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Qian L, Wang L, Zou Z, Luan F, Cai X, Zhou J, Zhu D, Ye J, Dai C. Distinct composition and metabolic potential of biliary microbiota in patients with malignant bile duct obstruction. Eur J Gastroenterol Hepatol 2025; 37:585-593. [PMID: 40207470 PMCID: PMC11949207 DOI: 10.1097/meg.0000000000002948] [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: 01/11/2025] [Accepted: 02/03/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND Emerging evidence highlights the role of biliary microbiota in hepato-biliary-pancreatic diseases. The characteristics of biliary microbiota in malignant bile duct obstruction remain poorly understood. This study aims to investigate the composition and metabolic functions of biliary microbiota in patients with malignant obstruction. METHODS Eligible patients were enrolled in this prospective study at First Affiliated Hospital of Soochow University between December 2022 and October 2023, including distal cholangiocarcinoma, hilar cholangiocarcinoma, pancreatic ductal adenocarcinoma, periampullary carcinoma, and gallbladder carcinoma. The patients with choledocholithiasis served as controls. Bile samples were collected via endoscopic retrograde cholangiopancreatography. Microbiota identification was performed using 16S rRNA sequencing, while bile acids were analyzed using mass spectrometry. RESULTS A total of 56 patients were successfully enrolled in this study, 25 in the tumor group and 31 in the stone group. A distinct biliary microbial community was observed in patients with malignant bile duct obstruction, consisting of Prevotella, Uruburuella, Atopostipes, Clostridium IV, Halomonas, Tannerella, Porphyromonas, Achromobacter, Rouxiella, Campylobacter, Corynebacterium, Turicibacter, Muribaculum, Selenomonas, and Alloprevotella at genus level. Notably, Clostridium IV, Halomonas, Rouxiella, and Turicibacter were exclusively present in the tumor group. Bile acid levels were significantly lower in the tumor group (P < 0.05), except for ursodeoxycholic acid and taurocholic acid. Additionally, 22 metabolic pathways were enriched in the tumor group. CONCLUSIONS This study elucidates the community and metabolic potential of biliary microbiota in malignant bile duct obstruction. The findings offer valuable insights for disease assessment and provide a foundation for further research into the role of biliary microbiota in malignancy.
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Affiliation(s)
| | | | | | | | | | | | - Dongming Zhu
- General Surgery, First Affiliated Hospital of Soochow University, Suzhou, China
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Dong L, Zhang H, Kang Y, Wang F, Bai T, Yang Y. NLRP3 and Gut-Liver Axis: New Possibility for the Treatment of Alcohol-Associated Liver Disease. J Gastroenterol Hepatol 2025; 40:1070-1078. [PMID: 40091479 DOI: 10.1111/jgh.16935] [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: 11/18/2024] [Revised: 02/04/2025] [Accepted: 03/01/2025] [Indexed: 03/19/2025]
Abstract
Alcohol-associated liver disease (ALD) is one of the most prevalent chronic diseases worldwide, with persistently high morbidity and mortality rates. Previous studies have identified NLRP3 inflammasome as a class of receptors of intracellular intrinsic immunity. These receptors can be activated by both intrinsic and extracellular danger signals, leading to the release of downstream pro-inflammatory factors, including interleukin IL-1β and IL-18. These vesicles are critical for maintaining host defense. Concurrently, researchers have identified a close relationship between the microbiome, gut-liver axis, and NLRP3 inflammasome with ALD. Consequently, the present study focus on the structure and activation of the NLRP3 inflammasome, the gut-liver axis, and intestinal microecological regulation, as well as the relationship between bile acid metabolism and the gut-liver axis. The objective of this study is to provide a foundation of knowledge and references for the development of targeted therapeutic interventions of ALD that are informed by the dynamic interplay between the NLRP3 inflammasome and the gut-liver axis.
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Affiliation(s)
- Lu Dong
- Dalian key Laboratory of Chronic Disease Research Center, Dalian University, Dalian, Liaoning Province, China
| | - Haotian Zhang
- Dalian key Laboratory of Chronic Disease Research Center, Dalian University, Dalian, Liaoning Province, China
| | - Yanyu Kang
- Dalian key Laboratory of Chronic Disease Research Center, Dalian University, Dalian, Liaoning Province, China
| | - Fei Wang
- Dalian key Laboratory of Chronic Disease Research Center, Dalian University, Dalian, Liaoning Province, China
| | - Ting Bai
- Dalian key Laboratory of Chronic Disease Research Center, Dalian University, Dalian, Liaoning Province, China
| | - Yong Yang
- Dalian key Laboratory of Chronic Disease Research Center, Dalian University, Dalian, Liaoning Province, China
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Liu M, Ji YL, Hu YJ, Su YX, Yang J, Wang XY, Chu HY, Zhang X, Dong SJ, Yang H, Liu YH, Zhou SM, Guo LP, Ran Y, Li YN, Zhao JW, Zhang ZG, Piao MY, Zhou L. Lactococcus garvieae aggravates cholestatic liver disease by increasing intestinal permeability and enhancing bile acid reabsorption. World J Gastroenterol 2025; 31:101014. [PMID: 40093673 PMCID: PMC11886528 DOI: 10.3748/wjg.v31.i10.101014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 12/19/2024] [Accepted: 02/05/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Although an association between gut microbiota and cholestatic liver disease (CLD) has been reported, the precise functional roles of these microbes in CLD pathogenesis remain largely unknown. AIM To explore the function of gut microbes in CLD pathogenesis and the effects of gut microbiota on intestinal barrier and bile acid (BA) metabolism in CLD. METHODS Male C57BL/6J mice were fed a 0.05% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet for 2 weeks to induce CLD. The sterile liver tissues of mice were then meticulously harvested, and bacteria in homogenates were identified through culture methods. Furthermore, 16S ribosomal DNA sequencing was employed to analyze sterile liver samples collected from eight patients with primary biliary cholangitis (PBC) and three control individuals with hepatic cysts. The functional roles of the identified bacteria in CLD pathogenesis were assessed through microbiota transfer experiments, involving the evaluation of changes in intestinal permeability and BA dynamics. RESULTS Ligilactobacillus murinus (L. murinus) and Lactococcus garvieae (L. garvieae) were isolated from the bacterial culture of livers from CLD mice. L. murinus was prevalently detected in PBC patients and controls, whereas L. garvieae was detected only in patients with PBC but not in controls. Mice inoculated with L. garvieae exhibited increased susceptibility to experimental CLD, with both in vitro and in vivo indicating that L. garvieae disrupted the intestinal barrier function by down-regulating the expression of occludin and zonula occludens-1. Moreover, L. garvieae administration significantly upregulated the expression of the apical sodium-dependent BA transporter in the terminal ileum and increased serum BA levels. CONCLUSION L. garvieae contributes to excessive BA-induced hepatobiliary injury and liver fibrosis by increasing intestinal permeability and enhancing BA reabsorption.
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Affiliation(s)
- Man Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Ying-Lan Ji
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Yu-Jie Hu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Ying-Xi Su
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Jie Yang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin 300308, China
| | - Xiao-Yi Wang
- Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Hong-Yu Chu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Xue Zhang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Shi-Jing Dong
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Hui Yang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Yu-Hang Liu
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Si-Min Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Li-Ping Guo
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Ying Ran
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Yan-Ni Li
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Jing-Wen Zhao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Zhi-Guang Zhang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Mei-Yu Piao
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin 300070, China
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Del Chierico F, Cardile S, Baldelli V, Alterio T, Reddel S, Bramuzzo M, Knafelz D, Lega S, Bracci F, Torre G, Maggiore G, Putignani L. Characterization of the Gut Microbiota and Mycobiota in Italian Pediatric Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis. Inflamm Bowel Dis 2024; 30:529-537. [PMID: 37696680 PMCID: PMC10988104 DOI: 10.1093/ibd/izad203] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis, often associated with inflammatory bowel diseases. Recent evidence ascribes, together with immunologic and environmental components, a significant role to the intestinal microbiota or its molecules in the PSC pathogenesis. METHODS By metagenomic sequencing of 16S rRNA and ITS2 loci, we describe the fecal microbiota and mycobiota of 26 pediatric patients affected by PSC and concomitant ulcerative colitis (PSC-UC), 27 patients without PSC but with UC (UC), and 26 healthy subjects (CTRLs). RESULTS Compared with CTRL, the bacterial and fungal gut dysbiosis was evident for both PSC-UC and UC groups; in particular, Streptococcus, Saccharomyces, Sporobolomyces, Tilletiopsis, and Debaryomyces appeared increased in PSC-UC, whereas Klebsiella, Haemophilus, Enterococcus Collinsella, Piptoporus, Candida, and Hyphodontia in UC. In both patient groups, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma and Malassezia were decreased. Co-occurrence analysis evidenced the lowest number of nodes and edges for fungi networks compared with bacteria. Finally, we identified a specific patient profile, based on liver function tests, bacterial and fungal signatures, that is able to distinguish PSC-UC from UC patients. CONCLUSIONS We describe the gut microbiota and mycobiota dysbiosis associated to PSC-UC disease. Our results evidenced a gut imbalance, with the reduction of gut commensal microorganisms with stated anti-inflammatory properties (ie, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma, and Malassezia) and the increase of pathobionts (ie, Streptococcus, Saccharomyces, and Debaryomyces) that could be involved in PSC progression. Altogether, these events may concur in the pathophysiology of PSC in the framework of UC.
