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Cheng Z, Yang L, Chu H. The role of gut microbiota, exosomes, and their interaction in the pathogenesis of ALD. J Adv Res 2025; 72:353-367. [PMID: 38969094 DOI: 10.1016/j.jare.2024.07.002] [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: 05/06/2024] [Revised: 06/30/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND The liver disorders caused by alcohol abuse are termed alcoholic-related liver disease (ALD), including alcoholic steatosis, alcoholic steatohepatitis, alcoholic hepatitis, and alcoholic cirrhosis, posing a significant threat to human health. Currently, ALD pathogenesis has not been completely clarified, which is likely to be related to the direct damage caused by alcohol and its metabolic products, oxidative stress, gut dysbiosis, and exosomes. AIMS The existing studies suggest that both the gut microbiota and exosomes contribute to the development of ALD. Moreover, there exists an interaction between the gut microbiota and exosomes. We discuss whether this interaction plays a role in the pathogenesis of ALD and whether it can be a potential therapeutic target for ALD treatment. KEY SCIENTIFIC CONCEPTS OF REVIEW Chronic alcohol intake alters the diversity and composition of gut microbiota, which greatly contributes to ALD's progression. Some approaches targeting the gut microbiota, including probiotics, fecal microbiota transplantation, and phage therapy, have been confirmed to effectively ameliorate ALD in many animal experiments and/or several clinical trials. In ALD, the levels of exosomes and the expression profile of microRNA have also changed, which affects the pathogenesis of ALD. Moreover, there is an interplay between exosomes and the gut microbiota, which also putatively acts as a pathogenic factor of ALD.
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Affiliation(s)
- Zilu Cheng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
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Girisa S, Aswani BS, Manickasamy MK, Hegde M, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders. Expert Opin Ther Targets 2025; 29:193-221. [PMID: 40169227 DOI: 10.1080/14728222.2025.2487465] [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: 12/08/2024] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
INTRODUCTION Liver cancer is a leading cause of cancer-associated mortality and is often linked to preexisting liver conditions. Emerging research demonstrates FXR dysregulation, particularly its reduced expression, in the pathogenesis of liver diseases, including inflammation, fibrosis, cholestatic disorders, metabolic dysregulation, and liver cancer. Therefore, this review explores the role of FXR and its agonists in mitigating these conditions. AREAS COVERED This article summarizes FXR's involvement in liver disorders, primarily emphasizing on hepatic neoplasms, and examines the potential of FXR agonists in restoring FXR activity in liver diseases, thereby preventing their progression to liver cancer. The information presented is drawn from existing preclinical and clinical studies specific to each liver disorder, sourced from PubMed. EXPERT OPINION It is well established that FXR expression is downregulated in liver disorders, contributing to disease progression. Notably, FXR agonists have demonstrated therapeutic potential in ameliorating liver diseases, including hepatocellular carcinoma. We believe that activating or restoring FXR expression with agonists offers significant promise for the treatment of liver cancer and other liver conditions. Therefore, FXR modulation by agonists, particularly in combination with other therapeutic agents, could lead to more targeted treatments, improving efficacy while reducing side effects.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Leicester, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
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Farhadi S, Mohammadi S, AlKindi AY, Al-Amri IS. Therapeutic potential of elafibranor in alcohol-associated liver disease: Insights into macrophage modulation and fibrosis reduction. World J Biol Chem 2025; 16:104535. [PMID: 40070853 PMCID: PMC11891553 DOI: 10.4331/wjbc.v16.i1.104535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 03/05/2025] Open
Abstract
Alcohol-associated liver disease (ALD) is a major global health concern, contributing to liver injury, morbidity, and mortality. Elafibranor (EFN), a dual peroxisome proliferator-activated receptor α/δ agonist, has shown promise as a therapeutic candidate in preclinical studies. EFN reduces liver fibrosis by inhibiting lipid accumulation, apoptosis, and inflammatory pathways (LPS/TLR4/NF-κB), while enhancing autophagy and antioxidant responses. It also improves intestinal barrier function and modulates gut microbiota, reducing endotoxin-producing bacteria and increasing beneficial species. By strengthening the intestinal barrier and suppressing pro-inflammatory mediators like tumor necrosis factor-alpha and interleukin-6, EFN mitigates hepatic stellate cell activation and fibrogenic signaling. Macrophages play a central role in ALD progression, and EFN's ability to modulate macrophage activity further highlights its anti-inflammatory properties. This review emphasizes EFN's dual-targeted approach, addressing both hepatic and intestinal dysfunctions, distinguishing it from conventional ALD treatments. While preclinical results are promising, EFN remains under clinical investigation, with ongoing trials evaluating its safety and efficacy. Future research should focus on elucidating EFN's molecular mechanisms and advancing its clinical application to establish its therapeutic potential in human populations. EFN represents a novel, comprehensive strategy for ALD management, targeting both liver and gut pathologies.
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Affiliation(s)
- Samira Farhadi
- Department of Biological Sciences and Chemistry, College of Arts and Sciences, University of Nizwa, Nizwa 616, Ad Dākhilīyah, Oman
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Ad Dākhilīyah, Oman
- Department of Agricultural Biotechnology, Faculty of Agricultural Sciences, University of Guilan, Rasht 4188958643, Gīlān, Iran
| | - Saeed Mohammadi
- Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Ad Dākhilīyah, Oman
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan 4934174515, Golestān, Iran
| | - Abdulaziz Y AlKindi
- Department of Biological Sciences and Chemistry, College of Arts and Sciences, University of Nizwa, Nizwa 616, Ad Dākhilīyah, Oman
| | - Issa S Al-Amri
- Department of Biological Sciences and Chemistry, College of Arts and Sciences, University of Nizwa, Nizwa 616, Ad Dākhilīyah, Oman
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Le XN, Long DP, Yin SS, Qing RY, Chi ZZ, Gao MQ, Zhu MQ. The efficient separation of bioactive components from Eucommia ulmoides Oliver using membrane filtration technology and its mechanisms in preventing alcoholic liver disease. Carbohydr Polym 2025; 351:123100. [PMID: 39779014 DOI: 10.1016/j.carbpol.2024.123100] [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: 07/03/2024] [Revised: 11/29/2024] [Accepted: 12/01/2024] [Indexed: 01/11/2025]
Abstract
The efficient extraction and purification of active components from Eucommia ulmoides Oliver (EUO) are crucial for their utilization. The structure and properties of the prepared EUO leaf polysaccharides (ELPs) and extractum (ELE) were comprehensively characterized in this study, and the intervention mechanism of the EUO polysaccharides and extractum in alcoholic liver disease (ALD) were investigated. The yield of EUO extractum was 24.82 %, from which nine active components were identified. The yield of EUO leaf polysaccharides was 8.06 %, and the polysaccharides were fractionated into three components ELP1, ELP2, and ELP3 through ultrafiltration technology, with yields of 4.19 %, 1.26 %, and 2.59 %, respectively. Ultrafiltration significantly reduced protein content, enhanced polysaccharide homogeneity, and altered monosaccharide composition. ELP3 exhibited higher scavenging efficacy on •OH and ABTS•+ than ELP1 and ELP2, reaching 82.53 % and 88.41 % respectively. ELP3 and ELE intervention preserved liver integrity, mitigated lipid accumulation and inflammation, and regulated hepatic oxidative stress. Moreover, they maintained intestinal barrier function, suppressed harmful bacteria (Escherichia-Shigella, and UBA1819), and promoted beneficial bacteria (Dubosiella, Monoglobus, and Lachnospiraceae). Thirteen hallmark differential metabolites were identified, and KEGG pathway enrichment analysis suggested that ELP3 and ELE may ameliorate ALD through pathways like longevity regulation, choline metabolism in cancer, oxidative phosphorylation, and AMPK signaling pathway. This investigation holds significance in delineating the beneficial effects of ELP3 and ELE in ALD alleviation.
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Affiliation(s)
- Xiao-Na Le
- College of Mechanical and Electronic Engineering, Northwest A&F University, Yangling 712100, China; Western Scientific Observation and Experiment Station for Development and Utilization of Rural Renewable Energy, M.O.A, Northwest Agriculture & Forestry University, Yangling 712100, China
| | - Da-Ping Long
- College of Forestry, Northwest A&F University, Yangling 712100, China; Western Scientific Observation and Experiment Station for Development and Utilization of Rural Renewable Energy, M.O.A, Northwest Agriculture & Forestry University, Yangling 712100, China
| | - Shuang-Shuang Yin
- College of Mechanical and Electronic Engineering, Northwest A&F University, Yangling 712100, China; Western Scientific Observation and Experiment Station for Development and Utilization of Rural Renewable Energy, M.O.A, Northwest Agriculture & Forestry University, Yangling 712100, China
| | - Ren-Yan Qing
- College of Chemistry and Pharmacy, Northwest A&F University, Yangling 712100, China; Western Scientific Observation and Experiment Station for Development and Utilization of Rural Renewable Energy, M.O.A, Northwest Agriculture & Forestry University, Yangling 712100, China
| | - Zhi-Zheng Chi
- College of Forestry, Northwest A&F University, Yangling 712100, China; Western Scientific Observation and Experiment Station for Development and Utilization of Rural Renewable Energy, M.O.A, Northwest Agriculture & Forestry University, Yangling 712100, China
| | - Ming-Qing Gao
- School of Medicine, Northwest University, Xi'an 710000, China.
| | - Ming-Qiang Zhu
- College of Mechanical and Electronic Engineering, Northwest A&F University, Yangling 712100, China; College of Forestry, Northwest A&F University, Yangling 712100, China; Western Scientific Observation and Experiment Station for Development and Utilization of Rural Renewable Energy, M.O.A, Northwest Agriculture & Forestry University, Yangling 712100, China.
