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Perumal SK, Arumugam MK, Osna NA, Rasineni K, Kharbanda KK. Betaine regulates the gut-liver axis: a therapeutic approach for chronic liver diseases. Front Nutr 2025; 12:1478542. [PMID: 40196019 PMCID: PMC11973089 DOI: 10.3389/fnut.2025.1478542] [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: 08/10/2024] [Accepted: 03/03/2025] [Indexed: 04/09/2025] Open
Abstract
Chronic liver disease is defined by persistent harm to the liver that might result in decreased liver function. The two prevalent chronic liver diseases are alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). There is ample evidence that the pathogenesis of these two chronic liver diseases is closely linked to gastrointestinal dysfunctions that alters the gut-liver crosstalk. These alterations are mediated through the imbalances in the gut microbiota composition/function that combined with disruption in the gut barrier integrity allows for harmful gut microbes and their toxins to enter the portal circulation and reach the liver to elicit an inflammatory response. This leads to further recruitment of systemic inflammatory cells, such as neutrophils, T-cells, and monocytes into the liver, which perpetuate additional inflammation and the development of progressive liver damage. Many therapeutic modalities, currently used to prevent, attenuate, or treat chronic liver diseases are aimed at modulating gut dysbiosis and improving intestinal barrier function. Betaine is a choline-derived metabolite and a methyl group donor with antioxidant, anti-inflammatory and osmoprotectant properties. Studies have shown that low betaine levels are associated with higher levels of organ damage. There have been several publications demonstrating the role of betaine supplementation in preventing the development of ALD and MASLD. This review explores the protective effects of betaine through its role as a methyl donor and its capacity to regulate the protective gut microbiota and maintain intestinal barrier integrity to prevent the development of these chronic liver diseases. Further studies are needed to enhance our understanding of its therapeutic potential that could pave the way for targeted interventions in the management of not only chronic liver diseases, but other inflammatory bowel diseases or systemic inflammatory conditions.
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Affiliation(s)
- Sathish Kumar Perumal
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Madan Kumar Arumugam
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Karuna Rasineni
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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Sun YQ, Wu Y, Li MR, Wei YY, Guo M, Zhang ZL. Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function. World J Gastroenterol 2024; 30:4660-4668. [PMID: 39575408 PMCID: PMC11572637 DOI: 10.3748/wjg.v30.i43.4660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/29/2024] [Accepted: 10/18/2024] [Indexed: 10/31/2024] Open
Abstract
We discuss the article by Koizumi et al published in the World Journal of Gastroenterology. Our focus is on the therapeutic targets for fibrosis associated with alcohol-related liver disease (ALD) and the mechanism of action of elafibranor (EFN), a dual agonist of peroxisome proliferator-activated receptor α (PPARα) and peroxisome PPAR δ (PPARδ). EFN is currently in phase III clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis. ALD progresses from alcoholic fatty liver to alcoholic steatohepatitis (ASH), with chronic ASH eventually leading to fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. The pathogenesis of ALD is driven by hepatic steatosis, oxidative stress, and acetaldehyde toxicity. Alcohol consumption disrupts lipid metabolism by inactivating PPARα, exacerbating the progression of ALD. EFN primarily activates PPARα, promoting lipolysis and β-oxidation in ethanol-stimulated HepG2 cells, which significantly reduces hepatic steatosis, apoptosis, and fibrosis in an ALD mouse model. Additionally, alcohol disrupts the gut-liver axis at several interconnected levels, contributing to a proinflammatory environment in the liver. EFN helps alleviate intestinal hyperpermeability by restoring tight junction protein expression and autophagy, inhibiting apoptosis and inflammatory responses, and enhancing intestinal barrier function through PPARδ activation.
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Affiliation(s)
- Yu-Qi Sun
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Yang Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Meng-Ran Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Yu-Yao Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Mei Guo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Zi-Li Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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Xiang B, Hu J, Zhang M, Zhi M. The involvement of oral bacteria in inflammatory bowel disease. Gastroenterol Rep (Oxf) 2024; 12:goae076. [PMID: 39188957 PMCID: PMC11346772 DOI: 10.1093/gastro/goae076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 02/23/2024] [Accepted: 03/25/2024] [Indexed: 08/28/2024] Open
Abstract
Microorganisms play an important role in the pathogenesis of inflammatory bowel disease (IBD). The oral cavity, the second-largest microbial niche, is connected to the gastro-intestinal tract. Ectopic gut colonization by oral microbes is a signature of IBD. Current studies suggest that patients with IBD often report more oral manifestations and these oral issues are closely linked with disease activity. Murine studies have indicated that several oral microbes exacerbate intestinal inflammation. Moreover, intestinal inflammation can promote oral microbial dysbiosis and the migration of oral microbes to the gastro-intestinal tract. The reciprocal consequences of oral microbial dysbiosis and IBD, specifically through metabolic alterations, have not yet been elucidated. In this review, we summarize the relationship between oral bacteria and IBD from multiple perspectives, including clinical manifestations, microbial dysbiosis, and metabolic alterations, and find that oral pathogens increase anti-inflammatory metabolites and decrease inflammation-related metabolites.
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Affiliation(s)
- Bingjie Xiang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jun Hu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Min Zhang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Min Zhi
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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Sausa M, Fucarino A, Paladino L, Zummo FP, Fabbrizio A, Di Felice V, Rappa F, Barone R, Marino Gammazza A, Macaluso F. Probiotics as Potential Therapeutic Agents: Safeguarding Skeletal Muscle against Alcohol-Induced Damage through the Gut-Liver-Muscle Axis. Biomedicines 2024; 12:382. [PMID: 38397983 PMCID: PMC10886686 DOI: 10.3390/biomedicines12020382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Probiotics have shown the potential to counteract the loss of muscle mass, reduce physical fatigue, and mitigate inflammatory response following intense exercise, although the mechanisms by which they work are not very clear. The objective of this review is to describe the main harmful effects of alcohol on skeletal muscle and to provide important strategies based on the use of probiotics. The excessive consumption of alcohol is a worldwide problem and has been shown to be crucial in the progression of alcoholic liver disease (ALD), for which, to date, the only therapy available is lifestyle modification, including cessation of drinking. In ALD, alcohol contributes significantly to the loss of skeletal muscle, and also to changes in the intestinal microbiota, which are the basis for a series of problems related to the onset of sarcopenia. Some of the main effects of alcohol on the skeletal muscle are described in this review, with particular emphasis on the "gut-liver-muscle axis", which seems to be the primary cause of a series of muscle dysfunctions related to the onset of ALD. The modulation of the intestinal microbiota through probiotics utilization has appeared to be crucial in mitigating the muscle damage induced by the high amounts of alcohol consumed.
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Affiliation(s)
- Martina Sausa
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
| | - Alberto Fucarino
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
| | - Letizia Paladino
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Francesco Paolo Zummo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Antonio Fabbrizio
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
| | - Valentina Di Felice
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Francesca Rappa
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Rosario Barone
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Antonella Marino Gammazza
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
| | - Filippo Macaluso
- Department of Theoretical and Applied Sciences, eCampus University, 22060 Novedrate, Italy; (M.S.); (A.F.); (A.F.)
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (L.P.); (F.P.Z.); (V.D.F.); (F.R.); (R.B.); (A.M.G.)
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
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5
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Yarahmadi A, Afkhami H. The role of microbiomes in gastrointestinal cancers: new insights. Front Oncol 2024; 13:1344328. [PMID: 38361500 PMCID: PMC10867565 DOI: 10.3389/fonc.2023.1344328] [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: 12/01/2023] [Accepted: 12/20/2023] [Indexed: 02/17/2024] Open
Abstract
Gastrointestinal (GI) cancers constitute more than 33% of new cancer cases worldwide and pose a considerable burden on public health. There exists a growing body of evidence that has systematically recorded an upward trajectory in GI malignancies within the last 5 to 10 years, thus presenting a formidable menace to the health of the human population. The perturbations in GI microbiota may have a noteworthy influence on the advancement of GI cancers; however, the precise mechanisms behind this association are still not comprehensively understood. Some bacteria have been observed to support cancer development, while others seem to provide a safeguard against it. Recent studies have indicated that alterations in the composition and abundance of microbiomes could be associated with the progression of various GI cancers, such as colorectal, gastric, hepatic, and esophageal cancers. Within this comprehensive analysis, we examine the significance of microbiomes, particularly those located in the intestines, in GI cancers. Furthermore, we explore the impact of microbiomes on various treatment modalities for GI cancer, including chemotherapy, immunotherapy, and radiotherapy. Additionally, we delve into the intricate mechanisms through which intestinal microbes influence the efficacy of GI cancer treatments.
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Affiliation(s)
- Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
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Nie G, Zhang H, Xie D, Yan J, Li X. Liver cirrhosis and complications from the perspective of dysbiosis. Front Med (Lausanne) 2024; 10:1320015. [PMID: 38293307 PMCID: PMC10824916 DOI: 10.3389/fmed.2023.1320015] [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: 10/11/2023] [Accepted: 12/26/2023] [Indexed: 02/01/2024] Open
Abstract
The gut-liver axis refers to the intimate relationship and rigorous interaction between the gut and the liver. The intestinal barrier's integrity is critical for maintaining liver homeostasis. The liver operates as a second firewall in this interaction, limiting the movement of potentially dangerous compounds from the gut and, as a result, contributing in barrier management. An increasing amount of evidence shows that increased intestinal permeability and subsequent bacterial translocation play a role in liver damage development. The major pathogenic causes in cirrhotic individuals include poor intestinal permeability, nutrition, and intestinal flora dysbiosis. Portal hypertension promotes intestinal permeability and bacterial translocation in advanced liver disease, increasing liver damage. Bacterial dysbiosis is closely related to the development of cirrhosis and its related complications. This article describes the potential mechanisms of dysbiosis in liver cirrhosis and related complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma, using dysbiosis of the intestinal flora as an entry point.
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Affiliation(s)
- Guole Nie
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Honglong Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Danna Xie
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Jun Yan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Cancer Prevention and Control Center of Lanzhou University Medical School, Lanzhou, China
- Gansu Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- Gansu Clinical Medical Research Center of General Surgery, Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Cancer Prevention and Control Center of Lanzhou University Medical School, Lanzhou, China
- Gansu Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- Gansu Clinical Medical Research Center of General Surgery, Lanzhou, China
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7
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Park SY, Kang JH, Jung HJ, Hwang JH, Chun HS, Yoon YS, Oh SH. Okadaic Acid Is at Least as Toxic as Dinophysistoxin-1 after Repeated Administration to Mice by Gavage. Toxins (Basel) 2023; 15:587. [PMID: 37888618 PMCID: PMC10611360 DOI: 10.3390/toxins15100587] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/07/2023] [Accepted: 09/21/2023] [Indexed: 10/28/2023] Open
Abstract
Okadaic acid (OA) and its analogues cause diarrhetic shellfish poisoning (DSP) in humans, and risk assessments of these toxins require toxicity equivalency factors (TEFs), which represent the relative toxicities of analogues. However, no human death by DSP toxin has been reported, and its current TEF value is based on acute lethality. To properly reflect the symptoms of DSP, such as diarrhea without death, the chronic toxicity of DSP toxins at sublethal doses should be considered. In this study, we obtained acute oral LD50 values for OA and dinophysistoxin-1 (DTX-1) (1069 and 897 μg/kg, respectively) to set sublethal doses. Mice were treated with sublethal doses of OA and DTX-1 for 7 days. The mice lost body weight, and the disease activity index and intestinal crypt depths increased. Furthermore, these changes were more severe in OA-treated mice than in the DTX-1-treated mice. Strikingly, ascites was observed, and its severity was greater in mice treated with OA. Our findings suggest that OA is at least as toxic as DTX-1 after repeated oral administration at a low dose. This is the first study to compare repeated oral dosing of DSP toxins. Further sub-chronic and chronic studies are warranted to determine appropriate TEF values for DSP toxins.