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Affiliation(s)
- Federica Del Chierico
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Sabrina Cardile
- Hepatology, Gastroenterology, Nutrition and Liver transplantation Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Valerio Baldelli
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Tommaso Alterio
- Hepatology, Gastroenterology, Nutrition and Liver transplantation Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Sofia Reddel
- Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Matteo Bramuzzo
- Gastroenterology, Digestive Endoscopy and Nutrition Unit, Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,”Trieste, Italy
| | - Daniela Knafelz
- Hepatology, Gastroenterology, Nutrition and Liver transplantation Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Sara Lega
- Gastroenterology, Digestive Endoscopy and Nutrition Unit, Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,”Trieste, Italy
| | - Fiammetta Bracci
- Hepatology, Gastroenterology, Nutrition and Liver transplantation Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Giuliano Torre
- Hepatology, Gastroenterology, Nutrition and Liver transplantation Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Giuseppe Maggiore
- Hepatology, Gastroenterology, Nutrition and Liver transplantation Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
| | - Lorenza Putignani
- Unit of Microbiology and Diagnostic Immunology, Unit of Microbiomics and Immunology, Rheumatology and Infectious Diseases Research Area, Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Dai C, Xu C, Zheng L, Wang M, Fan Z, Ye J, Su D. Characteristics and metabolic potential of biliary microbiota in patients with giant common bile duct stones. Front Cell Infect Microbiol 2023; 13:1259761. [PMID: 38029241 PMCID: PMC10661410 DOI: 10.3389/fcimb.2023.1259761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Endoscopic retrograde cholangiopancreatography (ERCP) is an effective minimally invasive operation for the management of choledocholithiasis, while successful extraction is hampered by large diameter of stones. Emerging studies have revealed the close correlation between biliary microbiota and common bile duct stones (CBDS). In this study, we aimed to investigate the community characteristics and metabolic functions of biliary microbiota in patients with giant CBDS. METHODS Eligible patients were prospectively enrolled in this study in First Affiliated Hospital of Soochow University from February 2022 to October 2022. Bile samples were collected through ERCP. The microbiota was analyzed using 16S rRNA sequencing. Metabolic functions were predicted by PICRUSTs 2.0 calculation based on MetaCyc database. Bile acids were tested and identified using ultra performance liquid chromatography-tandem mass spectrometry. RESULTS A total of 26 patients were successfully included into final analysis, 8 in giant stone (GS) group and 18 in control group. Distinct biliary microbial composition was identified in patients with giant CBDS, with a significantly higher abundance of Firmicutes at phylum level. The unique composition at genus level mainly consisted of Enterococcus, Citrobacter, Lactobacillus, Pyramidobacter, Bifidobacterium and Shewanella. Pyramidobacter was exclusively found in GS group, along with the absence of Robinsoniella and Coprococcus. The contents of free bile acids were significantly higher in GS group, including cholic acid (98.39μmol/mL vs. 26.15μmol/mL, p=0.035), chenodesoxycholic acid (54.69μmol/mL vs. 5.86μmol/mL, p=0.022) and ursodeoxycholic acid (2.70μmol/mL vs. 0.17μmol/mL, p=0.047). Decreasing tendency of conjugated bile acids were also observed. Metabolic pathways concerning cholelithiasis were abundant in GS group, including geranylgeranyl diphosphate biosynthesis, gluconeogenesis, glycolysis and L-methionine biosynthesis. CONCLUSIONS This study demonstrated the community structure and metabolic potential of biliary microbiota in patients with giant CBDS. The unique biliary microbial composition holds valuable predictive potential for clinical conditions. These findings provide new insights into the etiology of giant CBDS from the perspective of biliary microbiota.
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Affiliation(s)
- Chenguang Dai
- Department of Pathology, Nanjing Medical University, Nanjing, China
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chunfang Xu
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lu Zheng
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Wang
- Digestive Endoscopy Department, First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Zhining Fan
- Digestive Endoscopy Department, First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Jianxin Ye
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China
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Ceci L, Han Y, Krutsinger K, Baiocchi L, Wu N, Kundu D, Kyritsi K, Zhou T, Gaudio E, Francis H, Alpini G, Kennedy L. Gallstone and Gallbladder Disease: Biliary Tract and Cholangiopathies. Compr Physiol 2023; 13:4909-4943. [PMID: 37358507 DOI: 10.1002/cphy.c220028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Cholestatic liver diseases are named primarily due to the blockage of bile flow and buildup of bile acids in the liver. Cholestasis can occur in cholangiopathies, fatty liver diseases, and during COVID-19 infection. Most literature evaluates damage occurring to the intrahepatic biliary tree during cholestasis; however, there may be associations between liver damage and gallbladder damage. Gallbladder damage can manifest as acute or chronic inflammation, perforation, polyps, cancer, and most commonly gallstones. Considering the gallbladder is an extension of the intrahepatic biliary network, and both tissues are lined by biliary epithelial cells that share common mechanisms and properties, it is worth further evaluation to understand the association between bile duct and gallbladder damage. In this comprehensive article, we discuss background information of the biliary tree and gallbladder, from function, damage, and therapeutic approaches. We then discuss published findings that identify gallbladder disorders in various liver diseases. Lastly, we provide the clinical aspect of gallbladder disorders in liver diseases and ways to enhance diagnostic and therapeutic approaches for congruent diagnosis. © 2023 American Physiological Society. Compr Physiol 13:4909-4943, 2023.
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Affiliation(s)
- Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Yuyan Han
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA
| | - Kelsey Krutsinger
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA
| | | | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
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Bragazzi MC, Venere R, Vignone A, Alvaro D, Cardinale V. Role of the Gut–Liver Axis in the Pathobiology of Cholangiopathies: Basic and Clinical Evidence. Int J Mol Sci 2023; 24:ijms24076660. [PMID: 37047635 PMCID: PMC10095354 DOI: 10.3390/ijms24076660] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/23/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
The “Gut–Liver Axis” refers to the physiological bidirectional interplay between the gut and its microbiota and the liver which, in health, occurs thanks to a condition of immune tolerance. In recent years, several studies have shown that, in case of a change in gut bacterial homeostasis or impairment of intestinal barrier functions, cholangiocytes, which are the epithelial cells lining the bile ducts, activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Intestinal dysbiosis or impaired intestinal barrier functions cause cholangiocytes to be exposed to an increasing amount of microorganisms that can reactivate inflammatory responses, thus inducing the onset of liver fibrosis. The present review focuses on the role of the gut–liver axis in the pathogenesis of cholangiopathies.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, 04100 Roma, Italy
| | - Rosanna Venere
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, 04100 Roma, Italy
| | - Anthony Vignone
- Department of Translational and Precision Medicine, Sapienza University of Rome, 04100 Roma, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, 04100 Roma, Italy
| | - Vincenzo Cardinale
- Department of Translational and Precision Medicine, Sapienza University of Rome, 04100 Roma, Italy
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Ito Z, Koido S, Kato K, Odamaki T, Horiuchi S, Akasu T, Saruta M, Hata T, Kumagai Y, Fujioka S, Misawa T, Xiao JZ, Sato N, Ohkusa T. Dysbiosis of the Fecal and Biliary Microbiota in Biliary Tract Cancer. Cancers (Basel) 2022; 14:5379. [PMID: 36358797 PMCID: PMC9653963 DOI: 10.3390/cancers14215379] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 09/29/2023] Open
Abstract
Characteristic bile duct and gut microbiota have been identified in patients with chronic biliary tract disease. This study aimed to characterize the fecal and bile microbiota in biliary tract cancer (BTC) patients and their relationship. Patients with BTC (n = 30) and benign biliary disease (BBD) without cholangitis (n = 11) were included. Ten healthy, age-matched subjects were also recruited for fecal microbiota comparison. The fecal and bile duct microbiotas were analyzed by sequencing the 16S rRNA gene V3-V4 region. Live bacteria were obtained in the bile from three BTC patients by culture, and metagenomics-based identification was performed. Linear discriminant analysis effect size showed a higher Enterobacteriaceae abundance and a lower Clostridia abundance, including that of Faecalibacterium and Coprococcus, in the BTC patients than in the other subjects. Ten of 17 operational taxonomic units (OTUs) assigned to Enterobacteriaceae in the bile were matched with the OTUs found in the BTC subject fecal samples. Furthermore, a bile-isolated strain possessed the carcinogenic bacterial colipolyketide synthase-encoding gene. Enterobacteriaceae was enriched in the BTC feces, and more than half of Enterobacteriaceae in the bile matched that in the feces at the OTU level. Our data suggests that fecal microbiota dysbiosis may contribute to BTC onset.
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Affiliation(s)
- Zensho Ito
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City 277-8567, Chiba, Japan
| | - Shigeo Koido
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City 277-8567, Chiba, Japan
| | - Kumiko Kato
- Gut Microbiota Department, Next Generation Science Institute, Morinaga Milk Industry Co., Ltd., Higashihara 252-8583, Zama, Japan
| | - Toshitaka Odamaki
- Gut Microbiota Department, Next Generation Science Institute, Morinaga Milk Industry Co., Ltd., Higashihara 252-8583, Zama, Japan
| | - Sankichi Horiuchi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City 277-8567, Chiba, Japan
| | - Takafumi Akasu
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
| | - Masayuki Saruta
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Tokyo 105-8471, Japan
| | - Taigo Hata
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
| | - Yu Kumagai
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
| | - Shuichi Fujioka
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
| | - Takeyuki Misawa
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
| | - Jin-zhong Xiao
- Gut Microbiota Department, Next Generation Science Institute, Morinaga Milk Industry Co., Ltd., Higashihara 252-8583, Zama, Japan
| | - Nobuhiro Sato
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Tokyo 113-0033, Japan
| | - Toshifumi Ohkusa
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City 277-8567, Chiba, Japan
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Tokyo 113-0033, Japan
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Wang C, Shi Y, Wang X, Ma H, Liu Q, Gao Y, Niu J. Peroxisome Proliferator-Activated Receptors Regulate Hepatic Immunity and Assist in the Treatment of Primary Biliary Cholangitis. Front Immunol 2022; 13:940688. [PMID: 35880178 PMCID: PMC9307989 DOI: 10.3389/fimmu.2022.940688] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/13/2022] [Indexed: 11/26/2022] Open
Abstract
Fibrates, which are agonists of peroxisome proliferator-activated receptor alpha, have received increasing attention in the treatment of primary biliary cholangitis. Reduced alkaline phosphatase levels and improved clinical outcomes were observed in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid (UDCA) monotherapy4 when treated with bezafibrate or fenofibrate combined with UDCA. In contrast to obeticholic acid, which exacerbates pruritus in patients, fibrates have been shown to relieve pruritus. Clinical trial outcomes show potential for the treatment of primary biliary cholangitis by targeting peroxisome proliferator-activated receptors. It is currently agreed that primary biliary cholangitis is an autoimmune-mediated cholestatic liver disease, and peroxisome proliferator-activated receptor is a nuclear receptor that regulates the functions of multiple immune cells, thus playing an important role in regulating innate and adaptive immunity. Therefore, this review focuses on the immune disorder of primary biliary cholangitis and summarizes the regulation of hepatic immunity when peroxisome proliferator-activated receptors are targeted for treating primary biliary cholangitis.
