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Khunger S, Mewara A, Kaur U, Duseja A, Ray P, Kalra N, Sharma N, Sehgal R. Toll-like receptor upregulation in liver and peripheral blood mononuclear cells of patients with amoebic liver abscess. Immunobiology 2025; 230:152869. [PMID: 39919544 DOI: 10.1016/j.imbio.2025.152869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 12/24/2024] [Accepted: 01/08/2025] [Indexed: 02/09/2025]
Abstract
AIM We aimed to understand the host and microbe interactions at the time of infection and inflammatory response in amoebic liver abscess (ALA) patients based on toll-like receptor (TLR) expression (mRNA), cytokine and IgG subtypes levels. METHODS AND RESULTS Liver aspirates from 100 ALA patients and 11 liver autopsy samples were used as negative controls. Blood samples from 100 ALA and 41 healthy individuals were collected. mRNA expression of TLR 1 to 9 genes was measured using reverse transcriptase polymerase chain reaction (RT-PCR). Serum cytokines level was quantified by flow cytometry. In-house ELISA for the analysis of IgG and its subtypes in the serum samples was performed. A total of 7 TLR genes (TLR1, TLR2, TLR4, TLR6, TLR7, TLR8 and TLR9) and 6 TLR genes (TLR1, TLR2, TLR3, TLR4, TLR5 and TLR8) were found to be elevated in liver aspirates and PBMCs respectively. Increased serum cytokine levels were observed in ALA patients vs. healthy controls. Interestingly, a significant increase in IgG and its subtypes (IgG1, IgG3 and IgG4) was found in the serum of ALA patients. CONCLUSION Increased levels of TLR, pro- and anti-inflammatory cytokines, IgG and its subtypes, are possibly linked with early-stage infection in ALA patients. IMPACT STATEMENT The role of TLRs in association with ALA might provide insights into new therapeutic strategies.
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Affiliation(s)
- Sandhya Khunger
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India; Department of Microbiology (FAHS), Shree Guru Gobind Singh Tricentenary (SGT) University, Gurugram, (Haryana) 122505,India
| | - Abhishek Mewara
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Upninder Kaur
- Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pallab Ray
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Naveen Kalra
- Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Navneet Sharma
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rakesh Sehgal
- Department of Microbiology, Aarupadai Veed Medical College and Hospital, Vinayaka Mission's Research Foundation- DU, Pondicherry, India.
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Termite F, Archilei S, D’Ambrosio F, Petrucci L, Viceconti N, Iaccarino R, Liguori A, Gasbarrini A, Miele L. Gut Microbiota at the Crossroad of Hepatic Oxidative Stress and MASLD. Antioxidants (Basel) 2025; 14:56. [PMID: 39857390 PMCID: PMC11759774 DOI: 10.3390/antiox14010056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver condition marked by excessive lipid accumulation in hepatic tissue. This disorder can lead to a range of pathological outcomes, including metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Despite extensive research, the molecular mechanisms driving MASLD initiation and progression remain incompletely understood. Oxidative stress and lipid peroxidation are pivotal in the "multiple parallel hit model", contributing to hepatic cell death and tissue damage. Gut microbiota plays a substantial role in modulating hepatic oxidative stress through multiple pathways: impairing the intestinal barrier, which results in bacterial translocation and chronic hepatic inflammation; modifying bile acid structure, which impacts signaling cascades involved in lipidic metabolism; influencing hepatocytes' ferroptosis, a form of programmed cell death; regulating trimethylamine N-oxide (TMAO) metabolism; and activating platelet function, both recently identified as pathogenetic factors in MASH progression. Moreover, various exogenous factors impact gut microbiota and its involvement in MASLD-related oxidative stress, such as air pollution, physical activity, cigarette smoke, alcohol, and dietary patterns. This manuscript aims to provide a state-of-the-art overview focused on the intricate interplay between gut microbiota, lipid peroxidation, and MASLD pathogenesis, offering insights into potential strategies to prevent disease progression and its associated complications.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Luca Miele
- CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy (S.A.)
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Gao H, Jiang Y, Zeng G, Huda N, Thoudam T, Yang Z, Liangpunsakul S, Ma J. Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease. EGASTROENTEROLOGY 2024; 2:e100104. [PMID: 39735421 PMCID: PMC11674000 DOI: 10.1136/egastro-2024-100104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/08/2024] [Indexed: 12/31/2024]
Abstract
Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence and severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation is a well-established key factor, recent evidence highlights the critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced liver injury. This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD. It examines the contributions of both parenchymal cells, like hepatocytes, and non-parenchymal cells, such as hepatic stellate cells, Kupffer cells, neutrophils, and liver sinusoidal endothelial cells, in driving the progression of the disease. Additionally, we explored the involvement of key mediators, including cytokines, chemokines and inflammasomes, which regulate inflammatory responses and promote liver injury and fibrosis. A particular focus has been placed on extracellular vesicles (EVs) as essential mediators of intercellular communication both within and beyond the liver. These vesicles facilitate the transfer of signalling molecules, such as microRNAs and proteins, which modulate immune responses, fibrogenesis and lipid metabolism, thereby influencing disease progression. Moreover, we underscore the importance of organ-to-organ crosstalk, particularly in the gut-liver axis, where dysbiosis and increased intestinal permeability lead to microbial translocation, exacerbating hepatic inflammation. The adipose-liver axis is also highlighted, particularly the impact of adipokines and free fatty acids from adipose tissue on hepatic steatosis and inflammation in the context of alcohol consumption.
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Affiliation(s)
- Hui Gao
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yanchao Jiang
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ge Zeng
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Infectious Diseases, Southern Medical University, Guangzhou, China
| | - Nazmul Huda
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Themis Thoudam
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Zhihong Yang
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Jing Ma
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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4
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Choi YJ, Kim Y, Hwang S. Role of Neutrophils in the Development of Steatotic Liver Disease. Semin Liver Dis 2024; 44:300-318. [PMID: 39117322 DOI: 10.1055/s-0044-1789207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear.
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Affiliation(s)
- You-Jin Choi
- College of Pharmacy, Daegu Catholic University, Gyeongsan, Republic of Korea
| | - Yeonsoo Kim
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
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5
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Matthewman C, Krishnakumar IM, Swick AG. Review: bioavailability and efficacy of 'free' curcuminoids from curcumagalactomannoside (CGM) curcumin formulation. Nutr Res Rev 2024; 37:14-31. [PMID: 36655498 DOI: 10.1017/s0954422423000033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The golden spice turmeric with its main bioactive component curcumin is one of the most popular and extensively studied nutraceuticals. Despite numerous pre-clinical studies reporting positive pharmacodynamics of turmeric extracts and curcumin, the main issues in translating the pharmacological effects to clinical efficacy have been to overcome its poor pharmacokinetics and to deliver significant amounts of the biologically relevant forms of the actives to various tissues. This review is aimed at providing a first critical evaluation of the current published literature with the novel curcumagalactomannoside (CGM) formulation of curcumin using fenugreek galactomannan dietary fibre, specifically designed to address curcumin poor pharmacokinetics. We describe CGM and its technology as a food-grade formulation to deliver 'free' unconjugated curcuminoids with enhanced bioavailability and improved pharmacokinetic properties. The therapeutic relevance of improving bioavailability of 'free' curcuminoids and some of the technical challenges in the measurement of the 'free' form of curcuminoids in plasma and tissues are also discussed. A total of twenty-six manuscripts are reviewed here, including fourteen pre-clinical and twelve clinical studies that have investigated CGM pharmacokinetics, safety and efficacy in various animal models and human conditions. Overall current scientific evidence suggests CGM formulation has improved bioavailability and tissue distribution of the biologically relevant unconjugated forms of turmeric actives called 'free' curcuminoids that may be responsible for the superior clinical outcomes reported with CGM treatments in comparison with unformulated standard curcumin across multiple studies.
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6
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Li Y, Huan Y, Qin W, Yu X, Chang Y, Xue C, Tang Q. Fucoidan from Apostichopus japonicus ameliorates alcoholic liver disease by regulating gut-liver axis homeostasis. Int J Biol Macromol 2024; 270:132093. [PMID: 38710247 DOI: 10.1016/j.ijbiomac.2024.132093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 04/17/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
Long-term and excessive alcohol consumption can lead to the development of alcoholic liver disease (ALD), characterized by oxidative damage, intestinal barrier injury, and disruption of intestinal microbiota. In this study, we extracted fucoidan (Aj-FUC) from Apostichopus japonicus using enzymatic methods and characterized its structure. The ALD model was established in male Balb/c mice using 56° Baijiu, with silymarin as a positive control. Mice were orally administered 100 mg/kg·bw and 300 mg/kg·bw of Aj-FUC for 28 days to evaluate its effects on liver injury in ALD mice and explore its potential role in modulating the gut-liver axis. The results showed significant improvements in histopathological changes and liver disease in the Aj-FUC group. Aj-FUC treatment significantly increased the levels of glutathione (GSH) and glutathione peroxidase (GSH-Px) while weakly reduced the elevation of malondialdehyde (MDA) induced by ALD. It also regulated the Nrf2/HO-1 signaling pathway, collectively alleviating hepatic oxidative stress. Aj-FUC intervention upregulated the expression of ZO-1 and Occludin, thus contributing to repair the intestinal barrier. Additionally, Aj-FUC increased the content of short-chain fatty acids (SCFAs) and regulated the imbalance in gut microbiota. These results suggested that Aj-FUC alleviates ALD by modulating the gut-liver axis homeostasis. It may prove to be a useful dietary supplement in the treatment of alcoholic liver damage.
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Affiliation(s)
- Yuan Li
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, China
| | - Yuchen Huan
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, China
| | - Wanting Qin
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, China
| | - Xinyue Yu
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, China
| | - Yaoguang Chang
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, China
| | - Changhu Xue
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, China; Laboratory of Marine Drugs and Biological Products, Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong 266235, China
| | - Qingjuan Tang
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong 266003, China.
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Roychowdhury S, Pant B, Cross E, Scheraga R, Vachharajani V. Effect of ethanol exposure on innate immune response in sepsis. J Leukoc Biol 2024; 115:1029-1041. [PMID: 38066660 PMCID: PMC11136611 DOI: 10.1093/jleuko/qiad156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 11/08/2023] [Accepted: 11/17/2023] [Indexed: 01/06/2024] Open
Abstract
Alcohol use disorder, reported by 1 in 8 critically ill patients, is a risk factor for death in sepsis patients. Sepsis, the leading cause of death, kills over 270,000 patients in the United States alone and remains without targeted therapy. Immune response in sepsis transitions from an early hyperinflammation to persistent inflammation and immunosuppression and multiple organ dysfunction during late sepsis. Innate immunity is the first line of defense against pathogen invasion. Ethanol exposure is known to impair innate and adaptive immune response and bacterial clearance in sepsis patients. Specifically, ethanol exposure is known to modulate every aspect of innate immune response with and without sepsis. Multiple molecular mechanisms are implicated in causing dysregulated immune response in ethanol exposure with sepsis, but targeted treatments have remained elusive. In this article, we outline the effects of ethanol exposure on various innate immune cell types in general and during sepsis.