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Affiliation(s)
- Se Yong Park
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea;
| | - Ju-Hee Kang
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea; (J.-H.K.); (H.J.J.); (J.H.H.)
| | - Hyun Jin Jung
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea; (J.-H.K.); (H.J.J.); (J.H.H.)
| | - Jung Ho Hwang
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea; (J.-H.K.); (H.J.J.); (J.H.H.)
| | - Hyang Sook Chun
- Food Toxicology Laboratory, School of Food Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea;
| | - Yeo Sung Yoon
- Department of Anatomy and Cell Biology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea;
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, Incheon 21963, Republic of Korea; (J.-H.K.); (H.J.J.); (J.H.H.)
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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: 19] [Impact Index Per Article: 9.5] [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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Chancharoenthana W, Kamolratanakul S, Yiengwattananon P, Phuengmaung P, Udompornpitak K, Saisorn W, Hiengrach P, Visitchanakun P, Schultz MJ, Leelahavanichkul A. Enhanced lupus progression in alcohol-administered Fc gamma receptor-IIb-deficiency lupus mice, partly through leaky gut-induced inflammation. Immunol Cell Biol 2023; 101:746-765. [PMID: 37575046 DOI: 10.1111/imcb.12675] [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: 04/01/2023] [Revised: 06/21/2023] [Accepted: 07/17/2023] [Indexed: 08/15/2023]
Abstract
Alcohol can induce a leaky gut, with translocation of microbial molecules from the gut into the blood circulation. Although the contribution of inflammation to organ-mediated damage in lupus has been previously demonstrated, the mechanistic roles of alcohol consumption in lupus activation are not known. Herein, we tested the effects of 10-week lasting alcohol administration on organ damages and immune responses in 8-week-old lupus-prone Fc gamma receptor IIb-deficient (FcγRIIb-/- ) mice. Our study endpoints were evaluation of systemic inflammation and assessment of fecal dysbiosis along with endotoxemia. In comparison with alcohol-administered wild-type mice, FcγRIIb-/- mice demonstrated more prominent liver damage (enzyme, histological score, apoptosis, malondialdehyde oxidant) and serum interleukin(IL)-6 levels, despite a similarity in leaky gut (fluorescein isothiocyanate-dextran assay, endotoxemia and gut occludin-1 immunofluorescence), fecal dysbiosis (microbiome analysis) and endotoxemia. All alcohol-administered FcγRIIb-/- mice developed lupus-like characteristics (serum anti-dsDNA, proteinuria, serum creatinine and kidney injury score) with spleen apoptosis, whereas control FcγRIIb-/- mice showed only a subtle anti-dsDNA. Both alcohol and lipopolysaccharide (LPS) similarly impaired enterocyte integrity (transepithelial electrical resistance), and only LPS, but not alcohol, upregulated the IL-8 gene in Caco-2 cells. In macrophages, alcohol mildly activated supernatant cytokines (tumor necrosis factor-α and IL-6), but not M1 polarization-associated genes (IL-1β and iNOS), whereas LPS prominently induced both parameters (more prominent in FcγRIIb-/- macrophages than wild type). There was no synergy in LPS plus alcohol compared with LPS alone in both enterocytes and macrophages. In conclusion, alcohol might exacerbate lupus-like activity partly through a profound inflammation from the leaky gut in FcγRIIb-/- mice.
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Affiliation(s)
- Wiwat Chancharoenthana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Tropical Immunology and Translational Research Unit (TITRU), Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Supitcha Kamolratanakul
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Tropical Immunology and Translational Research Unit (TITRU), Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | | | - Pornpimol Phuengmaung
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
| | - Kanyarat Udompornpitak
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Wilasinee Saisorn
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
| | - Pratsanee Hiengrach
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
| | - Peerapat Visitchanakun
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
| | - Marcus J Schultz
- Department of Intensive Care & Laboratory of Experimental Intensive Care and Anesthesiology (LEICA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK
| | - Asada Leelahavanichkul
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Ding Q, Pi A, Hao L, Xu T, Zhu Q, Shu L, Yu X, Wang W, Si C, Li S. Genistein Protects against Acetaldehyde-Induced Oxidative Stress and Hepatocyte Injury in Chronic Alcohol-Fed Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:1930-1943. [PMID: 36653166 DOI: 10.1021/acs.jafc.2c05747] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Alcohol-related liver disease (ALD) is one of the most prevalent forms of liver disease in the world. Acetaldehyde, an intermediate product of alcohol catabolism, is a cause of liver injury caused by alcohol. This study was designed to evaluate the protective role and mechanism(s) of genistein against acetaldehyde-induced liver injury in the pathological process of ALD. We found that genistein administration significantly ameliorated alcohol-induced hepatic steatosis, injury, and inflammation in mice. Genistein supplementation markedly reversed hepatic oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and hepatocellular apoptosis in both alcohol-fed mice liver and acetaldehyde-treated hepatocytes. The mechanistic experiments revealed that the restoration of genistein administration rescued heme oxygenase-1 (HO-1) reduction at both transcriptional and protein levels in either alcohol-fed mice liver or acetaldehyde-treated hepatocytes, and the beneficial aspects derived from genistein were abolished in antioxidase heme oxygenase-1 (HO-1)-deficient hepatocytes. Moreover, we confirmed that genistein administration-restored hepatic nuclear factor erythroid 2-related factor 2 (NRF2), a key transcriptional regulator of HO-1, was involved in the protective role of genistein in ALD. This study demonstrated that genistein ameliorated acetaldehyde-induced oxidative stress and liver injury by restoring the hepatic NRF2-HO-1 signaling pathway in response to chronic alcohol consumption. Therefore, genistein may serve as a potential therapeutic choice for the treatment of ALD.
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Affiliation(s)
- Qinchao Ding
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, P. R. China
- College of Animal Science, Zhejiang University, Hangzhou 310058, Zhejiang, P. R. China
| | - Aiwen Pi
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, P. R. China
| | - Liuyi Hao
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, P. R. China
| | - Tiantian Xu
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, P. R. China
| | - Qin Zhu
- Department of Clinical Nutrition, Affiliated Zhejiang Hospital, School of Medicine, Zhejiang University, Hangzhou 310013, Zhejiang, P. R. China
| | - Long Shu
- Department of Clinical Nutrition, Affiliated Zhejiang Hospital, School of Medicine, Zhejiang University, Hangzhou 310013, Zhejiang, P. R. China
| | - Xiaolong Yu
- Department of Clinical Nutrition, Affiliated Zhejiang Hospital, School of Medicine, Zhejiang University, Hangzhou 310013, Zhejiang, P. R. China
| | - Weiguang Wang
- Department of Clinical Nutrition, Affiliated Zhejiang Hospital, School of Medicine, Zhejiang University, Hangzhou 310013, Zhejiang, P. R. China
| | - Caijuan Si
- Department of Clinical Nutrition, Affiliated Zhejiang Hospital, School of Medicine, Zhejiang University, Hangzhou 310013, Zhejiang, P. R. China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, P. R. China
- Department of Clinical Nutrition, Affiliated Zhejiang Hospital, School of Medicine, Zhejiang University, Hangzhou 310013, Zhejiang, P. R. China
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11
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Kono G, Yoshida K, Kokubo E, Ikeda M, Matsubara T, Koyama T, Iwamoto H, Miyaji K. Fermentation Supernatant of Elderly Feces with Inulin and Partially Hydrolyzed Guar Gum Maintains the Barrier of Inflammation-Induced Caco-2/HT29-MTX-E12 Co-Cultured Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:1510-1517. [PMID: 36622307 PMCID: PMC9880993 DOI: 10.1021/acs.jafc.2c06232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 12/22/2022] [Accepted: 12/28/2022] [Indexed: 06/17/2023]
Abstract
Intestinal barrier function declines with aging. We evaluated the effect of dietary fibers and indigestible oligosaccharides on intestinal barrier function by altering the microbiota of the elderly. The feces were anaerobically cultured with indigestible dextrin, inulin, partially hydrolyzed guar gum (PHGG), lactulose, raffinose, or alginate, and the fermented supernatant was added to inflammation-induced Caco-2/HT29-MTX-E12 co-cultured cells. Our data showed that inulin- and PHGG-derived supernatants exerted a protective effect on the intestinal barrier. The protective effect was significantly positively correlated with total short-chain fatty acids (SCFAs) and butyric acid production in the supernatant and negatively correlated with the claudin-2 (CLDN2) gene expression in the cultured cells. Furthermore, we showed that the CLDN2 levels are regulated by butyric acid. Thus, inulin and PHGG can change the intestinal environment of the elderly and maintain the intestinal barrier by accelerating the production of SCFAs and modifying the expression levels of barrier function-related genes.
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12
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Wakil A, Niazi M, Meybodi MA, Pyrsopoulos NT. Emerging Pharmacotherapies in Alcohol-Associated Hepatitis. J Clin Exp Hepatol 2023; 13:116-126. [PMID: 36647403 PMCID: PMC9840076 DOI: 10.1016/j.jceh.2022.06.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/25/2022] [Indexed: 02/07/2023] Open
Abstract
The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis. Conclusion A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.