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Affiliation(s)
- Chang Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Ying Shi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Heming Ma
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
| | - Quan Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China
| | - Yanhang Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yanhang Gao, ; Junqi Niu,
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
- Center of Infectious Disease and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, State Key Laboratory of Zoonotic Disease, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yanhang Gao, ; Junqi Niu,
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10
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Binda C, Gibiino G, Coluccio C, Sbrancia M, Dajti E, Sinagra E, Capurso G, Sambri V, Cucchetti A, Ercolani G, Fabbri C. Biliary Diseases from the Microbiome Perspective: How Microorganisms Could Change the Approach to Benign and Malignant Diseases. Microorganisms 2022; 10:312. [PMID: 35208765 PMCID: PMC8877314 DOI: 10.3390/microorganisms10020312] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 11/18/2022] Open
Abstract
Recent evidence regarding microbiota is modifying the cornerstones on pathogenesis and the approaches to several gastrointestinal diseases, including biliary diseases. The burden of biliary diseases, indeed, is progressively increasing, considering that gallstone disease affects up to 20% of the European population. At the same time, neoplasms of the biliary system have an increasing incidence and poor prognosis. Framing the specific state of biliary eubiosis or dysbiosis is made difficult by the use of heterogeneous techniques and the sometimes unwarranted invasive sampling in healthy subjects. The influence of the microbial balance on the health status of the biliary tract could also account for some of the complications surrounding the post-liver-transplant phase. The aim of this extensive narrative review is to summarize the current evidence on this topic, to highlight gaps in the available evidence in order to guide further clinical research in these settings, and, eventually, to provide new tools to treat biliary lithiasis, biliopancreatic cancers, and even cholestatic disease.
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Affiliation(s)
- Cecilia Binda
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Giulia Gibiino
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Chiara Coluccio
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Monica Sbrancia
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
| | - Elton Dajti
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
| | - Emanuele Sinagra
- Endoscopy Unit, Fondazione Istituto San Raffaele-G. Giglio, 90015 Cefalù, Italy;
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90100 Palermo, Italy
| | - Gabriele Capurso
- Division of Pancreato-Biliary Endoscopy and EUS, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, 20132 Milano, Italy;
| | - Vittorio Sambri
- Unit of Microbiology, The Great Romagna Hub Laboratory, 47522 Pievesestina, Italy;
- Unit of Microbiology, Department of Pathological Anatomy, Trasfusion Medicine and Laboratory Medicine, University of Bologna, 40125 Bologna, Italy
| | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Ausl Romagna, 47121 Forlì, Italy
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences–DIMEC, Alma Mater Studiorum–University of Bologna, 90015 Bologna, Italy; (A.C.); (G.E.)
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Ausl Romagna, 47121 Forlì, Italy
| | - Carlo Fabbri
- Gastroenterology and Digestive Endoscopy Unit, Forlì-Cesena Hospitals, Ausl Romagna, 47121 Forlì, Italy; (C.B.); (G.G.); (M.S.); (E.D.); (C.F.)
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11
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Center SA, Randolph JF, Warner KL, McDonough SP, Lucy JM, Sapa KC. Bacterial culture and immunohistochemical detection of bacteria and endotoxin in cats with suppurative cholangitis-cholangiohepatitis syndrome. J Am Vet Med Assoc 2021; 260:194-211. [PMID: 34936576 DOI: 10.2460/javma.20.10.0552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To characterize the frequency and type of bacterial infection by culture- and immunohistochemical (IHC)-based methods and determine the impact of infection on clinical features and survival time in cats with suppurative cholangitis-cholangiohepatitis syndrome (S-CCHS). ANIMALS 168 client-owned cats with S-CCHS (cases). PROCEDURES Clinical features, bacterial culture results, culture-inoculate sources, and survival details were recorded. Cases were subcategorized by comorbidity (extrahepatic bile duct obstruction, cholelithiasis, cholecystitis, ductal plate malformation, biopsy-confirmed inflammatory bowel disease, and biopsy-confirmed pancreatitis) or treatment by cholecystectomy or cholecystoenterostomy. Culture results, bacterial isolates, Gram-stain characteristics, and IHC staining were compared among comorbidities. Lipoteichoic acid IHC staining detected gram-positive bacterial cell wall components, and toll-like receptor expression IHC reflected pathologic endotoxin (gram-negative bacteria) exposure. RESULTS Clinical features were similar among cases except for more frequent abdominal pain and lethargy in cats with positive culture results and pyrexia, abdominal pain, and hepatomegaly for cats with polymicrobial infections. Bacteria were cultured in 93 of 135 (69%) cats, with common isolates including Enterococcus spp and Escherichia coli. IHC staining was positive in 142 of 151 (94%) cats (lipoteichoic acid, 107/142 [75%]; toll-like receptor 4, 99/142 [70%]). With in-parallel interpretation of culture and IHC-based bacterial detection, 154 of 166 (93%) cats had bacterial infections (gram-positive, 118/154 [77%]; gram-negative, 111/154 [72%]; polymicrobial, 79/154 [51%]). Greater frequency of bacterial isolation occurred with combined tissue, bile, and crushed cholelith inoculates. Infection and gram-positive bacterial isolates were associated with significantly shorter long-term survival times. CLINICAL RELEVANCE S-CCHS was associated with bacterial infection, pathologic endotoxin exposure, and frequent polymicrobial infection in cats. Combined tissue inoculates improved culture detection of associated bacteria.
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Affiliation(s)
- Sharon A Center
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - John F Randolph
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - Karen L Warner
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | - Sean P McDonough
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
| | | | - Kirk C Sapa
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
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12
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Zheng Y, Ran Y, Zhang H, Wang B, Zhou L. The Microbiome in Autoimmune Liver Diseases: Metagenomic and Metabolomic Changes. Front Physiol 2021; 12:715852. [PMID: 34690796 PMCID: PMC8531204 DOI: 10.3389/fphys.2021.715852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Recent studies have identified the critical role of microbiota in the pathophysiology of autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Metagenomic studies reveal significant decrease of gut bacterial diversity in AILDs. Although profiles of metagenomic vary widely, Veillonella is commonly enriched in AIH, PBC, and PSC. Apart from gut microbiome, the oral and bile microbiome seem to be associated with these diseases as well. The functional analysis of metagenomics suggests that metabolic pathways changed in the gut microbiome of the patients. Microbial metabolites, including short-chain fatty acids (SCFAs) and microbial bile acid metabolites, have been shown to modulate innate immunity, adaptive immunity, and inflammation. Taken together, the evidence of host–microbiome interactions and in-depth mechanistic studies needs further accumulation, which will offer more possibilities to clarify the mechanisms of AILDs and provide potential molecular targets for the prevention and treatment in the future.
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Affiliation(s)
- Yanping Zheng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Ying Ran
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hongxia Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.,Department of Gastroenterology and Hepatology, Hotan People's Hospital, Xinjiang, China
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13
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The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies. Int J Mol Sci 2021; 22:ijms22136975. [PMID: 34203536 PMCID: PMC8268159 DOI: 10.3390/ijms22136975] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.
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14
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Characterization of biliary microbiota dysbiosis in extrahepatic cholangiocarcinoma. PLoS One 2021; 16:e0247798. [PMID: 33690612 PMCID: PMC7943025 DOI: 10.1371/journal.pone.0247798] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 02/12/2021] [Indexed: 12/11/2022] Open
Abstract
Extrahepatic cholangiocarcinoma (CCA) accounts for 3% of digestive cancers. The role of biliary microbiota as an environment-related modulator has been scarcely investigated in CCA, and the putative impact of associated diseases has not been yet assessed. We characterized the biliary microbiota in CCA patients in order to identify a specific CCA-related dysbiosis. The biliary effluents were collected through an endoscopic retrograde pancreatic cholangiography (ERCP) examination involving 28 CCA and 47 patients with gallstones, herein considered as controls. The biliary effluents were submitted to bacterial DNA extraction and 16S rRNA sequencing, using Illumina technology. Overall, 32% of CCA and 22% of controls displayed another associated disease, such as diabetes, pancreatitis, inflammatory bowel disease, or primary sclerosing cholangitis. Such associated diseases were considered in the comparisons that were made. Principal coordinate analysis (PCoA) detected a significant disparity of biliary microbiota composition between CCA patients and controls without an associated disease. Amongst the most abundant phyla, Proteobacteria did not significantly differ between CCA patients and controls, whereas Firmicutes levels were lower and Bacteroidetes higher in CCAs’ biliary microbiota than in the controls’ microbiota. The most abundant genera were Enterococcus, Streptococcus, Bacteroides, Klebsiella, and Pyramidobacter in CCA’s biliary microbiota. Additionally, levels of Bacteroides, Geobacillus, Meiothermus, and Anoxybacillus genera were significantly higher in CCA patients’ biliary microbiota, without an associated disease, in comparison with controls. A specific CCA-related dysbiosis was identified as compared to controls independently from associated diseases. This suggests that a microorganism community may be involved in CCA pathogenesis.
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15
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Floreani A, De Martin S, Ikeura T, Okazaki K, Gershwin ME. Gut microbial profiling as a therapeutic and diagnostic target for managing primary biliary cholangitis. Expert Opin Orphan Drugs 2020. [DOI: 10.1080/21678707.2020.1865917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Affiliation(s)
- Annarosa Floreani
- Scientific Consultant, IRCCS Negrar, Verona, Italy
- Studiosa Senior, University of Padova, Padova, Italy
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
| | - Tsukasa Ikeura
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Merrill Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
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16
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Maroni L, Ninfole E, Pinto C, Benedetti A, Marzioni M. Gut-Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology. Cells 2020; 9:cells9030736. [PMID: 32192118 PMCID: PMC7140657 DOI: 10.3390/cells9030736] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/10/2020] [Accepted: 03/13/2020] [Indexed: 12/15/2022] Open
Abstract
The Nlrp3 inflammasome is a multiprotein complex activated by a number of bacterial products or danger signals and is involved in the regulation of inflammatory processes through caspase-1 activation. The Nlrp3 is expressed in immune cells but also in hepatocytes and cholangiocytes, where it appears to be involved in regulation of biliary damage, epithelial barrier integrity and development of fibrosis. Activation of the pathways of innate immunity is crucial in the pathophysiology of hepatobiliary diseases, given the strong link between the gut and the liver. The liver secretes bile acids, which influence the bacterial composition of the gut microbiota and, in turn, are heavily modified by microbial metabolism. Alterations of this balance, as for the development of dysbiosis, may deeply influence the composition of the bacterial products that reach the liver and are able to activate a number of intracellular pathways. This alteration may be particularly important in the pathogenesis of cholangiopathies and, in particular, of primary sclerosing cholangitis, given its strong association with inflammatory bowel disease. In the present review, we summarize current knowledge on the gut–liver axis in cholangiopathies and discuss the role of Nlrp3 inflammasome activation in cholestatic conditions.