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Affiliation(s)
- Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Bishnu Pant
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Emily Cross
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
| | - Rachel Scheraga
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States
- Department of Pulmonary and Critical Care Medicine, Integrated Hospital-Care Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland OH 44195, United States
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8
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Kang S, Koh JM, Im DS. N-3 Polyunsaturated Fatty Acids Protect against Alcoholic Liver Steatosis by Activating FFA4 in Kupffer Cells. Int J Mol Sci 2024; 25:5476. [PMID: 38791514 PMCID: PMC11122576 DOI: 10.3390/ijms25105476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/11/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
Supplementation with fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) effectively reduces acute and chronic alcohol-induced hepatic steatosis. We aimed to find molecular mechanisms underlying the effects of n-3 PUFAs in alcohol-induced hepatic steatosis. Because free fatty acid receptor 4 (FFA4, also known as GPR120) has been found as a receptor for n-3 PUFAs in an ethanol-induced liver steatosis model, we investigated whether n-3 PUFAs protect against liver steatosis via FFA4 using AH7614, an FFA4 antagonist, and Ffa4 knockout (KO) mice. N-3 PUFAs and compound A (CpdA), a selective FFA4 agonist, reduced the ethanol-induced increase in lipid accumulation in hepatocytes, triglyceride content, and serum ALT levels, which were not observed in Ffa4 KO mice. N-3 PUFAs and CpdA also reduced the ethanol-induced increase in lipogenic sterol regulatory element-binding protein-1c expression in an FFA4-dependent manner. In Kupffer cells, treatment with n-3 PUFA and CpdA reversed the ethanol-induced increase in tumor necrosis factor-α, cyclooxygenase-2, and NLR family pyrin domain-containing 3 expression levels in an FFA4-dependent manner. In summary, n-3 PUFAs protect against ethanol-induced hepatic steatosis via the anti-inflammatory actions of FFA4 on Kupffer cells. Our findings suggest FFA4 as a therapeutic target for alcoholic hepatic steatosis.
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Affiliation(s)
- Saeromi Kang
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea;
| | - Jung-Min Koh
- Division of Endocrinology and Metabolism, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 05505, Republic of Korea;
| | - Dong-Soon Im
- Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea;
- Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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9
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Rabelo ACS, Andrade AKDL, Costa DC. The Role of Oxidative Stress in Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Preclinical Studies. Nutrients 2024; 16:1174. [PMID: 38674865 PMCID: PMC11055095 DOI: 10.3390/nu16081174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/05/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Alcoholic Fatty Liver Disease (AFLD) is characterized by the accumulation of lipids in liver cells owing to the metabolism of ethanol. This process leads to a decrease in the NAD+/NADH ratio and the generation of reactive oxygen species. A systematic review and meta-analysis were conducted to investigate the role of oxidative stress in AFLD. A total of 201 eligible manuscripts were included, which revealed that animals with AFLD exhibited elevated expression of CYP2E1, decreased enzymatic activity of antioxidant enzymes, and reduced levels of the transcription factor Nrf2, which plays a pivotal role in the synthesis of antioxidant enzymes. Furthermore, animals with AFLD exhibited increased levels of lipid peroxidation markers and carbonylated proteins, collectively contributing to a weakened antioxidant defense and increased oxidative damage. The liver damage in AFLD was supported by significantly higher activity of alanine and aspartate aminotransferase enzymes. Moreover, animals with AFLD had increased levels of triacylglycerol in the serum and liver, likely due to reduced fatty acid metabolism caused by decreased PPAR-α expression, which is responsible for fatty acid oxidation, and increased expression of SREBP-1c, which is involved in fatty acid synthesis. With regard to inflammation, animals with AFLD exhibited elevated levels of pro-inflammatory cytokines, including TNF-a, IL-1β, and IL-6. The heightened oxidative stress, along with inflammation, led to an upregulation of cell death markers, such as caspase-3, and an increased Bax/Bcl-2 ratio. Overall, the findings of the review and meta-analysis indicate that ethanol metabolism reduces important markers of antioxidant defense while increasing inflammatory and apoptotic markers, thereby contributing to the development of AFLD.
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Affiliation(s)
- Ana Carolina Silveira Rabelo
- Postgraduate Program in Biological Sciences, Federal University of Ouro Preto, Ouro Preto 35402-163, Brazil
- Department of Biochemistry, Federal University of Alfenas, Alfenas 37130-001, Brazil
| | | | - Daniela Caldeira Costa
- Postgraduate Program in Biological Sciences, Federal University of Ouro Preto, Ouro Preto 35402-163, Brazil
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10
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Wang G, Jiang Z, Song Y, Xing Y, He S, Boomi P. Gut microbiota contribution to selenium deficiency-induced gut-liver inflammation. Biofactors 2024; 50:311-325. [PMID: 37676478 DOI: 10.1002/biof.2006] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/05/2023] [Indexed: 09/08/2023]
Abstract
There is limited knowledge about the factors that drive gut-liver axis changes after selenium (Se) deficiency-induced gut or liver injuries. Thus, we tested Se deficiency in mice to determine its effects on intestinal bacterial balance and whether it induced liver injury. Serum Se concentration, lipopolysaccharide (LPS) level, and liver injury biomarkers were tested using a biochemical method, while pathological changes in the liver and jejunum were observed via hematoxylin and eosin stain, and a fluorescence spectrophotometer was used to evaluate intestinal permeability. Tight junction (TJ)-related and toll-like receptor (TLR) signaling-related pathway genes and proteins were tested using quantitative polymerase chain reaction, western blotting, immunohistochemistry, and 16S ribosomal ribonucleic acid gene-targeted sequencing of jejunum microorganisms. Se deficiency significantly decreased glutathione peroxidase activity and disrupted the intestinal flora, with the most significant effect being a decrease in Lactobacillus reuteri. The expression of TJ-related genes and proteins decreased significantly with increased treatment time, whereas supplementation with Se, fecal microbiota transplantation, or L. reuteri reversed these decreases. Signs of liver injury and LPS content were significantly increased after intestinal flora imbalance or jejunum injury, and the levels of TLR signaling-related genes were significantly increased. The results indicated that Se deficiency disrupted the microbiota balance, decreased the expression of intestinal TJ factors, and increased intestinal permeability. By contrast, LPS increased due to a bacterial imbalance, which may induce inflammatory liver injury via the TLR4 signaling pathway.
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Affiliation(s)
- Guodong Wang
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Anyang Institute of Technology, Anyang, Henan, China
| | - Zhihui Jiang
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Anyang Institute of Technology, Anyang, Henan, China
| | - Yuwei Song
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Anyang Institute of Technology, Anyang, Henan, China
| | - Yueteng Xing
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Anyang Institute of Technology, Anyang, Henan, China
| | - Simin He
- Henan Joint International Research Laboratory of Veterinary Biologics Research and Application, Anyang Institute of Technology, Anyang, Henan, China
| | - P Boomi
- Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India
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11
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Tharmalingam J, Gangadaran P, Rajendran RL, Ahn BC. Impact of Alcohol on Inflammation, Immunity, Infections, and Extracellular Vesicles in Pathogenesis. Cureus 2024; 16:e56923. [PMID: 38665743 PMCID: PMC11043057 DOI: 10.7759/cureus.56923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
Alcohol consumption is a widespread social activity with a complex and multifaceted impact on human health. Although moderate alcohol consumption has been associated with certain potential health benefits, excessive or chronic alcohol use can disrupt the body's immune balance, promote inflammation, and increase susceptibility to infections. The deleterious effects associated with alcohol toxicity include the loss of cell integrity. When cells lose their integrity, they also lose the capacity to communicate with other systems. One of the systems disturbed by alcohol toxicity is extracellular vesicle (EV)-mediated communication. EVs are critical mediators of cell-to-cell communication. They play a significant role in alcohol-induced pathogenesis, facilitating communication and molecular exchange between cells, thereby potentially contributing to alcohol-related health issues. Investigating their involvement in this context is fundamental to resolving the intricate mechanisms behind the health consequences of alcohol use and may pave the way for innovative approaches for mitigating the adverse effects of alcohol on immune health. Understanding the role of EVs in the context of alcohol-induced pathogenesis is essential for comprehending the mechanisms behind alcohol-related health issues.
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Affiliation(s)
| | - Prakash Gangadaran
- Department of Nuclear Medicine, Kyungpook National University, Daegu, KOR
- Department of Biomedical Science, BK (Brain Korea) 21 FOUR (Fostering Outstanding Universities for Research) Program, Kyungpook National University, Daegu, KOR
| | | | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, Kyungpook National University, Daegu, KOR
- Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, KOR
- Department of Biomedical Science, BK (Brain Korea) 21 FOUR (Fostering Outstanding Universities for Research) Program, Kyungpook National University, Daegu, KOR
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12
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McCall KD, Walter D, Patton A, Thuma JR, Courreges MC, Palczewski G, Goetz DJ, Bergmeier S, Schwartz FL. Anti-Inflammatory and Therapeutic Effects of a Novel Small-Molecule Inhibitor of Inflammation in a Male C57BL/6J Mouse Model of Obesity-Induced NAFLD/MAFLD. J Inflamm Res 2023; 16:5339-5366. [PMID: 38026235 PMCID: PMC10658948 DOI: 10.2147/jir.s413565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Purpose Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic (dysfunction) associated fatty liver disease (MAFLD), is the most common chronic liver disease in the United States. Presently, there is an intense and ongoing effort to identify and develop novel therapeutics for this disease. In this study, we explored the anti-inflammatory activity of a new compound, termed IOI-214, and its therapeutic potential to ameliorate NAFLD/MAFLD in male C57BL/6J mice fed a high fat (HF) diet. Methods Murine macrophages and hepatocytes in culture were treated with lipopolysaccharide (LPS) ± IOI-214 or DMSO (vehicle), and RT-qPCR analyses of inflammatory cytokine gene expression were used to assess IOI-214's anti-inflammatory properties in vitro. Male C57BL/6J mice were also placed on a HF diet and treated once daily with IOI-214 or DMSO for 16 weeks. Tissues were collected and analyzed to determine the effects of IOI-214 on HF diet-induced NAFL D/MAFLD. Measurements such as weight, blood glucose, serum cholesterol, liver/serum triglyceride, insulin, and glucose tolerance tests, ELISAs, metabolomics, Western blots, histology, gut microbiome, and serum LPS binding protein analyses were conducted. Results IOI-214 inhibited LPS-induced inflammation in macrophages and hepatocytes in culture and abrogated HF diet-induced mesenteric fat accumulation, hepatic inflammation and steatosis/hepatocellular ballooning, as well as fasting hyperglycemia without affecting insulin resistance or fasting insulin, cholesterol or TG levels despite overall obesity in vivo in male C57BL/6J mice. IOI-214 also decreased systemic inflammation in vivo and improved gut microbiota dysbiosis and leaky gut. Conclusion Combined, these data indicate that IOI-214 works at multiple levels in parallel to inhibit the inflammation that drives HF diet-induced NAFLD/MAFLD, suggesting that it may have therapeutic potential for NAFLD/MAFLD.