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Key Words
- AH, alcohol-Associated hepatitis
- ALD, Alcohol-associated liver disease
- ASK-1, Apoptosis signal-regulating kinase-1
- AUD, alcohol use disorder
- CCL2, C–C chemokine ligand type 2
- CVC, Cenicriviroc
- ELAD, Extracorporeal liver assist device
- FMT, Fecal Microbiota Transplant
- G-CSF, Granulocyte colony-stimulating factor
- HA35, Hyaluronic Acid 35KD
- IL-1, interleukin 1
- IL-6, interleukin 6
- LCFA, saturated long-chain fatty acids
- LDL, low-density lipoprotein cholesterol
- LPS, Lipopolysaccharides
- MCP-1, monocyte chemoattractant protein −1
- MDF, Maddrey's discriminant function
- MELD, Model for end-stage disease
- NAC, N-acetylcysteine
- NLRs, nucleotide-binding oligomerization domain-like receptors
- PAMPs, Pathogen-associated molecular patterns
- RCT, Randomized controlled trial
- SAM, S-Adenosyl methionine
- SCFA, short-chain fatty acids. 5
- TLRs, Toll-like receptors
- TNF, tumor necrotic factor
- alcohol-associated hepatitis
- anti-inflammatory
- antioxidants
- liver-gut axis
- microbiome
- sAH, severe alcohol-associated hepatitis
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Affiliation(s)
- Ali Wakil
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, New York, New Jersey, USA
| | - Mumtaz Niazi
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, New York, New Jersey, USA
| | - Mohamad A. Meybodi
- Department of Internal Medicine, Rutgers New Jersey Medical School, New York, New Jersey, USA
| | - Nikolaos T. Pyrsopoulos
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, New York, New Jersey, USA
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13
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Liu J, Wu A, Cai J, She ZG, Li H. The contribution of the gut-liver axis to the immune signaling pathway of NAFLD. Front Immunol 2022; 13:968799. [PMID: 36119048 PMCID: PMC9471422 DOI: 10.3389/fimmu.2022.968799] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/12/2022] [Indexed: 11/24/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and is the most common chronic liver disease in the world. The pathogenesis of NAFLD has not been fully clarified; it involves metabolic disturbances, inflammation, oxidative stress, and various forms of cell death. The “intestinal-liver axis” theory, developed in recent years, holds that there is a certain relationship between liver disease and the intestinal tract, and changes in intestinal flora are closely involved in the development of NAFLD. Many studies have found that the intestinal flora regulates the pathogenesis of NAFLD by affecting energy metabolism, inducing endotoxemia, producing endogenous ethanol, and regulating bile acid and choline metabolism. In this review, we highlighted the updated discoveries in intestinal flora dysregulation and their link to the pathogenesis mechanism of NAFLD and summarized potential treatments of NAFLD related to the gut microbiome.
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Affiliation(s)
- Jiayi Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal of Wuhan University, Wuhan, China
| | - Anding Wu
- Department of general surgery, Huanggang Central Hospital, Huanggang, China
- Huanggang Institute of Translation Medicine, Huanggang, China
| | - Jingjing Cai
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal of Wuhan University, Wuhan, China
- *Correspondence: Zhi-Gang She, ; Hongliang Li,
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Institute of Model Animal of Wuhan University, Wuhan, China
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
- *Correspondence: Zhi-Gang She, ; Hongliang Li,
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14
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Redman JS, Kaspar M, Puri P. Implications of pre-transplant sarcopenia and frailty in patients with non-alcoholic steatohepatitis and alcoholic liver disease. Transl Gastroenterol Hepatol 2022; 7:29. [PMID: 35892054 PMCID: PMC9257536 DOI: 10.21037/tgh-20-236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 07/06/2020] [Indexed: 12/13/2023] Open
Abstract
Frailty manifesting as sarcopenia is an independent risk factor for mortality in cirrhosis, and often presents in low model for end-stage liver disease (MELD) patients. Its etiology is multifactorial, but key physiologic changes culminate in altered energy utilization in the fasting state, preferentially utilizing muscle amino acids for gluconeogenesis thereby promoting sarcopenia. Hyperammonemia alters the circulating amino acid profile, diminishing pro-muscle branched-chain amino acids like leucine. The metabolic syndrome worsens sarcopenia through multi-tissue insulin resistance. Alcohol also exacerbates sarcopenia as a direct muscle toxin and inhibitor of growth signaling. Therapy is aimed at alcohol cessation, frequent high-protein meals, branched-chain amino acid supplementation, and diminished time spent fasting. Moderate exercise can improve muscle mass and muscle quality, though precise exercise regimens have not yet been explicitly determined. Studies are ongoing into the effects of myostatin antagonists and insulin sensitizers. The Liver Frailty Index can predict patients most at risk of poor outcome and should be considered in the management of all cirrhotic patients. Specialty testing like dual-energy X-ray absorptiometry (DEXA) scanning and cross-sectional estimates of muscle mass are areas of active research and may play a future role in clinical risk-stratification.
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Affiliation(s)
- Joseph S. Redman
- Division of Gastroenterology, Hepatology and Nutrition, West Hospital, Virginia Commonwealth University, Richmond, VA, USA
| | - Matt Kaspar
- Division of Gastroenterology, Hepatology and Nutrition, West Hospital, Virginia Commonwealth University, Richmond, VA, USA
| | - Puneet Puri
- Division of Gastroenterology, Hepatology and Nutrition, West Hospital, Virginia Commonwealth University, Richmond, VA, USA
- Division of Gastroenterology, Hepatology and Nutrition, Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA
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15
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Kitamoto S, Kamada N. Periodontal connection with intestinal inflammation: Microbiological and immunological mechanisms. Periodontol 2000 2022; 89:142-153. [PMID: 35244953 PMCID: PMC9018512 DOI: 10.1111/prd.12424] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Humans have coevolved with the trillions of resident microbes that populate every nook and cranny of the body. At each site, the resident microbiota creates a unique ecosystem specialized to its environment, benefiting the development and maintenance of human physiology through harmonious symbiotic relationships with the host. However, when the resident microbiota is perturbed, significant complications may arise with disastrous consequences that affect the local and distant ecosystems. In this context, periodontal disease results in inflammation beyond the oral cavity, such as in the gastrointestinal tract. Accumulating evidence indicates that potentially harmful oral resident bacteria (referred to as pathobionts) and pathogenic immune cells in the oral mucosa can migrate to the lower gastrointestinal tract and contribute to intestinal inflammation. We will review the most recent advances concerning the periodontal connection with intestinal inflammation from microbiological and immunological perspectives. Potential therapeutic approaches that target the connection between the mouth and the gut to treat gastrointestinal diseases, such as inflammatory bowel disease, will be examined. Deciphering the complex interplay between microbes and immunity along the mouth-gut axis will provide a better understanding of the pathogenesis of both oral and gut pathologies and present therapeutic opportunities.
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Affiliation(s)
- Sho Kitamoto
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Nobuhiko Kamada
- Division of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
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16
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Ning H, Zhang T, Zhou X, Liu L, Shang C, Qi R, Ma T. PART1 destabilized by NOVA2 regulates blood-brain barrier permeability in endothelial cells via STAU1-mediated mRNA degradation. Gene X 2022; 815:146164. [PMID: 34990795 DOI: 10.1016/j.gene.2021.146164] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 11/16/2021] [Accepted: 12/06/2021] [Indexed: 12/26/2022] Open
Abstract
Blood-brain barrier dysfunction is recognized as a precursor of Alzheimer's disease development. Endothelial cells as structural basis of blood-brain barrier were observed tight junction failure in amyloid-β(1-42)-stimulated environment. In this study, we found NOVA2, PPP2R3A were down-regulated while PART1, p-NFκB-p65 were up-regulated in amyloid-β(1-42)-incubated endothelial cells. Knockdown of either NOVA2 or PPP2R3A and overexpression of PART1 all increased blood-brain barrier permeability. Lower blood-brain barrier permeability was observed in overexpression of NOVA2 and PPP2R3A and knockdown of PART1 and NFκB-p65. Same tendencies were found in the tight junction-related proteins expressions. Furthermore, overexpression and knockdown of NOVA2 and PART1 had no effect on cell viability. Mechanistically, NOVA2 overexpression was confirmed to reduce half-life of PART1. PART1 could destabilize PPP2R3A messenger RNA (mRNA) by interacting with STAU1. In addition, p-NFκB-p65 functioning as transcription factor reduced the expression of tight junction-related proteins, which was prompted by low protein level of PPP2R3A. Our study highlights the crucial role of NOVA2/PART1/PPP2R3A/p-NFκB-p65 pathway in amyloid-β(1-42)-incubated endothelial cells to modulating blood-brain barrier permeability through STAU1-mediated messenger RNA degradation, implying a potential mechanism of lncRNA and protein interaction in pathogenesis of Alzheimer's disease.
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Affiliation(s)
- Hao Ning
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China
| | - Tianyuan Zhang
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China
| | - Xinxin Zhou
- Liaoning University of Traditional Chinese Medicine, Shenyang 110034, China
| | - Libo Liu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China
| | - Chao Shang
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China
| | - Ruiqun Qi
- Department of Dermatology, The First Hospital of China Medical University, Shenyang 110122, China
| | - Teng Ma
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China.
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17
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Exploring the Inflammatory Pathogenesis of Colorectal Cancer. Diseases 2021; 9:diseases9040079. [PMID: 34842660 PMCID: PMC8628792 DOI: 10.3390/diseases9040079] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/21/2021] [Accepted: 10/23/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is one of the most commonly diagnosed cancers worldwide. Traditionally, mechanisms of colorectal cancer formation have focused on genetic alterations including chromosomal damage and microsatellite instability. In recent years, there has been a growing body of evidence supporting the role of inflammation in colorectal cancer formation. Multiple cytokines, immune cells such T cells and macrophages, and other immune mediators have been identified in pathways leading to the initiation, growth, and metastasis of colorectal cancer. Outside the previously explored mechanisms and pathways leading to colorectal cancer, initiatives have been shifted to further study the role of inflammation in pathogenesis. Inflammatory pathways have also been linked to some traditional risk factors of colorectal cancer such as obesity, smoking and diabetes, as well as more novel associations such as the gut microbiome, the gut mycobiome and exosomes. In this review, we will explore the roles of obesity and diet, smoking, diabetes, the microbiome, the mycobiome and exosomes in colorectal cancer, with a specific focus on the underlying inflammatory and metabolic pathways involved. We will also investigate how the study of colon cancer from an inflammatory background not only creates a more holistic and inclusive understanding of this disease, but also creates unique opportunities for prevention, early diagnosis and therapy.
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18
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Jiang W, Zhu H, Xu W, Liu C, Hu B, Guo Y, Cheng Y, Qian H. Echinacea purpurea polysaccharide prepared by fractional precipitation prevents alcoholic liver injury in mice by protecting the intestinal barrier and regulating liver-related pathways. Int J Biol Macromol 2021; 187:143-156. [PMID: 34293362 DOI: 10.1016/j.ijbiomac.2021.07.095] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/25/2021] [Accepted: 07/14/2021] [Indexed: 12/18/2022]
Abstract
Oxidative damage and intestinal dysbiosis are regarded as crucial culprits in alcoholic liver disease (ALD). This study aimed to examine the protective effects of Echinacea purpurea polysaccharides (EPPs) against ALD and explore the underlying mechanisms based on hepatic oxidative stress, inflammation, and intestinal barrier function. Three polysaccharide fractions, namely, EPP40, EPP60, and EPP80, were obtained by stepwise ethanol precipitation, and their antioxidant activity in vitro was investigated. The results showed that EPP80 with Mw 11.82 kDa had the strongest radical-scavenging capacity against DPPH, ABTS, and •OH radicals. Besides, EPP80 comprised arabinose, galactose, glucose, mannose, galacturonic acid, and glucuronic acid in molar ratios of 13.42:25.12:10.92:8.59:2.07:0.82. The in vivo results showed that EPP80 increased the activities of antioxidant enzymes and reduced the levels of inflammatory cytokines both in mouse serum and liver. Moreover, EPP80 upregulated the expression of Occludin and ZO-1, revealing its protective effect against intestinal barrier dysfunction. Furthermore, EPP80 inhibited alcohol-induced oxidative damage by promoting the expression of Nrf2, HO-1, and NQO1 in the liver. In summary, EPP80 markedly scavenged free radicals in vitro and ameliorated alcohol-induced liver injury via Nrf2/HO-1 pathways in vivo. These findings suggested that EPP80 could provide effective supplementary support in preventing and treating ALD.