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Affiliation(s)
- Luca Maroni
- Correspondence: ; Tel.: +39-071-220-6043; Fax: +39-071-220-6044
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17
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Berntsen NL, Fosby B, Tan C, Reims HM, Ogaard J, Jiang X, Schrumpf E, Valestrand L, Karlsen TH, Line PD, Blumberg RS, Melum E. Natural killer T cells mediate inflammation in the bile ducts. Mucosal Immunol 2018; 11:1582-1590. [PMID: 30115993 PMCID: PMC6402771 DOI: 10.1038/s41385-018-0066-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 06/29/2018] [Accepted: 07/09/2018] [Indexed: 02/04/2023]
Abstract
Cholangiocytes function as antigen-presenting cells with CD1d-dependent activation of natural killer T (NKT) cells in vitro. NKT cells may act both pro- and anti-inflammatory in liver immunopathology. We explored this immune pathway and the antigen-presenting potential of NKT cells in the bile ducts by challenging wild-type and Cd1d-/- mice with intrabiliary injection of the NKT cell activating agent oxazolone. Pharmacological blocking of CD1d-mediated activation was performed with a monoclonal antibody. Intrabiliary oxazolone injection in wild-type mice caused acute cholangitis with significant weight loss, elevated serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, increased histologic grade of cholangitis and number of T cells, macrophages, neutrophils and myofibroblasts per portal tract after 7 days. NKT cells were activated after intrabiliary injection of oxazolone with upregulation of activation markers. Cd1d-/- and wild-type mice pretreated with antibody blocking of CD1d were protected from disease. These findings implicate that cells in the bile ducts function as antigen-presenting cells in vivo and activate NKT cells in a CD1d-restricted manner. The elucidation of this biliary immune pathway opens up for potentially new therapeutic approaches for cholangiopathies.
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Affiliation(s)
- N L Berntsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - B Fosby
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - C Tan
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - H M Reims
- Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - J Ogaard
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - X Jiang
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - E Schrumpf
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - L Valestrand
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - T H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - P-D Line
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - R S Blumberg
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - E Melum
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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18
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Giordano DM, Pinto C, Maroni L, Benedetti A, Marzioni M. Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies. Int J Mol Sci 2018; 19:E3003. [PMID: 30275402 PMCID: PMC6213589 DOI: 10.3390/ijms19103003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/26/2018] [Accepted: 09/29/2018] [Indexed: 12/11/2022] Open
Abstract
Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.
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Affiliation(s)
- Debora Maria Giordano
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Claudio Pinto
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Luca Maroni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Antonio Benedetti
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Via Tronto 10, 60126 Ancona, Italy.
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19
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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] [Key Words] [MESH Headings] [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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Glassner K, Quigley EM, Franco L, Victor DW. Autoimmune liver disease and the enteric microbiome. AIMS Microbiol 2018; 4:334-346. [PMID: 31294219 PMCID: PMC6604930 DOI: 10.3934/microbiol.2018.2.334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/08/2018] [Indexed: 12/13/2022] Open
Abstract
The human enteric microbiome is highly complex and has more than 150 times more genes within it than its host. The host and the microbiome have a commensurate relationship that can evolve over time. The typically symbiotic relationship between the two can become pathogenic. The microbiome composition in adults reflects their history of exposure to bacteria and environmental factors during early life, their genetic background, age, interactions with the immune system, geographical location, and, most especially, their diet. Similarly, these factors are thought to contribute to the development of autoimmune disease. It is possible that alterations in the intestinal microbiome could lead to liver disease. There is emerging data for the contribution of the microbiome in development of primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; liver disorders associated with aberrant immune function in genetically susceptible individuals.
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Affiliation(s)
- Kerri Glassner
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
| | - Eamonn Mm Quigley
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
| | - Lissa Franco
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
| | - David W Victor
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA.,Sherrie and Alan Conover Center for Liver Disease, Houston Methodist Hospital, Weill Cornell Medical College, 6550 Fannin Street, SM 1201, Houston, TX 77030, USA
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21
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Tabibian JH, Bowlus CL. WITHDRAWN: Primary sclerosing cholangitis: A review and update. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2017.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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22
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Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1270-1278. [DOI: 10.1016/j.bbadis.2017.07.024] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 07/20/2017] [Accepted: 07/21/2017] [Indexed: 02/06/2023]
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23
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Tabibian JH, Bowlus CL. Primary sclerosing cholangitis: A review and update. LIVER RESEARCH (BEIJING, CHINA) 2017; 1:221-230. [PMID: 29977644 PMCID: PMC6028044 DOI: 10.1016/j.livres.2017.12.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease of uncertain etiology characterized biochemically by cholestasis and histologically and cholangiographically by fibro-obliterative inflammation of the bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and/or hepatobiliary cancer, though the disease course can be highly variable. Despite clinical trials of numerous pharmacotherapies over several decades, safe and effective medical therapy remains to be established. Liver transplantation is an option for select patients with severe complications of PSC, and its outcomes are generally favorable. Periodic surveillance testing for pre- as well as post-transplant patients is a cornerstone of preventive care and health maintenance. Here we provide an overview of PSC including its epidemiology, etiopathogenesis, clinical features, associated disorders, surveillance, and emerging potential therapies.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
- Division of Gastroenterology, Olive View-UCLA Medical Center, Sylmar, CA, USA
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
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Pereira P, Aho V, Arola J, Boyd S, Jokelainen K, Paulin L, Auvinen P, Färkkilä M. Bile microbiota in primary sclerosing cholangitis: Impact on disease progression and development of biliary dysplasia. PLoS One 2017; 12:e0182924. [PMID: 28796833 PMCID: PMC5552186 DOI: 10.1371/journal.pone.0182924] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/26/2017] [Indexed: 02/07/2023] Open
Abstract
Objective The etiopathogenesis and risk for development of biliary neoplasia in primary sclerosing cholangitis (PSC) are largely unknown. Microbes or their metabolites have been suggested to play a role. To explore this potential microbial involvement, we evaluated the differences in biliary microbiota in PSC patients at an early disease stage without previous endoscopic retrograde cholangiography (ERC) examinations, advanced disease stage, and with biliary dysplasia or cholangiocarcinoma. Design Bile samples from the common bile duct were collected from 46 controls and 80 patients with PSC during ERC (37 with early disease, 32 with advanced disease, and 11 with biliary dysplasia). DNA isolation, amplification, and Illumina MiSeq sequencing were performed for the V1-V3 regions of the bacterial 16S rRNA gene. Results The most common phyla found were Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, and Actinobacteria. The most common families were Prevotellaceae, Streptococcaceae, Veillonellaceae, Fusobacteriaceae, and Pasteurellaceae, and the most common genera were Prevotella, Streptococcus, Veillonella, Fusobacterium, and Haemophilus. The bacterial communities of non-PSC subjects and early stage PSC patients were similar. Alpha diversity was lower in patients with biliary dysplasia/cholangiocarcinoma than in other groups. An increase in Streptococcus abundance was positively correlated with the number of ERC examinations. Streptococcus abundance was also positively correlated with an increase in disease severity, even after controlling for the number of ERC examinations. Conclusions Our findings suggest that the aetiology of PSC is not associated with changes in bile microbial communities, but the genus Streptococcus may play a pathogenic role in the progression of the disease.
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Affiliation(s)
- Pedro Pereira
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
- * E-mail:
| | - Velma Aho
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Johanna Arola
- University of Helsinki, Department of Pathology, Helsinki University Hospital, Helsinki, Finland
| | - Sonja Boyd
- University of Helsinki, Department of Pathology, Helsinki University Hospital, Helsinki, Finland
| | - Kalle Jokelainen
- University of Helsinki and Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
| | - Lars Paulin
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Petri Auvinen
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Martti Färkkilä
- University of Helsinki and Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
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25
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Tabibian JH, Gossard A, El-Youssef M, Eaton JE, Petz J, Jorgensen R, Enders FB, Lindor KD. Prospective Clinical Trial of Rifaximin Therapy for Patients With Primary Sclerosing Cholangitis. Am J Ther 2017; 24:e56-e63. [PMID: 24914504 PMCID: PMC4261045 DOI: 10.1097/mjt.0000000000000102] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease in which emerging data suggest that oral antibiotics may offer therapeutic effects. We enrolled patients with PSC in a 12-week, open-label pilot study to investigate the efficacy and safety of 550 mg of oral rifaximin twice daily. The primary end point was serum alkaline phosphatase (ALK) at 12 weeks. Secondary end points included (1) serum bilirubin, gamma-glutamyl transpeptidase, and Mayo PSC risk score; (2) fatigue impact scale, chronic liver disease questionnaire, and short form health survey (SF-36) scores; and (3) adverse effects (AEs). Analyses were performed with nonparametric tests. Sixteen patients were enrolled, among whom the median age was 40 years; 13 (81%) were male, 13 had inflammatory bowel disease, and baseline ALK was 342 IU/mL (interquartile range, 275-520 IU/mL). After 12 weeks of treatment, there were no significant changes in ALK (median increase of 0.9% to 345 IU/mL; P = 0.47) or any of the secondary biochemical end points (all P > 0.05). Similarly, there were no significant changes in fatigue impact scale, chronic liver disease questionnaire, or SF-36 scores (all P > 0.05). Three patients withdrew from the study due to AEs; 4 others reported mild AEs but completed the study. In conclusion, although some antibiotics may have promise in treating PSC, oral rifaximin, based on the results herein, seems inefficacious for this indication. Future studies are needed to understand how the antimicrobial spectra and other properties of antibiotics might determine their utility in treating PSC.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
- Center for Clinical and Translational Sciences, Mayo Graduate School, Rochester, MN
| | - Andrea Gossard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Mounif El-Youssef
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - John E. Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Jan Petz
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Roberta Jorgensen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Felicity B. Enders
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
| | - Keith D. Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
- Executive Vice Provost & Dean, College of Health Solutions, Arizona State University, Phoenix, AZ
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Nlrp3 Activation Induces Il-18 Synthesis and Affects the Epithelial Barrier Function in Reactive Cholangiocytes. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 187:366-376. [PMID: 27912077 DOI: 10.1016/j.ajpath.2016.10.010] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 09/23/2016] [Accepted: 10/11/2016] [Indexed: 12/22/2022]
Abstract
Microbial products are thought to influence the progression of cholangiopathies, in particular primary sclerosing cholangitis (PSC). Inflammasomes are molecular platforms that respond to microbial products through the synthesis of proinflammatory cytokines. We investigated the role of inflammasome activation in cholangiocyte response to injury. Nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (Nlrp3) expression was tested in cholangiocytes of normal and cholestatic livers. Effects of Nlrp3 activation induced by incubation with lipopolysaccharide and ATP was studied in vitro in normal and siRNA-Nlrp3 knocked-down cholangiocytes. Wild-type and Nlrp3 knockout (Nlrp3-/-) mice were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; a model of sclerosing cholangitis) for 4 weeks. Nlrp3 and its components were overexpressed in cholangiocytes of mice subjected to DDC and in patients affected by PSC. In vitro, Nlrp3 activation stimulated expression of Il-18 but not of Il-1β and Il-6. Nlrp3 activation had no effect on cholangiocyte proliferation but significantly decreased the expression of Zonulin-1 and E-cadherin, whereas Nlrp3 knockdown increased the permeability of cholangiocyte monolayers. In vivo, the DDC-stimulated number of cytokeratin-19-positive cells in the liver of wild-type animals was slightly reduced in Nlrp3-/- mice, and expression of E-cadherin was reestablished. In conclusion, Nlrp3 is expressed in reactive cholangiocytes, in both murine models and patients with PSC. Activation of Nlrp3 leads to synthesis of proinflammatory cytokines and influences epithelial integrity of cholangiocytes.