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Affiliation(s)
- Kelly D McCall
- Molecular and Cellular Biology Program, Ohio University College of Arts & Sciences, Athens, OH, USA
- Department of Biological Sciences, Ohio University College of Arts & Sciences, Athens, OH, USA
- Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Biomedical Engineering Program, Ohio University Russ College of Engineering and Technology, Athens, OH, USA
| | - Debra Walter
- Molecular and Cellular Biology Program, Ohio University College of Arts & Sciences, Athens, OH, USA
- Department of Biological Sciences, Ohio University College of Arts & Sciences, Athens, OH, USA
| | - Ashley Patton
- Molecular and Cellular Biology Program, Ohio University College of Arts & Sciences, Athens, OH, USA
- Department of Biological Sciences, Ohio University College of Arts & Sciences, Athens, OH, USA
| | - Jean R Thuma
- Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
| | - Maria C Courreges
- Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
| | | | - Douglas J Goetz
- Molecular and Cellular Biology Program, Ohio University College of Arts & Sciences, Athens, OH, USA
- Biomedical Engineering Program, Ohio University Russ College of Engineering and Technology, Athens, OH, USA
- Department of Chemical & Biomolecular Engineering, Ohio University Russ College of Engineering and Technology, Athens, OH, USA
| | - Stephen Bergmeier
- Molecular and Cellular Biology Program, Ohio University College of Arts & Sciences, Athens, OH, USA
- Biomedical Engineering Program, Ohio University Russ College of Engineering and Technology, Athens, OH, USA
- Department of Chemistry & Biochemistry, Ohio University College of Arts & Sciences, Athens, OH, USA
| | - Frank L Schwartz
- Department of Specialty Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
- Biomedical Engineering Program, Ohio University Russ College of Engineering and Technology, Athens, OH, USA
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13
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Lin KY, Yang HY, Yang SC, Chen YL, Watanabe Y, Chen JR. Caulerpa lentillifera improves ethanol-induced liver injury and modulates the gut microbiota in rats. Curr Res Food Sci 2023; 7:100546. [PMID: 37483276 PMCID: PMC10362798 DOI: 10.1016/j.crfs.2023.100546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/25/2023] Open
Abstract
Caulerpa lentillifera (CL), also called sea grape, is a type of edible green alga which was reported to have antioxidative and immunomodulatory potential. This study aimed to investigate the hepatoprotective effects of CL in a rat model of chronic ethanol exposure. Wistar rats were assigned to four groups and supplied with an isocaloric control liquid diet (group C), an ethanol liquid diet (group E), a control liquid diet supplemented with 5% CL (group CC), or an ethanol liquid diet supplemented with 5% CL (group EC) for a 12-week experimental period. Ethanol feeding induced steatosis, inflammation, and changes in the gut microbiota by the end of the study, whereas CL supplementation significantly improved liver injuries and decreased circulatory endotoxin levels. Moreover, we also found that CL reversed ethanol-induced elevation of hepatic toll-like receptor 4 (TLR4), MyD88 protein expression, the phosphorylated-nuclear factor (NF)-κB-to-NF-κB ratio, and proinflammatory cytokine concentrations. Additionally, CL also increased the abundance of Akkermansia and tight junction proteins and diminished the Firmicutes-to-Bacteroidetes ratio. Dietary CL inhibited the progression of alcoholic liver disease, and some of the possible mechanisms may be strengthening the intestinal barrier function, alleviating dysbiosis, and modulating the TLR4 pathway.
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Affiliation(s)
- Kuan-Yu Lin
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
| | - Hsin-Yi Yang
- Department of Nutritional Science, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Suh-Ching Yang
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
| | - Ya-Ling Chen
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
| | - Y. Watanabe
- General Health Medical Center, Yokohama University of Pharmacy, Yokohama, Japan
| | - Jiun-Rong Chen
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan
- Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan
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14
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Parlar YE, Ayar SN, Cagdas D, Balaban YH. Liver immunity, autoimmunity, and inborn errors of immunity. World J Hepatol 2023; 15:52-67. [PMID: 36744162 PMCID: PMC9896502 DOI: 10.4254/wjh.v15.i1.52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/23/2022] [Accepted: 12/23/2022] [Indexed: 01/16/2023] Open
Abstract
The liver is the front line organ of the immune system. The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens. This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens, such as food antigens or pathogens. As an immune active organ, the liver functions as a gatekeeping barrier from the outside world, and it can create a rapid and strong immune response, under unfavorable conditions. However, the liver's assumed immune status is anti-inflammatory or immuno-tolerant. Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance. The anatomical structure of the liver can facilitate the preparation of lymphocytes, modulate the immune response against hepatotropic pathogens, and contribute to some of its unique immunological properties, particularly its capacity to induce antigen-specific tolerance. Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane, circulating lymphocytes can closely contact with antigens, displayed by endothelial cells, Kupffer cells, and dendritic cells while passing through the sinusoids. Loss of immune tolerance, leading to an autoaggressive immune response in the liver, if not controlled, can lead to the induction of autoimmune or autoinflammatory diseases. This review mentions the unique features of liver immunity, and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.
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Affiliation(s)
- Yavuz Emre Parlar
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey.
| | - Sefika Nur Ayar
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
| | - Deniz Cagdas
- Department of Pediatric Immunology, Hacettepe University Ihsan Dogramaci Children's Hospital, Ankara 06100, Turkey
| | - Yasemin H Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
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15
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Anwar MM, Sah R, Shrestha S, Ozaki A, Roy N, Fathah Z, Rodriguez-Morales AJ. Disengaging the COVID-19 Clutch as a Discerning Eye Over the Inflammatory Circuit During SARS-CoV-2 Infection. Inflammation 2022; 45:1875-1894. [PMID: 35639261 PMCID: PMC9153229 DOI: 10.1007/s10753-022-01674-5] [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] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/29/2022] [Accepted: 04/18/2022] [Indexed: 01/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the cytokine release syndrome (CRS) and leads to multiorgan dysfunction. Mitochondrial dynamics are fundamental to protect against environmental insults, but they are highly susceptible to viral infections. Defective mitochondria are potential sources of reactive oxygen species (ROS). Infection with SARS-CoV-2 damages mitochondria, alters autophagy, reduces nitric oxide (NO), and increases both nicotinamide adenine dinucleotide phosphate oxidases (NOX) and ROS. Patients with coronavirus disease 2019 (COVID-19) exhibited activated toll-like receptors (TLRs) and the Nucleotide-binding and oligomerization domain (NOD-), leucine-rich repeat (LRR-), pyrin domain-containing protein 3 (NLRP3) inflammasome. The activation of TLRs and NLRP3 by SARS-CoV-2 induces interleukin 6 (IL-6), IL-1β, IL-18, and lactate dehydrogenase (LDH). Herein, we outline the inflammatory circuit of COVID-19 and what occurs behind the scene, the interplay of NOX/ROS and their role in hypoxia and thrombosis, and the important role of ROS scavengers to reduce COVID-19-related inflammation.
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Affiliation(s)
- Mohammed Moustapha Anwar
- Department of Biotechnology, Institute of Graduate Studies and Research (IGSR), Alexandria University, Alexandria, Egypt.
| | - Ranjit Sah
- Tribhuvan University Institute of Medicine, Kathmandu, Nepal
| | - Sunil Shrestha
- Department of Pharmaceutical and Health Service Research, Nepal Health Research and Innovation Foundation, Lalitpur, Nepal
| | - Akihiko Ozaki
- Department of Breast Surgery, Jyoban Hospital of Tokiwa Foundation, Iwaki, Japan
- Medical Governance Research Institute, Tokyo, Japan
| | - Namrata Roy
- SRM University, SRM Nagar, Kattankulathur, Chengalpattu, Tamil Nadu, 603203, India
| | - Zareena Fathah
- Kings College London, London, UK
- College of Medicine and Health Sciences, United Arab University, Abu Dhabi, United Arab Emirates
| | - Alfonso J Rodriguez-Morales
- Grupo de Investigación Biomedicina, Faculty of Medicine, Fundacion Universitaria Autonoma de Las Americas, Pereira, Risaralda, Colombia.
- Institución Universitaria Visión de Las Americas, Pereira, Risaralda, Colombia.
- Faculty of Health Sciences, Universidad Cientifica del Sur, Lima, Peru.
- School of Medicine, Universidad Privada Franz Tamayo (UNIFRANZ), Cochabamba, Bolivia.
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16
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Zhu H, Jiang W, Liu C, Wang C, Hu B, Guo Y, Cheng Y, Qian H. Ameliorative effects of chlorogenic acid on alcoholic liver injury in mice via gut microbiota informatics. Eur J Pharmacol 2022; 928:175096. [PMID: 35697148 DOI: 10.1016/j.ejphar.2022.175096] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 05/22/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022]
Abstract
Chlorogenic acid (CGA) is a functional phenolic acid widely used in food and medicine-related fields. It has been proved to be effective in the treatment of alcoholic liver disease (ALD). However, the exact mechanism by which CGA prevents ALD, especially from the crosstalk between gut and liver, has not been previously reported. This work was aimed to explore the protective effects of CGA against ALD and its relationships to gut-liver axis abnormalities. Experimental results showed the increased (p < 0.05) serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), low density lipoprotein (LDL), total cholesterol (TC) and triglyceride (TG) levels of mice fed with ethanol were ameliorated by supplementing with CGA. Moreover, CGA promoted the production of n-butyric acid by nearly 3 times (1.78 vs 0.62 nM, p < 0.01), a short-chain fatty acid that helps maintain the integrity of the intestinal barrier. Furthermore, CGA alleviated microbial dysbiosis, evidenced by the increased relative abundances of beneficial bacteria Muribaculaceae, Bacteroides, Alloprevotella, and Parabacteroides, and decreased that of opportunistic pathogens Eubacterium_nodatum, Eubacterium_ruminantium, and Anaerotruncus. Correlation analysis further elucidated the microbiota altered after CGA intervention was positively correlated with short-chain fatty acids and antioxidant indexes, while negatively correlated with inflammatory cytokines. In summary, these findings suggested the hepatoprotective effect of CGA was ascribed to the modulation of gut-liver axis homeostasis.
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Affiliation(s)
- Hongkang Zhu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Wenhao Jiang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Chang Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Cheng Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Bin Hu
- School of Biotechnology, Jiangnan University, Wuxi, 214122, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China.
| | - He Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi, 214122, China.
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17
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Shao J, Ge T, Wei Y, Zhou Y, Shi M, Liu H, Chen Z, Xia Y. Co-interventions with Clostridium butyricum and soluble dietary fiber targeting the gut microbiota improve MAFLD via the Acly/Nrf2/NF-κB signaling pathway. Food Funct 2022; 13:5807-5819. [PMID: 35543143 DOI: 10.1039/d1fo04224f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Purpose: The pathogenesis of metabolic associated fatty liver disease (MAFLD) is complex. Lipid metabolic disorder, chronic inflammation, and oxidative stress are the core events for MAFLD. Dietary intervention is an important treatment strategy for preventing the onset and progression of MAFLD. Clostridium butyricum (CB) and soluble dietary fiber (SDF) are often considered beneficial for health. We explored how two microbiota-targeted interventions (SDF and CB) influence the hepatic immune system, oxidative stress, and lipid metabolism in MAFLD mice. Methods: To explore the role of SDF and CB in MAFLD, we generated MAFLD mouse models by feeding C57BL/6 mice with a high-fat diet (HFD). After 8 weeks of intervention, we measured immune cell function, lipid metabolism, and oxidative stress levels in the livers of mice. Results: Single intervention with SDF or CB was not effective in improving MAFLD; however, co-interventions with SDF and CB increased microbiota diversity and decreased inflammation, oxidative stress, and lipid synthesis. Moreover, we determined that co-intervention with SDF and CB mediated fatty acid oxidation by activating the Acly/Nrf2/NF-κB signaling pathway. Most importantly, co-intervention exerted anti-inflammatory effects by inhibiting the differentiation of macrophages into pro-inflammatory M1 macrophages. Conclusion: This study show that co-intervention with SDF and CB can improve MAFLD, and co-intervention with SDF and CB are suggested to be potential gut microbiota modulators and therapeutic substances for MAFLD.