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Affiliation(s)
- Wenhao Jiang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi 214122, China
| | - Hongkang Zhu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi 214122, China
| | - Wenqian Xu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi 214122, China
| | - Chang Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi 214122, China
| | - Bin Hu
- School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi 214122, China
| | - He Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Synergetic Innovation Center for Food Safety and Nutrition, Jiangnan University, Wuxi 214122, China.
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19
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Fernandez-Cantos MV, Garcia-Morena D, Iannone V, El-Nezami H, Kolehmainen M, Kuipers OP. Role of microbiota and related metabolites in gastrointestinal tract barrier function in NAFLD. Tissue Barriers 2021; 9:1879719. [PMID: 34280073 PMCID: PMC8489918 DOI: 10.1080/21688370.2021.1879719] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/13/2021] [Accepted: 01/18/2021] [Indexed: 11/06/2022] Open
Abstract
The Gastrointestinal (GI) tract is composed of four main barriers: microbiological, chemical, physical and immunological. These barriers play important roles in maintaining GI tract homeostasis. In the crosstalk between these barriers, microbiota and related metabolites have been shown to influence GI tract barrier integrity, and alterations of the gut microbiome might lead to an increase in intestinal permeability. As a consequence, translocation of bacteria and their products into the circulatory system increases, reaching proximal and distal tissues, such as the liver. One of the most prevalent chronic liver diseases, Nonalcoholic Fatty Liver Disease (NAFLD), has been associated with an altered gut microbiota and barrier integrity. However, the causal link between them has not been fully elucidated yet. In this review, we aim to highlight relevant bacterial taxa and their related metabolites affecting the GI tract barriers in the context of NAFLD, discussing their implications in gut homeostasis and in disease.
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Affiliation(s)
- Maria Victoria Fernandez-Cantos
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
| | - Diego Garcia-Morena
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
| | - Valeria Iannone
- Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Hani El-Nezami
- Molecular and Cell Biology Division, School of Biological Sciences, University of Hong Kong, Hong Kong SAR
| | - Marjukka Kolehmainen
- Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Oscar P. Kuipers
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
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20
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Chen TT, Xiao F, Li N, Shan S, Qi M, Wang ZY, Zhang SN, Wei W, Sun WY. Inflammasome as an Effective Platform for Fibrosis Therapy. J Inflamm Res 2021; 14:1575-1590. [PMID: 33907438 PMCID: PMC8069677 DOI: 10.2147/jir.s304180] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/19/2021] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is the final stage of the development of chronic inflammation. It is characterized by excessive deposition of the extracellular matrix, leading to tissue structure damage and organ dysfunction, which is a serious threat to human health and life. However, the molecular mechanism of fibrosis is still unclear. Inflammasome is a molecular complex of proteins that has been becoming a key innate sensor for host immunity and is involved in pyroptosis, pathogen infection, metabolic syndrome, cellular stress, and tumor metastasis. Inflammasome signaling and downstream cytokine responses mediated by the inflammasome have been found to play an important role in fibrosis. The inflammasome regulates the secretion of IL-1β and IL-18, which are both critical for the process of fibrosis. Recently, researches on the function of inflammasome have attracted extensive attention, and data derived from these researches have increased our understanding of the effects and regulation of inflammasome during fibrosis. In this review, we emphasize the growing evidence for both indirect and direct effects of inflammasomes in triggering fibrosis as well as potential novel targets for antifibrotic therapies.
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Affiliation(s)
- Ting-Ting Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Feng Xiao
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Nan Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Shan Shan
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Meng Qi
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Zi-Ying Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Sheng-Nan Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, Anhui Province, 230032, People's Republic of China
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21
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Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants (Basel) 2021; 10:antiox10030384. [PMID: 33806556 PMCID: PMC8000766 DOI: 10.3390/antiox10030384] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.
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22
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Qin C, Hu J, Wan Y, Cai M, Wang Z, Peng Z, Liao Y, Li D, Yao P, Liu L, Rong S, Bao W, Xu G, Yang W. Narrative review on potential role of gut microbiota in certain substance addiction. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106:110093. [PMID: 32898589 DOI: 10.1016/j.pnpbp.2020.110093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 08/22/2020] [Accepted: 08/30/2020] [Indexed: 12/14/2022]
Abstract
As a neuropsychiatric disorder, substance addiction represents a major public health issue with high prevalence and mortality in many countries. Recently, gut microbiota has been certified to play a part in substance addiction through various mechanisms. Hence, we mainly focused on three substance including alcohol, cocaine and methamphetamine in this review, and summarized their relationships with gut microbiota, respectively. Besides, we also concluded the possible treatments for substance addiction from the perspective of applying gut microbiota. This review aims to build a bridge between substance addiction and gut microbiota according to existing evidences, so as to excavate the possible bi-directional function of microbiota-gut-brain axis in substance addiction for developing therapeutic strategies in the future.
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Affiliation(s)
- Chenyuan Qin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Jiawei Hu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Yiming Wan
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Mengyao Cai
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Zhenting Wang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Zhao Peng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Yuxiao Liao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Dan Li
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Shuang Rong
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene, School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Wei Bao
- Department of Epidemiology, College of Public Health, University of Iowa, IA 52242, USA
| | - Guifeng Xu
- Department of Epidemiology, College of Public Health, University of Iowa, IA 52242, USA; Center for Disabilities and Development, University of Iowa Stead Family Children's Hospital, Iowa City, IA 52242, USA
| | - Wei Yang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China.
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23
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García-Cabrerizo R, Carbia C, O Riordan KJ, Schellekens H, Cryan JF. Microbiota-gut-brain axis as a regulator of reward processes. J Neurochem 2021; 157:1495-1524. [PMID: 33368280 DOI: 10.1111/jnc.15284] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 12/08/2020] [Accepted: 12/21/2020] [Indexed: 12/14/2022]
Abstract
Our gut harbours trillions of microorganisms essential for the maintenance of homeostasis and host physiology in health and disease. In the last decade, there has been a growing interest in understanding the bidirectional pathway of communication between our microbiota and the central nervous system. With regard to reward processes there is accumulating evidence from both animal and human studies that this axis may be a key factor in gating reward valence. Focusing on the mesocorticolimbic pathway, we will discuss how the intestinal microbiota is involved in regulating brain reward functions, both in natural (i.e. eating, social or sexual behaviours) and non-natural reinforcers (drug addiction behaviours including those relevant to alcohol, psychostimulants, opioids and cannabinoids). We will integrate preclinical and clinical evidence suggesting that the microbiota-gut-brain axis could be implicated in the development of disorders associated with alterations in the reward system and how it may be targeted as a promising therapeutic strategy. Cover Image for this issue: https://doi.org/10.1111/jnc.15065.
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Affiliation(s)
| | - Carina Carbia
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | | | - Harriet Schellekens
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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24
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Bruellman R, Llorente C. A Perspective Of Intestinal Immune-Microbiome Interactions In Alcohol-Associated Liver Disease. Int J Biol Sci 2021; 17:307-327. [PMID: 33390852 PMCID: PMC7757023 DOI: 10.7150/ijbs.53589] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Uncovering the intricacies of the gut microbiome and how it interacts with the host immune system has opened up pathways in the search for the treatment of disease conditions. Alcohol-associated liver disease is a major cause of death worldwide. Research has shed light on the breakdown of the protective gut barriers, translocation of gut microbes to the liver and inflammatory immune response to microbes all contributing to alcohol-associated liver disease. This knowledge has opened up avenues for alternative therapies to alleviate alcohol-associated liver disease based on the interaction of the commensal gut microbiome as a key player in the regulation of the immune response. This review describes the relevance of the intestinal immune system, the gut microbiota, and specialized and non-specialized intestinal cells in the regulation of intestinal homeostasis. It also reflects how these components are altered during alcohol-associated liver disease and discusses new approaches for potential future therapies in alcohol-associated liver disease.
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Affiliation(s)
- Ryan Bruellman
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
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25
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Skinner C, Thompson AJ, Thursz MR, Marchesi JR, Vergis N. Intestinal permeability and bacterial translocation in patients with liver disease, focusing on alcoholic aetiology: methods of assessment and therapeutic intervention. Therap Adv Gastroenterol 2020; 13:1756284820942616. [PMID: 33149761 PMCID: PMC7580143 DOI: 10.1177/1756284820942616] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/25/2020] [Indexed: 02/04/2023] Open
Abstract
Increased bacterial translocation (BT) across the gut barrier due to greater intestinal permeability (IP) is seen across a range of conditions, including alcohol-related liver disease (ArLD). The phenomenon of BT may contribute to both the pathogenesis and the development of complications in ArLD. There are a number of methods available to assess IP and in this review we look at their various advantages and limitations. The knowledge around BT and IP in ArLD is also reviewed, as well as the therapeutic strategies currently in use and in development.
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Affiliation(s)
- Charlotte Skinner
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
| | - Alex J. Thompson
- Department of Surgery & Cancer, St. Mary’s Hospital Campus, Imperial College London, London, UK
| | - Mark R. Thursz
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
| | - Julian R. Marchesi
- Department of Metabolism, Digestion and Reproduction, St Mary’s Hospital Campus, Imperial College London, London, UK
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26
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Kamran U, Towey J, Khanna A, Chauhan A, Rajoriya N, Holt A. Nutrition in alcohol-related liver disease: Physiopathology and management. World J Gastroenterol 2020; 26:2916-2930. [PMID: 32587439 PMCID: PMC7304106 DOI: 10.3748/wjg.v26.i22.2916] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/08/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
Malnutrition encompassing both macro- and micro-nutrient deficiency, remains one of the most frequent complications of alcohol-related liver disease (ArLD). Protein-energy malnutrition can cause significant complications including sarcopenia, frailty and immunodepression in cirrhotic patients. Malnutrition reduces patient’s survival and negatively affects the quality of life of individuals with ArLD. Moreover, nutritional deficit increases the likelihood of hepatic decompensation in cirrhosis. Prompt recognition of at-risk individuals, early diagnosis and treatment of malnutrition remains a key component of ArLD management. In this review, we describe the pathophysiology of malnutrition in ArLD, review the screening tools available for nutritional assessment and discuss nutritional management strategies relevant to the different stages of ArLD, ranging from acute alcoholic hepatitis through to decompensated end stage liver disease.
