, Alicante, Spain
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
- Department of Health Psychology, Alicante University, Alicante, Spain
| | - Sergio Reus
- Department of Infectious Diseases, General University Hospital of Alicante, Alicante, Spain
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
- Department of Clinical Medicine, Miguel Hernández University, Alicante, Spain
| | - Rafael León
- Department of Infectious Diseases, General University Hospital of Alicante, Alicante, Spain
| | - Carlos van-der Hofstadt
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
- Department of Clinical Psychology, General University Hospital of Alicante, Alicante, Spain
- Department of Health Psychology, Miguel Hernández University, Alicante, Spain
| | - José Sánchez
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
- Department of Epidemiology and Public Health, General University Hospital of Alicante, Alicante, Spain
| | - Nicolás López
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
- Department of Neurology, General University Hospital of Alicante, Alicante, Spain
| | - Vicente Boix
- Department of Infectious Diseases, General University Hospital of Alicante, Alicante, Spain
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
- Department of Clinical Medicine, Miguel Hernández University, Alicante, Spain
| | - Esperanza Merino
- Department of Infectious Diseases, General University Hospital of Alicante, Alicante, Spain
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
| | - Joaquín Portilla
- Department of Infectious Diseases, General University Hospital of Alicante, Alicante, Spain
- HIV and Infectious Diseases Researching Group, Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
- Department of Health Psychology, Alicante University, Alicante, Spain
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Morbidity and mortality after transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis. Eur J Gastroenterol Hepatol 2019; 31:626-632. [PMID: 30550458 DOI: 10.1097/meg.0000000000001342] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Transjugular intrahepatic portosystemic shunt (TIPS) is adopted to treat refractory complications of portal hypertension, such as variceal bleeding and ascites. This study aimed to assess predictors of hepatic encephalopathy (HE) development and cumulative transplant-free survival after TIPS placement in patients with cirrhosis complicated by refractory ascites and major gastroesophageal bleeding. MATERIALS AND METHODS Sixty-three cirrhotic patients who underwent TIPS positioning as a secondary prophylaxis of major upper gastroesophageal bleeding (N=30) or to control refractory ascites (N=33) were enrolled. RESULTS After a median follow-up of 26 months following TIPS insertion, only 1/30 (3.3%) patients developed reoccurrence of bleeding. Complete control of refractory ascites was recorded in 19/23 (82.6%) patients. Within the first month after TIPS placement, 34/63 (53.9%) patients developed clinically significant HE, which was associated with the baseline presence of type 2 hepatorenal syndrome (P=0.022). At the end of 90 months of follow-up, 35 (55.6%) patients were alive, 12 (19.0%) patients underwent liver transplantation, and 16 (25.4%) patients died. Independent predictors of transplant-free survival were a model for end-stage liver disease score up to 15 (P<0.001), the absence of a history of spontaneous bacterial peritonitis (P=0.010) pre-TIPS, and no HE within 1 month post-TIPS (P=0.040). CONCLUSION TIPS insertion can be considered a safe and effective treatment in patients with cirrhosis and severe complications of portal hypertension that are not manageable with standard treatments. Interestingly, if confirmed in future studies, the history of spontaneous bacterial peritonitis pre-TIPS could be added to the model for end-stage liver disease score as a strong baseline predictor of post-TIPS mortality.
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Irvine KM, Ratnasekera I, Powell EE, Hume DA. Causes and Consequences of Innate Immune Dysfunction in Cirrhosis. Front Immunol 2019; 10:293. [PMID: 30873165 PMCID: PMC6401613 DOI: 10.3389/fimmu.2019.00293] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 02/05/2019] [Indexed: 12/15/2022] Open
Abstract
Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. At the two extremes of the CAID spectrum are systemic inflammation, which can exacerbate clinical manifestations of cirrhosis such as hemodynamic derangement and kidney injury; and immunodeficiency, which contributes to the high rate of infection in patients with decompensated cirrhosis. Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies.
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Affiliation(s)
- Katharine Margaret Irvine
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Isanka Ratnasekera
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Elizabeth E. Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - David Arthur Hume
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
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Bacterial DNA translocation contributes to systemic inflammation and to minor changes in the clinical outcome of liver transplantation. Sci Rep 2019; 9:835. [PMID: 30696924 PMCID: PMC6351615 DOI: 10.1038/s41598-018-36904-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/21/2018] [Indexed: 12/19/2022] Open
Abstract
Bacterial (bact)DNA is an immunogenic product that frequently translocates into the blood in cirrhosis. We evaluated bactDNA clearance in patients undergoing liver transplantation (LT) and its association with inflammation and clinically relevant complications. We prospectively included patients consecutively admitted for LT in a one-year follow-up study. We evaluated bactDNA before and during the first month after LT, quantifying cytokine response at 30 days. One hundred patients were included. BactDNA was present in the blood of twenty-six patients undergoing LT. Twenty-four of these showed bactDNA in the portal vein, matching peripheral blood-identified bactDNA in 18 cases. Thirty-four patients showed bactDNA in blood during the first month after LT. Median TNF-α and IL-6 levels one month after LT were significantly increased in patients with versus without bactDNA. Serum TNF-α at baseline was an independent risk factor for bactDNA translocation during the first month after LT in the multivariate analysis (Odds ratio (OR) 1.14 [1.04 to 1.29], P = 0.015). One-year readmission was independently associated with the presence of bactDNA during the first month after LT (Hazard ratio (HR) 2.75 [1.39 to 5.45], P = 0.004). The presence of bactDNA in the blood of LT recipients was not shown to have any impact on complications such as death, graft rejection, bacterial or CMV infections. The rate of bactDNA translocation persists during the first month after LT and contributes to sustained inflammation. This is associated with an increased rate of readmissions in the one-year clinical outcome after LT.