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Mattner J. Impact of Microbes on the Pathogenesis of Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC). Int J Mol Sci 2016; 17:1864. [PMID: 27834858 PMCID: PMC5133864 DOI: 10.3390/ijms17111864] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/02/2016] [Accepted: 11/04/2016] [Indexed: 02/07/2023] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent the major clinical entities of chronic cholestatic liver diseases. Both disorders are characterized by portal inflammation and slowly progress to obliterative fibrosis and eventually liver cirrhosis. Although immune-pathogenic mechanisms have been implicated in the pathogenesis of PBC and PSC, neither disorder is considered to be a classical autoimmune disease, as PSC and PBC patients do not respond to immune-suppressants. Furthermore, the decreased bile flow resulting from the immune-mediated tissue assault and the subsequent accumulation of toxic bile products in PBC and PSC not only perpetuates biliary epithelial damage, but also alters the composition of the intestinal and biliary microbiota and its mutual interactions with the host. Consistent with the close association of PSC and inflammatory bowel disease (IBD), the polyclonal hyper IgM response in PBC and (auto-)antibodies which cross-react to microbial antigens in both diseases, an expansion of individual microbes leads to shifts in the composition of the intestinal or biliary microbiota and a subsequent altered integrity of epithelial layers, promoting microbial translocation. These changes have been implicated in the pathogenesis of both devastating disorders. Thus, we will discuss here these recent findings in the context of novel and alternative therapeutic options.
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MESH Headings
- Anti-Bacterial Agents/therapeutic use
- Antibodies, Bacterial/biosynthesis
- Bacterial Translocation
- Bile/drug effects
- Bile/microbiology
- Cholangiopancreatography, Endoscopic Retrograde
- Cholangitis, Sclerosing/diagnostic imaging
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/microbiology
- Gastrointestinal Microbiome/drug effects
- Host-Pathogen Interactions
- Humans
- Immunoglobulin M/biosynthesis
- Liver Cirrhosis, Biliary/diagnostic imaging
- Liver Cirrhosis, Biliary/drug therapy
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/microbiology
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Affiliation(s)
- Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Wasserturmstr. 3/5, D-91054 Erlangen, Germany.
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Tabibian JH, Varghese C, LaRusso NF, O'Hara SP. The enteric microbiome in hepatobiliary health and disease. Liver Int 2016; 36:480-487. [PMID: 26561779 PMCID: PMC4825184 DOI: 10.1111/liv.13009] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 11/02/2015] [Indexed: 12/15/2022]
Abstract
Increasing evidence points to the contribution of the intestinal microbiome as a potentially key determinant in the initiation and/or progression of hepatobiliary disease. While current understanding of this dynamic is incomplete, exciting insights are continually being made and more are expected given the developments in molecular and high-throughput omics techniques. In this brief review, we provide a practical and updated synopsis of the interaction of the intestinal microbiome with the liver and its downstream impact on the initiation, progression and complications of hepatobiliary disease.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA
| | - Cyril Varghese
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Steven P. O'Hara
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Tabibian JH, O’Hara SP, Trussoni CE, Tietz PS, Splinter PL, Mounajjed T, Hagey LR, LaRusso NF. Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. Hepatology 2016; 63:185-196. [PMID: 26044703 PMCID: PMC4670294 DOI: 10.1002/hep.27927] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 07/01/2015] [Indexed: 02/06/2023]
Abstract
UNLABELLED Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested the hypothesis that germ-free (GF) mutltidrug resistance 2 knockout (mdr2(-/-) ) mice develop a distinct PSC phenotype, compared to conventionally housed (CV) mdr2(-/-) mice. Mdr2(-/-) mice (n = 12) were rederived as GF by embryo transfer, maintained in isolators, and sacrificed at 60 days in parallel with age-matched CV mdr2(-/-) mice. Serum biochemistries, gallbladder bile acids, and liver sections were examined. Histological findings were validated morphometrically, biochemically, and by immunofluorescence microscopy (IFM). Cholangiocyte senescence was assessed by p16(INK4a) in situ hybridization in liver tissue and by senescence-associated β-galactosidase staining in a culture-based model of insult-induced senescence. Serum biochemistries, including alkaline phosphatase, aspartate aminotransferase, and bilirubin, were significantly higher in GF mdr2(-/-) (P < 0.01). Primary bile acids were similar, whereas secondary bile acids were absent, in GF mdr2(-/-) mice. Fibrosis, ductular reaction, and ductopenia were significantly more severe histopathologically in GF mdr2(-/-) mice (P < 0.01) and were confirmed by hepatic morphometry, hydroxyproline assay, and IFM. Cholangiocyte senescence was significantly increased in GF mdr2(-/-) mice and abrogated in vitro by ursodeoxycholic acid (UDCA) treatment. CONCLUSIONS GF mdr2(-/-) mice exhibit exacerbated biochemical and histological features of PSC and increased cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease. UDCA, a commensal microbial metabolite, abrogates senescence in vitro. These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and suggest avenues for future studies of biomarkers and therapeutic interventions in PSC.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester
| | - Steven P. O’Hara
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester
| | - Christy E. Trussoni
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester
| | - Pamela S. Tietz
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester
| | - Patrick L. Splinter
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester
| | | | - Lee R. Hagey
- Division of Gastroenterology, University of California, San Diego, La Jolla
| | - Nicholas F. LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester
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30
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Abstract
Background The biliary system is in continuous contact with the complex microbiota of the intestine. Microbial products have recently been proposed as potential triggers for biliary diseases. Methods The aim of this review is to provide a summary of the current knowledge regarding the role of the biliary and intestinal microbiome in biliary inflammatory diseases. Results Previously, it was suggested that the healthy biliary system is a sterile organ, while acute cholangitis and cholecystitis may occur from ascending infections. Although non-inflammatory biliary colonization by certain bacteria such as Salmonella spp. has been already recognized since several decades, human and animal studies indicated only very recently that the gallbladder harbors a complex microbiota also under non-pathologic conditions. Novel findings suggested that – similar to the situation in the intestine – the biliary mucosa features a chemical, mechanical, and immunological barrier, ensuring immunological tolerance against commensals. However, microbial triggers might influence acute and chronic inflammatory disease of the biliary system and the whole liver. Conclusion Although yet undefined, dysbiosis of the biliary or intestinal microbiota rather than a single microorganism may influence disease progression.
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Affiliation(s)
- Julien Verdier
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Tom Luedde
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Gernot Sellge
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Trussoni CE, Tabibian JH, Splinter PL, O’Hara SP. Lipopolysaccharide (LPS)-Induced Biliary Epithelial Cell NRas Activation Requires Epidermal Growth Factor Receptor (EGFR). PLoS One 2015; 10:e0125793. [PMID: 25915403 PMCID: PMC4411066 DOI: 10.1371/journal.pone.0125793] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 03/19/2015] [Indexed: 12/27/2022] Open
Abstract
Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously demonstrated that cholangiocyte TLR-dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal human cholangiocytes (NHC), were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE) inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (p<0.05) and proliferation (p<0.01). Additionally, cholangiocytes from LPS-treated mouse livers and human primary sclerosing cholangitis (PSC) livers exhibited increased phospho-EGFR (p<0.01). Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes.
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Affiliation(s)
- Christy E. Trussoni
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota, 55905, United States of America
| | - James H. Tabibian
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota, 55905, United States of America
| | - Patrick L. Splinter
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota, 55905, United States of America
| | - Steven P. O’Hara
- Division of Gastroenterology and Hepatology, and the Mayo Clinic Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, Minnesota, 55905, United States of America
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32
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Nakanuma Y, Sasaki M, Harada K. Autophagy and senescence in fibrosing cholangiopathies. J Hepatol 2015; 62:934-45. [PMID: 25435435 DOI: 10.1016/j.jhep.2014.11.027] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 11/08/2014] [Accepted: 11/16/2014] [Indexed: 12/16/2022]
Abstract
Fibrosing cholangiopathy such as primary sclerosing cholangitis (PSC) and biliary atresia (BA) is characterized by biliary epithelial injuries and concentric fibrous obliteration of the biliary tree together with inflammatory cell infiltration. In these diseases, inappropriate innate immunity is reported to contribute more to bile duct pathology as compared with various aspects of "classical" autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by chronic cholangitis with bile duct loss and classical autoimmune features. Cellular senescence of cholangiocytes and a senescence-associated secretory phenotype lead to the production of proinflammatory cytokines and chemokines that may modify the milieu of the bile duct and then trigger fibroinflammatory responses in PSC and PBC. Furthermore, deregulated autophagy might be involved in cholangiocyte senescence and possibly in the autoimmune process in PBC, and the deregulated innate immunity against enteric microbes or their products that is associated with cholangiocyte senescence might result in the fibrosing cholangitis that develops in PBC and PSC. In BA, innate immunity against double-stranded RNA viruses might be involved in cholangiocyte apoptosis and also in the development of the epithelial-mesenchymal transition of cholangiocytes that results in fibrous obliteration of bile ducts. These recent advances in the understanding of immune-mediated biliary diseases represent a paradigm shift: the cholangiocyte is no longer viewed merely as a passive victim of injury; it is now also considered to function as a potential effector in bile duct pathology.