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Affiliation(s)
- Umair Kamran
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, United Kingdom
| | - Jennifer Towey
- Department of Dietetics, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, United Kingdom
| | - Amardeep Khanna
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, United Kingdom
| | - Abhishek Chauhan
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, United Kingdom
- Centre for Liver Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Neil Rajoriya
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, United Kingdom
| | - Andrew Holt
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2GW, United Kingdom
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27
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Wang F, Cui Q, Zeng Y, Chen P. [Gut microbiota-an important contributor to liver diseases]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:595-600. [PMID: 32895142 DOI: 10.12122/j.issn.1673-4254.2020.04.23] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Gut microbiota constitute a complicated but manifold ecosystem, in which specific symbiotic relationships are formed among various bacteria. To maintain a steady state, the gastrointestinal tract and the liver form a close anatomical and functional two-way, interconnected network through the portal circulation. "Gut-liver axis" plays a key role in the pathogenesis of liver diseases. Accumulating evidence indicates that gut microbiota can influence the liver pathophysiology directly or indirectly via a variety of signal pathways. In a pathological state where an ecological imbalance occurs at the compositional and functional levels, gut microbes would interact with the host immune system and other type of cells to cause liver steatosis, inflammation and fibrosis, which in turn give rise to the development of such liver diseases as alcoholic liver disease, nonalcoholic fatty liver disease, primary sclerosing cholangitis, and acute liver failure, to name a few. Studies have shown that microorganisms, such as prebiotics and probiotics, can improve the prognosis of certain diseases, which open a new era of treating liver diseases with bacteria. There are many unknowns and hidden values in the gut microbiome. To explore the pathophysiological mechanism of various complex diseases and develop scientific and effective clinical treatment strategies, efforts should be made to obtain insights into how certain intestinal microbiota participates in the occurrence and progression of liver diseases. As the connection between gut microbiota and liver diseases at both the acute and chronic phases was not elaborated in previously published review articles, herein we discuss the association between gut microbiota and both acute and chronic liver injury. The anatomical structure of the liver enables it to form a close network with the gut microbiota, which is an important mediator in the regulation of the hepatic physiological and pathological functions.
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Affiliation(s)
- Fangzhao Wang
- Department of Pathophysiology, College of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qianru Cui
- Department of Pathophysiology, College of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yunong Zeng
- Department of Pathophysiology, College of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Peng Chen
- Department of Pathophysiology, College of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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28
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Li T, Chiang JYL. Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease. Hepatobiliary Surg Nutr 2020; 9:152-169. [PMID: 32355674 PMCID: PMC7188552 DOI: 10.21037/hbsn.2019.09.03] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/26/2019] [Indexed: 12/12/2022]
Abstract
Bile acids are synthesized from cholesterol only in hepatocytes. Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine. Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor TGR5. FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis. In addition, bile acid-activated cellular signaling pathways regulate metabolic homeostasis, immunity, and cell proliferation in various metabolically active organs. In the small and large intestine, gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects. In turn, bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity. Currently, bile acid-based therapies including systemic and intestine-restricted FXR agonists, TGR5 agonists, fibroblast growth factor 19 analogue, intestine FXR antagonists, and intestine apical sodium-bile acid transporter (ASBT) inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis (NASH). These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest. More recently, human and experimental alcoholic liver disease (ALD) has been associated with disrupted bile acid homeostasis. In additional, new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.
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Affiliation(s)
- Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - John Y. L. Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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29
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Arab JP, Arrese M, Shah VH. Gut microbiota in non-alcoholic fatty liver disease and alcohol-related liver disease: Current concepts and perspectives. Hepatol Res 2020; 50:407-418. [PMID: 31840358 PMCID: PMC7187400 DOI: 10.1111/hepr.13473] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/05/2020] [Accepted: 12/10/2020] [Indexed: 12/17/2022]
Abstract
The term, gut-liver axis, is used to highlight the close anatomical and functional relationship between the intestine and the liver. It has been increasingly recognized that the gut-liver axis plays an essential role in the development and progression of liver disease. In particular, in non-alcoholic fatty liver disease and alcohol-related liver disease, the two most common causes of chronic liver disease, a dysbiotic gut microbiota can influence intestinal permeability, allowing some pathogens or bacteria-derived factors from the gut reaching the liver through the enterohepatic circulation contributing to liver injury, steatohepatitis, and fibrosis progression. Pathways involved are multiple, including changes in bile acid metabolism, intestinal ethanol production, generation of short-chain fatty acids, and other by-products. Bile acids act through dedicated bile acid receptors, farnesoid X receptor and TGR5, in both the ileum and the liver, influencing lipid metabolism, inflammation, and fibrogenesis. Currently, both non-alcoholic fatty liver disease and alcohol-related liver disease lack effective therapies, and therapeutic targeting of gut microbiota and bile acids enterohepatic circulation holds promise. In this review, we summarize current knowledge about the role of gut microbiota in the pathogenesis of non-alcoholic fatty liver disease and alcohol-related liver disease, as well as the relevance of microbiota or bile acid-based approaches in the management of those liver diseases.
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Affiliation(s)
- Juan P. Arab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.,Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile,Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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30
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Stremmel W, Staffer S, Weiskirchen R. Phosphatidylcholine Passes by Paracellular Transport to the Apical Side of the Polarized Biliary Tumor Cell Line Mz-ChA-1. Int J Mol Sci 2019; 20:ijms20164034. [PMID: 31430850 PMCID: PMC6720464 DOI: 10.3390/ijms20164034] [Citation(s) in RCA: 5] [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: 07/06/2019] [Revised: 08/15/2019] [Accepted: 08/16/2019] [Indexed: 01/09/2023] Open
Abstract
Phosphatidylcholine (PC) translocation into mucus of the intestine was shown to occur via a paracellular transport across the apical/lateral tight junction (TJ) barrier. In case this could also be operative in biliary epithelial cells, this may have implication for the pathogenesis of primary sclerosing cholangitis (PSC). We here evaluated the transport of PC across polarized cholangiocytes. Therefore, the biliary tumor cell line Mz-ChA-1 was grown to confluency. In transwell culture systems the translocation of PC to the apical compartment was analyzed. After 21 days in culture, polarized Mz-ChA-1 cells revealed a predominant apical translocation of choline containing phospholipids including PC with minimal intracellular accumulation. Transport was suppressed by TJ destruction employing chemical inhibitors and pretreatment with siRNA to TJ forming proteins as well as the apical transmembrane mucin 3 as PC acceptor. Apical translocation was dependent on a negative apical electrical potential created by the cystic fibrosis transmembrane conductance regulator (CFTR) and the anion exchange protein 2 (AE2). It was stimulated by apical application of secretory mucins. The results indicated the existence of a paracellular PC passage across apical/lateral TJ of the polarized biliary epithelial tumor cell line Mz-ChA-1. This has implication for the generation of a protective mucus barrier in the biliary tree.
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Affiliation(s)
- Wolfgang Stremmel
- Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, D-69120 Heidelberg, Germany.
| | - Simone Staffer
- University Clinics of Heidelberg, D-69120 Heidelberg, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, D-52074 Aachen, Germany
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31
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Schuhmacher D, Sontag JM, Sontag E. Protein Phosphatase 2A: More Than a Passenger in the Regulation of Epithelial Cell-Cell Junctions. Front Cell Dev Biol 2019; 7:30. [PMID: 30895176 PMCID: PMC6414416 DOI: 10.3389/fcell.2019.00030] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/22/2019] [Indexed: 12/17/2022] Open
Abstract
Cell–cell adhesion plays a key role in the maintenance of the epithelial barrier and apicobasal cell polarity, which is crucial for homeostasis. Disruption of cell–cell adhesion is a hallmark of numerous pathological conditions, including invasive carcinomas. Adhesion between apposing cells is primarily regulated by three types of junctional structures: desmosomes, adherens junctions, and tight junctions. Cell junctional structures are highly regulated multiprotein complexes that also serve as signaling platforms to control epithelial cell function. The biogenesis, integrity, and stability of cell junctions is controlled by complex regulatory interactions with cytoskeletal and polarity proteins, as well as modulation of key component proteins by phosphorylation/dephosphorylation processes. Not surprisingly, many essential signaling molecules, including protein Ser/Thr phosphatase 2A (PP2A) are associated with intercellular junctions. Here, we examine how major PP2A enzymes regulate epithelial cell–cell junctions, either directly by associating with and dephosphorylating component proteins, or indirectly by affecting signaling pathways that control junctional integrity and cytoskeletal dynamics. PP2A deregulation has severe consequences on the stability and functionality of these structures, and disruption of cell–cell adhesion and cell polarity likely contribute to the link between PP2A dysfunction and human carcinomas.
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Affiliation(s)
- Diana Schuhmacher
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia
| | - Jean-Marie Sontag
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
| | - Estelle Sontag
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.,Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
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32
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Deng Y, Cai Y, Liu L, Lin X, Lu P, Guo Y, Han M, Xu G. Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels. FASEB J 2018; 33:3718-3730. [PMID: 30521379 DOI: 10.1096/fj.201800885rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Protein tyrosine (Tyr) nitration, the covalent addition of a nitro group (•NO2) to Tyr residues, is emerging as a candidate mechanism of endothelial dysfunction. Previous studies have shown that Tyr nitration is primarily induced by nitrosative stress, a process characterized by the production of reactive nitrogen species, especially peroxynitrite anion (ONOO-), which is considered a secondary product of NO in the presence of superoxide radicals (O2•-). However, the impact of nitrosative stress-induced Tyr nitration on endothelial dysfunction has not been thoroughly elucidated to date. We developed an endothelial dysfunction model, a process called "endothelial-to-mesenchymal transition (EndMT)," and evaluated the production of NO, O2•-, and protein nitration during EndMT. The results showed that TGF-β1 stimulation induced EndMT and elevated endothelial NO and O2•- production as well as nitration of the catalytic subunit of protein phosphatase (PP)2A. Mass spectrometry analysis showed that Tyr265 was the nitration site in the catalytic subunit of protein phosphatase (PP)2A, and this Tyr nitration increased PP2A activity and disrupted endothelial integrity. To devise an endothelial-targeted anti-PP2Ac nitration strategy, a mimic peptide, tyrosine 265 wild type (Y265WT), conjugated with the cell-penetrating peptide HIV-1 TAT protein (TAT) was synthesized. PP2Ac nitration and PP2A activity were significantly inhibited by pretreatment with TAT-265WT, and the integrity of endothelial cells was maintained. Furthermore, injection of TAT-265WT attenuated renal nitration formation and caused anticapillary rarefaction in a unilateral urethral obstructive nephropathy model. Taken together, these results offer preclinical proof of concept for TAT-265WT as a tractable agent to protect against nitrosative stress-induced endothelial dysfunction in renal microvessels.-Deng,Y., Cai, Y., Liu, L., Lin, X., Lu, P., Guo, Y., Han, M., Xu, G. Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels.