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Whittle E, Leonard MO, Harrison R, Gant TW, Tonge DP. Multi-Method Characterization of the Human Circulating Microbiome. Front Microbiol 2019; 9:3266. [PMID: 30705670 PMCID: PMC6345098 DOI: 10.3389/fmicb.2018.03266] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 12/17/2018] [Indexed: 01/14/2023] Open
Abstract
The term microbiome describes the genetic material encoding the various microbial populations that inhabit our body. Whilst colonization of various body niches (e.g., the gut) by dynamic communities of microorganisms is now universally accepted, the existence of microbial populations in other "classically sterile" locations, including the blood, is a relatively new concept. The presence of bacteria-specific DNA in the blood has been reported in the literature for some time, yet the true origin of this is still the subject of much deliberation. The aim of this study was to investigate the phenomenon of a "blood microbiome" by providing a comprehensive description of bacterially derived nucleic acids using a range of complementary molecular and classical microbiological techniques. For this purpose we utilized a set of plasma samples from healthy subjects (n = 5) and asthmatic subjects (n = 5). DNA-level analyses involved the amplification and sequencing of the 16S rRNA gene. RNA-level analyses were based upon the de novo assembly of unmapped mRNA reads and subsequent taxonomic identification. Molecular studies were complemented by viability data from classical aerobic and anaerobic microbial culture experiments. At the phylum level, the blood microbiome was predominated by Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes. The key phyla detected were consistent irrespective of molecular method (DNA vs. RNA), and consistent with the results of other published studies. In silico comparison of our data with that of the Human Microbiome Project revealed that members of the blood microbiome were most likely to have originated from the oral or skin communities. To our surprise, aerobic and anaerobic cultures were positive in eight of out the ten donor samples investigated, and we reflect upon their source. Our data provide further evidence of a core blood microbiome, and provide insight into the potential source of the bacterial DNA/RNA detected in the blood. Further, data reveal the importance of robust experimental procedures, and identify areas for future consideration.
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Affiliation(s)
- Emma Whittle
- School of Life Sciences, Faculty of Natural Sciences, Keele University, Keele, United Kingdom
| | - Martin O. Leonard
- Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, United Kingdom
| | - Rebecca Harrison
- School of Life Sciences, Faculty of Natural Sciences, Keele University, Keele, United Kingdom
| | - Timothy W. Gant
- Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, United Kingdom
| | - Daniel Paul Tonge
- School of Life Sciences, Faculty of Natural Sciences, Keele University, Keele, United Kingdom
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Determinación de la microbiota intestinal en pacientes cirróticos de población mestizo-mexicana. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2019; 84:26-35. [DOI: 10.1016/j.rgmx.2018.02.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/08/2018] [Accepted: 02/26/2018] [Indexed: 12/11/2022]
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Pérez-Monter C, Escalona-Nandez I, Estanes-Hernández A, Noriega-López L, Torre-Delgadillo A. Intestinal microbiota assessment in cirrhotic patients from a Mexican mestizo population. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2019. [DOI: 10.1016/j.rgmxen.2018.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Malli E, Gatselis NK, Dalekos GN, Petinaki E. Combination of vial culture and broad-range PCR for the diagnosis of spontaneous bacterial peritonitis: experience in a Greek tertiary care hospital. New Microbes New Infect 2018; 28:1-5. [PMID: 30671251 PMCID: PMC6330367 DOI: 10.1016/j.nmni.2018.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/30/2018] [Accepted: 12/03/2018] [Indexed: 12/15/2022] Open
Abstract
Spontaneous bacterial peritonitis (SBP) is often difficult to diagnose because bacteria in ascites cannot be detected accurately by conventional culture. In this study, we evaluated the use of broad-range 16S rRNA PCR, applied either directly to a total of 32 ascitic fluids (AFs) or to the AF vial cultures, after a long incubation of 14 days; the results were compared with those of AF vial cultures. Escherichia coli was isolated in four of 32 AF vial cultures (12.5%). The application of 16S rRNA PCR directly to AF detected only one of the four positive samples (sensitivity 25%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value (NPV) 90.32%). However, the application of 16S rRNA PCR to AF vial cultures after 14 days of incubation correctly identified all the positive samples, including one more that was positive for Brucella mellitensis (sensitivity 100%, specificity 80%, PPV 80%, NPV 100%). The elongation of the incubation period of the AF vial cultures, combined with the use of 16S rRNA in negative vials, increases the possibility of identifying the causative agents of SBP and could be applied in the clinical laboratory.