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Affiliation(s)
- Junwei Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, China.
| | - Tiantian Ge
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, China.
| | - Yingliang Wei
- Department of Orthopedics, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, Liaoning, 110004, China
| | - Yuhan Zhou
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Mengyuan Shi
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Huiyuan Liu
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, China.
| | - Yang Xia
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China.
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18
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Abdel-Latif R, Heeba GH, Hassanin SO, Waz S, Amin A. TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity. Front Pharmacol 2022; 13:850066. [PMID: 35517830 PMCID: PMC9065287 DOI: 10.3389/fphar.2022.850066] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/11/2022] [Indexed: 12/11/2022] Open
Abstract
Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-α) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H2S. Taken together, the present study suggested that exogenously applied H2S rather than the endogenously generated H2S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK/NF-κB pathways.
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Affiliation(s)
- Rania Abdel-Latif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Gehan Hussein Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Soha Osama Hassanin
- Department of Biochemistry, Faculty of Pharmacy, MTI University, Cairo, Egypt
| | - Shaimaa Waz
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Amr Amin
- The College, The University of Chicago, Chicago, IL, United States.,Department of Biology, UAE University, Al Ain, United Arab Emirates
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19
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Shaker ME. The contribution of sterile inflammation to the fatty liver disease and the potential therapies. Biomed Pharmacother 2022; 148:112789. [PMID: 35272137 DOI: 10.1016/j.biopha.2022.112789] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 11/02/2022] Open
Abstract
Hepatic inflammation is prevalent in several metabolic liver diseases. Recent scientific advances about the pathogenesis of metabolic liver diseases showed an emerging role of several damage-associated molecular patterns (DAMPs), including DNA, high-mobility group box 1 (HMGB1), ATP and uric acid. For these DAMPs to induce inflammation, they should stimulate pattern recognition receptors (PRRs), which are located in the hepatic immune cells like resident Kupffer cells, infiltrated neutrophils, monocytes or dendritic cells. As a consequence, proinflammatory cytokines like interleukins (ILs)-1β and 18 alongside tumor necrosis factor (TNF)-α are overproduced and released, leading to pronounced hepatic inflammation and cellular death. This review highlights the contribution of these DAMPs and PRRs in the settings of alcoholic and nonalcoholic steatohepatitis. The review also summarizes the therapeutic usefulness of targeting NLR family pyrin domain containing 3 (NLRP3)-inflammasome, Toll-like receptors (TLRs) 4 and 9, IL-1 receptor (IL-1R), caspase 1, uric acid and GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) in these hepatic inflammatory disorders.
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Affiliation(s)
- Mohamed E Shaker
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia.
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20
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Malherbe DC, Messaoudi I. Transcriptional and Epigenetic Regulation of Monocyte and Macrophage Dysfunction by Chronic Alcohol Consumption. Front Immunol 2022; 13:911951. [PMID: 35844518 PMCID: PMC9277054 DOI: 10.3389/fimmu.2022.911951] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
Drinking alcohol, even in moderation, can affect the immune system. Studies have shown disproportionate effects of alcohol on circulating and tissue-resident myeloid cells (granulocytes, monocytes, macrophages, dendritic cells). These cells orchestrate the body's first line of defense against microbial challenges as well as maintain tissue homeostasis and repair. Alcohol's effects on these cells are dependent on exposure pattern, with acute drinking dampening but chronic drinking enhancing production of inflammatory mediators. Although chronic drinking is associated with heightened systemic inflammation, studies on tissue resident macrophage populations in several organs including the spleen, liver, brain, and lung have also shown compromised functional and metabolic capacities of these cells. Many of these effects are thought to be mediated by oxidative stress caused by alcohol and its metabolites which can directly impact the cellular epigenetic landscapes. In addition, since myeloid cells are relatively short-lived in circulation and are under constant repopulation from the bone marrow compartment, alcohol's effects on bone marrow progenitors and hematopoiesis are important for understanding the impact of alcohol systemically on these myeloid populations. Alcohol-induced disruption of progenitor, circulating, and tissue resident myeloid populations contribute to the increased susceptibility of patients with alcohol use disorders to viral and bacterial infections. In this review, we provide an overview of the impact of chronic alcohol consumption on the function of monocytes and macrophages in host defense, tissue repair and inflammation. We then summarize our current understanding of the mechanisms underlying alcohol-induced disruption and examine changes in transcriptome and epigenome of monocytes and mcrophages. Overall, chronic alcohol consumption leads to hyper-inflammation concomitant with decreased microbial and wound healing responses by monocytes/macrophages due to a rewiring of the epigentic and transcriptional landscape. However, in advanced alcoholic liver disease, myeloid cells become immunosuppressed as a response to the surrounding hyper-inflammatory milieu. Therefore, the effect of chronic alcohol on the inflammatory response depends on disease state and the immune cell population.
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21
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MOU WL, CHEN SR, WU ZT, HU LH, ZHANG JY, CHANG HJ, ZHOU H, LIU Y. LPS-TLR4/MD-2–TNF-α signaling mediates alcohol-induced liver fibrosis in rats. J Toxicol Pathol 2022; 35:193-203. [PMID: 35516842 PMCID: PMC9018403 DOI: 10.1293/tox.2021-0018] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 01/07/2022] [Indexed: 11/19/2022] Open
Affiliation(s)
- Wen-Ling MOU
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
| | - Shi-ru CHEN
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
| | - Zhen-ting WU
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
| | - Li-hua HU
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
| | - Ji-ye ZHANG
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
| | - Hong-jie CHANG
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
| | - Hang ZHOU
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
| | - Ying LIU
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150000, China
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22
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Li BY, Li HY, Zhou DD, Huang SY, Luo M, Gan RY, Mao QQ, Saimaiti A, Shang A, Li HB. Effects of Different Green Tea Extracts on Chronic Alcohol Induced-Fatty Liver Disease by Ameliorating Oxidative Stress and Inflammation in Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5188205. [PMID: 35003517 PMCID: PMC8731271 DOI: 10.1155/2021/5188205] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 10/06/2021] [Accepted: 12/05/2021] [Indexed: 12/20/2022]
Abstract
Alcoholic fatty liver disease (AFLD) is a common chronic liver disease and has become a critical global public health problem. Green tea is a popular drink worldwide and contains several bioactive compounds. Different green teas could contain diverse compounds and possess distinct bioactivities. In the present study, the effects of 10 green teas on chronic alcohol induced-fatty liver disease in mice were explored and compared. The results showed that several green teas significantly reduced triacylglycerol levels in serum and liver as well as the aminotransferase activities in mice at a dose of 200 mg/kg, suggesting that they possess hepatoprotective effects. Moreover, several green teas remarkably decreased the expression of cytochrome P450 2E1, the levels of malondialdehyde and 4-hydroxynonenoic acid, and the contents of proinflammatory cytokines, indicating that they could alleviate oxidation damage and inflammation induced by chronic alcohol exposure. In addition, Seven Star Matcha Tea and Selenium-Enriched Matcha Tea could increase glutathione level. Furthermore, the main phytochemical components in green teas were determined and quantified by high-performance liquid chromatography, and the correlation analysis showed that gallic acid, gallocatechin, catechin, chlorogenic acid, and epigallocatechin gallate might at least partially contribute to protective effects on AFLD. In conclusion, Selenium-Enriched Chaoqing Green Tea, Xihu Longjing Tea, Taiping Houkui Tea, and Selenium-Enriched Matcha Tea showed the strongest preventive effects on AFLD. This research also provides the public with new insights about the effects of different green teas on AFLD.
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Affiliation(s)
- Bang-Yan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Hang-Yu Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Dan-Dan Zhou
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Si-Yu Huang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Min Luo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Ren-You Gan
- Research Center for Plants and Human Health, Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu 610213, China
| | - Qian-Qian Mao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Adila Saimaiti
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Ao Shang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
| | - Hua-Bin Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
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Morcuende A, Navarrete F, Nieto E, Manzanares J, Femenía T. Inflammatory Biomarkers in Addictive Disorders. Biomolecules 2021; 11:biom11121824. [PMID: 34944470 PMCID: PMC8699452 DOI: 10.3390/biom11121824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/23/2021] [Accepted: 11/30/2021] [Indexed: 12/21/2022] Open
Abstract
Substance use disorders are a group of diseases that are associated with social, professional, and family impairment and that represent a high socio-economic impact on the health systems of countries around the world. These disorders present a very complex diagnosis and treatment regimen due to the lack of suitable biomarkers supporting the correct diagnosis and classification and the difficulty of selecting effective therapies. Over the last few years, several studies have pointed out that these addictive disorders are associated with systemic and central nervous system inflammation, which could play a relevant role in the onset and progression of these diseases. Therefore, identifying different immune system components as biomarkers of such addictive disorders could be a crucial step to promote appropriate diagnosis and treatment. Thus, this work aims to provide an overview of the immune system alterations that may be biomarkers of various addictive disorders.
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Affiliation(s)
- Alvaro Morcuende
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
| | - Francisco Navarrete
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
- Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain
| | - Elena Nieto
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
| | - Jorge Manzanares
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
- Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain
| | - Teresa Femenía
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
- Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-965-919-553
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Maccioni L, Leclercq IA, Schnabl B, Stärkel P. Host Factors in Dysregulation of the Gut Barrier Function during Alcohol-Associated Liver Disease. Int J Mol Sci 2021; 22:12687. [PMID: 34884492 PMCID: PMC8657823 DOI: 10.3390/ijms222312687] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/18/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic alcohol consumption and alcohol-associated liver disease (ALD) represent a major public health problem worldwide. Only a minority of patients with an alcohol-use disorder (AUD) develop severe forms of liver disease (e.g., steatohepatitis and fibrosis) and finally progress to the more advanced stages of ALD, such as severe alcohol-associated hepatitis and decompensated cirrhosis. Emerging evidence suggests that gut barrier dysfunction is multifactorial, implicating microbiota changes, alterations in the intestinal epithelium, and immune dysfunction. This failing gut barrier ultimately allows microbial antigens, microbes, and metabolites to translocate to the liver and into systemic circulation. Subsequent activation of immune and inflammatory responses contributes to liver disease progression. Here we review the literature about the disturbance of the different host defense mechanisms linked to gut barrier dysfunction, increased microbial translocation, and impairment of liver and systemic inflammatory responses in the different stages of ALD.
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Affiliation(s)
- Luca Maccioni
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Unversité Catholique de Louvain, 1200 Brussels, Belgium; (L.M.); (I.A.L.)
| | - Isabelle A. Leclercq
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Unversité Catholique de Louvain, 1200 Brussels, Belgium; (L.M.); (I.A.L.)
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA;
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Peter Stärkel
- Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, UCLouvain, Unversité Catholique de Louvain, 1200 Brussels, Belgium; (L.M.); (I.A.L.)
- Department of Hepato-Gastroenterology, Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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25
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Bruneau A, Hundertmark J, Guillot A, Tacke F. Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases. Front Med (Lausanne) 2021; 8:725390. [PMID: 34650994 PMCID: PMC8505679 DOI: 10.3389/fmed.2021.725390] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/01/2021] [Indexed: 12/15/2022] Open
Abstract
The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases.