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Deng W, Yang QN, Wu DT, Li J, Liu HY, Hu YC, Zou L, Gan RY, Yan HL, Huang JW. Comparison of Protective Effects of Polyphenol-Enriched Extracts from Thinned Immature Kiwifruits and Mature Kiwifruits against Alcoholic Liver Disease in Mice. Foods 2024; 13:3072. [PMID: 39410107 PMCID: PMC11475074 DOI: 10.3390/foods13193072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/20/2024] [Accepted: 09/24/2024] [Indexed: 10/20/2024] Open
Abstract
Alcoholic liver disease (ALD) is regarded as one of the main global health problems. Accumulated evidence indicates that fruit-derived polyphenols can lower the risk of ALD, this attributed to their strong antioxidant capacities. Thinned immature kiwifruits (TIK) are the major agro-byproducts in the production of kiwifruits, which have abundantly valuable polyphenols. However, knowledge about the protective effects of polyphenol-enriched extract from TIK against ALD is still lacking, which ultimately restricts their application as value-added functional products. To promote their potential applications, phenolic compounds from TIK and their corresponding mature fruits were compared, and their protective effects against ALD were studied in the present study. The findings revealed that TIK possessed extremely high levels of total phenolics (116.39 ± 1.51 mg GAE/g DW) and total flavonoids (33.88 ± 0.59 mg RE/g DW), which were about 7.4 times and 4.8 times greater than those of their corresponding mature fruits, respectively. Furthermore, the level of major phenolic components in TIK was measured to be 29,558.19 ± 1170.58 μg/g DW, which was about 5.4 times greater than that of mature fruits. In particular, neochlorogenic acid, epicatechin, procyanidin B1, and procyanidin B2 were found as the predominant polyphenols in TIK. In addition, TIK exerted stronger in vitro antioxidant and anti-inflammatory effects than those of mature fruits, which was probably because of their higher levels of polyphenols. Most importantly, compared with mature fruits, TIK exhibited superior hepatoprotective effects on alcohol-induced liver damage in mice. The administration of polyphenol-enriched extract from TIK (YK) could increase the body weight of mice, reduce the serum levels of ALP, AST, and ALT, lower the levels of hepatic TG and TC, and diminish lipid droplet accumulation and hepatic tissue damage. In addition, the treatment of YK could also significantly restore the levels of antioxidant enzymes (e.g., SOD and CAT) in the liver and lower the levels of hepatic proinflammatory cytokines (e.g., IL-6, IL-1β, and TNF-α), indicating that YK could effectively ameliorate ALD in mice by reducing hepatic oxidative stress and hepatic inflammation. Collectively, our findings can provide sufficient evidence for the development of TIK and their extracts as high value-added functional products for the intervention of ALD.
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Affiliation(s)
- Wen Deng
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
- Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Qian-Ni Yang
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
- Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Ding-Tao Wu
- Institute for Advanced Study, Chengdu University, Chengdu 610106, China
| | - Jie Li
- Research Center for Plants and Human Health, Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, National Agricultural Science and Technology Center, Chengdu 610213, China
| | - Hong-Yan Liu
- Research Center for Plants and Human Health, Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, National Agricultural Science and Technology Center, Chengdu 610213, China
| | - Yi-Chen Hu
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
| | - Ren-You Gan
- Department of Food Science and Nutrition, Faculty of Science, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Hui-Ling Yan
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
| | - Jing-Wei Huang
- Key Laboratory of Coarse Cereal Processing of Ministry of Agriculture and Rural Affairs, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, China
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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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Huang J, Huang T, Li J. Regulation Mechanism and Potential Value of Active Substances in Spices in Alcohol-Liver-Intestine Axis Health. Int J Mol Sci 2024; 25:3728. [PMID: 38612538 PMCID: PMC11011869 DOI: 10.3390/ijms25073728] [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: 01/23/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Excessive alcohol intake will aggravate the health risk between the liver and intestine and affect the multi-directional information exchange of metabolites between host cells and microbial communities. Because of the side effects of clinical drugs, people tend to explore the intervention value of natural drugs on diseases. As a flavor substance, spices have been proven to have medicinal value, but they are still rare in treating hepatointestinal diseases caused by alcohol. This paper summarized the metabolic transformation of alcohol in the liver and intestine and summarized the potential value of various perfume active substances in improving liver and intestine diseases caused by alcohol. It is also found that bioactive substances in spices can exert antioxidant activity in the liver and intestine environment and reduce the oxidative stress caused by diseases. These substances can interfere with fatty acid synthesis, promote sugar and lipid metabolism, and reduce liver injury caused by steatosis. They can effectively regulate the balance of intestinal flora, promote the production of SCFAs, and restore the intestinal microenvironment.
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Affiliation(s)
- Jianyu Huang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China;
- College of Food and Pharmaceutical Science, Ningbo University, Ningbo 315211, China
| | - Tao Huang
- College of Food and Pharmaceutical Science, Ningbo University, Ningbo 315211, China
| | - Jinjun Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China;
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Rao PL, Shen YH, Song YJ, Xu Y, Xu HX. Prunella vulgaris L. attenuates gut dysbiosis and endotoxin leakage against alcoholic liver disease. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117237. [PMID: 37769885 DOI: 10.1016/j.jep.2023.117237] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/14/2023] [Accepted: 09/26/2023] [Indexed: 10/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Prunella vulgaris L. (PVL) is a perennial herb belonging to the Labiate family, first recorded in the "Shen Nong's Classic of the Materia Medica". PVL can enter the liver and gallbladder channel to show its function in clearing the liver fire, dispersing nodules, dissolving swelling, and improving vision. The traditional use of PVL is to protect liver function and has clinical applications in liver diseases therapy. The modern pharmacological studies have been shown to possess potential hepatoprotection, but its underlying mechanisms against alcoholic liver disease (ALD) in mice remains to be elucidated. AIM OF THE STUDY This study aimed to explore the protective effect and potential mechanism of PVL on alcohol induced liver injury. MATERIALS AND METHODS We used Lieber-DeCarli ethanol liquid diet fed Male C57BL/6 mice for four weeks plus a single binge (NIAAA modified model) to establish an ALD model and explored the protective effects of PVL extract against ALD. Western blot, Flow cytometry and RT-qPCR methods were used to detect lipid metabolism disorders and the inflammatory response induced by macrophages in ALD mice, and the gut microbiota composition changes were detected by 16s rRNA to reveal the potential mechanism of PVL against ALD. RESULTS In ALD mice, PVL can ameliorate excessive alcohol intake-induced liver injury and lipid metabolism disorders associated with improvement of gut microbiota dysbiosis and intestinal barrier damage. PVL reduced the translocation of endotoxin, which subsequently inhibits hepatic inflammation mediated by the TLR4/MyD88 signaling pathway. CONCLUSION These findings demonstrated the protective potential of PVL against gut dysbiosis and endotoxin leakage in ALD mice, which provides a theoretical basis for PVL against liver diseases.
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Affiliation(s)
- Pei-Li Rao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yun-Hui Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China
| | - Yi-Jie Song
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China
| | - Yu Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, PR China.
| | - Hong-Xi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China.
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Yang Y, Liu S, Li H, Liu Y, Ren P, Liu Y, Liu S, Guan L. The protective effect of Nostoc commune Vauch. polysaccharide on alcohol-induced acute alcoholic liver disease and gut microbiota disturbance in mice. J Gastroenterol Hepatol 2023; 38:2185-2194. [PMID: 37731216 DOI: 10.1111/jgh.16335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 06/12/2023] [Accepted: 08/07/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND In recent years, the incidence of alcoholic liver disease (ALD) has gradually increased, the development of ALD is attached great attentions. Nostoc commune Vauch. polysaccharide (NCVP) is beneficial to maintain the gut health, but the protective effect of NCVP on the liver has not been reported yet. PURPOSE To study the protective effect and the underlying mechanisms of NCVP on ALD, a mouse model of acute ALD was established. STUDY DESIGN AND METHODS We built an acute ALD mouse model and explored the protective effect of NCVP through the detection of cytokines, histological examination, determination of short chain fatty acids, and 16S rRNA analysis of gut microbiota. RESULTS NCVP had hepatoprotective effects on acute alcohol-induced mice by improving antioxidant capacity, reducing oxidative stress and the serum cytokine levels (IL-1β, IL-6, and TNF-α). Simultaneously, histopathological changes in liver indicated that NCVP could inhibit local hepatocyte necrosis, cytoplasmic vacuolation and inflammatory cell infiltration induced by alcohol. NCVP also increased the level of total short-chain fatty acids of acute ALD mice. In addition, NCVP could significantly decrease the Firmicutes/Bacteroidetes ratio and the abundance of Patescibacteria, Helicobacter, and Actinomycetes and increase the abundance of Lachospiraceae, Prevotellaceae-UCG-003, Lactobacillaceae, and Desulfovibrio. CONCLUSION Our study proved that NCVP had in vivo hepatoprotective effect on acute ALD mice and provided scientific evidences that NCVP might be a promising drug candidate for the prevention and treatment of ALD.
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Affiliation(s)
- Yiting Yang
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin, China
| | - Su Liu
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin, China
| | - Hailong Li
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin, China
| | - Yue Liu
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin, China
| | - Ping Ren
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin, China
| | - Yingying Liu
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin, China
| | - Shuming Liu
- Key Laboratory for Research and Development of New Veterinary Drugs, Changchun, 130118, Jilin, China
| | - Lili Guan
- College of Life Sciences, Jilin Agricultural University, Changchun, 130118, Jilin, China
- Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, 130118, Jilin, China
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Tornai D, Mitchell M, McClain CJ, Dasarathy S, McCullough A, Radaeva S, Kroll-Desrosiers A, Lee J, Barton B, Szabo G. A novel score of IL-13 and age predicts 90-day mortality in severe alcohol-associated hepatitis: A multicenter plasma biomarker analysis. Hepatol Commun 2023; 7:e0296. [PMID: 37994498 PMCID: PMC10666984 DOI: 10.1097/hc9.0000000000000296] [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] [Received: 01/26/2023] [Accepted: 08/15/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Severe alcoholic hepatitis (AH) has a high short-term mortality rate. The MELD assesses disease severity and mortality; however, it is not specific for AH. We screened plasma samples from patients with severe AH for biomarkers of multiple pathological processes and identified predictors of short-term mortality. METHODS Plasma was collected at baseline from 85 patients with severe AH (MELD≥20, Maddrey's discriminant function≥32) enrolled in the Defeat Alcoholic Steatohepatitis clinical trial (investigating IL-1 receptor antagonist+pentoxifylline+zinc vs. methylprednisolone+placebo). Samples were analyzed for 43 biomarkers and the markers' association with 28- and 90-day mortalities was assessed. RESULTS Thirty-one (36.5%) patients died during the 90-day follow-up with similar ratios in the treatment groups. Eight biomarkers showed an association with mortality. IL-6, IL-22, interferon-α2, soluble TNF receptor 1, lipocalin-2, and α-fetoprotein levels were associated with 28-day mortality, while IL-6, IL-13, and endotoxin levels with 90-day mortality. In multivariable Cox regression, encephalopathy, lipocalin-2, and α-fetoprotein levels were independent predictors of 28-day mortality, and IL-6, IL-13, international normalized ratio levels, and age were independent predictors of 90-day mortality. The combination of IL-13 and age had superior performance in predicting 90-day mortality compared with MELD in the total cohort and the individual treatment groups. CONCLUSIONS We identified predictors of short-term mortality in a cohort exclusively involving patients with severe AH. We created a composite score of IL-13 and age that predicts 90-day mortality regardless of the treatment type with a performance superior to MELD in severe AH.