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Affiliation(s)
- E Malli
- )Department of Microbiology, University Hospital of Larissa, Larissa, Greece
| | - N K Gatselis
- )Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - G N Dalekos
- )Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - E Petinaki
- )Department of Microbiology, University Hospital of Larissa, Larissa, Greece
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Gimenez P, Garcia‐Martinez I, Francés R, Gonzalez‐Navajas JM, Mauri M, Alfayate R, Almenara S, Miralles C, Palazon JM, Carnicer F, Pascual S, Such J, Horga JF, Zapater P. Treatment with non-selective beta-blockers affects the systemic inflammatory response to bacterial DNA in patients with cirrhosis. Liver Int 2018; 38:2219-2227. [PMID: 29802788 PMCID: PMC6282820 DOI: 10.1111/liv.13890] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 05/20/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The use of non-selective beta-blockers has been associated with lower rates of infection and reduced infection-associated morbidity in patients with cirrhosis. However, it is unknown if these drugs modify the systemic inflammatory response to circulating bacterial DNA. METHODS Sixty-three patients with cirrhosis were included during an episode of decompensation by ascites. Thirty of those patients were on beta-blockers. Blood samples were obtained after each patient had been in the supine position for at least 30 minutes in a quiet atmosphere. Bacterial DNA, serum cytokines, nitric oxide, and LPS were determined. Phagocytic and oxidative burst activities were determined in polymorphonuclear cells from the patients. RESULTS The detection rate of bacterial DNA in the blood was the same (33%) for patients not treated and treated with non-selective beta-blockers. Patients naive to non-selective beta-blockers showed significantly higher serum levels of IL6, IFN-gamma and IL10 in response to the presence of bacterial DNA. Patients treated with non-selective beta-blockers showed higher basal inflammatory activity that did not change with the presence of bacterial DNA. Monocytes and granulocytes from patients treated with non-selective beta-blockers showed a significantly increased phagocytic capacity in the presence of bacterial DNA. CONCLUSIONS In patients with cirrhosis, chronic treatment with beta-blockers is associated with a higher unstimulated production of serum cytokines and an increased phagocytic activity in the presence of bacterial DNA.
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Affiliation(s)
| | | | - Rubén Francés
- CIBERehdInstituto de Salud Carlos IIIMadridSpain,Departamento Medicina ClínicaUniversidad Miguel HernándezElche, AlicanteSpain
| | | | - Montserrat Mauri
- Servicio de Análisis ClínicosHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain
| | - Rocío Alfayate
- Servicio de Análisis ClínicosHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain
| | - Susana Almenara
- Unidad de Farmacología ClínicaHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain
| | - Cayetano Miralles
- Unidad HepáticaHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain
| | - Jose M. Palazon
- CIBERehdInstituto de Salud Carlos IIIMadridSpain,Departamento Medicina ClínicaUniversidad Miguel HernándezElche, AlicanteSpain,Unidad HepáticaHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain
| | - Fernando Carnicer
- Unidad HepáticaHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain
| | - Sonia Pascual
- CIBERehdInstituto de Salud Carlos IIIMadridSpain,Unidad HepáticaHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain
| | - José Such
- Digestive Disease InstituteCleveland Clinic Abu DhabiAbu DhabiUAE,Lerner School of MedicineCase Western Reserve UniversityClevelandOHUSA
| | - José F. Horga
- Unidad de Farmacología ClínicaHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain,Instituto de BioingenieriaUniversidad Miguel HernándezElche, AlicanteSpain
| | - Pedro Zapater
- CIBERehdInstituto de Salud Carlos IIIMadridSpain,Unidad de Farmacología ClínicaHospital General Universitario de AlicanteInstituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL‐Fundación FISABIO)AlicanteSpain,Instituto de BioingenieriaUniversidad Miguel HernándezElche, AlicanteSpain
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Chen Y, Guo J, Shi D, Fang D, Chen C, Li L. Ascitic Bacterial Composition Is Associated With Clinical Outcomes in Cirrhotic Patients With Culture-Negative and Non-neutrocytic Ascites. Front Cell Infect Microbiol 2018; 8:420. [PMID: 30555804 PMCID: PMC6284044 DOI: 10.3389/fcimb.2018.00420] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 11/16/2018] [Indexed: 12/12/2022] Open
Abstract
Ascites bacterial burden is associated with poor clinical outcomes in patients with end-stage liver disease. However, the impact of ascitic microbial composition on clinical course was still not clear. In this study, the ascitic microbiota composition of 100 cirrhotic patients with culture-negative and non-neutrocytic ascites were researched with 16S rRNA pyrosequencing and enterotype-like cluster analysis. Results: By characterizing the ascitic microbial composition, two distinct microbial clusters were observed, Cluster 1 (86 patients) and Cluster 2 (14 patients). Cluster 1 showed lower microbial richness than Cluster 2. At the phylum level, Cluster 1 had greater abundance of Bacteroidetes and Firmicutes, but less abundance of Proteobacteria and Actinobacteria than Cluster 2. At the family level, family Bacteroidales S24-7 group, Prevotellaceae, Lachnospiraceae, Lactobacillaceae, Rikenellaceae, and Vibrionaceae were found over-represented in Cluster 1. And family Acetobacteraceae, Erysipelotrichaceae, Rickettsiaceae, and Streptococcaceae were found enriched in Cluster 2. The levels of plasma cytokine IL-17A, IL-7, and PDGF-BB were found significantly higher in Cluster 1 than in Cluster 2. There were four OTUs closely correlated with plasma cytokines, which were OTU 140 and OTU 271 (both from Bacteroidales S24-7 group), OTU 68 (Veillonellaceae), and OTU 53 (Helicobacteraceae). Patients from Cluster 1 showed significant higher short-term mortality than patients from Cluster 2. Conclusion: Our study demonstrated that the microbial composition of culture-negative and non-neutrocytic ascites in cirrhotic patients is associated with short-term clinical outcomes. The results here offer a rational for the identification of patients with high risk, and provide references for selective use of prophylactic methods.