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Affiliation(s)
- Alix Bruneau
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Jana Hundertmark
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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26
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Pi A, Jiang K, Ding Q, Lai S, Yang W, Zhu J, Guo R, Fan Y, Chi L, Li S. Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice. Front Pharmacol 2021; 12:752148. [PMID: 34603062 PMCID: PMC8481816 DOI: 10.3389/fphar.2021.752148] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Alcoholic liver disease (ALD) caused by chronic ethanol overconsumption is a common type of liver disease with a severe mortality burden throughout the world. The pathogenesis of ALD is complex, and no effective clinical treatment for the disease has advanced so far. Prolonged alcohol abstinence is the most effective therapy to attenuate the clinical course of ALD and even reverse liver damage. However, the molecular mechanisms involved in alcohol abstinence-improved recovery from alcoholic fatty liver remain unclear. This study aims to systematically evaluate the beneficial effect of alcohol abstinence on pathological changes in ALD. Methods: Using the Lieber-DeCarli mouse model of ALD, we analysed whether 1-week alcohol withdrawal reversed alcohol-induced detrimental alterations, including oxidative stress, liver injury, lipids metabolism, and hepatic inflammation, by detecting biomarkers and potential targets. Results: Alcohol withdrawal ameliorated alcohol-induced hepatic steatosis by improving liver lipid metabolism reprogramming via upregulating phosphorylated 5'-AMP -activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor-α (PPAR-α), and carnitine palmitoyltransferase-1 (CPT-1), and downregulating fatty acid synthase (FAS) and diacylglycerol acyltransferase-2 (DGAT-2). The activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were significantly enhanced by alcohol withdrawal. Importantly, the abstinence recovered alcohol-fed induced liver injury, as evidenced by the improvements in haematoxylin and eosin (H&E) staining, plasma alanine aminotransferase (ALT) levels, and liver weight/body weight ratio. Alcohol-stimulated toll-like receptor 4/mitogen-activated protein kinases (TLR4/MAPKs) were significantly reversed by alcohol withdrawal, which might mechanistically contribute to the amelioration of liver injury. Accordingly, the hepatic inflammatory factor represented by tumour necrosis factor-alpha (TNF-α) was improved by alcohol abstinence. Conclusion: In summary, we reported that alcohol withdrawal effectively restored hepatic lipid metabolism and reversed liver injury and inflammation by improving metabolism reprogramming. These findings enhanced our understanding of the biological mechanisms involved in the beneficial role of alcohol abstinence as an effective treatment for ALD.
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Affiliation(s)
- Aiwen Pi
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kai Jiang
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qinchao Ding
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shanglei Lai
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wenwen Yang
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jinyan Zhu
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rui Guo
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yibin Fan
- Department of Dermatology, People’s Hospital of Hangzhou Medical College, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Linfeng Chi
- School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
- Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, China
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27
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The Gut Microbiota-Derived Immune Response in Chronic Liver Disease. Int J Mol Sci 2021; 22:ijms22158309. [PMID: 34361075 PMCID: PMC8347749 DOI: 10.3390/ijms22158309] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut–liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.
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28
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Yan X, Ren X, Liu X, Wang Y, Ma J, Song R, Wang X, Dong Y, Fan Q, Wei J, Yu A, She G. Dietary Ursolic Acid Prevents Alcohol-Induced Liver Injury via Gut-Liver Axis Homeostasis Modulation: The Key Role of Microbiome Manipulation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:7074-7083. [PMID: 34152776 DOI: 10.1021/acs.jafc.1c02362] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Ursolic acid (UA), a natural triterpenoid widely distributed within fruits and edible plants, has been proven to relieve alcoholic liver disease (ALD). However, the mechanisms involved largely remain unclear. This study investigated whether the beneficial effects of UA on ALD could be related to gut-liver axis (GLA) modulation. Special attention was paid to the contribution of gut microbiome manipulation. UA ameliorated intestinal oxidative stress and barrier dysfunction induced by alcohol. As a consequence of gut leakiness amelioration, the related endotoxemia-mediated liver toll-like receptor 4 pathway induction and the subsequent reactive oxygen species overproduction were reverted. UA also counteracted alcohol-induced gut dysbiosis. A fecal microbiota transplantation study indicated that liver injury as well as ileum oxidative stress and gut barrier dysfunction of recipient mice were partly ameliorated as a result of microbiome remodeling. These results suggest that dietary UA alleviates ALD through GLA homeostasis modulation. Gut microbiome manipulation contributes to the hepatoprotective activity and GLA modulating effect of UA.
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Affiliation(s)
- Xin Yan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Xueyang Ren
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Xiaoyun Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Yu Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Jiamu Ma
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Ruolan Song
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Xiuhuan Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Ying Dong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Qiqi Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Jing Wei
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Axiang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
| | - Gaimei She
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
- Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, People's Republic of China
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Silva CBP, Elias-Oliveira J, McCarthy CG, Wenceslau CF, Carlos D, Tostes RC. Ethanol: striking the cardiovascular system by harming the gut microbiota. Am J Physiol Heart Circ Physiol 2021; 321:H275-H291. [PMID: 34142885 DOI: 10.1152/ajpheart.00225.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Ethanol consumption represents a significant public health problem, and excessive ethanol intake is a risk factor for cardiovascular disease (CVD), one of the leading causes of death and disability worldwide. The mechanisms underlying the effects of ethanol on the cardiovascular system are complex and not fully comprehended. The gut microbiota and their metabolites are indispensable symbionts essential for health and homeostasis and therefore, have emerged as potential contributors to ethanol-induced cardiovascular system dysfunction. By mechanisms that are not completely understood, the gut microbiota modulates the immune system and activates several signaling pathways that stimulate inflammatory responses, which in turn, contribute to the development and progression of CVD. This review summarizes preclinical and clinical evidence on the effects of ethanol in the gut microbiota and discusses the mechanisms by which ethanol-induced gut dysbiosis leads to the activation of the immune system and cardiovascular dysfunction. The cross talk between ethanol consumption and the gut microbiota and its implications are detailed. In summary, an imbalance in the symbiotic relationship between the host and the commensal microbiota in a holobiont, as seen with ethanol consumption, may contribute to CVD. Therefore, manipulating the gut microbiota, by using antibiotics, probiotics, prebiotics, and fecal microbiota transplantation might prove a valuable opportunity to prevent/mitigate the deleterious effects of ethanol and improve cardiovascular health and risk prevention.
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Affiliation(s)
- Carla B P Silva
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Jefferson Elias-Oliveira
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Cameron G McCarthy
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Camilla F Wenceslau
- Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Daniela Carlos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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30
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Onufer EJ, Han YH, Courtney C, Steinberger A, Tecos M, Sutton S, Sescleifer A, Ou J, Sanguinetti Czepielewski R, Randolph GJ, Warner BW. Liver injury after small bowel resection is prevented in obesity-resistant 129S1/SvImJ mice. Am J Physiol Gastrointest Liver Physiol 2021; 320:G907-G918. [PMID: 33729834 PMCID: PMC8202193 DOI: 10.1152/ajpgi.00284.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARα expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome.NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 in C57BL/6 mice with short bowel syndrome.
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Affiliation(s)
- Emily J. Onufer
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Yong-Hyun Han
- 2Laboratory of Pathology and Physiology, College of Pharmacy,
Kangwon National University, Chuncheon, South Korea,3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Cathleen Courtney
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Allie Steinberger
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Maria Tecos
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Stephanie Sutton
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Anne Sescleifer
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Jocelyn Ou
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | | | - Gwendalyn J. Randolph
- 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Brad W. Warner
- 1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
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31
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Baumann A, Hernández-Arriaga A, Brandt A, Sánchez V, Nier A, Jung F, Kehm R, Höhn A, Grune T, Frahm C, Witte OW, Camarinha-Silva A, Bergheim I. Microbiota profiling in aging-associated inflammation and liver degeneration. Int J Med Microbiol 2021; 311:151500. [PMID: 33813306 DOI: 10.1016/j.ijmm.2021.151500] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 03/18/2021] [Accepted: 03/26/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The number of people above the age of 60 years is raising world-wide being associated with an increase in the prevalence of aging-associated impairments and even diseases. Recent studies suggest that aging is associated with alterations in bacterial endotoxin levels and that these changes may add to low-grade inflammation, the so-called 'inflammaging', and aging-associated liver degeneration. However, mechanisms involved, and especially, the interaction of intestinal microbiota and barrier in the development of aging-associated inflammation and liver degeneration have not been fully understood. OBJECTIVE The aim of the present study was to determine if intestinal microbiota composition changes with age and if these alterations are associated with changes of markers of intestinal barrier function and the development of inflammation and liver degeneration. METHODS Blood, liver, small and large intestinal tissue of male 2-, 15-, 24- and 30-months old C57BL/6 mice fed standard chow were obtained. Intestinal microbiota composition, expression levels of antimicrobial peptides in small intestine and markers of intestinal barrier function were measured. Furthermore, indices of liver damage, inflammation and expression levels of lipopolysaccharide binding protein (Lbp) as well as of toll-like receptors (Tlr) 1-9 in liver tissue were assessed. RESULTS Pairwise comparisons of the microbial community in the small intestine showed differences between 2- and 24-, 15- and 24-, as well as 15- and 30-months old animals while Shannon's diversity, species richness and evenness indexes did not differ in both small and large intestine, respectively, between age groups. Concentrations of nitric oxide were significantly lower in small intestine of 15-, 24- and 30-months old mice compared to 2-months old mice while mRNA expression of the antimicrobial peptides defensin alpha 1 and lysozyme 1 was unchanged. In contrast, in liver tissue, older age of animals was associated with increasing inflammation and the development of fibrosis in 24- and 30-months old mice. Numbers of inflammatory foci and neutrophils in livers of 24- and 30-months old mice were significantly higher compared to 2-months old mice. These alterations were also associated with higher endotoxin levels in plasma as well as an increased mRNA expression of Lbp and Tlr1, Tlr2, Tlr4, Tlr6 and Tlr9 in livers in older mice. CONCLUSION Despite no consistent and robust changes of microbiota composition in small and/or large intestine of mice of different age were observed, our data suggest that alterations of markers of intestinal barrier function in small intestine are associated with an induction of several Tlrs and beginning hepatic inflammation in older mice and increase with age.
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Affiliation(s)
- Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | | | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Victor Sánchez
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Anika Nier
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Richard Kehm
- German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
| | - Annika Höhn
- German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany
| | - Tilman Grune
- German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany; German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany; Department of Physiological Chemistry, University of Vienna, Vienna, Austria
| | - Christiane Frahm
- Hans-Berger Department of Neurology, University Hospital Jena, Jena, Germany
| | - Otto Wilhelm Witte
- Hans-Berger Department of Neurology, University Hospital Jena, Jena, Germany
| | | | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.