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Affiliation(s)
- David Tornai
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Mack Mitchell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Srinivasan Dasarathy
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Arthur McCullough
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
- Department of Inflammation and Immunity, Lerner Research Institute of the Cleveland Clinic, Cleveland, Ohio, USA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, Marylansd, USA
| | - Aimee Kroll-Desrosiers
- Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- VA Central Western Massachusetts Healthcare System, Leeds, Massachusetts, USA
| | - JungAe Lee
- Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Bruce Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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11
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Zheng J, Li Z, Xu H. Intestinal Microbiotas and Alcoholic Hepatitis: Pathogenesis and Therapeutic Value. Int J Mol Sci 2023; 24:14809. [PMID: 37834256 PMCID: PMC10573193 DOI: 10.3390/ijms241914809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/21/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several underlying mechanisms that contribute to the development of AH, including metabolic alterations, immune stimulation, and intestinal dysbiosis. These pathological changes intricately intertwine during the progression of AH. Notably, recent studies have increasingly highlighted the pivotal role of alterations in the intestinal microbiota in the pathogenesis of AH. Consequently, future investigations should place significant emphasis on exploring the dynamics of intestinal microbiota. In this comprehensive review, we consolidate the primary causes of AH while underscoring the influence of gut microbes. Furthermore, by examining AH treatment strategies, we delineate the potential therapeutic value of interventions targeting the gut microbiota. Given the existing limitations in AH treatment options, we anticipate that this review will contribute to forthcoming research endeavors aimed at advancing AH treatment modalities.
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Affiliation(s)
- Jiazhen Zheng
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; (J.Z.); (Z.L.)
| | - Ziyi Li
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; (J.Z.); (Z.L.)
| | - Hengyi Xu
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, China
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12
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Yang K, Song M. New Insights into the Pathogenesis of Metabolic-Associated Fatty Liver Disease (MAFLD): Gut-Liver-Heart Crosstalk. Nutrients 2023; 15:3970. [PMID: 37764755 PMCID: PMC10534946 DOI: 10.3390/nu15183970] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/11/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Metabolism-associated fatty liver disease (MAFLD) is a multifaceted disease that involves complex interactions between various organs, including the gut and heart. It is defined by hepatic lipid accumulation and is related to metabolic dysfunction, obesity, and diabetes. Understanding the intricate interplay of the gut-liver-heart crosstalk is crucial for unraveling the complexities of MAFLD and developing effective treatment and prevention strategies. The gut-liver crosstalk participates in the regulation of the metabolic and inflammatory processes through host-microbiome interactions. Gut microbiota have been associated with the development and progression of MAFLD, and its dysbiosis contributes to insulin resistance, inflammation, and oxidative stress. Metabolites derived from the gut microbiota enter the systemic circulation and influence both the liver and heart, resulting in the gut-liver-heart axis playing an important role in MAFLD. Furthermore, growing evidence suggests that insulin resistance, endothelial dysfunction, and systemic inflammation in MAFLD may contribute to an increased risk of cardiovascular disease (CVD). Additionally, the dysregulation of lipid metabolism in MAFLD may also lead to cardiac dysfunction and heart failure. Overall, the crosstalk between the liver and heart involves a complex interplay of molecular pathways that contribute to the development of CVD in patients with MAFLD. This review emphasizes the current understanding of the gut-liver-heart crosstalk as a foundation for optimizing patient outcomes with MAFLD.
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Affiliation(s)
| | - Myeongjun Song
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
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13
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Babu G, Mohanty B. Neurotensin modulation of lipopolysaccharide induced inflammation of gut-liver axis: Evaluation using neurotensin receptor agonist and antagonist. Neuropeptides 2023; 97:102297. [PMID: 36368076 DOI: 10.1016/j.npep.2022.102297] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 10/13/2022] [Accepted: 10/16/2022] [Indexed: 11/07/2022]
Abstract
Lipopolysaccharide (LPS), a toxic component of the cell wall of Gram-negative bacteria, is a potent immune stressor. LPS-induced inflammation of the gut-liver axis is well demonstrated. Neurotensin (NTS), a tri-decapeptide present in the gastrointestinal tract, has anti-inflammatory, anti-oxidative, and growth-promoting properties. This study elucidated the efficacy of PD149163, the type I NTS receptor agonist (NTS1) in the modulation of LPS-induced inflammation of the gut-liver axis of mice. Young-adult female mice (Age: 8 weeks; BW: 25 ± 2.5 g) were maintained in six groups (6/group); Group I as control and Group II, III & IV were exposed to LPS (1 mg/kg BW/Day; i.p.) for five days. LPS pre-exposed Group III and Group IV mice were treated with NTS1 agonist PD149163 (100 μg/kg BW i.p.) and antagonist SR48692 (0.5 mg/kg BW i.p.) respectively for 28 days. Group V and Group VI mice were exposed to only PD149163 and only SR48692 respectively with the doses as mentioned above for 28 days. Group I and LPS-exposed Group II mice were also maintained four weeks without further treatment. Histopathology revealed LPS-induced inflammation of the gut and liver. Significant elevation of plasma TNF-α and IL-6 and serum ALT and AST reflected as biomarkers of inflammation. Oxidative stress on both organs was distinct from decreased glutathione reductase and increased lipid peroxidation. PD149163 but not SR48692 ameliorated LPS-induced inflammation in both gut and liver counteracting inflammatory responses and oxidative stress. The use of NTS agonists including PD149163 could be exploited for therapeutic intervention of inflammatory diseases including that of the gut-liver axis.
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Affiliation(s)
- Gyan Babu
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh 211002, India
| | - Banalata Mohanty
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh 211002, India.
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14
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Thakral N, Deutsch-Link S, Singal AK. Therapeutic Pipeline in Alcohol-Associated Liver Disease. Semin Liver Dis 2023; 43:60-76. [PMID: 36572032 PMCID: PMC11503467 DOI: 10.1055/s-0042-1759614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.
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Affiliation(s)
- Nimish Thakral
- Division of Gastroenterology and Hepatology, University of Kentucky, Lexington, Kentucky
| | - Sasha Deutsch-Link
- Department of Medicine, University of North Carolina at Chapel Hill, North Carolina
| | - Ashwani K. Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
- Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota
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15
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Zogona D, Zongo AWS, Elkhedir AE, Salah M, Tao M, Li R, Wu T, Xu X. Red raspberry supplementation mitigates alcohol-induced liver injury associated with gut microbiota alteration and intestinal barrier dysfunction in mice. Food Funct 2023; 14:1209-1226. [PMID: 36602148 DOI: 10.1039/d2fo03245g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Alcoholic liver disease (ALD) is still a global health concern. Long-term alcohol intake alters the gut microbiota diversity and metabolic activity, and causes intestinal barrier dysfunction, leading to the development of ALD. This research explored the protective effects and underlying mechanisms of red raspberry (RR) on alcohol-related disorders in mice. Male C57BL/6J mice were fed a standard diet or a standard diet supplemented with 2%, 4%, and 8% weight/weight RR. Meanwhile, mice were administered 35% (v/v) ethanol (EtOH, 10 mL per kg body weight) intragastrically once daily for six weeks, except the control group mice. The results showed that RR supplementation decreased liver injury markers (alanine and aspartate transaminases) in the serum, reduced triglyceride level in the liver and downregulated hepatic cytochrome P450 2E1 mRNA expression in mice administered EtOH. In addition, EtOH-mediated oxidative stress in the liver was attenuated by RR supplementation through decreased hepatic malondialdehyde content and increased antioxidant (glutathione, glutathione peroxidase, and catalase) levels and activities in mice exposed to EtOH. Moreover, RR supplementation reversed EtOH-induced alteration in the cecal microbial composition at the phylum, order, genus, and species levels and improved the intestinal barrier function associated with the inhibition of the NF-κB/MLCK pathway, which was accompanied by upregulation of tight junctions (zonula occludens 1, occludin, claudin-1, and claudin-4) and E-cadherin mRNA and protein expressions. Accordingly, RR supplementation resulted in a decreased level of endotoxins in the serum and attenuation of the inflammatory response in the liver, illustrated by a significant decrease in tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6 levels. Overall, RR supplementation alleviated the adverse effects of chronic alcohol intake in C57BL/6J mice and could be a potential supplement for improving ALD.
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Affiliation(s)
- Daniel Zogona
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Center for Research in Biological Sciences, Food and Nutrition, Department of Biochemistry and Microbiology, University Joseph Ki-Zerbo, BP 7021 Ouagadougou 03, Burkina Faso
| | - Abel Wend-Soo Zongo
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Center for Research in Biological Sciences, Food and Nutrition, Department of Biochemistry and Microbiology, University Joseph Ki-Zerbo, BP 7021 Ouagadougou 03, Burkina Faso
| | - Abdeen E Elkhedir
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Mahmoud Salah
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China. .,Department of Environmental Agricultural Science, Faculty of Graduate Studies and Environmental Research, Ain Shams University, Cairo 11566, Egypt
| | - Mingfang Tao
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Rong Li
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Ting Wu
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
| | - Xiaoyun Xu
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit & Vegetable Processing & Quality Control (Huazhong Agricultural University), College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
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16
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Hou S, Wang D, Yuan X, Yuan X, Yuan Q. Identification of biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis in alcoholic hepatitis by bioinformatics and experimental verification. Front Immunol 2023; 14:1146693. [PMID: 37090703 PMCID: PMC10117880 DOI: 10.3389/fimmu.2023.1146693] [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: 01/17/2023] [Accepted: 03/30/2023] [Indexed: 04/25/2023] Open
Abstract
Backgrounds Alcoholic hepatitis (AH) is a major health problem worldwide. There is increasing evidence that immune cells, iron metabolism and copper metabolism play important roles in the development of AH. We aimed to explore biomarkers that are co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients. Methods GSE28619 and GSE103580 datasets were integrated, CIBERSORT algorithm was used to analyze the infiltration of 22 types of immune cells and GSVA algorithm was used to calculate ferroptosis and cuproptosis scores. Using the "WGCNA" R package, we established a gene co-expression network and analyzed the correlation between M1 macrophages, ferroptosis and cuproptosis scores and module characteristic genes. Subsequently, candidate genes were screened by WGCNA and differential expression gene analysis. The LASSO-SVM analysis was used to identify biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis. Finally, we validated these potential biomarkers using GEO datasets (GSE155907, GSE142530 and GSE97234) and a mouse model of AH. Results The infiltration level of M1 macrophages was significantly increased in AH patients. Ferroptosis and cuproptosis scores were also increased in AH patients. In addition, M1 macrophages, ferroptosis and cuproptosis were positively correlated with each other. Combining bioinformatics analysis with a mouse model of AH, we found that ALDOA, COL3A1, LUM, THBS2 and TIMP1 may be potential biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients. Conclusion We identified 5 potential biomarkers that are promising new targets for the treatment and diagnosis of AH patients.