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Affiliation(s)
- Yanfei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jing Guo
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Daiqiong Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Chunlei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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Ponziani FR, Zocco MA, Cerrito L, Gasbarrini A, Pompili M. Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications. Expert Rev Gastroenterol Hepatol 2018; 12:641-656. [PMID: 29806487 DOI: 10.1080/17474124.2018.1481747] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gut liver axis is an operative unit that works to protect the human body against potentially harmful substances and microorganisms, maintaining the homeostasis of the immune system. Liver cirrhosis profoundly alters this complex system. The intestine becomes more permeable allowing the translocation of bacteria, bacterial products and fragments into the portal circulation, triggering an abnormal local and systemic inflammatory response and a condition of perpetual immunologic alarm. This immune-inflammatory disorder related to dysbiosis is involved in the development of liver damage and liver cirrhosis complications and increases intestinal permeability in a vicious circle. Areas covered: The most relevant studies on bacterial translocation, the mechanism of intestinal barrier dysfunction and its consequences in patients with liver cirrhosis have been revised through a PubMed search. Data have been discussed with particular regard to their significance in clinical practice. Expert commentary: The assessment of bacterial translocation and intestinal permeability is not currently used in clinical practice but may be useful to stratify patients' prognosis.
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Affiliation(s)
- Francesca Romana Ponziani
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maria Assunta Zocco
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Lucia Cerrito
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Antonio Gasbarrini
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maurizio Pompili
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
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Enomoto H, Inoue SI, Matsuhisa A, Iwata Y, Aizawa N, Sakai Y, Takata R, Ikeda N, Hasegawa K, Nakano C, Nishimura T, Yoh K, Miyamoto Y, Ishii N, Yuri Y, Ishii A, Takashima T, Nishikawa H, Iijima H, Nishiguchi S. Amplification of bacterial genomic DNA from all ascitic fluids with a highly sensitive polymerase chain reaction. Mol Med Rep 2018; 18:2117-2123. [PMID: 29901148 PMCID: PMC6072169 DOI: 10.3892/mmr.2018.9159] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Accepted: 04/06/2018] [Indexed: 12/21/2022] Open
Abstract
Due to varying positive rates of polymerase chain reaction (PCR) amplification, interpretation of conventional PCR results for non-infectious ascites remains problematic. The present study developed a highly sensitive PCR protocol and investigated the positive rate of PCR for the 16S ribosomal (r)RNA gene in non-infectious ascites. Following the design of a new PCR primer pair for the 16S rRNA gene (800F and 1400R), the sequences of PCR products were analyzed and the lower limit for bacterial DNA detection evaluated. The positive rate of PCR for 16S rRNA gene in non-infectious ascites was also evaluated. PCR with the primer pair amplified the genomic DNA of 16S rRNA genes of major disease-causing bacterial strains. Additionally, PCR with this primer pair provided highly sensitive detection of bacterial genomic DNA (lower limit, 0.1 pg of template DNA). When DNA samples isolated from ascites were used, the 16S rRNA gene was amplified independently of the presence of bacterial infection. PCR products contained the genomic DNA fragments of multiple bacterial species. Bacterial genomic DNA can be amplified from all ascitic fluids using a highly sensitive PCR protocol. Careful attention is required to interpret the results based on simple amplification of 16S rRNA gene with conventional PCR.
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Affiliation(s)
- Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Shin-Ichi Inoue
- Research and Development Center, Fuso Pharmaceutical Industries, Ltd., Osaka 536‑8523, Japan
| | - Akio Matsuhisa
- Research and Development Center, Fuso Pharmaceutical Industries, Ltd., Osaka 536‑8523, Japan
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Chikage Nakano
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Kazunori Yoh
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Yuho Miyamoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Noriko Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Yukihisa Yuri
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Akio Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663‑8501, Japan
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Moharem HA, Fetouh FA, Darwish HM, Ghaith D, Elayashy M, Hussein A, Elsayed R, Khalil MM, Abdelaal A, ElMeteini M, Mukhtar A. Effects of bacterial translocation on hemodynamic and coagulation parameters during living-donor liver transplant. BMC Anesthesiol 2018; 18:46. [PMID: 29699477 PMCID: PMC5921288 DOI: 10.1186/s12871-018-0507-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 04/13/2018] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Bacterial translocation (BT) has been proposed as a trigger for stimulation of the immune system with consequent hemodynamic alteration in patients with liver cirrhosis. However, no information is available regarding its hemodynamic and coagulation consequences during liver transplantation. METHODS We screened 30 consecutive adult patients undergoing living-donor liver transplant for the presence of BT. Bacterial DNA, Anti factor Xa (aFXa), thromboelastometry, tumor necrosis factor-α TNF-α, and interleukin-17 (IL-17) values were measured in sera before induction of anesthesia. Systemic hemodynamic data were recorded throughout the procedures. RESULTS Bacterial DNA was detected in 10 patients (33%) (bactDNA(+)). Demographic, clinical, and hemodynamic data were similar in patients with presence or absence of bacterial DNA. BactDNA(+) patients showed significantly higher circulating values of TNF-α and IL-17, and had significantly higher clotting times and clot formation times as well as significantly lower alpha angle and maximal clot firmness than bactDNA(-) patients, P < 0.05. We found no statistically significant difference in aFXa between the groups, P = 0.4. Additionally, 4 patients in each group needed vasopressor agents, P = 0.2. And, the amount of transfused blood and blood products used were similar between both groups. CONCLUSION Bacterial translocation was found in one-third of patients at the time of transplantation and was largely associated with increased markers of inflammation along with decreased activity of coagulation factors. TRIAL REGISTRATION Trial Registration Number: NCT03230214 . (Retrospective registered). Initial registration date was 20/7/2017.