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Affiliation(s)
- Yasuni Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan; Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan.
| | - Motoko Sasaki
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
| | - Kenichi Harada
- Department of Pathology, Kanazawa University Graduate School of Medical Science, Japan
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Matsushita H, Miyake Y, Takaki A, Yasunaka T, Koike K, Ikeda F, Shiraha H, Nouso K, Yamamoto K. TLR4, TLR9, and NLRP3 in biliary epithelial cells of primary sclerosing cholangitis: relationship with clinical characteristics. J Gastroenterol Hepatol 2015; 30:600-8. [PMID: 25160604 DOI: 10.1111/jgh.12711] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Inappropriate innate immune responses have been suggested to contribute to the pathogenesis of primary sclerosing cholangitis (PSC). We evaluated the associations of expressions of toll-like receptor (TLR) 4, TLR9, and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in the biliary epithelial cells (BECs) with clinical features of PSC patients. METHODS We retrospectively evaluated the expressions of TLR4, TLR9, and NLRP3 in the intrahepatic BECs by immunohistochemical staining in 21 PSC patients and 10 normal controls. In PSC, 17 patients underwent liver biopsy, and, in the other four patients, liver specimens were obtained at the time of liver transplantation. RESULTS TLR9 expressions in BECs were higher in PSC patients than in normal controls. TLR9 expressions were correlated with Ludwig fibrosis scores in PSC patients. TLR4 and NLRP3 expressions were similar between PSC patients and normal controls. Seventeen PSC patients undergoing liver biopsy were followed up during a median period of 55.7 months. Four reached to liver transplantation and four developed cholangiocarcinoma. Patients developing cholangiocarcinoma showed lower NLRP3 expressions than the others. Patients reaching to liver transplantation showed higher TLR9 expressions. Expression levels of TLR9 and NLRP3 were not correlated with liver biochemical tests and Mayo risk scores. CONCLUSIONS In PSC, excessive immune responses through TLR9 signaling may be associated with the disease progression. Insufficient immune response through NLRP3 signaling may be associated with the development of cholangiocarcinoma. Evaluation of TLR9 and NLRP3 expressions in BECs may be useful for predicting the prognosis as an auxiliary marker.
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Affiliation(s)
- Hiroshi Matsushita
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Tabibian JH, O’hara SP, Lindor KD. Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroenterol 2014; 49:901-908. [PMID: 24990660 PMCID: PMC4210190 DOI: 10.3109/00365521.2014.913189] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis. PSC generally progresses to liver cirrhosis, is a major risk factor for hepatobiliary and colonic neoplasia, and confers a median survival to death or liver transplantation of only 12 years. Although it is well recognized that approximately 75% of patients with PSC also have inflammatory bowel disease (IBD), the significance of this association remains elusive. Accumulating evidence now suggests a potentially important role for the intestinal microbiota, and enterohepatic circulation of molecules derived therefrom, as a putative mechanistic link between PSC and IBD and a central pathobiological driver of PSC. In this concise review, we provide a summary of and perspectives regarding the relevant basic, translational, and clinical data, which, taken together, encourage further investigation of the role of the microbiota and microbial metabolites in the etiopathogenesis of PSC and as a potential target for novel pharmacotherapies.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Center for Clinical and Translational Sciences, Mayo Graduate School, Rochester, MN, USA
| | - Steven P. O’hara
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Keith D. Lindor
- Executive Vice Provost & Dean, College of Health Solutions, Arizona State University, Phoenix, AZ, USA
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Tabibian JH, Talwalkar JA, Lindor KD. Role of the microbiota and antibiotics in primary sclerosing cholangitis. BIOMED RESEARCH INTERNATIONAL 2013; 2013:389537. [PMID: 24232746 PMCID: PMC3819830 DOI: 10.1155/2013/389537] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 09/05/2013] [Indexed: 12/18/2022]
Abstract
Primary sclerosing cholangitis (PSC) is an idiopathic, progressive, cholestatic liver disease with considerable morbidity and mortality and no established pharmacotherapy. In addition to the long-recognized association between PSC and inflammatory bowel disease, several lines of preclinical and clinical evidence implicate the microbiota in the etiopathogenesis of PSC. Here we provide a concise review of these data which, taken together, support further investigation of the role of the microbiota and antibiotics in PSC as potential avenues toward elucidating safe and effective pharmacotherapy for patients afflicted by this illness.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Sreet SW, Rochester, MN 55905, USA
| | - Jayant A. Talwalkar
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Sreet SW, Rochester, MN 55905, USA
| | - Keith D. Lindor
- Executive Vice Provost & Dean, College of Health Solutions, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA
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PPARγ ligand attenuates portal inflammation in the MRL-lpr mouse: a new strategy to restrain cholangiopathy in primary biliary cirrhosis. Med Mol Morphol 2013; 46:153-9. [DOI: 10.1007/s00795-013-0017-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Accepted: 07/13/2012] [Indexed: 12/17/2022]
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Abstract
Cholangiocytes, or bile duct epithelia, were once thought to be the simple lining of the conduit system comprising the intra- and extrahepatic bile ducts. Growing experimental evidence demonstrated that cholangiocytes are in fact the first line of defense of the biliary system against foreign substances. Experimental advances in recent years have unveiled previously unknown roles of cholangiocytes in both innate and adaptive immune responses. Cholangiocytes can release inflammatory modulators in a regulated fashion. Moreover, they express specialized pattern-recognizing molecules that identify microbial components and activate intracellular signaling cascades leading to a variety of downstream responses. The cytokines secreted by cholangiocytes, in conjunction with the adhesion molecules expressed on their surface, play a role in recruitment, localization, and modulation of immune responses in the liver and biliary tract. Cholangiocyte survival and function is further modulated by cytokines and inflammatory mediators secreted by immune cells and cholangiocytes themselves. Because cholangiocytes act as professional APCs via expression of major histocompatibility complex antigens and secrete antimicrobial peptides in bile, their role in response to biliary infection is critical. Finally, because cholangiocytes release mediators critical to myofibroblastic differentiation of portal fibroblasts and hepatic stellate cells, cholangiocytes may be essential in the pathogenesis of biliary cirrhosis.
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Affiliation(s)
- Gaurav Syal
- Division of Gastroenterology & Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Michel Fausther
- Division of Gastroenterology & Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Jonathan A. Dranoff
- Division of Gastroenterology & Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Haruta I, Kikuchi K, Nakamura M, Hirota K, Kato H, Miyakawa H, Shibata N, Miyake Y, Hashimoto E, Shiratori K, Yagi J. Involvement of commensal bacteria may lead to dysregulated inflammatory and autoimmune responses in a mouse model for chronic nonsuppurative destructive cholangitis. J Clin Immunol 2012; 32:1026-37. [PMID: 22661269 DOI: 10.1007/s10875-012-9712-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 05/22/2012] [Indexed: 01/02/2023]
Abstract
BACKGROUND We previously reported a mouse model of primary biliary cirrhosis (PBC)-like chronic nonsuppurative destructive cholangitis (CNSDC), in which frequent injections of Streptococcus intermedius induced CNSDC and autoantibody production. The present study was performed to verify the model by examining 1) the reappearance of the PBC-like CNSDC after lymphocyte transfer from model to naïve mice, 2) the involvement of autophagy, and 3) the influence of the strain difference. METHODS Mice were inoculated with S. intermedius weekly for 8 weeks, then sacrificed to obtain samples. Spleen cells obtained from S. intermedius-inoculated mice were transferred to RAG2(-/-) mice. RESULTS CNSDC and elevated serum level of anti-gp210 titers were observed in S. intermedius-inoculated C57BL/6 mice, similar to the results of our previous report using BALB/c mice. Portal inflammation was induced in the livers of RAG2(-/-) mice by the transfer of spleen cells from S. intermedius-inoculated C57BL/6 mice. Among the inflammatory cells in the RAG2(-/-) mice, CD3-positive cells were predominant. Autophagosome-like structures were detected histologically, in the cytoplasm of infiltrated cells around the bile ducts in the livers of S. intermedius-inoculated both C57BL/6 and BALB/c mice. In S. intermedius-inoculated C3H/HeJ mice, inflammation in the portal area was less extensive than that in the hepatic parenchyma. CONCLUSION Bacterial component(s) and sequentially upregulated innate and acquired immune responses, accompanied by autophagy, might trigger CNSDC, via autoimmune mechanisms. Throughout the generation of bacteria-triggered PBC-like CNSDC, strain difference may influence the response to S. intermedius-inoculation in the liver.
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Affiliation(s)
- Ikuko Haruta
- Department of Microbiology and Immunology, Tokyo Women's Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
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Abstract
The biliary tree consists of intrahepatic and extrahepatic bile ducts and is lined by biliary epithelial cells (or cholangiocytes). There are also peribiliary glands around the intrahepatic large bile ducts and extrahepatic bile ducts. The biliary tree is a conduit of bile secreted by hepatocytes and biliary epithelial cells and also of the peribiliary glands and has several physiological roles. A number of diseases affect mainly the intrahepatic and extrahepatic biliary tree, and, in this special issue, these cholangiopathies are reviewed in detail with respect to genetics, pathogenesis, and pathology. In this paper, the anatomy and physiology of the biliary tree, basic injuries to biliary epithelial cells from stress and bile duct damage, and representative cholangiopathies are briefly reviewed.
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Abstract
Biliary innate immunity is involved in the pathogenesis of cholangiopathies in cases of biliary disease. Cholangiocytes possess Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and play a pivotal role in the innate immune response. Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. Moreover, in primary biliary cirrhosis (PBC) and biliary atresia, biliary innate immunity is closely associated with the dysregulation of the periductal cytokine milieu and the induction of biliary apoptosis and epithelial-mesenchymal transition (EMT), forming in disease-specific cholangiopathy. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems.