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3-B-RUT, a derivative of RUT, protected against alcohol-induced liver injury by attenuating inflammation and oxidative stress. Int Immunopharmacol 2021; 95:107471. [PMID: 33756231 DOI: 10.1016/j.intimp.2021.107471] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 12/25/2022]
Abstract
Alcoholic liver disease (ALD) is the most common chronic liver disease worldwide. Currently, there is no definitive treatment for alcohol-induced liver injury (ALI). Inflammatory response and oxidative stress play a crucial role in ALI. Cyclooxygenase 2 (COX-2) can be induced by inflammation and it has been reported that the enhanced expression of COX-2 in alcoholic liver injury. Rutaecarpine (RUT) was extracted from evodia rutaecarpa. RUT has a wide range of pharmacological activities. In order to increase its anti-inflammatory activity, our group introduced sulfonyl group to synthesized the 3-[2-(trifluoromethoxy)benzenesulfonamide]-rutaecarpine (3-B-RUT). In this study, we explored the protective effect of 3-B-RUT on alcoholic liver injury in vivo and in vitro and preliminarily explore its mechanism. Mice ALI model was established according to the chronic-plus-binge ethanol model. Results showed that 3-B-RUT (20 μg/kg) attenuated alcohol-induced liver injury and suppressed liver inflammation and oxidative stress, and the effect was comparable to RUT (20 mg/kg). In vitro results are consistent with in vivo results. Mechanistically, the 3-B-RUT might suppress inflammatory response and oxidative stress by regulating activation of NF-κB/COX-2 pathway. In summary, 3-B-RUT, a derivative of RUT, may be a promising clinical candidate for ALI treatment.
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Le Daré B, Ferron PJ, Gicquel T. The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease? Int J Mol Sci 2021; 22:2139. [PMID: 33670021 PMCID: PMC7926651 DOI: 10.3390/ijms22042139] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 12/24/2022] Open
Abstract
The World Health Organization has estimated that approximately 3 million deaths are attributable to alcohol consumption each year. Alcohol consumption is notably associated with the development and/or progression of many non-communicable inflammatory diseases-particularly in the liver. Although these alcoholic liver diseases were initially thought to be caused by the toxicity of ethanol on hepatocytes, the latest research indicates Kupffer cells (the liver macrophages) are at the heart of this "inflammatory shift". Purinergic signaling (notably through P2X7 receptors and the NLRP3 inflammasome) by Kupffer cells appears to be a decisive factor in the pathophysiology of alcoholic liver disease. Hence, the modulation of purinergic signaling might represent a new means of treating alcoholic liver disease. Here, we review current knowledge on the pathophysiology of alcoholic liver diseases and therapeutic perspectives for targeting these inflammatory pathways.
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Affiliation(s)
- Brendan Le Daré
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
- Forensic and Toxicology Laboratory, Rennes University Hospital, 2 rue Henri Le Guilloux, F-35033 Rennes, France
| | - Pierre-Jean Ferron
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
| | - Thomas Gicquel
- NuMeCan Institute (Nutrition, Metabolisms and Cancer), INSERM, INRAE, CHU—University Rennes, PREVITOX Network, F-35000 Rennes, France; (B.L.D.); (P.-J.F.)
- Forensic and Toxicology Laboratory, Rennes University Hospital, 2 rue Henri Le Guilloux, F-35033 Rennes, France
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Bruellman R, Llorente C. A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease. Int J Biol Sci 2021; 17:307-327. [PMID: 33390852 PMCID: PMC7757023 DOI: 10.7150/ijbs.53589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.
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Affiliation(s)
- Ryan Bruellman
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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35
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Cross-Talk between Diet-Associated Dysbiosis and Hand Osteoarthritis. Nutrients 2020; 12:nu12113469. [PMID: 33198220 PMCID: PMC7696908 DOI: 10.3390/nu12113469] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/09/2020] [Accepted: 11/09/2020] [Indexed: 12/12/2022] Open
Abstract
Hand osteoarthritis (OA) is a degenerative joint disease which leads to pain and disability. Recent studies focus on the role of obesity and metabolic syndrome in inducing or worsening joint damage in hand OA patients, suggesting that chronic low-grade systemic inflammation may represent a possible linking factor. The gut microbiome has a crucial metabolic role which is fundamental for immune system development, among other important functions. Intestinal microbiota dysbiosis may favour metabolic syndrome and low-grade inflammation-two important components of hand OA onset and evolution. The aim of this narrative is to review the recent literature concerning the possible contribution of dysbiosis to hand OA onset and progression, and to discuss the importance of gut dysbiosis on general health and disease.
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Arteel GE. Liver-lung axes in alcohol-related liver disease. Clin Mol Hepatol 2020; 26:670-676. [PMID: 33053938 PMCID: PMC7641553 DOI: 10.3350/cmh.2020.0174] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/25/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023] Open
Abstract
Alcohol-related liver disease (ALD) and alcohol-related susceptibility to acute lung injury are the leading causes of morbidity and mortality due to chronic alcohol abuse. Most commonly, alcohol-induced injury to both organs are evaluated independently, although they share many parallel mechanisms of injury. Moreover, recent studies indicate that there is a potential liver lung axis that may contribute to organ pathology. This mini-review explores established and potential mechanisms of organ-organ crosstalk in ALD and alcohol-related lung injury.
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Affiliation(s)
- Gavin E. Arteel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
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Lockyer S, Aguirre M, Durrant L, Pot B, Suzuki K. The role of probiotics on the roadmap to a healthy microbiota: a symposium report. GUT MICROBIOME (CAMBRIDGE, ENGLAND) 2020; 1:e2. [PMID: 39296722 PMCID: PMC11406418 DOI: 10.1017/gmb.2020.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/23/2020] [Accepted: 05/01/2020] [Indexed: 09/21/2024]
Abstract
The ninth International Yakult Symposium was held in Ghent, Belgium in April 2018. Keynote lectures were from Professor Wijmenga on using biobanks to understand the relationship between the gut microbiota and health; and Professor Hill on phage-probiotic interactions. Session one included talks from Professor Plӧsch on epigenetic programming by nutritional and environmental factors; Professor Wilmes on the use of "omics" methodologies in microbiome research and Professor Rescigno on the gut vascular barrier. Session two explored the evidence behind Lactobacillus casei Shirota with Dr Nanno explaining the plasticity in immunomodulation that enables the strain to balance immune functions; Dr Macnaughtan outlining its potential therapeutic use in cirrhosis and Professor Nishida detailing effects in subjects under stress. The third session saw Professor Marchesi describing that both the host genes and the gut microbiota can play a role in cancer; Professor Bergheim highlighting crosstalk between the gut and the liver and Professor Cani describing the relationship between the gut microbiota and the endocrine system. The final session explored probiotic mechanisms, with Professor Lebeer dissecting the challenges in conducting mechanistic studies; Professor Wehkamp describing the mucosal defence system and Professor Van de Wiele detailing methods for modelling the gut microbiota in vitro.
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Affiliation(s)
| | | | | | - Bruno Pot
- Yakult Europe B.V., Almere, The Netherlands
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Idalsoaga F, Kulkarni AV, Mousa OY, Arrese M, Arab JP. Non-alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities. Front Med (Lausanne) 2020; 7:448. [PMID: 32974366 PMCID: PMC7468507 DOI: 10.3389/fmed.2020.00448] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with a prevalence of 25-30%. Since its first description in 1980, NAFLD has been conceived as a different entity from alcohol-related fatty liver disease (ALD), despite that, both diseases have an overlap in the pathophysiology, share genetic-epigenetic factors, and frequently coexist. Both entities are characterized by a broad spectrum of histological features ranging from isolated steatosis to steatohepatitis and cirrhosis. Distinction between NAFLD and ALD is based on the amount of consumed alcohol, which has been arbitrarily established. In this context, a proposal of positive criteria for NAFLD diagnosis not considering exclusion of alcohol consumption as a prerequisite criterion for diagnosis had emerged, recognizing the possibility of a dual etiology of fatty liver in some individuals. The impact of moderate alcohol use on the severity of NAFLD is ill-defined. Some studies suggest protective effects in moderate doses, but current evidence shows that there is no safe threshold for alcohol consumption for NAFLD. In fact, given the synergistic effect between alcohol consumption, obesity, and metabolic dysfunction, it is likely that alcohol use serves as a significant risk factor for the progression of liver disease in NAFLD and metabolic syndrome. This also affects the incidence of hepatocellular carcinoma. In this review, we summarize the overlapping pathophysiology of NAFLD and ALD, the current data on alcohol consumption in patients with NAFLD, and the effects of metabolic dysfunction and overweight in ALD.
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Affiliation(s)
- Francisco Idalsoaga
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Omar Y Mousa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.,Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Mankato, MN, United States
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Sangineto M, Grabherr F, Adolph TE, Grander C, Reider S, Jaschke N, Mayr L, Schwärzler J, Dallio M, Moschen AR, Moschetta A, Sabbà C, Tilg H. Dimethyl fumarate ameliorates hepatic inflammation in alcohol related liver disease. Liver Int 2020; 40:1610-1619. [PMID: 32306456 PMCID: PMC7383968 DOI: 10.1111/liv.14483] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/25/2020] [Accepted: 04/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Alcohol-related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl-fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. METHODS Dimethyl-fumarate or vehicle was orally administered to wild-type mice receiving a Lieber-DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical- and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol-induced intestinal barrier disruption. RESULTS Dimethyl-fumarate protected against ethanol-induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines (Tnf-α, Il-1β, Cxcl1) and reduced abundance of neutrophils and macrophages in ethanol-fed and DMF-treated mice when compared to vehicle. DMF protected against ethanol-induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS-induced cytokine responses of KCs. CONCLUSIONS Dimethyl-fumarate counteracts ethanol-induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.
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Affiliation(s)
- Moris Sangineto
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Department of Interdisciplinary MedicineUniversity of BariBariItaly
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Simon Reider
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Christian Doppler Laboratory for Mucosal ImmunologyMedical University InnsbruckInnsbruckAustria
| | - Nikolai Jaschke
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Marcello Dallio
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Department of Precision MedicineUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Alexander R. Moschen
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Christian Doppler Laboratory for Mucosal ImmunologyMedical University InnsbruckInnsbruckAustria
| | | | - Carlo Sabbà
- Department of Interdisciplinary MedicineUniversity of BariBariItaly
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
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Recent advances of sterile inflammation and inter-organ cross-talk in alcoholic liver disease. Exp Mol Med 2020; 52:772-780. [PMID: 32457490 PMCID: PMC7272465 DOI: 10.1038/s12276-020-0438-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 04/07/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver disease (ALD) is one of the fastest-growing concerns worldwide. In addition to bacterial endotoxins in the portal circulation, recent lines of evidence have suggested that sterile inflammation caused by a wide range of stimuli induces alcoholic liver injury, in which damage-associated molecular patterns (DAMPs) play critical roles in inducing de novo lipogenesis and inflammation through the activation of cellular pattern recognition receptors such as Toll-like receptors in non-parenchymal cells. Interestingly, alcohol-mediated metabolic, neurological, and immune stresses stimulate the generation of DAMPs that are released not only in the liver, but also in other organs, such as adipose tissue, intestine, and bone marrow. Thus, diverse DAMPs, including retinoic acids, proteins, lipids, microRNAs, mitochondrial DNA, and mitochondrial double-stranded RNA, contribute to a broad spectrum of ALD through the production of multiple pro-inflammatory cytokines, chemokines, and ligands in non-parenchymal cells, such as Kupffer cells, hepatic stellate cells, and various immune cells. Therefore, this review summarizes recent studies on the identification and understanding of DAMPs, their receptors, and cross-talk between the liver and other organs, and highlights successful therapeutic targets and potential strategies in drug development that can be used to combat ALD.