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Affiliation(s)
- Heba A. Moharem
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Fawzia Aboul Fetouh
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
| | - Hamed M. Darwish
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Doaa Ghaith
- Department of clinical and chemical pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Elayashy
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
| | - Amr Hussein
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
| | - Riham Elsayed
- Department of clinical and chemical pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohammad M. Khalil
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Amr Abdelaal
- Department of surgery, Ainshams University, Cairo, Egypt
| | | | - Ahmed Mukhtar
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
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Gut microbial composition in patients with psoriasis. Sci Rep 2018; 8:3812. [PMID: 29491401 PMCID: PMC5830498 DOI: 10.1038/s41598-018-22125-y] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 02/16/2018] [Indexed: 12/28/2022] Open
Abstract
Since the last 5–10 years the relevance of the gut microbiome on different intestinal illnesses has been revealed. Recent findings indicate the effect of gut microbiome on certain dermatological diseases such as atopic dermatitis. However, data on other skin diseases such as psoriasis are limited. This is the first time attempting to reveal the gut microbiome composition of psoriatic patients with a prospective study including a group of patients with plaque psoriasis, analyzing their gut microbiome and the relationship between the microbiome composition and bacterial translocation. The microbiome of a cohort of 52 psoriatic patients (PASI score ≥6) was obtained by 16s rRNA massive sequencing with MiSeq platform (Illumina inc, San Diego) with an average of 85,000 sequences per sample. The study of the gut microbiome and enterotype shows from the first time a specific “psoriatic core intestinal microbiome” that clearly differs from the one present in healthy population. In addition, those psoriatic patients classified as belonging to enterotype 2 tended to experience more frequent bacterial translocation and higher inflammatory status (71%) than patients with other enterotypes (16% for enterotype 1; and 21% for enterotype 3).
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Mancini A, Campagna F, Amodio P, Tuohy KM. Gut : liver : brain axis: the microbial challenge in the hepatic encephalopathy. Food Funct 2018; 9:1373-1388. [PMID: 29485654 DOI: 10.1039/c7fo01528c] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) is a debilitating neuropsychiatric condition often associated with acute liver failure or cirrhosis. Advanced liver diseases are characterized by a leaky gut and systemic inflammation. There is strong evidence that the pathogenesis of HE is linked to a dysbiotic gut microbiota and to harmful microbial by-products, such as ammonia, indoles, oxindoles and endotoxins. Increased concentrations of these toxic metabolites together with the inability of the diseased liver to clear such products is thought to play an important patho-ethiological role. Current first line clinical treatments target microbiota dysbiosis by decreasing the counts of pathogenic bacteria, blood endotoxemia and ammonia levels. This review will focus on the role of the gut microbiota and its metabolism in HE and advanced cirrhosis. It will critically assess data from different clinical trials measuring the efficacy of the prebiotic lactulose, the probiotic VSL#3 and the antibiotic rifaximin in treating HE and advanced cirrhosis, through gut microbiota modulation. Additionally data from Randomised Controlled Trials using pre-, pro- and synbiotic will be also considered by reporting meta-analysis studies. The large amount of existing data showed that HE is a clear example of how an altered gut microbiota homeostasis can influence and impact on physiological functions outside the intestine, with implication for host health at the systems level. Nevertheless, a strong effort should be made to increase the information on gut microbiota ecology and its metabolic function in liver diseases and HE.
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Affiliation(s)
- Andrea Mancini
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all'Adige, Trento, Italy.
| | - Francesca Campagna
- Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy
| | - Piero Amodio
- Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy
| | - Kieran M Tuohy
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all'Adige, Trento, Italy.
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Gómez-Hurtado I, Gimenez P, García I, Zapater P, Francés R, González-Navajas JM, Manichanh C, Ramos JM, Bellot P, Guarner F, Such J. Norfloxacin is more effective than Rifaximin in avoiding bacterial translocation in an animal model of cirrhosis. Liver Int 2018; 38:295-302. [PMID: 28834270 DOI: 10.1111/liv.13551] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 08/09/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Norfloxacin administration is useful in preventing bacterial infections in cirrhosis but associated to the generation of resistant species. Rifaximin is known to reach high concentrations in the intestinal lumen without generating relevant resistance in the intestinal flora. Our aim was to compare the effect of Norfloxacin and Rifaximin on intestinal flora composition, bacterial translocation and survival in cirrhotic rats. METHODS Cirrhosis was induced in rats by oral administration of CCl4 . Animals were divided into three groups: only CCl4 (group I, n = 10); CCl4 + Norfloxacin (group II, n = 17) and CCl4 + Rifaximin (group III, n = 14). Gut bacterial composition, bacterial translocation and cytokine levels were measured. RESULTS Forty-one rats were finally included. The incidence of viable and non-viable bacterial translocation was significantly reduced in animals receiving Norfloxacin; Rifaximin also decreased the incidence of viable and non-viable bacterial translocation, but did not reach statistical significance. Serum TNF-α levels were significantly lower in antibiotic groups. Norfloxacin modified intestinal microbiota, depleting significantly more pathobionts than Rifaximin. CONCLUSION Norfloxacin is more effective than Rifaximin in preventing bacterial translocation in rats with cirrhosis probably because of its capacity to reduce pathobionts from intestinal microbiota.