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Affiliation(s)
- Yuanjun Deng
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Cai
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lele Liu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xueping Lin
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pingfan Lu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiyan Guo
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Han
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Xu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Choksi YA, Reddy VK, Singh K, Barrett CW, Short SP, Parang B, Keating CE, Thompson JJ, Verriere TG, Brown RE, Piazuelo MB, Bader DM, Washington MK, Mittal MK, Brand T, Gobert AP, Coburn LA, Wilson KT, Williams CS. BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability. Mucosal Immunol 2018; 11:1363-1374. [PMID: 29907869 PMCID: PMC6162166 DOI: 10.1038/s41385-018-0043-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 03/31/2018] [Accepted: 04/15/2018] [Indexed: 02/04/2023]
Abstract
Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves-/- mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves-/- mice inoculated with Citrobacter rodentium had greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves-/- mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. coli showed increased attaching/effacing lesions in the absence of BVES. Finally, BVES mRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.
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Affiliation(s)
- Yash A Choksi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Vishruth K Reddy
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kshipra Singh
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Caitlyn W Barrett
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Sarah P Short
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Bobak Parang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Cody E Keating
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Joshua J Thompson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Thomas G Verriere
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rachel E Brown
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - David M Bader
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Mukul K Mittal
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Thomas Brand
- Developmental Dynamics, Heart Science Centre, Imperial College London, London, UK
| | - Alain P Gobert
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lori A Coburn
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA
| | - Keith T Wilson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Christopher S Williams
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA.
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
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Wang C, Tanataweethum N, Karnik S, Bhushan A. Novel Microfluidic Colon with an Extracellular Matrix Membrane. ACS Biomater Sci Eng 2018; 4:1377-1385. [DOI: 10.1021/acsbiomaterials.7b00883] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Chengyao Wang
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, United States
| | - Nida Tanataweethum
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, United States
| | - Sonali Karnik
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, United States
| | - Abhinav Bhushan
- Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, United States
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35
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Intestinal dysbiosis and permeability: the yin and yang in alcohol dependence and alcoholic liver disease. Clin Sci (Lond) 2018; 132:199-212. [PMID: 29352076 DOI: 10.1042/cs20171055] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 12/07/2017] [Accepted: 12/19/2017] [Indexed: 02/07/2023]
Abstract
Alcohol dependence and alcoholic liver disease represent a major public health problem with substantial morbidity and mortality. By yet incompletely understood mechanisms, chronic alcohol abuse is associated with increased intestinal permeability and alterations of the gut microbiota composition, allowing bacterial components, bacteria, and metabolites to reach the portal and the systemic circulation. These gut-derived bacterial products are recognized by immune cells circulating in the blood or residing in remote organs such as the liver leading to the release of pro-inflammatory cytokines which are considered important mediators of the liver-gut-brain communication. Although circulating cytokines are likely not the sole factors involved, they can induce liver inflammation/damage and reach the central nervous system where they favor neuroinflammation which is associated with change in mood, cognition, and drinking behavior. In this review, the authors focus on the current evidence describing the changes that occur in the intestinal microbiota with chronic alcohol consumption in conjunction with intestinal barrier breakdown and inflammatory changes sustaining the concept of a gut-liver-brain axis in the pathophysiology of alcohol dependence and alcoholic liver disease.
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36
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Yang G, Bibi S, Du M, Suzuki T, Zhu MJ. Regulation of the intestinal tight junction by natural polyphenols: A mechanistic perspective. Crit Rev Food Sci Nutr 2018; 57:3830-3839. [PMID: 27008212 DOI: 10.1080/10408398.2016.1152230] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Impairment of the epithelial barrier function is closely linked to the pathogenesis of various gastrointestinal diseases, food allergies, type I diabetes, and other systematic diseases. Plant-derived polyphenols are natural secondary metabolites and exert various physiological benefits, including anti-inflammatory, anti-oxidative, anti-carcinogenic, and anti-aging effects. Recent studies also show the role of plant polyphenols in regulation of the intestinal barrier and prevention of intestinal inflammatory diseases. Here we summarize the regulatory pathways and mediators linking polyphenols to their beneficial effects on tight junction and gut epithelial barrier functions, and provide useful information about using polyphenols as nutraceuticals for intestinal diseases.
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Affiliation(s)
- Guan Yang
- a School of Food Science , Washington State University , Pullman , Washington , USA
| | - Shima Bibi
- a School of Food Science , Washington State University , Pullman , Washington , USA
| | - Min Du
- b Department of Animal Science , Washington State University , Pullman , Washington , USA
| | - Takuya Suzuki
- c Department of Biofunctional Science and Technology , Hiroshima University , Higashi-Hiroshima , Japan
| | - Mei-Jun Zhu
- a School of Food Science , Washington State University , Pullman , Washington , USA
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37
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Zhou Z, Zhong W. Targeting the gut barrier for the treatment of alcoholic liver disease. LIVER RESEARCH 2017; 1:197-207. [PMID: 30034913 PMCID: PMC6051712 DOI: 10.1016/j.livres.2017.12.004] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcohol consumption remains one of the predominant causes of liver disease and liver-related death worldwide. Intriguingly, dysregulation of the gut barrier is a key factor promoting the pathogenesis of alcoholic liver disease (ALD). A functional gut barrier, which consists of a mucus layer, an intact epithelial monolayer and mucosal immune cells, supports nutrient absorption and prevents bacterial penetration. Compromised gut barrier function is associated with the progression of ALD. Indeed, alcohol consumption disrupts the gut barrier, increases gut permeability, and induces bacterial translocation both in ALD patients and in experimental models with ALD. Moreover, alcohol consumption also causes enteric dysbiosis with both numerical and proportional perturbations. Here, we review and discuss mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD. Unfortunately, there is no effectual Food and Drug Administration-approved treatment for any stage of ALD. Therefore, we conclude with a discussion of potential strategies aimed at restoring the gut barrier in ALD. The principle behind antibiotics, prebiotics, probiotics and fecal microbiota transplants is to restore microbial symbiosis and subsequently gut barrier function. Nutrient-based treatments, such as dietary supplementation with zinc, niacin or fatty acids, have been shown to regulate tight junction expression, reduce intestinal inflammation, and prevent endotoxemia as well as liver injury caused by alcohol in experimental settings. Interestingly, saturated fatty acids may also directly control the gut microbiome. In summary, clinical and experimental studies highlight the significance and efficacy of the gut barrier in treating ALD.
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Affiliation(s)
- Zhanxiang Zhou
- Center for Translational Biomedical Research, School of Health and Human Sciences, University of North Carolina at Greensboro, Kannapolis, NC, USA
- Department of Nutrition, School of Health and Human Sciences, University of North Carolina at Greensboro, Greensboro, NC, USA
| | - Wei Zhong
- Center for Translational Biomedical Research, School of Health and Human Sciences, University of North Carolina at Greensboro, Kannapolis, NC, USA
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Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease. Redox Biol 2017; 14:626-636. [PMID: 29156373 PMCID: PMC5700831 DOI: 10.1016/j.redox.2017.11.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 11/03/2017] [Accepted: 11/07/2017] [Indexed: 12/15/2022] Open
Abstract
Alcohol metabolism in the liver generates highly toxic acetaldehyde. Breakdown of acetaldehyde by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria consumes NAD+ and generates reactive oxygen/nitrogen species, which represents a fundamental mechanism in the pathogenesis of alcoholic liver disease (ALD). A mitochondria-targeted lipophilic ubiquinone (MitoQ) has been shown to confer greater protection against oxidative damage in the mitochondria compared to untargeted antioxidants. The present study aimed to investigate if MitoQ could preserve mitochondrial ALDH2 activity and speed up acetaldehyde clearance, thereby protects against ALD. Male C57BL/6 J mice were exposed to alcohol for 8 weeks with MitoQ supplementation (5 mg/kg/d) for the last 4 weeks. MitoQ ameliorated alcohol-induced oxidative/nitrosative stress and glutathione deficiency. It also reversed alcohol-reduced hepatic ALDH activity and accelerated acetaldehyde clearance through modulating ALDH2 cysteine S-nitrosylation, tyrosine nitration and 4-hydroxynonenol adducts formation. MitoQ ameliorated nitric oxide (NO) donor-mediated ADLH2 S-nitrosylation and nitration in Hepa-1c1c7 cells under glutathion depletion condition. In addition, alcohol-increased circulating acetaldehyde levels were accompanied by reduced intestinal ALDH activity and impaired intestinal barrier. In accordance, MitoQ reversed alcohol-increased plasma endotoxin levels and hepatic toll-like receptor 4 (TLR4)-NF-κB signaling along with subsequent inhibition of inflammatory cell infiltration. MitoQ also reversed alcohol-induced hepatic lipid accumulation through enhancing fatty acid β-oxidation. Alcohol-induced ER stress and apoptotic cell death signaling were reversed by MitoQ. This study demonstrated that speeding up acetaldehyde clearance by preserving ALDH2 activity critically mediates the beneficial effect of MitoQ on alcohol-induced pathogenesis at the gut-liver axis.
PTMs of ALDH2 participated in the pathogenesis of alcoholic liver disease. MitoQ treatment accelerated acetaldehyde detoxification. MitoQ ameliorated acetaldehyde-related tight junction disruption. MitoQ reversed TLR4-mediated inflammatory response in alcoholic liver disease. MitoQ counteracts alcohol-induced ER stress and cell apoptosis.
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Dasarathy J, McCullough AJ, Dasarathy S. Sarcopenia in Alcoholic Liver Disease: Clinical and Molecular Advances. Alcohol Clin Exp Res 2017; 41:1419-1431. [PMID: 28557005 DOI: 10.1111/acer.13425] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 05/16/2017] [Indexed: 12/18/2022]
Abstract
Despite advances in treatment of alcohol use disorders that focus on increasing abstinence and reducing recidivism, alcoholic liver disease (ALD) is projected to be the major cause of cirrhosis and its complications. Malnutrition is recognized as the most frequent complication in ALD, and despite the high clinical significance, there are no effective therapies to reverse malnutrition in ALD. Malnutrition is a relatively imprecise term, and sarcopenia or skeletal muscle loss, the major component of malnutrition, is primarily responsible for the adverse clinical consequences in patients with liver disease. It is, therefore, critical to define the specific abnormality (sarcopenia) rather than malnutrition in ALD, so that therapies targeting sarcopenia can be developed. Skeletal muscle mass is maintained by a balance between protein synthesis and proteolysis. Both direct effects of ethanol (EtOH) and its metabolites on the skeletal muscle and the consequences of liver disease result in disturbed proteostasis (protein homeostasis) and consequent sarcopenia. Once cirrhosis develops in patients with ALD, abstinence is unlikely to be effective in completely reversing sarcopenia, as other contributors including hyperammonemia, hormonal, and cytokine abnormalities aggravate sarcopenia and maintain a state of anabolic resistance initiated by EtOH. Cirrhosis is also a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from signaling and substrate functions. Novel therapeutic options are being recognized that are likely to supplant the current "deficiency replacement" approach and instead focus on specific molecular perturbations, given the increasing availability of small molecules that can target specific signaling components. Myostatin antagonists, leucine supplementation, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis in general, and ALD, specifically. Translation of these data to human studies and clinical application requires priority for allocation of resources.