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Affiliation(s)
- Shasha Hou
- Department of Life Science and Engineering, Jining University, Jining, China
| | - Dan Wang
- College of Life Science, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaxia Yuan
- Department of Life Science and Engineering, Jining University, Jining, China
| | - Xiaohuan Yuan
- College of Life Science, Mudanjiang Medical University, Mudanjiang, China
| | - Qi Yuan
- College of Life Science, Mudanjiang Medical University, Mudanjiang, China
- *Correspondence: Qi Yuan,
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17
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Ding Q, Zhang G, Wang Y, Xu L, Wu M, Zhou Y, Xu T, Meng X, Huang C, Zhang L. β-catenin ISGylation promotes lipid deposition and apoptosis in ethanol-stimulated liver injury models. Redox Rep 2022; 27:239-248. [PMID: 36259544 PMCID: PMC9586657 DOI: 10.1080/13510002.2022.2109360] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Background The restoration of the Wnt/β-catenin pathway to alleviate alcoholic fatty liver disease (AFLD) progression is under study as a new strategy for alcoholic liver disease (ALD) treatment. Recent studies have indicated that interferon-stimulated gene 15 (ISG15) can covalently bind to β-catenin by HECT E3 ubiquitin ligase 5 (HERC5), leading to ISG degradation and downregulation of β-catenin levels. However, the relationship between β-catenin and the ISG15 system in AFLD remains unclear. Methods Here, we explored the roles of the ISG15 system in β-catenin activation and in the pathogenesis of alcohol-induced liver injury and steatosis. Results In this study, HERC5 silencing upregulated β-catenin protein expression and inhibited lipid metabolism disorders and cell apoptosis. Reduced β-catenin protein expression, increased lipid metabolism disorders, and cell apoptosis were detected in cells induced with HERC5 overexpression, which was reversible with the reactive oxygen species (ROS) inhibitor. All the above results were statistically analyzed. Thus, these observations demonstrate that β-catenin ISGylation is a prominent regulator of ALD pathology, which works by regulating ROS to induce lipid metabolism disorders and cell apoptosis. Conclusion Our findings provided the mechanism involved in the β-catenin ISGylation, allowing for future studies on the prevention or amelioration of liver injury in ALD.
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Affiliation(s)
- Qi Ding
- Anhui No.2 Provincial People's Hospital, Hefei, People's Republic of China
| | - Guodong Zhang
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Yang Wang
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Lei Xu
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Meifei Wu
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Yiwen Zhou
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Tao Xu
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Xiaoming Meng
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,Key Laboratory of major autoimmune disease, Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, People's Republic of China.,The Key Laboratory of Anti-inflammatory and Immune medicines, Ministry of Education, Anhui Medical University, Hefei, People's Republic of China
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18
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Qin D, Ma Y, Wang Y, Hou X, Yu L. Contribution of Lactobacilli on Intestinal Mucosal Barrier and Diseases: Perspectives and Challenges of Lactobacillus casei. LIFE (BASEL, SWITZERLAND) 2022; 12:life12111910. [PMID: 36431045 PMCID: PMC9696601 DOI: 10.3390/life12111910] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022]
Abstract
The intestine barrier, the front line of normal body defense, relies on its structural integrity, microbial composition and barrier immunity. The intestinal mucosal surface is continuously exposed to a complex and dynamic community of microorganisms. Although it occupies a relatively small proportion of the intestinal microbiota, Lactobacilli has been discovered to have a significant impact on the intestine tract in previous studies. It is undeniable that some Lactobacillus strains present probiotic properties through maintaining the micro-ecological balance via different mechanisms, such as mucosal barrier function and barrier immunity, to prevent infection and even to solve some neurology issues by microbiota-gut-brain/liver/lung axis communication. Notably, not only living cells but also Lactobacillus derivatives (postbiotics: soluble secreted products and para-probiotics: cell structural components) may exert antipathogenic effects and beneficial functions for the gut mucosal barrier. However, substantial research on specific effects, safety and action mechanisms in vivo should be done. In clinical application of humans and animals, there are still doubts about the precise evaluation of Lactobacilli's safety, therapeutic effect, dosage and other aspects. Therefore, we provide an overview of central issues on the impacts of Lactobacillus casei (L. casei) and their products on the intestinal mucosal barrier and some diseases and highlight the urgent need for further studies.
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Affiliation(s)
- Da Qin
- Heilongjiang Provincial Key Laboratory of Environmental Microbiology and Recycling of Argo-Waste in Cold Region, College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yixuan Ma
- Heilongjiang Provincial Key Laboratory of Environmental Microbiology and Recycling of Argo-Waste in Cold Region, College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yanhong Wang
- Heilongjiang Provincial Key Laboratory of Environmental Microbiology and Recycling of Argo-Waste in Cold Region, College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Xilin Hou
- Colleges of Animal Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
- Correspondence: (X.H.); (L.Y.); Tel.: +86-4596-819-290 (X.H. & L.Y.); Fax: +86-4596-819-292 (X.H. & L.Y.)
| | - Liyun Yu
- Heilongjiang Provincial Key Laboratory of Environmental Microbiology and Recycling of Argo-Waste in Cold Region, College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
- Colleges of Animal Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
- Correspondence: (X.H.); (L.Y.); Tel.: +86-4596-819-290 (X.H. & L.Y.); Fax: +86-4596-819-292 (X.H. & L.Y.)
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19
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Samuvel DJ, Li L, Krishnasamy Y, Gooz M, Takemoto K, Woster PM, Lemasters JJ, Zhong Z. Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice. Autophagy 2022; 18:2671-2685. [PMID: 35293288 PMCID: PMC9629059 DOI: 10.1080/15548627.2022.2046457] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/15/2022] Open
Abstract
Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In Type 2, mitochondrial depolarization (mtDepo) initiates mitophagy to remove the damaged organelles. Previously, we showed that acute ethanol administration produces reversible hepatic mtDepo. Here, we tested the hypothesis that ethanol-induced mtDepo initiates Type 2 mitophagy. GFP-LC3 transgenic mice were gavaged with ethanol (2-6 g/kg) with and without pre-treatment with agents that decrease or increase mtDepo-Alda-1, tacrolimus, or disulfiram. Without ethanol, virtually all hepatocytes contained polarized mitochondria with infrequent autophagic GFP-LC3 puncta visualized by intravital microscopy. At ~4 h after ethanol treatment, mtDepo occurred in an all-or-none fashion within individual hepatocytes, which increased dose dependently. GFP-LC3 puncta increased in parallel, predominantly in hepatocytes with mtDepo. Mitochondrial PINK1 and PRKN/parkin also increased. After covalent labeling of mitochondria with MitoTracker Red (MTR), GFP-LC3 puncta encircled MTR-labeled mitochondria after ethanol treatment, directly demonstrating mitophagy. GFP-LC3 puncta did not associate with fat droplets visualized with BODIPY558/568, indicating that increased autophagy was not due to lipophagy. Before ethanol administration, rhodamine-dextran (RhDex)-labeled lysosomes showed little association with GFP-LC3. After ethanol treatment, TFEB (transcription factor EB) translocated to nuclei, and lysosomal mass increased. Many GFP-LC3 puncta merged with RhDex-labeled lysosomes, showing autophagosomal processing into lysosomes. After ethanol treatment, disulfiram increased, whereas Alda-1 and tacrolimus decreased mtDepo, and mitophagy changed proportionately. In conclusion, mtDepo after acute ethanol treatment induces mitophagic sequestration and subsequent lysosomal processing.Abbreviations : AcAld, acetaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ALD, alcoholic liver disease; Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LMNB1, lamin B1; MAA, malondialdehyde-acetaldehyde adducts; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MPT, mitochondrial permeability transition; mtDAMPS, mitochondrial damage-associated molecular patterns; mtDepo, mitochondrial depolarization; mtDNA, mitochondrial DNA; MTR, MitoTracker Red; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PRKN, parkin; RhDex, rhodamine dextran; TFEB, transcription factor EB; Tg, transgenic; TMRM, tetramethylrhodamine methylester; TOMM20, translocase of outer mitochondrial membrane 20; VDAC, voltage-dependent anion channel.
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Affiliation(s)
- Devadoss J. Samuvel
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Li Li
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Yasodha Krishnasamy
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Monika Gooz
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Kenji Takemoto
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - Patrick M. Woster
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
| | - John J. Lemasters
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Zhi Zhong
- Departments of Drug Discovery & Biomedical Science, Medical University of South Carolin, Charleston, SC, USA
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20
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Zhang H, Zuo Y, Zhao H, Zhao H, Wang Y, Zhang X, Zhang J, Wang P, Sun L, Zhang H, Liang H. Folic acid ameliorates alcohol-induced liver injury via gut–liver axis homeostasis. Front Nutr 2022; 9:989311. [PMID: 36337656 PMCID: PMC9632181 DOI: 10.3389/fnut.2022.989311] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/28/2022] [Indexed: 11/23/2022] Open
Abstract
The gut–liver axis (GLA) plays an important role in the development of alcohol-induced liver injury. Alcohol consumption is typically associated with folic acid deficiency. However, no clear evidence has confirmed the effect of folic acid supplementation on alcohol-induced liver injury via GLA homeostasis. In this study, male C57BL/6J mice were given 56% (v/v) ethanol and 5.0 mg/kg folic acid daily by gavage for 10 weeks to investigate potential protective mechanisms of folic acid in alcohol-induced liver injury via GLA homeostasis. Histopathological and biochemical analyses showed that folic acid improved lipid deposition and inflammation in the liver caused by alcohol consumption and decreased the level of ALT, AST, TG, and LPS in serum. Folic acid inhibited the expression of the TLR4 signaling pathway and its downstream inflammatory mediators in the liver and upregulated the expression of ZO-1, claudin 1, and occludin in the intestine. But compared with the CON group, folic acid did not completely eliminate alcohol-induced intestine and liver injury. Furthermore, folic acid regulated alcohol-induced alterations in gut microbiota. In alcohol-exposed mice, the relative abundance of Bacteroidota was significantly increased, and the relative abundance of unclassified_Lachnospiraceae was significantly decreased. Folic acid supplementation significantly increased the relative abundance of Verrucomicrobia, Lachnospiraceae_NK4A136_group and Akkermansia, and decreased the relative abundance of Proteobacteria. The results of Spearman’s correlation analysis showed that serum parameters and hepatic inflammatory cytokines were significantly correlated with several bacteria, mainly including Bacteroidota, Firmicutes, and unclassified_Lachnospiraceae. In conclusion, folic acid could ameliorate alcohol-induced liver injury in mice via GLA homeostasis to some extent, providing a new idea and method for prevention of alcohol-induced liver injury.
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Affiliation(s)
- Huaqi Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Yuwei Zuo
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Huichao Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Hui Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Yutong Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Xinyu Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Jiacheng Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Peng Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Lirui Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
| | - Huizhen Zhang
- Qingdao Institute for Food and Drug Control, Qingdao, China
| | - Hui Liang
- Department of Nutrition and Food Hygiene, School of Public Health, Qingdao University, Qingdao, China
- *Correspondence: Hui Liang,
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21
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Wolstenholme JT, Saunders JM, Smith M, Kang JD, Hylemon PB, González-Maeso J, Fagan A, Zhao D, Sikaroodi M, Herzog J, Shamsaddini A, Peña-Rodríguez M, Su L, Tai YL, Zheng J, Cheng PC, Sartor RB, Gillevet PM, Zhou H, Bajaj JS. Reduced alcohol preference and intake after fecal transplant in patients with alcohol use disorder is transmissible to germ-free mice. Nat Commun 2022; 13:6198. [PMID: 36261423 PMCID: PMC9581985 DOI: 10.1038/s41467-022-34054-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 10/07/2022] [Indexed: 01/11/2023] Open
Abstract
Alcohol use disorder is a major cause of morbidity, which requires newer treatment approaches. We previously showed in a randomized clinical trial that alcohol craving and consumption reduces after fecal transplantation. Here, to determine if this could be transmitted through microbial transfer, germ-free male C57BL/6 mice received stool or sterile supernatants collected from the trial participants pre-/post-fecal transplant. We found that mice colonized with post-fecal transplant stool but not supernatants reduced ethanol acceptance, intake and preference versus pre-fecal transplant colonized mice. Microbial taxa that were higher in post-fecal transplant humans were also associated with lower murine alcohol intake and preference. A majority of the differentially expressed genes (immune response, inflammation, oxidative stress response, and epithelial cell proliferation) occurred in the intestine rather than the liver and prefrontal cortex. These findings suggest a potential for therapeutically targeting gut microbiota and the microbial-intestinal interface to alter gut-liver-brain axis and reduce alcohol consumption in humans.