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Affiliation(s)
- Isabel Gómez-Hurtado
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Paula Gimenez
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Irma García
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
- Departamento Farmacología Clínica, UMH, Alicante, Spain
| | - Rubén Francés
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
- Departamento Medicina Clínica, UMH, Alicante, Spain
| | - José M González-Navajas
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Chaysavanh Manichanh
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Departamento Gastroenterología, VHIR, Barcelona, Spain
| | - José M Ramos
- Departamento Medicina Interna, HGUA, Alicante, Spain
| | - Pablo Bellot
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Francisco Guarner
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Departamento Gastroenterología, VHIR, Barcelona, Spain
| | - José Such
- Cleveland Clinic, Digestive Disease institute, Abu Dhabi, UAE
- Lerner School of Medicine, Case Western Reserve University, Cleveland, OH, USA
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43
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Ison MG, Heldman M. Bacterial Infections. HEPATIC CRITICAL CARE 2018. [PMCID: PMC7120903 DOI: 10.1007/978-3-319-66432-3_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Bacterial infections are the most significant infectious source of morbidity and mortality in cirrhotic patients. Bacteria infections result is both acute decompensation in chronic liver disease and mortality in patients with decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP), bacteremia, pneumonia, urinary tract infections (UTI) and skin and soft tissue infection (SSTI) are the most significant sources of infection in cirrhosis. Bacterial infections can precipitate renal failure and worsening hepatic encephalopathy, and patients with sepsis and liver disease have higher rates of acute respiratory distress syndrome (ARDS) and coagulopathy.
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Kimer N, Pedersen JS, Tavenier J, Christensen JE, Busk TM, Hobolth L, Krag A, Al-Soud WA, Mortensen MS, Sørensen SJ, Møller S, Bendtsen F. Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial. J Gastroenterol Hepatol 2018; 33:307-314. [PMID: 28671712 DOI: 10.1111/jgh.13852] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/30/2017] [Accepted: 06/18/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. METHODS Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end-stage liver disease score 12 (± 3.9). Patients received rifaximin 550-mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing. RESULTS Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-α, transforming growth factor β-1, and high sensitivity C-reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin. CONCLUSION Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).
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Affiliation(s)
- Nina Kimer
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Julie S Pedersen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Juliette Tavenier
- Clinical Research Centre, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jeffrey E Christensen
- Vaiomer SAS, Toulouse, France.,Institute of Cardiovascular and Metabolic Diseases (I2MC), INSERM U1048, Toulouse, France
| | - Troels M Busk
- Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Lise Hobolth
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Department of Gastroenterology and Hepatology, Copenhagen University Hospital Bispebjerg, Bispebjerg, Denmark
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Waleed Abu Al-Soud
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Martin S Mortensen
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Søren J Sørensen
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Søren Møller
- Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
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Aitbaev KA, Murkamilov IT, Fomin VV. [Liver diseases: The pathogenetic role of the gut microbiome and the potential of treatment for its modulation]. TERAPEVT ARKH 2017; 89:120-128. [PMID: 28914862 DOI: 10.17116/terarkh2017898120-128] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The paper gives an update on the role of the gut microbiome (GM) in the development of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver cirrhosis (LC), and its complications, such as hepatic encephalopathy (HE) and hepatocellular carcinoma (HCC), and discusses the possibilities of its correction with prebiotics, probiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). The pathophysiology of the liver diseases in question demonstrates some common features that are characterized by pathogenic changes in the composition of the gastrointestinal tract microflora, by intestinal barrier impairments, by development of endotoxemia, by increased liver expression of proinflammatory factors, and by development of liver inflammation. In progressive liver disease, the above changes are more pronounced, which contributes to the development of LC, HE, and HCC. GM modulation using prebiotics, probiotics, synbiotics, antibiotics, and FMT diminishes dysbacteriosis, strengthens the intestinal mucosal barrier, reduces endotoxemia and liver damage, and positively affects the clinical manifestations of HE. Further investigations are needed, especially in humans, firstly, to assess a relationship of GM to the development of liver diseases in more detail and, secondly, to obtain evidence indicating the therapeutic efficacy of GM-modulating agents in large-scale, well-designed, randomized, controlled, multicenter studies.