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Miranda-Díaz AG, Alonso-Martínez H, Hernández-Ojeda J, Arias-Carvajal O, Rodríguez-Carrizalez AD, Román-Pintos LM. Toll-like receptors in secondary obstructive cholangiopathy. Gastroenterol Res Pract 2011; 2011:265093. [PMID: 22114589 PMCID: PMC3205723 DOI: 10.1155/2011/265093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 08/16/2011] [Accepted: 08/22/2011] [Indexed: 12/19/2022] Open
Abstract
Secondary obstructive cholangiopathy is characterized by intra- or extrahepatic bile tract obstruction. Liver inflammation and structural alterations develop due to progressive bile stagnation. Most frequent etiologies are biliary atresia in children, and hepatolithiasis, postcholecystectomy bile duct injury, and biliary primary cirrhosis in adults, which causes chronic biliary cholangitis. Bile ectasia predisposes to multiple pathogens: viral infections in biliary atresia; Gram-positive and/or Gram-negative bacteria cholangitis found in hepatolithiasis and postcholecystectomy bile duct injury. Transmembrane toll-like receptors (TLRs) are activated by virus, bacteria, fungi, and parasite stimuli. Even though TLR-2 and TLR-4 are the most studied receptors related to liver infectious diseases, other TLRs play an important role in response to microorganism damage. Acquired immune response is not vertically transmitted and reflects the infectious diseases history of individuals; in contrast, innate immunity is based on antigen recognition by specific receptors designated as pattern recognition receptors and is transmitted vertically through the germ cells. Understanding the mechanisms for bile duct inflammation is essential for the future development of therapeutic alternatives in order to avoid immune-mediated destruction on secondary obstructive cholangiopathy. The role of TLRs in biliary atresia, hepatolithiasis, bile duct injury, and primary biliary cirrhosis is described in this paper.
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Affiliation(s)
- A. G. Miranda-Díaz
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - H. Alonso-Martínez
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - J. Hernández-Ojeda
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - O. Arias-Carvajal
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - A. D. Rodríguez-Carrizalez
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
| | - L. M. Román-Pintos
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, 44340 JAL, Mexico
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Zhao J, Zhao S, Zhou G, Liang L, Guo X, Mao P, Zhou X, Wang H, Nan Y, Xu D, Yu J. Altered biliary epithelial cell and monocyte responses to lipopolysaccharide as a TLR ligand in patients with primary biliary cirrhosis. Scand J Gastroenterol 2011; 46:485-94. [PMID: 21275501 DOI: 10.3109/00365521.2010.539624] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Lipopolysaccharide (LPS) is suspected to trigger primary biliary cirrhosis (PBC) in susceptible individuals, yet the precise mechanism of its effect in PBC remains largely unknown. The aim of this study was to investigate altered responses to LPS ligand for Toll-like receptors (TLRs) in pathogenesis of PBC in vivo and in vitro. MATERIAL AND METHODS In vivo, we investigated levels of LPS and pro-inflammatory cytokines in sera and expression of LPS receptors in liver tissues from 162 patients with PBC, 325 patients with other liver diseases and 80 healthy controls. In vitro, altered responses to LPS on monocytes and cultured human biliary epithelial cells (BECs) from patients with PBC were determined. RESULTS Significantly higher levels of LPS in patients with PBC were detected, compared with patients with other liver diseases and healthy controls. Immunohistochemically, expression of TLR4, CD14, CD68 and NF-κB was significantly enhanced in liver tissues from patients with PBC. Before LPS stimulation, we found significantly higher serum levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-8 in patients with PBC than those in healthy controls. After LPS stimulation, TLR4 expression and pro-inflammatory cytokine production in CD14-positive monocytes and cultured BEC from patients with PBC increased significantly. CONCLUSIONS These results indicated that patients with PBC were prone to exhibit higher serum LPS level, hypersensitivity of monocytes and BEC to LPS, and enhanced production of pro-inflammatory cytokines. LPS altered expression of TLR4, CD14 and NF-κB on monocytes and BEC, which may be implicated in the pathogenesis and progression of PBC.
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MESH Headings
- Adult
- Alkaline Phosphatase/blood
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/immunology
- Antigens, Differentiation, Myelomonocytic/metabolism
- Bilirubin/blood
- Cells, Cultured
- Cross-Sectional Studies
- Epithelial Cells/immunology
- Epithelial Cells/metabolism
- Female
- Hepatitis B, Chronic/metabolism
- Hepatitis, Autoimmune/metabolism
- Humans
- Immunoglobulins/immunology
- Immunoglobulins/metabolism
- Inflammation/metabolism
- Interleukin-1beta/immunology
- Interleukin-1beta/metabolism
- Interleukin-6/immunology
- Interleukin-6/metabolism
- Interleukin-8/immunology
- Interleukin-8/metabolism
- Lipopolysaccharide Receptors/immunology
- Lipopolysaccharide Receptors/metabolism
- Lipopolysaccharides/immunology
- Lipopolysaccharides/metabolism
- Liver Cirrhosis, Biliary/etiology
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/metabolism
- Liver Diseases, Alcoholic/metabolism
- Male
- Membrane Glycoproteins/immunology
- Membrane Glycoproteins/metabolism
- Middle Aged
- Monocytes/immunology
- Monocytes/metabolism
- NF-kappa B/immunology
- NF-kappa B/metabolism
- Toll-Like Receptor 4/immunology
- Toll-Like Receptor 4/metabolism
- Toll-Like Receptors/immunology
- Toll-Like Receptors/metabolism
- Tumor Necrosis Factor-alpha/immunology
- Tumor Necrosis Factor-alpha/metabolism
- gamma-Glutamyltransferase/blood
- CD83 Antigen
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Affiliation(s)
- Jingmin Zhao
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
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Biliary innate immunity: function and modulation. Mediators Inflamm 2010; 2010. [PMID: 20798866 PMCID: PMC2926654 DOI: 10.1155/2010/373878] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Accepted: 06/22/2010] [Indexed: 12/18/2022] Open
Abstract
Biliary innate immunity is involved in the pathogenesis of cholangiopathies in patients with primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess an innate immune system consisting of the Toll-like receptor (TLR) family and recognize pathogen-associated molecular patterns (PAMPs). Tolerance to bacterial PAMPs such as lipopolysaccharides is also important to maintain homeostasis in the biliary tree, but tolerance to double-stranded RNA (dsRNA) is not found. In PBC, CD4-positive Th17 cells characterized by the secretion of IL-17 are implicated in the chronic inflammation of bile ducts and the presence of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. Moreover, a negative regulator of intracellular TLR signaling, peroxisome proliferator-activated receptor-γ (PPARγ), is involved in the pathogenesis of cholangitis. Immunosuppression using PPARγ ligands may help to attenuate the bile duct damage in PBC patients. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses are speculated to be an etiological agent and to directly induce enhanced biliary apoptosis via the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Moreover, the epithelial-mesenchymal transition (EMT) of biliary epithelial cells is also evoked by the biliary innate immune response to dsRNA.
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Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation. J Transl Med 2010; 90:577-88. [PMID: 20142809 DOI: 10.1038/labinvest.2010.40] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). We earlier reported that the bacterial lipoteichoic acid was detected at the sites of inflammation around damaged bile ducts in the livers of PBC, and PBC patients' sera showed high titers against streptococcal histone-like protein. Here, we investigated whether chronic bacterial exposure could trigger PBC-like epithelial cell damage in normal mouse. BALB/c mice were repeatedly inoculated with various bacteria for 8 weeks. At 1 week (Group 1) and 3, 4, or 20 months (long term; Group 2) after the final inoculation, mice were killed to obtain samples. In the livers of the Streptococcus intermedius (S.i.)-inoculated mice in Group 1, cellular infiltration was predominantly observed around the bile ducts over the hepatic parenchyma. In the S.i.-inoculated mice in Group 2, portal but not parenchymal inflammation was observed in the livers, and periductal cellular infiltrates were detected in the salivary glands. Both S.i.-inoculated Groups 1 and 2 BALB/c mice sera had antibodies against HuCCT1 biliary epithelial cells, anti-nuclear antibodies, and anti-gp210 antibodies, but not anti-mitochondrial antibodies. Immunoreactivity to histone-like DNA-binding protein of S.i. (S.i.-HLP) was detectable around the sites of chronic nonsuppurative destructive cholangitis in the portal area in the livers of both S.i.-inoculated Groups 1 and 2 BALB/c mice. Furthermore, anti-S.i.-HLP antibody bound to synthetic gp210 peptide, as well. Bacteria triggered PBC-like cholangitis, multifocal epithelial inflammation, and autoantibody production. Bacteria are likely involved in the pathogenesis of PBC and of associated multifocal epithelial inflammation.
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Lemos R, França PHC, Ferreira LE, Gonçalves AR, Campos ACL, Pinho M. Detection of bacterial DNA in acute and chronic cholecystitis. Br J Surg 2010; 97:532-6. [PMID: 20169571 DOI: 10.1002/bjs.6940] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND The incidence of bacterbilia in cholelithiasis remains controversial. The positivity of cultures ranges from 0 to 73 per cent. The aim of this study was to employ the polymerase chain reaction (PCR) to detect bacterial DNA in gallbladder bile extracted during elective laparoscopic cholecystectomy, and to compare PCR findings with those of bile culture. METHODS Bile samples from 84 laparoscopic cholecystectomies were collected for culture and PCR analysis. RESULTS Positive results for bacterbilia were found in 42 (50 per cent) of 84 patients by PCR but in only 16 patients (19 per cent) by culture (P < 0.001). Agreement between the two methods was seen in 44 samples (52 per cent), which were negative in 35 cases. Pathological examination showed chronic cholecystitis in 69 cases (82 per cent) and acute cholecystitis in 15 (18 per cent). Thirty-three (48 per cent) of the patients with chronic cholecystitis were PCR positive but only ten (14 per cent) were culture positive (P < 0.001). Only culture results correlated with findings on pathological examination (P = 0.033). CONCLUSION PCR is more sensitive in detecting bacterial contamination of gallbladder bile in cholecystitis than conventional culture. The clinical relevance of this high sensitivity remains unclear.