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Affiliation(s)
| | - Arthur J McCullough
- Department of Gastreoenterology, Hepatology and Pathobiology, Cleveland Clinic, Cleveland, Ohio
| | - Srinivasan Dasarathy
- Department of Gastreoenterology, Hepatology and Pathobiology, Cleveland Clinic, Cleveland, Ohio
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40
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Szabo G, Petrasek J. Gut-liver axis and sterile signals in the development of alcoholic liver disease. Alcohol Alcohol 2017; 52:414-424. [PMID: 28482064 PMCID: PMC5860369 DOI: 10.1093/alcalc/agx025] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/04/2017] [Accepted: 04/25/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Innate immunity plays a critical role in the development of alcohol-induced liver inflammation. Understanding the inter-relationship of signals from within and outside of the liver that trigger liver inflammation is pivotal for development of novel therapeutic targets of alcoholic liver disease (ALD). AIM The aim of this paper is to review recent advances in the field of alcohol-induced liver inflammation. METHODS A detailed literature review was performed using the PubMed database published between January 1980 and December 2016. RESULTS We provide an update on the role of intestinal microbiome, metabolome and the gut-liver axis in ALD, discuss the growing body of evidence on the diversity of liver macrophages and their differential contribution to alcohol-induced liver inflammation, and highlight the crucial role of inflammasomes in integration of inflammatory signals in ALD. Studies to date have identified a multitude of new therapeutic targets, some of which are currently being tested in patients with severe alcoholic hepatitis. These treatments aim to strengthen the intestinal barrier, ameliorate liver inflammation and augment hepatocyte regeneration. CONCLUSION Given the complexity of inflammation in ALD, multiple pathobiological mechanisms may need to be targeted at the same time as it seems unlikely that there is a single dominant pathogenic pathway in ALD that would be easily targeted using a single target drug approach. SHORT SUMMARY Here, we focus on recent advances in immunopathogenesis of alcoholic liver disease (ALD), including gut-liver axis, hepatic macrophage activation, sterile inflammation and synergy between bacterial and sterile signals. We propose a multiple parallel hit model of inflammation in ALD and discuss its implications for clinical trials in alcoholic hepatitis.
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Affiliation(s)
- Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605,USA
| | - Jan Petrasek
- Department of Medicine, University of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605,USA
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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41
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Arab JP, Martin-Mateos RM, Shah VH. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg. Hepatol Int 2017; 12:24-33. [PMID: 28550391 DOI: 10.1007/s12072-017-9798-x] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 05/02/2017] [Indexed: 12/11/2022]
Abstract
The term gut-liver axis is used to highlight the close anatomical and functional relationship between the intestine and the liver. The intestine has a highly specialized epithelial membrane which regulates transport across the mucosa. Due to dysbiosis, impairment of the intestinal barrier and altered immunity status, bacterial products can reach the liver through the portal vein, where they are recognized by specific receptors, activate the immune system and lead to a proinflammatory response. Gut microbiota and bacterial translocation play an important role in the pathogenesis of chronic liver diseases, including alcoholic and non-alcoholic fatty liver disease, cirrhosis, and its complications, such as portal hypertension, spontaneous bacterial peritonitis and hepatic encephalopaty. The gut microbiota also plays a critical role as a modulator of bile acid metabolism which can also influence intestinal permeability and portal hypertension through the farnesoid-X receptor. On the other hand, cirrhosis and portal hypertension affect the microbiota and increase translocation, leading to a "chicken and egg" situation, where translocation increases portal pressure, and vice versa. A myriad of therapies targeting gut microbiota have been evaluated specifically in patients with chronic liver disease. Further studies targeting intestinal microbiota and its possible hemodynamic and metabolic effects are needed. This review summarizes the current knowledge about the role of gut microbiota in the pathogenesis of chronic liver diseases and portal hypertension.
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Affiliation(s)
- Juan P Arab
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First ST SW, Rochester, MN, USA.,Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Rosa M Martin-Mateos
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First ST SW, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First ST SW, Rochester, MN, USA.
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42
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Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE, Mittal MK, Naik RD, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Brand T, Bader DM, Tansey WP, Chen R, Brentnall TA, Grady WM, Williams CS. BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Gut 2017; 66:852-862. [PMID: 28389570 PMCID: PMC5385850 DOI: 10.1136/gutjnl-2015-310255] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 12/15/2015] [Accepted: 12/17/2015] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. DESIGN We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves-/- and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. RESULTS BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves-/- mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. CONCLUSION Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.
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Affiliation(s)
- Bobak Parang
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University
| | - Andrew M. Kaz
- Research and Development Service, VA Puget Sound Health Care System,Department of Medicine, Division of Gastroenterology, University of Washington, Seattle
| | - Caitlyn W. Barrett
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University
| | - Sarah P. Short
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University
| | - Wei Ning
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University
| | - Cody E. Keating
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University
| | - Mukul K. Mittal
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University
| | - Rishi D. Naik
- Department of Medicine, Division of Gastroenterology, Vanderbilt University
| | - Mary K. Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University
| | - Frank L. Revetta
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University
| | | | - Xi Chen
- Vanderbilt Ingram Cancer Center
| | - Keith T. Wilson
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University,Vanderbilt Ingram Cancer Center,Veterans Affairs Tennessee Valley Health Care System, Nashville, TN
| | - Thomas Brand
- Department of Developmental Dynamics, Imperial College of London
| | - David M. Bader
- Department of Cell and Developmental Biology, Vanderbilt University
| | - William P. Tansey
- Vanderbilt Ingram Cancer Center,Department of Cell and Developmental Biology, Vanderbilt University
| | - Ru Chen
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle
| | - Teresa A. Brentnall
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle
| | - William M. Grady
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle,Clinical Research Division, Fred Hutchinson Cancer Research Center
| | - Christopher S. Williams
- Department of Medicine, Division of Gastroenterology, Vanderbilt University,Department of Cancer Biology, Vanderbilt University,Vanderbilt Ingram Cancer Center,Veterans Affairs Tennessee Valley Health Care System, Nashville, TN
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43
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Morris NL, Hammer AM, Cannon AR, Gagnon RC, Li X, Choudhry MA. Dysregulation of microRNA biogenesis in the small intestine after ethanol and burn injury. Biochim Biophys Acta Mol Basis Dis 2017; 1863:2645-2653. [PMID: 28404517 DOI: 10.1016/j.bbadis.2017.03.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/08/2017] [Accepted: 03/31/2017] [Indexed: 12/11/2022]
Abstract
Ethanol exposure at the time of burn injury is a major contributor to post-burn pathogenesis. Many of the adverse effects associated with ethanol and burn injury are linked to an impaired intestinal barrier. The combined insult causes intestinal inflammation, resulting in tissue damage, altered tight junction expression, and increased intestinal permeability. MicroRNAs play a critical role in maintaining intestinal homeostasis including intestinal inflammation and barrier function. Specifically, miR-150 regulates inflammatory mediators which can contribute to gut barrier disruption. The present study examined whether ethanol and burn injury alter expression of microRNA processing enzymes (Drosha, Dicer, and Argonaute-2) and miR-150 in the small intestine. Male mice were gavaged with ethanol (~2.9g/kg) 4h prior to receiving a ~12.5% total body surface area full thickness burn. One or three days after injury, mice were euthanized and small intestinal epithelial cells (IECs) were isolated and analyzed for expression of microRNA biogenesis components and miR-150. Dicer mRNA and protein levels were not changed following the combined insult. Drosha and Argonaute-2 mRNA and protein levels were significantly reduced in IECs one day after injury; which accompanied reduced miR-150 expression. To further determine the role of miR-150 in intestinal inflammation, young adult mouse colonocytes were transfected with a miR-150 plasmid and stimulated with LPS (100ng/ml). miR-150 overexpression significantly reduced IL-6 and KC protein levels compared to vector control cells challenged with LPS. These results suggest that altered microRNA biogenesis and associated decrease in miR-150 likely contribute to increased intestinal inflammation following ethanol and burn injury.
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Affiliation(s)
- Niya L Morris
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.; Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.
| | - Adam M Hammer
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.; Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.
| | - Abigail R Cannon
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.; Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.
| | - Robin C Gagnon
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA..
| | - Xiaoling Li
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA..
| | - Mashkoor A Choudhry
- Alcohol Research Program, Burn and Shock Trauma Research Institute, Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.; Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA; Department of Microbiology and Immunology, Loyola University Chicago Health Sciences Campus, Maywood, IL 60153, USA.
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Bishehsari F, Magno E, Swanson G, Desai V, Voigt RM, Forsyth CB, Keshavarzian A. Alcohol and Gut-Derived Inflammation. Alcohol Res 2017; 38:163-171. [PMID: 28988571 PMCID: PMC5513683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In large amounts, alcohol and its metabolites can overwhelm the gastrointestinal tract (GI) and liver and lead to damage both within the GI and in other organs. Specifically, alcohol and its metabolites promote intestinal inflammation through multiple pathways. That inflammatory response, in turn, exacerbates alcohol-induced organ damage, creating a vicious cycle and leading to additional deleterious effects of alcohol both locally and systemically. This review summarizes the mechanisms by which chronic alcohol intake leads to intestinal inflammation, including altering intestinal microbiota composition and function, increasing the permeability of the intestinal lining, and affecting the intestinal immune homeostasis. Understanding the mechanisms of alcohol-induced intestinal inflammation can aid in the discovery of therapeutic approaches to mitigate alcohol-induced organ dysfunctions.
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Cao L, Quan XB, Zeng WJ, Yang XO, Wang MJ. Mechanism of Hepatocyte Apoptosis. J Cell Death 2016; 9:19-29. [PMID: 28058033 PMCID: PMC5201115 DOI: 10.4137/jcd.s39824] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/14/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocyte apoptosis plays important roles in both the removal of external microorganisms and the occurrence and development of liver diseases. Different conditions, such as virus infection, fatty liver disease, hepatic ischemia reperfusion, and drug-induced liver injury, are accompanied by hepatocyte apoptosis. This review summarizes recent research on the mechanism of hepatocyte apoptosis involving the classical extrinsic and intrinsic apoptotic pathways, endoplasmic reticulum stress, and oxidative stress-induced apoptosis. We emphasized the major causes of apoptosis according to the characteristics of different liver diseases. Several concerns regarding future research and clinical application are also raised.