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Affiliation(s)
- K A Aitbaev
- Research Institute of Molecular Biology and Medicine, National Center of Cardiology and Therapy, Ministry of Health of the Kyrgyz Republic, Bishkek, Kyrgyz Republic
| | - I T Murkamilov
- I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek, Kyrgyz Republic
| | - V V Fomin
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
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Moreno-Pérez Ó, Giner L, Reus S, Boix V, Alfayate R, Frances R, Merino E, Pico A, Portilla J. Impact of circulating bacterial DNA in long-term glucose homeostasis in non-diabetic patients with HIV infection: cohort study. Eur J Clin Microbiol Infect Dis 2017; 37:313-318. [PMID: 29197988 DOI: 10.1007/s10096-017-3134-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 11/02/2017] [Indexed: 10/18/2022]
Abstract
In HIV-infected patients, the damage in the gut mucosal immune system is not completely restored after antiretroviral therapy (ART). It results in microbial translocation, which could influence the immune and inflammatory response. We aimed at investigating the long-term impact of bacterial-DNA translocation (bactDNA) on glucose homeostasis in an HIV population. This was a cohort study in HIV-infected patients whereby inclusion criteria were: patients with age >18 years, ART-naïve or on effective ART (<50 HIV-1 RNA copies/mL) and without diabetes or chronic hepatitis C. Primary outcome was the change in HbA1c (%). Explanatory variables at baseline were: bactDNA (qualitatively detected in blood samples by PCR [broad-range PCR] and gene 16SrRNA - prokaryote), ART exposure, HOMA-R and a dynamic test HOMA-CIGMA [continuous infusion of glucose with model assessment], hepatic steatosis (hepatic triglyceride content - 1H-MRS), visceral fat / subcutaneous ratio and inflammatory markers. Fifty-four men (age 43.2 ± 8.3 years, BMI 24.9 ± 3 kg/m2, mean duration of HIV infection of 8.1 ± 5.3 years) were included. Baseline HbA1c was 4.4 ± 0.4% and baseline presence of BactDNA in six patients. After 8.5 ± 0.5 years of follow-up, change in HbA1c was 1.5 ± 0.47% in patients with BactDNA vs 0.87 ± 0.3% in the rest of the sample p < 0.001. The change in Hba1c was also influenced by protease inhibitors exposure, but not by baseline indices of insulin resistance, body composition, hepatic steatosis, inflammatory markers or anthropometric changes. In non-diabetic patients with HIV infection, baseline bacterial translocation and PI exposure time were the only factors associated with long-term impaired glucose homeostasis.
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Affiliation(s)
- Ó Moreno-Pérez
- Endocrinology and Nutrition Service, University General Hospital of Alicante, Alicante, Spain. .,Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain. .,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.
| | - L Giner
- Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.,Infectious Diseases Unit, University General Hospital of Alicante, Alicante, Spain
| | - S Reus
- Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.,Infectious Diseases Unit, University General Hospital of Alicante, Alicante, Spain
| | - V Boix
- Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.,Infectious Diseases Unit, University General Hospital of Alicante, Alicante, Spain
| | - R Alfayate
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.,Hormone Laboratory, University General Hospital of Alicante, Alicante, Spain
| | - R Frances
- Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.,CIBERehd, Carlos III Health Institute, Madrid, Spain
| | - E Merino
- Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.,Infectious Diseases Unit, University General Hospital of Alicante, Alicante, Spain
| | - A Pico
- Endocrinology and Nutrition Service, University General Hospital of Alicante, Alicante, Spain.,Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain
| | - J Portilla
- Department of Clinical Medicine, University Miguel Hernandez, Alicante, Spain.,Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL - FISABIO), Alicante, Spain.,Infectious Diseases Unit, University General Hospital of Alicante, Alicante, Spain
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Usui S, Ebinuma H, Chu PS, Nakamoto N, Yamagishi Y, Saito H, Kanai T. Detection of bacterial DNA by in situ hybridization in patients with decompensated liver cirrhosis. BMC Gastroenterol 2017; 17:106. [PMID: 29041907 PMCID: PMC5646152 DOI: 10.1186/s12876-017-0664-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 10/03/2017] [Indexed: 02/06/2023] Open
Abstract
Background Spontaneous bacterial peritonitis (SBP) is often difficult to diagnose because bacteria in ascites cannot be detected accurately by conventional culture. In situ hybridization (ISH) was previously developed for rapid detection of genes from bacteria phagocytized by neutrophils. SBP may develop after bacteria enter into the systemic circulation following bacterial translocation. Therefore, we performed ISH to identify bacteria in blood samples collected from patients with decompensated liver cirrhosis (LC). Methods In this retrospective study, peripheral blood samples were collected from 60 patients with decompensated LC, and bacteria were detected by both blood culture and ISH. Moreover, 35 patients underwent paracentesis for diagnosis of SBP. Results Eight of 35 patients were diagnosed with SBP by polymorphonuclear neutrophil counts, and one patient was diagnosed with bacterascites. Seven of the nine patients showed positive results for ISH, whereas bacteria were detected in only two cases by blood culture. Thirty-seven of 60 cases (62%) showed positive results for ISH, whereas only six samples (10%) were positive by blood culture analysis. Compared with the 23 cases of negative ISH, the 37 cases of positive ISH showed a higher frequency of fever, higher Child-Pugh scores, and lower albumin levels. Conclusions Detection of bacteria by ISH suggested that bacterial translocation, which cannot be proven by conventional culture, occurred in these patients, and that ISH could be helpful for the early diagnosis of some types of infection and prevention of SBP in these patients.