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Affiliation(s)
- R Lemos
- Biomolecular Laboratory, Medical Department, UNIVILLE University, Brazil
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Haruta I, Hashimoto E, Kato Y, Kikuchi K, Kato H, Yagi J, Uchiyama T, Kobayash M, Shiratori K. Lipoteichoic acid may affect the pathogenesis of bile duct damage in primary biliary cirrhosis. Autoimmunity 2009; 39:129-35. [PMID: 16698669 DOI: 10.1080/08916930600623841] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
AIM Intrahepatic bile ducts are the targets for inflammation in primary biliary cirrhosis (PBC), but their pathogenesis is not known. Gram-positive bacterial DNA was detected recently in gallbladder bile of PBC patients. In the present study, we assessed the possible pathological role of lipoteichoic acid (LTA), the gram-positive bacterial cell wall component, in PBC. METHODS Liver samples, obtained from 20 patients with PBC (stage 1-2 with CNSDC: stage 3-4 with loss of bile ducts = 10:10) and from 13 patients with chronic hepatitis due to hepatitis C virus (CH-C) with lymphocytic cholangitis, were subjected to immunohistochemical staining with polyclonal rabbit anti-LTA as the primary antibody. Serum reactivities to LTA were studied by ELISA. After 1 microg of purified LTA was placed in a 96-well microplate as an antigen, an antibody capture assay was carried out using serum samples from PBC (n = 20), CH-C (n = 13) and healthy subjects (n = 11). RESULTS LTA was localized around the sites of chronic non-suppurative destructive cholangitis (CNSDC) in the portal area in stage 1-2 PBC but was not detected in the portal area in CH-C. In stage 3-4 PBC, LTA was localized around sites of ductular proliferation at the periphery of portal tracts. IgM class anti-LTA serum titers were significantly higher in PBC than in CH-C. IgA class anti-LTA serum titers were significantly higher in PBC than in healthy subjects. CONCLUSIONS In the PBC livers, the profile of immunoreactivity to LTA changed markedly as the disease progressed. Sera from PBC showed higher levels of anti-LTA titers than CH-C (IgM) or from healthy subjects (IgA). The LTA-mediated immune system might affect the initiation and/or progression of PBC.
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MESH Headings
- Adult
- Aged
- Antibodies, Bacterial/blood
- Bile Ducts, Intrahepatic/drug effects
- Bile Ducts, Intrahepatic/metabolism
- Bile Ducts, Intrahepatic/microbiology
- Bile Ducts, Intrahepatic/pathology
- Female
- Gram-Positive Bacteria/immunology
- Gram-Positive Bacteria/pathogenicity
- Hepatitis C, Chronic/etiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/microbiology
- Hepatitis C, Chronic/pathology
- Humans
- Lipopolysaccharides/immunology
- Lipopolysaccharides/metabolism
- Liver Cirrhosis, Biliary/etiology
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/microbiology
- Liver Cirrhosis, Biliary/pathology
- Middle Aged
- Teichoic Acids/immunology
- Teichoic Acids/metabolism
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Affiliation(s)
- Ikuko Haruta
- Tokyo Women's Medical University, Department of Medicine and Gastroenterology, Tokyo, Japan.
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Abstract
Cholangiocytes, the epithelial cells lining bile ducts, provide the first line of defense against lumenal microbes in the biliary system. Recent advances in biliary immunity indicate that cholangiocytes express a variety of pathogen-recognition receptors and can activate a set of intracellular signaling cascades to initiate a profound antimicrobial defense, including release of proinflammatory cytokines and chemokines, production of antimicrobial peptides and maintenance of biliary epithelial integrity. Cholangiocytes also interact with other cell types in the liver (for example, lymphocytes and Kupffer cells) through expression and release of adhesion molecules and immune mediators. Subsequently, through an intricate feedback mechanism involving both epithelial and other liver cells, a set of intracellular signaling pathways are activated to regulate the functional state of cholangiocyte responses during microbial infection. Thus, cholangiocytes are actively involved in mucosal immunity of the biliary system and represent a fine-tuned, integral component of liver immunity.
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Affiliation(s)
- Xian-Ming Chen
- Department of Medical Microbiology and Immunology, Creighton University Medical Center, Omaha, NE 68178, USA.
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48
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Harada K, Sato Y, Isse K, Ikeda H, Nakanuma Y. Induction of innate immune response and absence of subsequent tolerance to dsRNA in biliary epithelial cells relate to the pathogenesis of biliary atresia. Liver Int 2008; 28:614-21. [PMID: 18433391 DOI: 10.1111/j.1478-3231.2008.01740.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Biliary epithelial cells (BECs) possess negative regulatory mechanisms of Toll-like receptor (TLR)-based tolerance to bacteria (e.g. endotoxin tolerance). Viral infections of the Reoviridae genus with a dsRNA genome are suspected to be part of the aetiology of biliary atresia (BA), but the negative biliary mechanisms remain unexplored. METHODS Cultured human intrahepatic BECs (HIBECs) pretreated with polyinosinic-polycytidylic acid [poly(I:C)] (a synthetic analogue of viral dsRNA) for 24 h were exposed to poly(I:C) in fresh medium. The activation of nuclear factor-kappaB (NF-kappaB) and the expression of myxovirus resistance protein A (MxA) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNAs were evaluated. Moreover, after the pretreatment, the transition of these molecules was examined in poly(I:C)-free conditions. RESULTS Treatment with poly(I:C) significantly upregulated NF-kappaB activity in fresh HIBECs, and pretreatment failed to show tolerance to poly(I:C). The production of MxA and TRAIL was also preserved. Moreover, upregulation in the pretreated HIBECs was well preserved in poly(I:C)-free medium for at least 72 h. CONCLUSIONS BECs fail to show tolerance to poly(I:C), and once innate immunity is activated it is sustained in poly(I:C)-free conditions, suggesting that the initiation of the immune response to dsRNA in HIBECs and its presence after the clearance of virus are closely associated with the progression of BA.
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Affiliation(s)
- Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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49
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Haruta I, Kikuchi K, Hashimoto E, Kato H, Hirota K, Kobayashi M, Miyake Y, Uchiyama T, Yagi J, Shiratori K. A possible role of histone-like DNA-binding protein of Streptococcus intermedius in the pathogenesis of bile duct damage in primary biliary cirrhosis. Clin Immunol 2008; 127:245-51. [PMID: 18337173 DOI: 10.1016/j.clim.2008.01.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Revised: 12/10/2007] [Accepted: 01/11/2008] [Indexed: 10/22/2022]
Abstract
Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). It was reported that anti-histone autoantibody was detected in PBC, suggesting that bacterial histone-like DNA-binding protein (HLP) may be involved in the pathogenesis of PBC. To identify bacterial species in PBC to confirm this possibility, serum reactivity to bacterial cells was studied by ELISA. The IgM class Streptococcus intermedius titers were significantly higher in PBC than chronic hepatitis due to hepatitis C virus (CH-C) and healthy subjects. Among the streptococci, S. intermedius was selected for further study. The antigenic peptide of S. intermedius of HLP was synthesized to examine the serum reactivity to Si-HLP. IgM class anti-Si-HLP peptide titers were significantly higher in PBC. Immunoreactivity to anti-Si-HLP was detected in the cytoplasm of biliary epithelial cells and inflammatory cells in the portal area in PBC patients' livers. Streptococci, especially S. intermedius, might play a key role in the pathogenesis of PBC, possibly involving HLP.
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Affiliation(s)
- Ikuko Haruta
- Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Japan.
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50
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Sawada S, Harada K, Isse K, Sato Y, Sasaki M, Kaizaki Y, Nakanuma Y. Involvement of Escherichia coli in pathogenesis of xanthogranulomatous cholecystitis with scavenger receptor class A and CXCL16-CXCR6 interaction. Pathol Int 2007; 57:652-63. [PMID: 17803654 DOI: 10.1111/j.1440-1827.2007.02154.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Xanthogranulomatous cholecystitis (XGC) is characterized by the infiltration of numerous foamy macrophages. Bacterial infection is thought to be involved in the pathogenesis of XGC. Using XGC and cultured murine biliary epithelial cells (BEC), the participation of E. coli and the role of the scavenger receptor class A (SCARA), as well as chemokine(C-X-C motif) ligand 16 (CXCL16) and its receptor chemokine(C-X-C motif) receptor 6 (CXCR6), were examined in the pathogenesis of XGC. E. coli components and genes were detected in XGC on immunohistochemistry and polymerase chain reaction (PCR), respectively. SCARA-recognizing E. coli was found in foamy macrophages aggregated in xanthogranulomatous lesions. CXCL16, which functions as a membrane-bound molecule and soluble chemokine to induce adhesion and migration of CXCR6(+) cells, was detected on gallbladder epithelia, and CXCR6(+)/CD8(+) T cells and CXCR6(+)/CD68(+) macrophages were also accumulated. In cultured BEC, CXCL16 mRNA and secreted soluble CXCL16 were constantly detected and upregulated by treatment with E. coli and lipopolysaccharide through Toll-like receptor 4. These suggest that SCARA in macrophages is involved in the phagocytosis of E. coli followed by foamy changes and that bacterial infection causes the upregulation of CXCL16 in gallbladder epithelia, leading to the chemoattraction of macrophages via CXCL16-CXCR6 interaction and formation of the characteristic histology of XGC.
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MESH Headings
- Aged
- Aged, 80 and over
- Animals
- Bile Ducts, Intrahepatic/cytology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/pathology
- Cells, Cultured
- Chemokine CXCL16
- Chemokines, CXC/metabolism
- Cholecystitis/metabolism
- Cholecystitis/microbiology
- Cholecystitis/pathology
- Epithelial Cells/cytology
- Epithelial Cells/metabolism
- Escherichia coli/genetics
- Escherichia coli/isolation & purification
- Escherichia coli/pathogenicity
- Female
- Foam Cells/metabolism
- Foam Cells/microbiology
- Genes, Bacterial/genetics
- Granuloma/metabolism
- Granuloma/microbiology
- Granuloma/pathology
- Humans
- Immunohistochemistry
- Male
- Mice
- Middle Aged
- Phagocytosis
- Receptors, CXCR6
- Receptors, Chemokine/metabolism
- Receptors, Scavenger/metabolism
- Receptors, Virus/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Scavenger Receptors, Class A/metabolism
- Up-Regulation
- Xanthomatosis/metabolism
- Xanthomatosis/microbiology
- Xanthomatosis/pathology
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Affiliation(s)
- Seiko Sawada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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