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Affiliation(s)
- Lei Cao
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xi-Bing Quan
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wen-Jiao Zeng
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiao-Ou Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Ming-Jie Wang
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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46
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Samak G, Gangwar R, Meena AS, Rao RG, Shukla PK, Manda B, Narayanan D, Jaggar JH, Rao R. Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers. Sci Rep 2016; 6:38899. [PMID: 27958326 PMCID: PMC5153649 DOI: 10.1038/srep38899] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 11/14/2016] [Indexed: 12/13/2022] Open
Abstract
Ethanol is metabolized into acetaldehyde in most tissues. In this study, we investigated the synergistic effect of ethanol and acetaldehyde on the tight junction integrity in Caco-2 cell monolayers. Expression of alcohol dehydrogenase sensitized Caco-2 cells to ethanol-induced tight junction disruption and barrier dysfunction, whereas aldehyde dehydrogenase attenuated acetaldehyde-induced tight junction disruption. Ethanol up to 150 mM did not affect tight junction integrity or barrier function, but it dose-dependently increased acetaldehyde-mediated tight junction disruption and barrier dysfunction. Src kinase and MLCK inhibitors blocked this synergistic effect of ethanol and acetaldehyde on tight junction. Ethanol and acetaldehyde caused a rapid and synergistic elevation of intracellular calcium. Calcium depletion by BAPTA or Ca2+-free medium blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. Diltiazem and selective knockdown of TRPV6 or CaV1.3 channels, by shRNA blocked ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. Ethanol and acetaldehyde induced a rapid and synergistic increase in reactive oxygen species by a calcium-dependent mechanism. N-acetyl-L-cysteine and cyclosporine A, blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. These results demonstrate that ethanol and acetaldehyde synergistically disrupt tight junctions by a mechanism involving calcium, oxidative stress, Src kinase and MLCK.
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Affiliation(s)
- Geetha Samak
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - Ruchika Gangwar
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - Avtar S Meena
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - Roshan G Rao
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - Pradeep K Shukla
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - Bhargavi Manda
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - Damodaran Narayanan
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - Jonathan H Jaggar
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
| | - RadhaKrishna Rao
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis TN 38163, USA
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Stremmel W, Staffer S, Gan-Schreier H, Wannhoff A, Bach M, Gauss A. Phosphatidylcholine passes through lateral tight junctions for paracellular transport to the apical side of the polarized intestinal tumor cell-line CaCo2. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1161-1169. [PMID: 27365309 DOI: 10.1016/j.bbalip.2016.06.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 06/15/2016] [Accepted: 06/25/2016] [Indexed: 01/18/2023]
Abstract
Phosphatidylcholine (PC) is the most abundant phospholipid in intestinal mucus, indicative of a specific transport system across the mucosal epithelium to the intestinal lumen. To elucidate this transport mechanism, we employed a transwell tissue culture system with polarized CaCo2 cells. It was shown that PC could not substantially be internalized by the cells. However, after basal application of increasing PC concentrations, an apical transport of 47.1±6.3nmolh(-1)mMPC(-1) was observed. Equilibrium distribution studies with PC applied in equal concentrations to the basal and apical compartments showed a 1.5-fold accumulation on the expense of basal PC. Disruption of tight junctions (TJ) by acetaldehyde or PPARγ inhibitors or by treatment with siRNA to TJ proteins suppressed paracellular transport by at least 50%. Transport was specific for the choline containing the phospholipids PC, lysoPC and sphingomyelin. We showed that translocation is driven by an electrochemical gradient generated by apical accumulation of Cl(-) and HCO3(-) through CFTR. Pretreatment with siRNA to mucin 3 which anchors in the apical plasma membrane of mucosal cells inhibited the final step of luminal PC secretion. PC accumulates in intestinal mucus using a paracellular, apically directed transport route across TJs.
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Affiliation(s)
- Wolfgang Stremmel
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany.
| | - Simone Staffer
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Hongying Gan-Schreier
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Andreas Wannhoff
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
| | - Margund Bach
- Department of Physics, Kirchhoff Institute of Physics, Heidelberg, Germany
| | - Annika Gauss
- Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany
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Deng Y, Guo Y, Liu P, Zeng R, Ning Y, Pei G, Li Y, Chen M, Guo S, Li X, Han M, Xu G. Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: a peptide-based drug therapy. Sci Rep 2016; 6:19821. [PMID: 26805394 PMCID: PMC4726189 DOI: 10.1038/srep19821] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/18/2015] [Indexed: 02/04/2023] Open
Abstract
Endothelial-to-mesenchymal transition (EndMT) contributes to the emergence of fibroblasts and plays a significant role in renal interstitial fibrosis. Protein phosphatase 2A (PP2A) is a major serine/threonine protein phosphatase in eukaryotic cells and regulates many signaling pathways. However, the significance of PP2A in EndMT is poorly understood. In present study, the role of PP2A in EndMT was evaluated. We demonstrated that PP2A activated in endothelial cells (EC) during their EndMT phenotype acquisition and in the mouse model of obstructive nephropathy (i.e., UUO). Inhibition of PP2A activity by its specific inhibitor prevented EC undergoing EndMT. Importantly, PP2A activation was dependent on tyrosine nitration at 127 in the catalytic subunit of PP2A (PP2Ac). Our renal-protective strategy was to block tyrosine127 nitration to inhibit PP2A activation by using a mimic peptide derived from PP2Ac conjugating a cell penetrating peptide (CPP: TAT), termed TAT-Y127WT. Pretreatment withTAT-Y127WT was able to prevent TGF-β1-induced EndMT. Administration of the peptide to UUO mice significantly ameliorated renal EndMT level, with preserved density of peritubular capillaries and reduction in extracellular matrix deposition. Taken together, these results suggest that inhibiting PP2Ac nitration using a mimic peptide is a potential preventive strategy for EndMT in renal fibrosis.
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Affiliation(s)
- Yuanjun Deng
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yanyan Guo
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Ping Liu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Rui Zeng
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yong Ning
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Guangchang Pei
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yueqiang Li
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Meixue Chen
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Shuiming Guo
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Xiaoqing Li
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Min Han
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Gang Xu
- Division of Nephrology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
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49
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Mir H, Meena AS, Chaudhry KK, Shukla PK, Gangwar R, Manda B, Padala MK, Shen L, Turner JR, Dietrich P, Dragatsis I, Rao R. Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice. Biochim Biophys Acta Gen Subj 2015; 1860:765-74. [PMID: 26721332 DOI: 10.1016/j.bbagen.2015.12.013] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 12/05/2015] [Accepted: 12/18/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Disruption of epithelial tight junctions (TJ), gut barrier dysfunction and endotoxemia play crucial role in the pathogenesis of alcoholic tissue injury. Occludin, a transmembrane protein of TJ, is depleted in colon by alcohol. However, it is unknown whether occludin depletion influences alcoholic gut and liver injury. METHODS Wild type (WT) and occludin deficient (Ocln(-/-)) mice were fed 1-6% ethanol in Lieber-DeCarli diet. Gut permeability was measured by vascular-to-luminal flux of FITC-inulin. Junctional integrity was analyzed by confocal microscopy. Liver injury was assessed by plasma transaminase, histopathology and triglyceride analyses. The effect of occludin depletion on acetaldehyde-induced TJ disruption was confirmed in Caco-2 cell monolayers. RESULTS Ethanol feeding significantly reduced body weight gain in Ocln(-/-) mice. Ethanol increased inulin permeability in colon of both WT and Ocln(-/-) mice, but the effect was 4-fold higher in Ocln(-/-) mice. The gross morphology of colonic mucosa was unaltered, but ethanol disrupted the actin cytoskeleton, induced redistribution of occludin, ZO-1, E-cadherin and β-catenin from the junctions and elevated TLR4, which was more severe in Ocln(-/-) mice. Occludin knockdown significantly enhanced acetaldehyde-induced TJ disruption and barrier dysfunction in Caco-2 cell monolayers. Ethanol significantly increased liver weight and plasma transaminase activity in Ocln(-/-) mice, but not in WT mice. Histological analysis indicated more severe lesions and fat deposition in the liver of ethanol-fed Ocln(-/-) mice. Ethanol-induced elevation of liver triglyceride was also higher in Ocln(-/-) mice. CONCLUSION This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice.
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Affiliation(s)
- Hina Mir
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Avtar S Meena
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Kamaljit K Chaudhry
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Pradeep K Shukla
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Ruchika Gangwar
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Bhargavi Manda
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Mythili K Padala
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Le Shen
- Department of Pathology, University of Chicago, Chicago, IL, United States
| | - Jerrold R Turner
- Department of Pathology, University of Chicago, Chicago, IL, United States
| | - Paula Dietrich
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - Ioannis Dragatsis
- Department of Physiology, University of Tennessee, Memphis, TN, United States
| | - RadhaKrishna Rao
- Department of Physiology, University of Tennessee, Memphis, TN, United States.
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50
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Neuman MG, Malnick S, Maor Y, Nanau RM, Melzer E, Ferenci P, Seitz HK, Mueller S, Mell H, Samuel D, Cohen LB, Kharbanda KK, Osna NA, Ganesan M, Thompson KJ, McKillop IH, Bautista A, Bataller R, French SW. Alcoholic liver disease: Clinical and translational research. Exp Mol Pathol 2015; 99:596-610. [PMID: 26342547 DOI: 10.1016/j.yexmp.2015.09.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 09/01/2015] [Indexed: 02/05/2023]
Abstract
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical research, translational research, pathogenesis and therapies. A special accent is placed on alcohol misuse, as alcohol is a legally commercialized and taxable product. Drinking alcohol, particularly from a young age, is a major health problem. Alcoholism is known to contribute to morbidity and mortality. A systematic literature search was performed in order to obtain updated data (2008-2015). The review is focused on genetic polymorphisms of alcohol metabolizing enzymes and the role of cytochrome p450 2E1 and iron in ALD. Alcohol-mediated hepatocarcinogenesis is also discussed in the presence or absence of co-morbidities such as viral hepatitis C as well as therapeutic the role of innate immunity in ALD-HCV. Moreover, emphasis was placed on alcohol and drug interactions, as well as liver transplantation for end-stage ALD. Finally, the time came to eradicate alcohol-induced liver and intestinal damage by using betaine.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Stephen Malnick
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel
| | - Yaakov Maor
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel
| | - Radu M Nanau
- In Vitro Drug Safety and Biotechnology, Toronto, Ontario, Canada
| | - Ehud Melzer
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot, Israel
| | | | - Helmut K Seitz
- University of Heidelberg, Heidelberg, Germany; Department of Medicine, Gastroenterology and Hepatology, Centre for Alcohol Research, Salem Medical Centre, Heidelberg, Germany
| | - Sebastian Mueller
- University of Heidelberg, Heidelberg, Germany; Department of Medicine, Gastroenterology and Hepatology, Centre for Alcohol Research, Salem Medical Centre, Heidelberg, Germany
| | - Haim Mell
- Israel Antidrug and Alcohol Authority, Jerusalem, Israel
| | - Didier Samuel
- Liver Transplant Unit, Research Inserm-Paris XI Unit 785, Centre Hepatobiliaire, Hopital Paul Brousse, Villejuif, Paris, France
| | - Lawrence B Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre and Department of Internal Medicine, University of Toronto, Toronto, Canada
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Internal Medicine, Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kyle J Thompson
- Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, USA
| | - Iain H McKillop
- Department of Surgery, Carolinas Medical Center, Charlotte, NC 28203, USA
| | - Abraham Bautista
- Office of Extramural Activities, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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