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Affiliation(s)
- Jennifer T Wolstenholme
- VCU-Alcohol Research Center and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Justin M Saunders
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Maren Smith
- VCU-Alcohol Research Center and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jason D Kang
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Phillip B Hylemon
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Javier González-Maeso
- Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA
| | - Andrew Fagan
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, VA, USA
| | - Derrick Zhao
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Jeremy Herzog
- National Gnotobiotic Rodent Research Center, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Marcela Peña-Rodríguez
- University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Lianyong Su
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Yun-Ling Tai
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jing Zheng
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Po-Cheng Cheng
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - R Balfour Sartor
- National Gnotobiotic Rodent Research Center, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Huiping Zhou
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and Richmond VA Medical Center, Richmond, VA, USA.
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22
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Sasaki-Tanaka R, Ray R, Moriyama M, Ray RB, Kanda T. Molecular Changes in Relation to Alcohol Consumption and Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23179679. [PMID: 36077080 PMCID: PMC9456124 DOI: 10.3390/ijms23179679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.
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Affiliation(s)
- Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
| | - Ranjit Ray
- Departments of Internal Medicine, and Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Ratna B. Ray
- Department of Pathology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
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23
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Hepatoprotective Mechanism of Ginsenoside Rg1 against Alcoholic Liver Damage Based on Gut Microbiota and Network Pharmacology. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5025237. [PMID: 36052161 PMCID: PMC9427247 DOI: 10.1155/2022/5025237] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 06/30/2022] [Accepted: 07/18/2022] [Indexed: 11/18/2022]
Abstract
Alcoholic liver disease (ALD) is a major public health problem worldwide, which needs to be effective prevention. Ginsenoside Rg1 (GRg1), a bioactive ingredient extracted from ginseng, has benefit effects on health. In this study, 11 potential targets of GRg1 against ALD were firstly obtained by network pharmacology. KEGG pathway enrichment showed that GRg1-target-ALD was closely related to Toll-like receptor (TLR) and nuclear factor-kappa B (NF-κB) signaling pathways. In addition, GRg1 decreased antioxidant levels and increased oxidative levels in alcohol-treated mice, which alleviated oxidative stress-induced hepatic damage. GRg1 enhanced intestinal barrier function via upregulating the levels of tight junction protein and immunoglobulin A. GRg1 also reduced alcohol-induced inflammation by suppressing TLR4/NF-κB pathway, which was consistent with the prediction of network targets. Moreover, GRg1 altered GM population, and Verrucomicrobia, Bacteroidetes, Akkermansia, Bacteroides, Lachnospiraceae_NK4A136_group, and Alloprevotella played positive association with intestinal barrier indicators and negative correlation with hepatic inflammation biomarkers. The results suggest that GRg1 administration might be a promising strategy for protection of alcohol-induced liver damage.
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24
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Das S, Song Z, Han H, Ge X, Desert R, Athavale D, Babu Komakula SS, Magdaleno F, Chen W, Lantvit D, Guzman G, Nieto N. Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function. Cell Mol Gastroenterol Hepatol 2022; 14:813-839. [PMID: 35811073 PMCID: PMC9425038 DOI: 10.1016/j.jcmgh.2022.06.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/30/2022] [Accepted: 06/30/2022] [Indexed: 12/10/2022]
Abstract
BACKGROUND & AIMS The gut-liver axis plays a key role in the pathogenesis of alcohol-associated liver disease (ALD). We demonstrated that Opn-/- develop worse ALD than wild-type (WT) mice; however, the role of intestinal osteopontin (OPN) in ALD remains unknown. We hypothesized that overexpression of OPN in intestinal epithelial cells (IECs) could ameliorate ALD by preserving the gut microbiome and the intestinal barrier function. METHODS OpnKI IEC, OpnΔIEC, and WT mice were fed control or ethanol Lieber-DeCarli diet for 6 weeks. RESULTS OpnKI IEC but not OpnΔIEC mice showed improved intestinal barrier function and protection from ALD. There were less pathogenic and more beneficial bacteria in ethanol-fed OpnKI IEC than in WT mice. Fecal microbiome transplant (FMT) from OpnKI IEC to WT mice protected from ALD. FMT from ethanol-fed WT to OpnKI IEC mice failed to induce ALD. Antimicrobial peptides, Il33, pSTAT3, aryl hydrocarbon receptor (Ahr), and tight-junction protein expression were higher in IECs from jejunum of ethanol-fed OpnKI IEC than of WT mice. Ethanol-fed OpnKI IEC showed more tryptophan metabolites and short-chain fatty acids in portal serum than WT mice. FMT from OpnKI IEC to WT mice enhanced IECs Ahr and tight-junction protein expression. Oral administration of milk OPN replicated the protective effect of OpnKI IEC mice in ALD. CONCLUSION Overexpression of OPN in IECs or administration of milk OPN maintain the intestinal microbiome by intestinal antimicrobial peptides. The increase in tryptophan metabolites and short-chain fatty acids signaling through the Ahr in IECs, preserve the intestinal barrier function and protect from ALD.
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Affiliation(s)
- Sukanta Das
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Zhuolun Song
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Hui Han
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Xiaodong Ge
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Romain Desert
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Dipti Athavale
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | | | - Fernando Magdaleno
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Wei Chen
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Daniel Lantvit
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Natalia Nieto
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois; Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, Illinois; Research Biologist, Research & Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.
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25
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In-depth investigation of the mechanisms of Echinacea purpurea polysaccharide mitigating alcoholic liver injury in mice via gut microbiota informatics and liver metabolomics. Int J Biol Macromol 2022; 209:1327-1338. [PMID: 35461865 DOI: 10.1016/j.ijbiomac.2022.04.131] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/12/2022] [Accepted: 04/17/2022] [Indexed: 12/12/2022]
Abstract
Accumulating evidence suggests that the pathogenesis of alcoholic liver disease (ALD) is strongly correlated with abnormalities of the gut-liver axis. Echinacea purpurea polysaccharide (EPP) is a homogeneous polysaccharide, which has been shown to mitigate ALD. However, the effects of EPP on gut microbiome and consequently on hepatic metabolism have yet to be explored. In this study, the microbiome and metabolomics were combined to explore the effects of EPP on gut microbiota and hepatic metabolism, and the relationship between both was further revealed by Spearman correlation analysis. Results exhibited EPP reversed alcohol-induced disturbances in gut microbiota, evidenced by increased abundance of Muribaculaceae, Lactobacillus, and Bacteroides and decreased abundance of Escherichia_Shigella and Enterococcus. Besides, EPP promoted the production of n-butyric acid, a short-chain fatty acid that maintains the integrity of the intestinal barrier. Moreover, EPP improved alterations in hepatic metabolites, and characteristic metabolites such as Berberine and Ponasterone as well as key metabolic pathways, particularly Nitrogen metabolism, were identified. Furthermore, correlation analysis suggested significant associations between gut microbes and hepatic metabolites, which in turn confirmed EPP alleviated ALD via the gut-liver axis. Therefore, these findings elucidated in-depth mechanisms of EPP against ALD and provided a new target for intervention in alcohol-related diseases.
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26
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Habash NW, Sehrawat TS, Shah VH, Cao S. Epigenetics of alcohol-related liver diseases. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100466. [PMID: 35462859 PMCID: PMC9018389 DOI: 10.1016/j.jhepr.2022.100466] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/14/2022] [Accepted: 02/22/2022] [Indexed: 02/07/2023]
Abstract
Alcohol-related liver disease (ARLD) is a primary cause of chronic liver disease in the United States. Despite advances in the diagnosis and management of ARLD, it remains a major public health problem associated with significant morbidity and mortality, emphasising the need to adopt novel approaches to the study of ARLD and its complications. Epigenetic changes are increasingly being recognised as contributing to the pathogenesis of multiple disease states. Harnessing the power of innovative technologies for the study of epigenetics (e.g., next-generation sequencing, DNA methylation assays, histone modification profiling and computational techniques like machine learning) has resulted in a seismic shift in our understanding of the pathophysiology of ARLD. Knowledge of these techniques and advances is of paramount importance for the practicing hepatologist and researchers alike. Accordingly, in this review article we will summarise the current knowledge about alcohol-induced epigenetic alterations in the context of ARLD, including but not limited to, DNA hyper/hypo methylation, histone modifications, changes in non-coding RNA, 3D chromatin architecture and enhancer-promoter interactions. Additionally, we will discuss the state-of-the-art techniques used in the study of ARLD (e.g. single-cell sequencing). We will also highlight the epigenetic regulation of chemokines and their proinflammatory role in the context of ARLD. Lastly, we will examine the clinical applications of epigenetics in the diagnosis and management of ARLD.
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Key Words
- 3C, chromosome conformation capture
- 4C, chromosome conformation capture-on-chip
- AH, alcohol-related hepatitis
- ARLD, alcohol-related liver disease
- ASH, alcohol-related steatohepatitis
- ATAC, assay for transposase-accessible chromatin
- Acetylation
- Alcohol liver disease
- BET, bromodomain and extraterminal motif
- BETi, BET inhibitor
- BRD, bromodomain
- CCL2, C-C motif chemokine ligand 2
- CTCF, CCCTC-binding factor
- CXCL, C-X-C motif chemokine ligand
- Chromatin architecture
- Computational biology
- DNA methylation
- DNMT, DNA methyltransferase
- E-P, enhancer-promoter
- Epidrugs
- Epigenetics
- FKBP5, FK506-binding protein 5
- HCC, hepatocellular carcinoma
- HDAC, histone deacetylase
- HIF1α, hypoxia inducible factor-1α
- HMGB1, high-mobility group box protein 1
- HNF4α, hepatocyte nuclear factor 4α
- HSC, hepatic stellate cell
- Hi-C, chromosome capture followed by high-throughput sequencing
- Histones
- IL, interleukin
- LPS, lipopolysaccharide
- MALAT1, metastasis-associated lung adenocarcinoma transcript 1
- MECP2, methyl-CpG binding protein 2
- NAFLD, non-alcohol-related fatty liver disease
- PPARG, peroxisome proliferator activated receptor-γ
- SAA, salvianolic acid A
- SIRT, sirtuin
- SREBPs, sterol regulatory element-binding proteins
- Single cell epigenome
- TAD, topologically associating domain
- TEAD, TEA domain transcription factor
- TLR, Toll-like receptor
- TNF, tumour necrosis factor
- YAP, Yes-associated protein
- lncRNA, long non-coding RNA
- miRNA, microRNA
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Affiliation(s)
| | | | - Vijay H. Shah
- Corresponding authors. Address: Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Tel. 507-255-6028, fax: 507-255-6318.
| | - Sheng Cao
- Corresponding authors. Address: Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Tel. 507-255-6028, fax: 507-255-6318.