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Affiliation(s)
- Shingo Usui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.,Department of Internal Medicine, International University of Health and Welfare Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo, 108-8329, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Yoshiyuki Yamagishi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.,Department of Internal Medicine, Tokyo Dental College Suidobashi Hospital, 2-9-18 Misakicho, Chiyoda-ku, Tokyo, 101-0061, Japan
| | - Hidetsugu Saito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.,Faculty of Pharmacy, Keio University, 1-5-30 Shiba-kohen, Minato-ku, Tokyo, 105-8512, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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Fukui H. Gut Microbiome-based Therapeutics in Liver Cirrhosis: Basic Consideration for the Next Step. J Clin Transl Hepatol 2017; 5:249-260. [PMID: 28936406 PMCID: PMC5606971 DOI: 10.14218/jcth.2017.00008] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 04/24/2017] [Accepted: 05/11/2017] [Indexed: 12/12/2022] Open
Abstract
Infections account for significant morbidity and mortality in liver cirrhosis and most are related to the gut microbiome. Fecal dysbiosis, characterized by an overgrowth of potentially pathogenic bacteria and a decrease in autochthonous non-pathogenic bacteria, becomes prominent with the progression of liver cirrhosis. In cirrhotic patients, disruption of the intestinal barrier causes intestinal hyperpermeability (i.e. leaky gut), which is closely related to gut dysmotility, dysbiosis and small intestinal bacterial overgrowth and may induce pathological bacterial translocation. Although the involved microbial taxa are somewhat different between the cirrhotic patients from the East and the West, the common manifestation of a shortage of bacteria that contribute to the production of short-chain fatty acids and secondary bile acids may facilitate intestinal inflammation, leaky gut and gut dysbiosis. Translocated endotoxin and bacterial DNA are capable of provoking potent inflammation and affecting the metabolic and hemodynamic systems, which may ultimately enhance the progression of liver cirrhosis and its various complications, such as hepatic encephalopathy (HE), variceal bleeding, infection and renal disturbances. Among studies on the microbiome-based therapeutics, findings of probiotic effects on HE have been contradictory in spite of several supportive results. However, the effects of synbiotics and prebiotics are substantially documented. The background of their effectiveness should be evaluated again in relation to the cirrhosis-related changes in gut microbiome and their metabolic effects. Strict indications for the antibiotic rifaximin remain unestablished, although its effect is promising, improving HE and other complications with little influence on microbial populations. The final goal of microbiome-based therapeutics is to adjust the gut-liver axis to the maximal benefit of cirrhotic patients, with the aid of evolving metagenomic and metabolomic analyses.
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Affiliation(s)
- Hiroshi Fukui
- *Correspondence to: Hiroshi Fukui, Department of Gastroenterology, Endocrinology and Metabolism, Nara Medical University, 840 Shijo-cho Kashihara, 634-8522 Nara, Japan. Tel: +81-744223051, E-mail:
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49
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Abstract
The gastrointestinal mucosa constitutes a critical barrier where millions of microbes and environmental antigens come in close contact with the host immune system. Intestinal barrier defects have been associated with a broad range of diseases and therefore denote a new therapeutic target. Areas covered: This review is based on an extensive literature search in PubMed of how the intestinal barrier contributes to health and as a trigger for disease. It discusses the anatomy of the intestinal barrier and explains the available methods to evaluate its function. Also reviewed is the importance of diet and lifestyle factors on intestinal barrier function, and three prototypes of chronic diseases (inflammatory bowel disease, celiac disease and nonalcoholic fatty liver disease) that have been linked to barrier defects are discussed. Expert commentary: The intestinal barrier has been investigated by various methods, but correlation of results across studies is difficult, representing a major shortcoming in the field. New upcoming techniques and research on the effect of barrier-restoring therapeutics may improve our current understanding of the gut barrier, and provide a step forward towards personalised medicine.
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50
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Kojima M, Gimenes-Junior JA, Chan TW, Eliceiri BP, Baird A, Costantini TW, Coimbra R. Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4. FASEB J 2017; 32:97-110. [PMID: 28855278 DOI: 10.1096/fj.201700488r] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 08/14/2017] [Indexed: 12/22/2022]
Abstract
Acute lung injury (ALI) is a common cause of morbidity in patients after severe injury due to dysregulated inflammation, which is believed to be driven by gut-derived inflammatory mediators carried via mesenteric lymph (ML). We have previously demonstrated that nano-sized extracellular vesicles, called exosomes, secreted into ML after trauma/hemorrhagic shock (T/HS) have the potential to activate immune cells in vitro Here, we assess the function of ML exosomes in the development of T/HS-induced ALI and the role of TLR4 in the ML exosome-mediated inflammatory response. ML exosomes isolated from rats subjected to T/HS stimulated NF-κB activation and caused proinflammatory cytokine production in alveolar macrophages. In vivo experiments revealed that intravenous injection of exosomes harvested after T/HS, but not before shock, caused recruitment of inflammatory cells in the lung, increased vascular permeability, and induced histologic ALI in naive mice. The exosome-depleted supernatant of ML had no effect on in vitro and in vivo inflammatory responses. We also demonstrated that both pharmacologic inhibition and genetic knockout of TLR4 completely abolished ML exosome-induced cytokine production in macrophages. Thus, our findings define the critical role of exosomes secreted into ML as a critical mediator of T/HS-induced ALI through macrophage TLR4 activation.-Kojima, M., Gimenes-Junior, J. A., Chan, T. W., Eliceiri, B. P., Baird, A., Costantini, T. W., Coimbra, R. Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4.
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Affiliation(s)
- Mitsuaki Kojima
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California, USA
| | - Joao A Gimenes-Junior
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California, USA
| | - Theresa W Chan
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California, USA
| | - Brian P Eliceiri
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California, USA
| | - Andrew Baird
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California, USA
| | - Todd W Costantini
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California, USA
| | - Raul Coimbra
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California San Diego Health Sciences, San Diego, California, USA
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