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Ntandja Wandji LC, Gnemmi V, Mathurin P, Louvet A. Combined alcoholic and non-alcoholic steatohepatitis. JHEP Rep 2020; 2:100101. [PMID: 32514497 PMCID: PMC7267467 DOI: 10.1016/j.jhepr.2020.100101] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/18/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
While metabolic syndrome and alcohol consumption are the two main causes of chronic liver disease, one of the two conditions is often predominant, with the other acting as a cofactor of morbimortality. It has been shown that obesity and alcohol act synergistically to increase the risk of fibrosis progression, hepatic carcinogenesis and mortality, while genetic polymorphisms can strongly influence disease progression. Based on common pathogenic pathways, there are several potential targets that could be used to treat both diseases; based on the prevalence and incidence of these diseases, new therapies and clinical trials are needed urgently.
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Key Words
- ACC, acetyl-CoA carboxylase
- ALD
- ALD, alcohol-related liver disease
- ASH
- ASH, alcohol-related steatohepatitis
- ASK-1, apoptosis signal-regulating kinase 1
- Alcohol
- BMI, body mass index
- CLD, chronic liver disease
- CPT, carnitine palmitoyltransferase
- DNL, de novo lipogenesis
- EASL, European Association for the Study of the Liver
- ER, endoplasmic reticulum
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HSD17B13, hydroxysteroid 17-beta dehydrogenase 13
- IL, interleukin
- LPS, lipopolysaccharide
- MBOAT7, membrane bound O-acyl transferase 7
- MELD, model for end-stage liver disease
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NASH
- NASH, non-alcoholic steatohepatitis
- OR, odds ratio
- PAMP, pathogen-associated molecular pattern
- PI3K, phosphatidylinositol-3-kinase
- PIP3, phosphatidylinositol 3,4,5-triphosphate
- PNPLA3, palatin-like phospholipase domain-containing 3
- PRKCE, protein kinase C Epsilon
- ROS, reactive oxygen species
- SREBP-1c, sterol regulatory element binding protein-1c
- TLR, Toll-like receptor
- TM6SF2, transmembrane 6 superfamily member 2
- TNF-α, tumour necrosis factor-α
- WHO, World Health Organization
- diabetes
- metabolic syndrome
- obesity
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Affiliation(s)
- Line Carolle Ntandja Wandji
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
| | | | - Philippe Mathurin
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
| | - Alexandre Louvet
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
- Corresponding author. Address: Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France. Tel.: +33 320445597; fax: +33 320445564.
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Talavera-Urquijo E, Beisani M, Balibrea JM, Alverdy JC. Is bariatric surgery resolving NAFLD via microbiota-mediated bile acid ratio reversal? A comprehensive review. Surg Obes Relat Dis 2020; 16:1361-1369. [PMID: 32336663 DOI: 10.1016/j.soard.2020.03.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 01/18/2020] [Accepted: 03/11/2020] [Indexed: 02/07/2023]
Abstract
Despite the fact that there is still insufficient evidence to consider non-alcoholic fatty liver disease (NAFLD) as an stand-alone indication for bariatric surgery, many clinical and histopathological beneficial effects on both NAFLD and non-alcoholic steatohepatitis (NASH) have been shown. Although weight loss seems to be the obvious mechanism, weight-loss independent factors are also believed to be involved. Among them, changes in gut microbiota and bile acids (BA) composition may be playing an unappreciated role in the improvement of NAFLD. In this review we examine the mechanisms and interdependence of the gut microbiota and BA, and their influence on NAFLD pathogenesis and its reversal following bariatric surgery. According to the currently available evidence, gut microbiota has a major influence on BA composition. In fact, both BA and microbiome disturbances (dysbiosis) play a role in the etiopathogenesis of NAFLD and might be potential therapeutic targets. In addition, bariatric surgery can modify the intraluminal ileal environment in a way that causes significant repopulation of the gut microbiota and a reversal of the plasma primary/secondary BA ratio, which, in turn, induces weigh-independent metabolic improvements.
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Affiliation(s)
- Eider Talavera-Urquijo
- Department of General & Digestive Surgery, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Marc Beisani
- Department of Surgery, Hospital del Mar, Barcelona, Spain
| | - José M Balibrea
- Department of Gastrointestinal Surgery, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
| | - John C Alverdy
- Department of Surgery University of Chicago, Pritzker School of Medicine, Chicago, Illinois
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Li Y, Chen M, Zhou Y, Tang C, Zhang W, Zhong Y, Chen Y, Zhou H, Sheng L. NIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease. Theranostics 2020; 10:3579-3593. [PMID: 32206109 PMCID: PMC7069072 DOI: 10.7150/thno.40149] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/31/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Inflammation and steatosis are the main pathological features of alcoholic liver disease (ALD), in which, inflammation is one of the critical drivers for the initiation and development of alcoholic steatosis. NIK, an inflammatory pathway component activated by inflammatory cytokines, was suspected to link inflammation to hepatic steatosis during ALD. However, the underlying pathogenesis is not well-elucidated. Methods: Alcoholic steatosis was induced in mice by chronic-plus-binge ethanol feeding. Both the loss- and gain-of-function experiments by the hepatocyte-specific deletion, pharmacological inhibition and adenoviral transfection of NIK were utilized to elucidate the role of NIK in alcoholic steatosis. Rate of fatty acid oxidation was assessed in vivo and in vitro. PPARα agonists or antagonists of MEK1/2 and ERK1/2 were used to identify the NIK-induced regulation of PPARα, MEK1/2, and ERK1/2. The potential interactions between NIK, MEK1/2, ERK1/2 and PPARα and the phosphorylation of PPARα were clarified by immunoprecipitation, immunoblotting and far-western blotting analysis. Results: Hepatocyte-specific deletion of NIK protected mice from alcoholic steatosis by sustaining hepatic fatty acid oxidation. Moreover, overexpression of NIK contributed to hepatic lipid accumulation with disrupted fatty acid oxidation. The pathological effect of NIK in ALD may be attributed to the suppression of PPARα, the main controller of fatty acid oxidation in the liver, because PPARα agonists reversed NIK-mediated hepatic steatosis and malfunction of fatty acid oxidation. Mechanistically, NIK recruited MEK1/2 and ERK1/2 to form a complex that catalyzed the inhibitory phosphorylation of PPARα. Importantly, pharmacological intervention against NIK significantly attenuated alcoholic steatosis in ethanol-fed mice. Conclusions: NIK targeting PPARα via MEK1/2 and ERK1/2 disrupts hepatic fatty acid oxidation and exhibits high value in ALD therapy.
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Affiliation(s)
- Yaru Li
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Mingming Chen
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
| | - Yu Zhou
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Chuanfeng Tang
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Wen Zhang
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Ying Zhong
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yadong Chen
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Hong Zhou
- Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Liang Sheng
- Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Department of Rehabilitation Medicine, Jiangsu Province People's Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu 210029, China
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Prolonged ethanol administration prevents the development of tolerance to morphine-induced respiratory depression. Drug Alcohol Depend 2019; 205:107674. [PMID: 31715438 DOI: 10.1016/j.drugalcdep.2019.107674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/23/2019] [Accepted: 10/01/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Opioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol can rapidly reverse tolerance to morphine-induced respiratory depression. However, alcohol consumption by opioid users is likely to occur over prolonged time periods. We have therefore sought to determine the effect of prolonged alcohol consumption on the development of tolerance to opioid respiratory depression. METHODS Mice were fed control or ethanol (5%) liquid diet for 16 days. On days 9-16 morphine tolerance was induced by administration of 3 priming injections of morphine followed by subcutaneous implantation of a morphine-filled osmotic mini-pump. Control mice received saline. Respiration was measured by plethysmography and the effect of an acute morphine challenge dose was measured on day 16 to assess the development of morphine tolerance. RESULTS Prolonged ethanol consumption for 14 days did not alter the respiratory depressant effect of an acute dose of morphine. Control mice treated with prolonged morphine developed tolerance to acute morphine respiratory depression whereas ethanol diet fed mice treated with prolonged morphine showed significant respiratory depression during morphine-pump treatment and remained sensitive to the respiratory depressant effect of the acute challenge dose of morphine. The ethanol consumption did not alter blood or brain levels of morphine, whilst conversely prolonged morphine treatment did not alter blood levels of ethanol. CONCLUSIONS Prolonged ethanol consumption prevents the development and maintenance of tolerance to the respiratory depressant effect of morphine. These data suggest that ethanol inhibition of tolerance will greatly increase the risk of fatal heroin overdose in humans.
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Duvigneau JC, Luís A, Gorman AM, Samali A, Kaltenecker D, Moriggl R, Kozlov AV. Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases. Cytokine 2019; 124:154577. [DOI: 10.1016/j.cyto.2018.10.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/18/2018] [Indexed: 12/11/2022]
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Kany S, Janicova A, Relja B. Innate Immunity and Alcohol. J Clin Med 2019; 8:jcm8111981. [PMID: 31739600 PMCID: PMC6912266 DOI: 10.3390/jcm8111981] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/11/2019] [Accepted: 11/11/2019] [Indexed: 02/07/2023] Open
Abstract
The innate immunity has evolved during millions of years, and thus, equivalent or comparable components are found in most vertebrates, invertebrates, and even plants. It constitutes the first line of defense against molecules, which are either pathogen-derived or a danger signal themselves, and not seldom both. These molecular patterns are comprised of highly conserved structures, a common trait in innate immunity, and constitute very potent triggers for inflammation mediated via extracellular or intracellular pattern recognition receptors. Human culture is often interweaved with the consumption of alcohol, in both drinking habits, its acute or chronical misuse. Apart from behavioral effects as often observed in intoxicated individuals, alcohol consumption also leads to immunological modulation on the humoral and cellular levels. In the last 20 years, major advances in this field of research have been made in clinical studies, as well as in vitro and in vivo research. As every physician will experience intoxicated patients, it is important to be aware of the changes that this cohort undergoes. This review will provide a summary of the current knowledge on the influence of alcohol consumption on certain factors of innate immunity after a hit, followed by the current studies that display the effect of alcohol with a description of the model, the mode of alcohol administration, as well as its dose. This will provide a way for the reader to evaluate the findings presented.
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Kitagawa R, Kon K, Uchiyama A, Arai K, Yamashina S, Kuwahara-Arai K, Kirikae T, Ueno T, Ikejima K. Rifaximin prevents ethanol-induced liver injury in obese KK-A y mice through modulation of small intestinal microbiota signature. Am J Physiol Gastrointest Liver Physiol 2019; 317:G707-G715. [PMID: 31509430 DOI: 10.1152/ajpgi.00372.2018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Exacerbation of alcoholic hepatitis (AH) with comorbid metabolic syndrome is an emerging clinical problem, where microbiota plays a profound role in the pathogenesis. Here, we investigated the effect of rifaximin (RFX) on liver injury following chronic-binge ethanol (EtOH) administration in KK-Ay mice, a rodent model of metabolic syndrome. Female, 8-wk-old KK-Ay mice were fed Lieber-DeCarli diet (5% EtOH) for 10 days, following a single EtOH gavage (4 g/kg body wt). Some mice were given RFX (0.1 g/L, in liquid diet) orally. Small intestinal contents were collected from mice without binge. Intestinal microbiota was quantified using aerobic and anaerobic culturing techniques and further analyzed by 16S rRNA sequencing in detail. EtOH feeding/binge caused hepatic steatosis, oxidative stress, and induction of inflammatory cytokines in KK-Ay mice, which were markedly prevented by RFX treatment. Hepatic mRNA levels for cluster of differentiation 14, Toll-like receptor (TLR) 4, TLR2, and NADPH oxidase 2 were increased following EtOH feeding/binge, and administration of RFX completely suppressed their increase. The net amount of small intestinal bacteria was increased over threefold after chronic EtOH feeding as expected; however, RFX did not prevent this net increase. Intriguingly, the profile of small intestinal microbiota was dramatically changed following EtOH feeding in the order level, where the Erysipelotrichales predominated in the relative abundance. In sharp contrast, RFX drastically blunted the EtOH-induced increases in the Erysipelotrichales almost completely, with increased proportion of the Bacteroidales. In conclusion, RFX prevents AH through modulation of small intestinal microbiota/innate immune responses in obese KK-Ay mice.NEW & NOTEWORTHY Here we demonstrated that rifaximin (RFX) prevents chronic-binge ethanol (EtOH)-induced steatohepatitis in KK-Ay mice. Chronic EtOH feeding caused small intestinal bacterial overgrowth, with drastic alteration in the microbiota profile predominating the order Erysipelotrichales. RFX minimized this EtOH induction in Erysipelotrichales with substitutive increases in Bacteroidales. RFX also prevented EtOH-induced increases in portal lipopolysaccharide, and hepatic cluster of differentiation 14, toll-like receptor (TLR) 2, and TLR4 mRNA levels, suggesting the potential involvement of microbiota-related innate immune responses.