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27
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Trebicka J, Louvet A, Arroyo V, Jalan R, Shah VH, Moreau R. Severe alcoholic hepatitis as precipitant for organ failure and ACLF. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:67-76. [PMID: 35042255 DOI: 10.1055/a-1713-3796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Alcoholic hepatitis is the acute deterioration of alcoholic liver disease with rapid onset or worsening of jaundice, which in severe cases, may transition to acute-on-chronic liver failure with extremely high short-term mortality, increasing with the number and severity of hepatic and extra-hepatic organ dysfunction. Diagnosis and treatment are insufficient and challenging, especially due to the complex, multi-factorial and as yet not fully understood pathogenesis. While current management is limited to steroids and best supportive care, debate is ongoing concerning liver transplantation for selected patients, and several novel approaches are under way with mixed results. These drawbacks in disease management together with increasing prevalence in Germany, and generally in Western countries, constitute an unmet need for the healthcare systems. This review tries to summarize the current status of these aspects and provides an overview for pathogenesis, management and potential future treatments.
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Affiliation(s)
- Jonel Trebicka
- Medizinische Klinik 1, University of Frankfurt, Frankfurt am Main, Germany
| | | | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Rajiv Jalan
- University College London, London, United Kingdom of Great Britain and Northern Ireland
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28
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Mainz RE, Albers S, Haque M, Sonntag R, Treichel NS, Clavel T, Latz E, Schneider KM, Trautwein C, Otto T. NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease. Cells 2022; 11:182. [PMID: 35053298 PMCID: PMC8773606 DOI: 10.3390/cells11020182] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/20/2021] [Accepted: 12/26/2021] [Indexed: 02/04/2023] Open
Abstract
A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.
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Affiliation(s)
- Rebecca Elena Mainz
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (R.E.M.); (S.A.); (M.H.); (R.S.); (K.M.S.)
| | - Stefanie Albers
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (R.E.M.); (S.A.); (M.H.); (R.S.); (K.M.S.)
| | - Madhuri Haque
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (R.E.M.); (S.A.); (M.H.); (R.S.); (K.M.S.)
| | - Roland Sonntag
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (R.E.M.); (S.A.); (M.H.); (R.S.); (K.M.S.)
| | - Nicole Simone Treichel
- Functional Microbiome Research Group, University Hospital RWTH Aachen, 52074 Aachen, Germany; (N.S.T.); (T.C.)
| | - Thomas Clavel
- Functional Microbiome Research Group, University Hospital RWTH Aachen, 52074 Aachen, Germany; (N.S.T.); (T.C.)
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany;
| | - Kai Markus Schneider
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (R.E.M.); (S.A.); (M.H.); (R.S.); (K.M.S.)
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (R.E.M.); (S.A.); (M.H.); (R.S.); (K.M.S.)
| | - Tobias Otto
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany; (R.E.M.); (S.A.); (M.H.); (R.S.); (K.M.S.)
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Das S, Ge X, Han H, Desert R, Song Z, Athavale D, Chen W, Gaskell H, Lantvit D, Guzman G, Nieto N. The Integrated "Multiomics" Landscape at Peak Injury and Resolution From Alcohol-Associated Liver Disease. Hepatol Commun 2022; 6:133-160. [PMID: 34558855 PMCID: PMC8710802 DOI: 10.1002/hep4.1793] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 01/09/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol-induced liver injury, female and male wild-type mice were fed the control or ethanol Lieber-DeCarli diets for 6 weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14 days, respectively. At peak injury, there was increased signal transducer and activator of transcription (Stat3), Rho-GTPases, Tec kinase and glycoprotein VI (Gp6), and decreased peroxisome proliferator-activated receptor signaling. During resolution from ALD, there was up-regulation of vitamin D receptor/retinoid X receptor, toll-like receptor, p38 and Stat3, and down-regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune-response pathways that decreased during resolution. The bacterial genus Alistipes and the metabolite dipeptide glycyl-L-leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen-activated protein kinase (Map3k1) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. Conclusion: Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender-specific manner. Integration of multiomics data identified Map3k1 as a key gene driving pathogenesis and resolution from ALD.
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Affiliation(s)
- Sukanta Das
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Xiaodong Ge
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Hui Han
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Romain Desert
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Zhuolun Song
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Dipti Athavale
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Wei Chen
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Harriet Gaskell
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Daniel Lantvit
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Grace Guzman
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
| | - Natalia Nieto
- Department of PathologyUniversity of Illinois at ChicagoChicagoILUSA
- Department of MedicineDivision of Gastroenterology and HepatologyUniversity of Illinois at ChicagoChicagoILUSA
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Chen YH, Chiu WC, Xiao Q, Chen YL, Shirakawa H, Yang SC. Synbiotics Alleviate Hepatic Damage, Intestinal Injury and Muscular Beclin-1 Elevation in Rats after Chronic Ethanol Administration. Int J Mol Sci 2021; 22:ijms222212547. [PMID: 34830430 PMCID: PMC8622351 DOI: 10.3390/ijms222212547] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/15/2021] [Accepted: 11/20/2021] [Indexed: 02/07/2023] Open
Abstract
The purpose of this study was to investigate the beneficial effects of synbiotics on liver damage, intestinal health, and muscle loss, and their relevance in rats with chronic ethanol feeding. Thirty Wistar rats fed with a control liquid diet were divided into control and synbiotics groups, which were respectively provided with water or synbiotics solution (1.5 g/kg body weight/day) for 2 weeks. From the 3rd to 8th week, the control group was divided into a C group (control liquid diet + water) and an E group (ethanol liquid diet + water). The synbiotics group was separated in to three groups, SC, ASE, and PSE. The SC group was given a control liquid diet with synbiotics solution; the ASE group was given ethanol liquid diet with synbiotics solution, and the PSE group was given ethanol liquid diet and water. As the results, the E group exhibited liver damage, including increased AST and ALT activities, hepatic fatty changes, and higher CYP2E1 expression. Intestinal mRNA expressions of occludin and claudin-1 were significantly decreased and the plasma endotoxin level was significantly higher in the E group. In muscles, beclin-1 was significantly increased in the E group. Compared to the E group, the PSE and ASE groups had lower plasma ALT activities, hepatic fatty changes, and CYP2E1 expression. The PSE and ASE groups had significantly higher intestinal occludin and claudin-1 mRNA expressions and lower muscular beclin-1 expression when compared to the E group. In conclusion, synbiotics supplementation might reduce protein expression of muscle protein degradation biomarkers such as beclin-1 in rats with chronic ethanol feeding, which is speculated to be linked to the improvement of intestinal tight junction and the reduction of liver damage.
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Affiliation(s)
- Yi-Hsiu Chen
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan; (Y.-H.C.); (W.-C.C.); (Q.X.); (Y.-L.C.)
| | - Wan-Chun Chiu
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan; (Y.-H.C.); (W.-C.C.); (Q.X.); (Y.-L.C.)
- Research Center of Geriatric Nutrition, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
| | - Qian Xiao
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan; (Y.-H.C.); (W.-C.C.); (Q.X.); (Y.-L.C.)
| | - Ya-Ling Chen
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan; (Y.-H.C.); (W.-C.C.); (Q.X.); (Y.-L.C.)
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8857, Japan;
| | - Suh-Ching Yang
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan; (Y.-H.C.); (W.-C.C.); (Q.X.); (Y.-L.C.)
- Research Center of Geriatric Nutrition, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
- Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Correspondence: ; Tel.: +886-2-27361661 (ext. 6553); Fax: +886-2-27373112
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De Muynck K, Vanderborght B, Van Vlierberghe H, Devisscher L. The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective. Cells 2021; 10:2959. [PMID: 34831182 PMCID: PMC8616442 DOI: 10.3390/cells10112959] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut-liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut-liver axis disruption in progressive stages of CLD.
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Affiliation(s)
- Kevin De Muynck
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Bart Vanderborght
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Hans Van Vlierberghe
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium;
| | - Lindsey Devisscher
- Gut-Liver Immunopharmacology Unit, Department of Basic and Applied Medical Sciences, Liver Research Center Ghent, Ghent University, 9000 Ghent, Belgium; (K.D.M.); (B.V.)
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Yan X, Wang Y, Ren XY, Liu XY, Ma JM, Song RL, Wang XH, Dong Y, Yu AX, Fan QQ, Wei J, She GM. Gut dysbiosis correction contributes to the hepatoprotective effects of Thymus quinquecostatus Celak extract against alcohol through the gut-liver axis. Food Funct 2021; 12:10281-10290. [PMID: 34549762 DOI: 10.1039/d1fo01117k] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alcoholic liver disease (ALD) is a major health issue globally due to the consumption of alcoholic beverages. Thymus quinquecostatus Celak is a food additive and an edible herb that is widely used in Asia and possesses hepatoprotective activity, but the underlying mechanisms behind this protective activity are not completely understood. The purpose of this study was to investigate the hepatoprotective effects of Thymus quinquecostatus Celak extract (TQE) against ALD as well as the underlying mechanism based on gut microbiota and the gut-liver axis. TQE supplementation markedly alleviated chronic alcohol-induced liver injury in C57 mice. TQE also ameliorated gut barrier dysfunction induced by alcohol. Consequently, the activation of the lipopolysaccharide (LPS) translocation-mediated TLR4 pathway and the subsequent inflammatory response and ROS overproduction in the liver were suppressed. Meanwhile, alcohol-induced gut microbiota dysbiosis was also corrected by TQE. To further investigate the contribution of gut dysbiosis correction to the beneficial effects of TQE on ALD, a fecal microbiota transplantation study was conducted. TQE-manipulated gut microbiota transplantation markedly counteracted the alcohol-induced gut dysbiosis in the recipient mice. In parallel with gut dysbiosis correction, liver damage was partly ameliorated in the recipient mice. Gut barrier dysfunction, endotoxemia, TLR4 pathway induction as well as downstream inflammatory response and ROS overproduction were also partly suppressed due to gut dysbiosis correction in alcohol-fed recipient mice. In summary, these results suggest that gut dysbiosis correction contributes to the hepatoprotective effects of TQE against alcohol through the gut-liver axis.
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Affiliation(s)
- Xin Yan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Yu Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Xue-Yang Ren
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Xiao-Yun Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Jia-Mu Ma
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Ruo-Lan Song
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Xiu-Huan Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Ying Dong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - A-Xiang Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Qi-Qi Fan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Jing Wei
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Gai-Mei She
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
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The Prophylactic Effects of Glutamine on Muscle Protein Synthesis and Degradation in Rats with Ethanol-Induced Liver Damage. Nutrients 2021; 13:nu13082788. [PMID: 34444950 PMCID: PMC8398394 DOI: 10.3390/nu13082788] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
The purpose of this research was to investigate the prophylactic effects of glutamine on muscle protein synthesis and degradation in rats with ethanol-induced liver injury. For the first 2 weeks, Wistar rats were divided into two groups and fed a control (n = 16) or glutamine-containing diet (n = 24). For the following 6 weeks, rats fed the control diet were further divided into two groups (n = 8 per group) according to whether their diet contained no ethanol (CC) or did contain ethanol (CE). Rats fed the glutamine-containing diet were also further divided into three groups (n = 8 per group), including a GG group (glutamine-containing diet without ethanol), GE group (control diet with ethanol), and GEG group (glutamine-containing diet with ethanol). After 6 weeks, results showed that hepatic fatty change, inflammation, altered liver function, and hyperammonemia had occurred in the CE group, but these were attenuated in the GE and GEG groups. Elevated intestinal permeability and a higher plasma endotoxin level were observed in the CE group, but both were lower in the GE and GEG groups. The level of a protein synthesis marker (p70S6K) was reduced in the CE group but was higher in both the GE and GEG groups. In conclusion, glutamine supplementation might elevate muscle protein synthesis by improving intestinal health and ameliorating liver damage in rats with chronic ethanol intake.
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Michalak A, Lach T, Cichoż-Lach H. Oxidative Stress-A Key Player in the Course of Alcohol-Related Liver Disease. J Clin Med 2021; 10:3011. [PMID: 34300175 PMCID: PMC8303854 DOI: 10.3390/jcm10143011] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress is known to be an inseparable factor involved in the presentation of liver disorders. Free radicals interfere with DNA, proteins, and lipids, which are crucial in liver metabolism, changing their expression and biological functions. Additionally, oxidative stress modifies the function of micro-RNAs, impairing the metabolism of hepatocytes. Free radicals have also been proven to influence the function of certain transcriptional factors and to alter the cell cycle. The pathological appearance of alcohol-related liver disease (ALD) constitutes an ideal example of harmful effects due to the redox state. Finally, ethanol-induced toxicity and overproduction of free radicals provoke irreversible changes within liver parenchyma. Understanding the underlying mechanisms associated with the redox state in the course of ALD creates new possibilities of treatment for patients. The future of hepatology may become directly dependent on the effective action against reactive oxygen species. This review summarizes current data on the redox state in the natural history of ALD, highlighting the newest reports on this topic.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
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35
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An iridoid glycoside from Cornus officinalis balances intestinal microbiome disorder and alleviates alcohol-induced liver injury. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104488] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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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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The Impact of the NLRP3 Pathway in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease. LIVERS 2021. [DOI: 10.3390/livers1020007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The presence of hepatic steatosis and inflammation is increasingly associated with both metabolic and alcohol-related liver conditions. Both are on the increase globally and, apart from liver transplantation, there are no licensed therapies that target the full complement of disease features. The presence of some shared pathogenic mechanisms and histological features in NAFLD and ALD suggests that it may be possible to develop markers for prognostication or staging, or indeed new therapeutic tools to treat both conditions. One such example of an approach exists in the form of the NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Activation of the NLRP3 inflammasome results in hepatocyte pyroptosis, persistence, and amplification of liver inflammation and activation of profibrogenic signaling cascades. Thus, targeting elements of the pathway in NAFLD and ALD may provide a tractable route to pharmacological therapy. In this review, we summarize the contribution of this inflammasome to disease and review the current options for therapy.
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Yang J, Syed F, Xia Y, Sanyal A, Shah V, Chalasani N, Zheng X, Yu Q, Lou Y, Li W. Blood Biomarkers of Intestinal Epithelium Damage Regenerating Islet-derived Protein 3α and Trefoil Factor 3 Are Persistently Elevated in Patients with Alcoholic Hepatitis. Alcohol Clin Exp Res 2021; 45:720-731. [PMID: 33587293 PMCID: PMC8076084 DOI: 10.1111/acer.14579] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/11/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). METHODS Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6- and 12-month follow-ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol. RESULTS At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels. CONCLUSIONS Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.
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Affiliation(s)
- Jing Yang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Fahim Syed
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Ying Xia
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
| | - Xiaoqun Zheng
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yongliang Lou
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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Tornai D, Szabo G. Emerging medical therapies for severe alcoholic hepatitis. Clin Mol Hepatol 2020; 26:686-696. [PMID: 32981291 PMCID: PMC7641578 DOI: 10.3350/cmh.2020.0145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 08/28/2020] [Indexed: 12/12/2022] Open
Abstract
Severe alcoholic hepatitis (AH) is an acute and often devastating form of alcohol-associated liver disease. Clinically, AH is characterized by elevated bilirubin, model for end stage liver disease scores >20, and nonspecific symptoms that are caused by underlying inflammation, hepatocyte injury, and impaired intestinal barrier function. Compromised immune defense in AH contributes to infections, sepsis and organ failure. To date, corticosteroids are the only recommended treatment for severe AH, however it does not provide survival benefits beyond 1 month. Recent preclinical and early clinical studies in AH aided understanding of the disease and presented opportunities for new therapeutic options targeting inflammation, oxidative stress, liver regeneration and modification of intestinal microbiota. In this comprehensive review, we discuss promising preclinical results and ongoing clinical trials evaluating novel therapeutic agents for the treatment of severe AH.
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Affiliation(s)
- David Tornai
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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40
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Li S, Wang N, Tan HY, Chueng F, Zhang ZJ, Yuen MF, Feng Y. Modulation of gut microbiota mediates berberine-induced expansion of immuno-suppressive cells to against alcoholic liver disease. Clin Transl Med 2020; 10:e112. [PMID: 32790968 PMCID: PMC7438809 DOI: 10.1002/ctm2.112] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/12/2022] Open
Abstract
Background Berberine is an isoquinoline alkaloid compound derived from many herbs, which has been used extensively to improve liver function. But action mechanism of its hepatoprotection in alcoholic liver disease (ALD) is far from being clear. Aim To investigate the underlying mechanism of berberine's therapeutic effect on ALD associated with gut microbiota‐immune system axis. Method An animal model fed with ethanol that mimics drinking pattern ideally in ALD patients was established. Liver function was evaluated by biochemical test and histological examination. Immune cells were detected by flow cytometry and feces samples were collected for 16S rRNA gene amplicon sequencing. Results We first reported the promising beneficial effect of berberine on ameliorating acute‐on‐chronic alcoholic hepatic damage and explored the underlying mechanism involving gut microbiota‐immune system axis. Notably, berberine activated a population with immune suppressive function, defined as granulocytic‐ myeloid‐derived suppressor cell (G‐MDSC)‐like population, in the liver of mice with alleviating alcohol‐induced hepatic injury. Berberine remarkably enhanced the increase of G‐MDSC‐like cells in blood and liver and decreased cytotoxic T cells correspondingly. Suppression of G‐MDSC‐like population significantly attenuated the protective effect of berberine against alcohol. Berberine activated IL6/STAT3 signaling in in vitro culture of G‐MSDCs‐like population, while inhibition of STAT3 activity attenuated the activation of this population by berberine. Moreover, berberine changed the overall gut microbial community, primarily increased the abundance of Akkermansia muciniphila. Of note, depletion of gut microbiota abolished the inducing effect of berberine on G‐MDSC‐like population, and attenuated its hepatoprotective effect against alcohol in mice, suggesting intestinal flora might be involved in mediating the expansion of this protective population. Conclusion Collectively, this study delivered insight into the role of immunosuppressive response in ALD, and facilitated the understanding of the pharmacological effects and action mechanisms of berberine.
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Affiliation(s)
- Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China
| | - Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China
| | - Fan Chueng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China
| | - Zhang-Jin Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China
| | - Man-Fung Yuen
- Division of Gastroenterology and Hepatology, Queen Mary Hospital, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong S.A.R, P. R. China
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41
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Avila MA, Dufour JF, Gerbes AL, Zoulim F, Bataller R, Burra P, Cortez-Pinto H, Gao B, Gilmore I, Mathurin P, Moreno C, Poznyak V, Schnabl B, Szabo G, Thiele M, Thursz MR. Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting. Gut 2020; 69:764-780. [PMID: 31879281 PMCID: PMC7236084 DOI: 10.1136/gutjnl-2019-319720] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 11/28/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022]
Abstract
Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.
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Affiliation(s)
- Matias A Avila
- Hepatology, CIBERehd, IdiSNA, CIMA, University of Navarra, Pamplona, Spain
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research and University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Alexander L Gerbes
- Liver Centre Munich, Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Fabien Zoulim
- Hepatology Department, INSERM U1052, Hospices Civils de Lyon, Cancer Research Centerl of Lyon, University of Lyon, Lyon, France
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Helena Cortez-Pinto
- Departamento de Gastroenterologia, CHLN, Laboratorio de Nutriçao, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Ian Gilmore
- Liverpool Centre for Alcohol Research, University of Liverpool, Liverpool, UK
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, INSERM U795, Hôpital Huriez, Lille, France
| | - Christophe Moreno
- Service de Gastroentérologie, Hépatopancréatologie et Oncologie Digestive, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Vladimir Poznyak
- Department of Mental Health and Substance Abuse, World Health Organization, Geneve, Switzerland
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Maja Thiele
- Department of Gastroenterology and Hepatology, and Department of Clinical Research, Odense University Hospital and University of Southern Denmark, Odense, Denmark
| | - Mark R Thursz
- Department of Metabolism, Faculty of Medicine, Imperial College, London, UK
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42
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Xu R, Xiu L, Sheng S, Liang Y, Zhang H, Liu Y, Tong H, Du R, Wang X. Exopolysaccharides from Lactobacillus buchneri TCP016 Attenuate LPS- and d-GalN-Induced Liver Injury by Modulating the Gut Microbiota. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:11627-11637. [PMID: 31553177 DOI: 10.1021/acs.jafc.9b04323] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Liver diseases alter the gut microbiota, but several lactic acid bacteria can reduce the degree of liver damage. The present study investigated whether Lactobacillus buchneri TCP016 reduces the degree of liver damage by modifying the gut microbiota via its exopolysaccharides (EPSs). First, it was illustrated that the main EPS (EPS016; molecular weight = 8.509 × 104 Da) comprised rhamnose, xylose, glucosamine, glucuronic acid, galactose, galacturonic acid, glucose, and mannose in molar ratios of 9.2:3.9:3.8:2.8:2.1:2.0:1.6:1.0. Our data showed that EPS016 alleviated the increase in plasma and hepatic enzyme and cytokine levels, increased superoxide dismutase and glutathione activity, and alleviated bacterial translocation to the liver and mesenteric lymph nodes in vivo. Furthermore, EPS016 ameliorated intestinal mucosal injury and gut flora dysbiosis, thereby decreasing the enrichment of Helicobacteraceae, Lachnospiraceae, and Enterobacteriaceae and increasing the abundance of Lactobacillus, Rikenellaceae, Bacteroidaceae, Bacteroidales_S24-7_group, and Prevotellaceae. These findings indicated that EPS016 inhibits lipopolysaccharides/d-galactosamine-induced liver injury and improves the modification of the gut microbiota.