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Affiliation(s)
- Ryuta Kitagawa
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kazuyoshi Kon
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akira Uchiyama
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kumiko Arai
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shunhei Yamashina
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kyoko Kuwahara-Arai
- Department of Microbiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Teruo Kirikae
- Department of Microbiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Ueno
- Laboratory of Proteomics and Medical Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kenichi Ikejima
- Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Luo P, Wang F, Wong NK, Lv Y, Li X, Li M, Tipoe GL, So KF, Xu A, Chen S, Xiao J, Wang H. Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG. Cell Mol Gastroenterol Hepatol 2019; 9:145-160. [PMID: 31562937 PMCID: PMC6909006 DOI: 10.1016/j.jcmgh.2019.09.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 09/11/2019] [Accepted: 09/16/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Toll-like receptor 2 (TLR2) and TLR3 regulate hepatic immunity under pathological conditions, but their functions and potential drug targets in alcoholic liver disease (ALD) remain poorly understood. METHODS ALD-associated liver injury were induced in TLR2 knockout (TLR2-/-), TLR3-/-, TLR2-/- bone marrow transplanted (BMT), TLR3-/- BMT, IL-10-/- mice, and their wild-type littermates through ethanol challenge with or without co-administered epigallocatechin-3-gallate (EGCG). Moreover, Kupffer cells were depleted by GdCl3 injection to evaluate their pathogenic roles in ALD. RESULTS We identified that deficiency of TLR2 and TLR3 significantly alleviated and aggravated ALD-induced liver injury, respectively. Mechanistically, Kupffer cell inactivation, M1 to M2 polarization, and IL-10 production via STAT3 activation contributed to hepatic protection mediated by concurrent TLR2 inhibition and TLR3 agonism. These findings were further confirmed in TLR2 and TLR3 BMT mice. We also identified a novel ALD-protective agent EGCG which directly interacted with Kupffer cell TLR2/3 to induce IL-10 production. Deficiency of IL-10 aggravated ALD injury and blunted EGCG-mediated hepatoprotection while depletion of Kupffer cells partially recovered liver injury but abolished EGCG's actions. CONCLUSIONS Altogether, our results illustrate the divergent roles of Kupffer cells TLR2/3 in ALD progression via anti-inflammatory cytokine IL-10 production.
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Affiliation(s)
- Pingping Luo
- Clinical Medicine Research Institute, First Affiliated Hospital of Jinan University, Guangzhou, China; Laboratory of Neuroendocrinology, School of Biological Sciences, Fujian Normal University, Fuzhou, China
| | - Fei Wang
- Digestive Disease Institute of Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Nai-Kei Wong
- State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Yi Lv
- Laboratory of Neuroendocrinology, School of Biological Sciences, Fujian Normal University, Fuzhou, China
| | - Xinxin Li
- Research Center for Clinical Sciences, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mianhuan Li
- Clinical Medicine Research Institute, First Affiliated Hospital of Jinan University, Guangzhou, China; Laboratory of Neuroendocrinology, School of Biological Sciences, Fujian Normal University, Fuzhou, China
| | - George L Tipoe
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Kwok-Fai So
- GMH Institute of CNS Regeneration, Guangdong Medical Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, China
| | - Aimin Xu
- Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Shuaiyin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Jia Xiao
- Clinical Medicine Research Institute, First Affiliated Hospital of Jinan University, Guangzhou, China; Laboratory of Neuroendocrinology, School of Biological Sciences, Fujian Normal University, Fuzhou, China; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.
| | - Hua Wang
- Department of Oncology, First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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Ohayon D, De Chiara A, Dang PMC, Thieblemont N, Chatfield S, Marzaioli V, Burgener SS, Mocek J, Candalh C, Pintard C, Tacnet-Delorme P, Renault G, Lagoutte I, Favier M, Walker F, Hurtado-Nedelec M, Desplancq D, Weiss E, Benarafa C, Housset D, Marie JC, Frachet P, El-Benna J, Witko-Sarsat V. Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils. J Exp Med 2019; 216:2669-2687. [PMID: 31492810 PMCID: PMC6829599 DOI: 10.1084/jem.20180371] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Revised: 06/17/2019] [Accepted: 08/16/2019] [Indexed: 12/29/2022] Open
Abstract
This study describes a novel function of cytosolic proliferating cell nuclear antigen (PCNA) in the control of neutrophil NADPH oxidase, a complex pivotal for ROS generation in inflammation. Inhibition of neutrophil PCNA results in a potent antiinflammatory effect in colitis. Neutrophils produce high levels of reactive oxygen species (ROS) by NADPH oxidase that are crucial for host defense but can lead to tissue injury when produced in excess. We previously described that proliferating cell nuclear antigen (PCNA), a nuclear scaffolding protein pivotal in DNA synthesis, controls neutrophil survival through its cytosolic association with procaspases. We herein showed that PCNA associated with p47phox, a key subunit of NADPH oxidase, and that this association regulated ROS production. Surface plasmon resonance and crystallography techniques demonstrated that the interdomain-connecting loop of PCNA interacted directly with the phox homology (PX) domain of the p47phox. PCNA inhibition by competing peptides or by T2AA, a small-molecule PCNA inhibitor, decreased NADPH oxidase activation in vitro. Furthermore, T2AA provided a therapeutic benefit in mice during trinitro-benzene-sulfonic acid (TNBS)–induced colitis by decreasing oxidative stress, accelerating mucosal repair, and promoting the resolution of inflammation. Our data suggest that targeting PCNA in inflammatory neutrophils holds promise as a multifaceted antiinflammatory strategy.
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Affiliation(s)
- Delphine Ohayon
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Alessia De Chiara
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Pham My-Chan Dang
- LabEx Inflamex, Sorbonne Paris Cité, Paris, France.,Institut National de la Santé et de la Recherche Médicale U1149, Centre National de la Recherche Scientifique ERL8252, Centre de Recherche sur l'Inflammation, Université Paris Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - Nathalie Thieblemont
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Simon Chatfield
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Viviana Marzaioli
- LabEx Inflamex, Sorbonne Paris Cité, Paris, France.,Institut National de la Santé et de la Recherche Médicale U1149, Centre National de la Recherche Scientifique ERL8252, Centre de Recherche sur l'Inflammation, Université Paris Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - Sabrina Sofia Burgener
- Institute of Virology and Immunology, Mittelhäusern, Switzerland.,Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Julie Mocek
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Céline Candalh
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Coralie Pintard
- LabEx Inflamex, Sorbonne Paris Cité, Paris, France.,Institut National de la Santé et de la Recherche Médicale U1149, Centre National de la Recherche Scientifique ERL8252, Centre de Recherche sur l'Inflammation, Université Paris Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - Pascale Tacnet-Delorme
- Université Grenoble Alpes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de la Recherche Scientifique, Institut de Biologie Structurale, Grenoble, France
| | - Gilles Renault
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Isabelle Lagoutte
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | - Maryline Favier
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France.,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
| | | | - Margarita Hurtado-Nedelec
- LabEx Inflamex, Sorbonne Paris Cité, Paris, France.,Institut National de la Santé et de la Recherche Médicale U1149, Centre National de la Recherche Scientifique ERL8252, Centre de Recherche sur l'Inflammation, Université Paris Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - Dominique Desplancq
- Ecole Supérieure de Biotechnologie de Strasbourg, Centre National de la Recherche Scientifique UMR 7242, Université de Strasbourg, Strasbourg, France
| | - Etienne Weiss
- Ecole Supérieure de Biotechnologie de Strasbourg, Centre National de la Recherche Scientifique UMR 7242, Université de Strasbourg, Strasbourg, France
| | - Charaf Benarafa
- Institute of Virology and Immunology, Mittelhäusern, Switzerland.,Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Dominique Housset
- Université Grenoble Alpes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de la Recherche Scientifique, Institut de Biologie Structurale, Grenoble, France
| | - Jean-Claude Marie
- LabEx Inflamex, Sorbonne Paris Cité, Paris, France.,Institut National de la Santé et de la Recherche Médicale U1149, Centre National de la Recherche Scientifique ERL8252, Centre de Recherche sur l'Inflammation, Université Paris Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - Philippe Frachet
- Université Grenoble Alpes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre National de la Recherche Scientifique, Institut de Biologie Structurale, Grenoble, France
| | - Jamel El-Benna
- LabEx Inflamex, Sorbonne Paris Cité, Paris, France.,Institut National de la Santé et de la Recherche Médicale U1149, Centre National de la Recherche Scientifique ERL8252, Centre de Recherche sur l'Inflammation, Université Paris Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - Véronique Witko-Sarsat
- Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique UMR 8104, Université Paris-Descartes, Cochin Institute, Paris, France .,LabEx Inflamex, Sorbonne Paris Cité, Paris, France
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Sangouni AA, Ghavamzadeh S. A review of synbiotic efficacy in non-alcoholic fatty liver disease as a therapeutic approach. Diabetes Metab Syndr 2019; 13:2917-2922. [PMID: 31425956 DOI: 10.1016/j.dsx.2019.07.063] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 07/30/2019] [Indexed: 02/07/2023]
Abstract
According to recent epidemiological studies, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the worldwide. Pathophysiological pathways and mechanisms involved in NAFLD are not fully clear, but Inflammation, insulin resistance, oxidative stress, obesity and dyslipidemia are among the main causes of NAFLD. There is still no standard drug for the treatment of NAFLD. Diet modification, weight loss and physical activity are considered as the main treatment line for this disease. It has been shown that gut microbiota imbalance is associated with the main factors causing of NAFLD. Synbiotics, which have positive effects on the balance of gut microbiota, are a combination of prebiotics and probiotics. It is believed that the consumption of synbiotics can help to treatment of NAFLD through effect on gut microbiota and subsequently improving the risk factors of this disease. The purpose of this review is to investigate the effects of synbiotics on the main causes of NAFLD based on existing evidence, especially the clinical effects of synbiotics supplementation in patients with NAFLD.
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Affiliation(s)
- Abbas Ali Sangouni
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Human Nutrition, Medicine Faculty, Urmia University of Medical Sciences, Urmia, Iran
| | - Saeid Ghavamzadeh
- Department of Human Nutrition, Medicine Faculty, Urmia University of Medical Sciences, Urmia, Iran; Food and Beverage Safety Research Center, Urmia University of Medical Sciences, Urmia, Iran.
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