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Affiliation(s)
- Rihua Xu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
| | - Lei Xiu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
| | - Shouxin Sheng
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
| | - Yanchen Liang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
| | - Haochi Zhang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
| | - Yang Liu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
| | - He Tong
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
| | - Ruiping Du
- Animal Nutrition Institute , Agriculture and Animal Husbandry Academy of Inner Mongolia , Hohhot 010031 , P. R. China
| | - Xiao Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of Life Science , Inner Mongolia University , Hohhot 010070 , P. R. China
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Abstract
Many studies have indicated that intestinal barrier dysfunction is the key mechanism of alcoholic liver disease (ALD). In this paper, we systematically review the causes of intestinal barrier dysfunction and the pathogenesis of ALD and discuss the treatment of intestinal barrier dysfunction.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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Saha B, Tornai D, Kodys K, Adejumo A, Lowe P, McClain C, Mitchell M, McCullough A, Srinivasan D, Kroll-Desrosiers A, Barton B, Radaeva S, Szabo G. Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis. Hepatology 2019; 70:1134-1149. [PMID: 30891779 PMCID: PMC6752989 DOI: 10.1002/hep.30617] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 03/06/2019] [Indexed: 12/17/2022]
Abstract
Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Conclusion: Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH.
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Affiliation(s)
- Banishree Saha
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - David Tornai
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Karen Kodys
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Adeyinka Adejumo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Patrick Lowe
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Craig McClain
- Department of Medicine, University of Louisville, Louisville, KY
| | - Mack Mitchell
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | | | | | - Aimee Kroll-Desrosiers
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA
| | - Bruce Barton
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
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Teschke R. Alcoholic Liver Disease: Current Mechanistic Aspects with Focus on Their Clinical Relevance. Biomedicines 2019; 7:E68. [PMID: 31491888 PMCID: PMC6783919 DOI: 10.3390/biomedicines7030068] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 09/03/2019] [Indexed: 12/11/2022] Open
Abstract
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Frankfurt/Main, Germany.
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46
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Li HD, Du XS, Huang HM, Chen X, Yang Y, Huang C, Meng XM, Li J. Noncoding RNAs in alcoholic liver disease. J Cell Physiol 2019; 234:14709-14720. [PMID: 30701547 DOI: 10.1002/jcp.28229] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 01/01/2019] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
Alcoholic liver disease (ALD) is a complex process with high morbitity and can cause liver dysfunction, which contains a wide spectrum of hepatic lesions, including steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. To date, the molecular mechanisms for ALD have not been fully explored and an effective therapy is still missing. Overwhelming evidence shows dysregulation of noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), is correlated with etiopathogenesis and progress of ALD including hepatocyte damage, disrupted lipid metabolism, aggressive inflammatory responses, oxidative stress, programmed cell death, fibrosis, and epigenetic changes induced by alcohol. For example, circulating miRNA-122 is a marker of hepatocyte damage, and miRNA-155 is a potential marker of inflammation, indicating their diagnosis therapeutic potential in ALD. In addition, roles for long noncoding RNAs (lncRNAs) and circular RNAs in ALD are being uncovered. Further, circulating ncRNAs and exosome-derived ncRNAs have attracted more attention lately, suggesting a role in the prevention and treatment of ALD. This review covers the roles of ncRNAs in ALD, and the potential uses as markers for diagnosis and therapeutic options.
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Affiliation(s)
- Hai-Di Li
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Sa Du
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hui-Min Huang
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xin Chen
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yang Yang
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Cheng Huang
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Xiao-Ming Meng
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Jun Li
- The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China.,The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, China.,Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, China
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47
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Wang HY, Chi C, Xu YQ, Wang C, Wang TY, Lv D, Li X. Occludin endocytosis is involved in the disruption of the intestinal epithelial barrier in a mouse model of alcoholic steatohepatitis. J Dig Dis 2019; 20:476-485. [PMID: 31298798 DOI: 10.1111/1751-2980.12800] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 06/27/2019] [Accepted: 07/09/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE We aimed to investigate the involvement of the endocytosis of occludin, a key component of tight junction (TJ), in the ethanol-induced disassembly of TJ in a model of alcoholic steatohepatitis. METHODS Wild-type mice were fed an ethanol-containing or isocaloric liquid diet for 8 weeks and then assessed for liver injury (histopathology and measurement of serum enzymes), gut permeability (in vivo lactulose/mannitol and ex vivo dye leakage assays), intestinal epithelium ultrastructure (transmission electron microscopy), and intestinal occludin localization (immunofluorescence microscopy). The human intestinal epithelial cell line Caco-2 was also analyzed in vitro for the effects of ethanol on the barrier function (transepithelial electrical resistance), occludin localization (immunofluorescence microscopy and Western blotting), and endocytosis pathways (double-labeling immunofluorescence microscopy with selective pathway inhibitors). RESULTS The ethanol-fed mice developed steatohepatitis and displayed intestinal barrier dysfunction, the disruption of intestinal TJ, and enhanced intestinal endocytosis of occluding compared with the control mice. In the Caco-2 monolayers, ethanol treatment decreased transepithelial electrical resistance, disrupted TJ formation, and enhanced occludin endocytosis in a dose- and time-dependent manner. These deleterious events were reversed by pretreating the Caco-2 cells with a selective pharmacological inhibitor of macropinocytosis, but not with the inhibitors of clathrin or caveolin-mediated endocytic pathways. CONCLUSION Chronic ethanol exposure may increase intestinal permeability by inducing the micropinocytosis of occludin, resulting in the disruption of intestinal TJ.
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Affiliation(s)
- Hong Yan Wang
- Department of International Physical Examination and Health Center, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Cheng Chi
- Department of Gastroenterology and Hepatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - You Qing Xu
- Department of Gastroenterology and Hepatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chen Wang
- Department of Gastroenterology and Hepatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Tian Yi Wang
- Department of Gastroenterology and Hepatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Dong Lv
- Department of Gastroenterology and Hepatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xin Li
- Department of Gastroenterology and Hepatology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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48
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Xu R, Xiu L, Zhang Y, Du R, Wang X. Probiotic and hepatoprotective activity of lactobacillus isolated from Mongolian camel milk products. Benef Microbes 2019; 10:699-710. [DOI: 10.3920/bm2018.0131] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The improving-intestinal-microbial-balance properties of lactic acid bacteria (LAB) are well known. Thus, LAB could play a vital role in the pathogenesis of liver diseases. In the present study, 107 LAB strains were isolated from Mongolian camel milk products and identified to species, then screened for their probiotic properties. As a result, we identified 71 Lactobacillus bacteria belonging to 9 different species, and 36 Lactococcus bacteria belonging to 8 different species. Among them, six strains of LAB with strong tolerance and adhesion ability were further studied for their protective effect on acute liver injury induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN). These six strains of LAB were fed to mice for 7 weeks, and on the final day of the experiment, LPS/D-GalN were used to induce acute liver injury. After challenging, the degree of liver pathological changes, secretion of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum and liver, and the expression of tumour necrosis factor (TNF)-α and interleukin (IL)-6 in the liver and intestines were observed and quantified. The results showed that the degree of liver pathological changes in mice fed with the six LAB strains were relieved to varying degrees compared with the LPS/D-GalN-induced model group, and the expressions of AST, ALT, IL-6, and TNF-α factor were also significantly decreased. Moreover, the expression levels of these factors in mice pretreated with Lactobacillus paracasei subsp. paracasei WXD5 were significantly decreased compared with other experimental groups. This suggests the probiotic potential and pharmacological value of L. paracasei subsp. paracasei as a liver injury inhibitor in the intervention of inflammation-based liver disease.
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Affiliation(s)
- R.H. Xu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of life Science, Inner Mongolia University, 010070 Hohhot, China P.R
| | - L. Xiu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of life Science, Inner Mongolia University, 010070 Hohhot, China P.R
| | - Y.L. Zhang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of life Science, Inner Mongolia University, 010070 Hohhot, China P.R
| | - R.P. Du
- Animal Nutrition Institute, Agriculture and Animal Husbandry Academy of Inner Mongolia, 010031 Hohhot, China P.R
| | - X. Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, School of life Science, Inner Mongolia University, 010070 Hohhot, China P.R
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Szabo G, Kamath PS, Shah VH, Thursz M, Mathurin P, Bataller R, Burra P, Castera L, Cortez Pinto H, Diehl AM, Gao B, Gilmore SI, Hampe J, Jürgen R, Karin M, Krag A, Leon D, Leptak C, Louvet A, Lucey M, McClain C, Nagy L, Pageaux G, Sanyal A, Schnabl B, Tiniakos D, Trautwein C, Tsukamoto H. Alcohol-Related Liver Disease: Areas of Consensus, Unmet Needs and Opportunities for Further Study. Hepatology 2019; 69:2271-2283. [PMID: 30645002 DOI: 10.1002/hep.30369] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/31/2018] [Indexed: 12/16/2022]
Abstract
A joint meeting of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) was held in London on September 30 and October 1, 2017. The goals of the meeting were to identify areas of broad agreement and disagreement, develop consensus, and determine future directions to ultimately reduce the burden, morbidity, and mortality of alcohol-related liver disease (previously termed alcoholic liver disease). The specific aims of the meeting were to identify unmet needs and areas for future investigation, in order to reduce alcohol consumption, develop markers for diagnosis and prognosis of disease, and create a framework to test novel pharmacological agents with pre-specified treatment endpoints. A table summary of these goals and aims is provided in the context of epidemiology, current management strategies, next steps for future trials and translational science.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, US
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, US
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, US
| | - Mark Thursz
- Digestive Diseases Division, Department of Surgery & Cancer, Imperial College, London, UK
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, Hôpital Claude Huriez, Lille, France
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Shen H, Jiang L, Lin JD, Omary MB, Rui L. Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice. J Clin Invest 2019; 129:2305-2317. [PMID: 30888335 PMCID: PMC6546460 DOI: 10.1172/jci124376] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 03/14/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic alcohol consumption causes liver injury, inflammation and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a novel hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT, and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin that suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.
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Affiliation(s)
- Hong Shen
- Department of Molecular & Integrative Physiology
| | - Lin Jiang
- Department of Molecular & Integrative Physiology
| | - Jiandie D. Lin
- Life Sciences Institute and Department of Cell & Developmental Biology, and
| | - M. Bishr Omary
- Department of Molecular & Integrative Physiology
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Liangyou Rui
- Department of Molecular & Integrative Physiology
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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