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Xiao M, Zhou N, Tian Z, Sun C. Endogenous Metabolites in Metabolic Diseases: Pathophysiologic Roles and Therapeutic Implications. J Nutr 2025:S0022-3166(25)00227-5. [PMID: 40250565 DOI: 10.1016/j.tjnut.2025.04.017] [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: 04/05/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025] Open
Abstract
Breakthroughs in metabolomics technology have revealed the direct regulatory role of metabolites in physiology and disease. Recent data have highlighted the bioactive metabolites involved in the etiology and prevention and treatment of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes mellitus, and atherosclerosis. Numerous studies reveal that endogenous metabolites biosynthesized by host organisms or gut microflora regulate metabolic responses and disorders. Lipids, amino acids, and bile acids, as endogenous metabolic modulators, regulate energy metabolism, insulin sensitivity, and immune response through multiple pathways, such as insulin signaling cascade, chemical modifications, and metabolite-macromolecule interactions. Furthermore, the gut microbial metabolites short-chain fatty acids, as signaling regulators have a variety of beneficial impacts in regulating energy metabolic homeostasis. In this review, we will summarize information about the roles of bioactive metabolites in the pathogenesis of many metabolic diseases. Furthermore, we discuss the potential value of metabolites in the promising preventive and therapeutic perspectives of human metabolic diseases.
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Affiliation(s)
- Mengjie Xiao
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China
| | - Ning Zhou
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China
| | - Zhen Tian
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China.
| | - Changhao Sun
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China.
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Gu Q, Liu J, Shen LL. FXR activation reduces the formation of macrophage foam cells and atherosclerotic plaque, possibly by down regulating hepatic lipase in macrophages. FEBS Open Bio 2025; 15:311-323. [PMID: 39601316 PMCID: PMC11788749 DOI: 10.1002/2211-5463.13925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/24/2024] [Accepted: 10/31/2024] [Indexed: 11/29/2024] Open
Abstract
Macrophages are the most important immune cells affecting the formation of atherosclerotic plaque. Nevertheless, the mechanisms that promote formation of foamy macrophages during atherogenesis remain poorly understood. This study explored the effects of Farnesoid X receptor (FXR) and hepatic lipase (HL, encoded by LIPC) on atherogenesis, particularly in foamy macrophage formation. A luciferase reporter assay indicated that FXR could bind to the LIPC promoter and inhibit LIPC transcription. FXR agonist GW4064 decreased HL expression, foam cell formation, and increased the expression of FXR downstream genes and polarization to M2 in ox-LDL-induced THP-1 and U937 foam cells. In addition, GW4064 exerted anti-atherosclerotic effects in ApoE-/- mice, manifested as decreased serum cholesterol and triglyceride levels, and alleviated atherosclerotic plaque formation. Collectively, FXR exerted anti-atherosclerotic effects, possibly by negatively regulating HL expression in macrophages.
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Affiliation(s)
- Qiang Gu
- Institute of Cardiovascular Surgery, Xinqiao HospitalSecond Affiliated Hospital of the Army Military Medical UniversityChongqingChina
| | - Jia Liu
- Department of PathologyChongqing University Cancer HospitalChina
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC)Chongqing University Cancer HospitalChina
| | - Li Li Shen
- Department of PathologyChongqing University Cancer HospitalChina
- Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC)Chongqing University Cancer HospitalChina
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3
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Sagmeister A, Matter CM, Stähli BE, Scharl M. The Gut-Heart Axis: Effects of Intestinal Microbiome Modulation on Cardiovascular Disease-Ready for Therapeutic Interventions? Int J Mol Sci 2024; 25:13529. [PMID: 39769292 PMCID: PMC11676197 DOI: 10.3390/ijms252413529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/10/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Recent reports demonstrate an association between distinct bacteria or bacteria-derived metabolites originating from the gut microbiome and the onset or progression of cardiovascular disease (CVD). This raises the opportunity to modulate the gut microbiome to prevent or treat CVD. To investigate whether intestinal microbiome modulation can prevent or treat CVD, this systematic literature review includes all randomized clinical trials on microbiome modulation and its effects on CVD risk published between August 2018 and August 2023. Within this review, we report the modulation of the gut microbiome by a variety of interventions and their effects on CVD, focusing on cardiovascular risk factors and risk markers of CVD. Beneficial effects were observed upon lifestyle intervention and probiotics use. The most promising diets for reducing risk factors of CVD were the Mediterranean diet, high-fiber diets, polyphenol-rich diets, and diets containing polyunsaturated fatty acids. Among drug interventions, only empagliflozin showed beneficial effects on CVD risk factors. Many dietary interventions were less conclusive because of the heterogeneity of study populations, small sample sizes, and short intervention windows or follow-up. Diet, lifestyle, probiotics, or drug interventions can modulate the gut microbiome and decrease risk markers or risk factors related to CVD. Yet, their effects on clinical endpoints remain to be determined.
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Affiliation(s)
- Alexandra Sagmeister
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Christian M. Matter
- Department of Cardiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; (C.M.M.); (B.E.S.)
| | - Barbara E. Stähli
- Department of Cardiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; (C.M.M.); (B.E.S.)
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
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Fang Y, Qin M, Zheng Q, Wang K, Han X, Yang Q, Sang X, Cao G. Role of Bile Acid Receptors in the Development and Function of Diabetic Nephropathy. Kidney Int Rep 2024; 9:3116-3133. [PMID: 39534198 PMCID: PMC11551060 DOI: 10.1016/j.ekir.2024.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/25/2024] [Accepted: 08/04/2024] [Indexed: 11/16/2024] Open
Abstract
Diabetic nephropathy (DN) is a prevalent microvascular complication that occurs often in individuals with diabetes. It significantly raises the mortality rate of affected patients. Therefore, there is an urgent need to identify therapeutic targets for controlling and preventing the occurrence and development of DN. Bile acids (BAs) are now recognized as intricate metabolic integrators and signaling molecules. The activation of BAs has great promise as a therapeutic approach for preventing DN, renal damage caused by obesity, and nephrosclerosis. The nuclear receptors (NRs), farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR); and the G protein-coupled BA receptor, Takeda G-protein-coupled receptor 5 (TGR5) have important functions in controlling lipid, glucose, and energy metabolism, inflammation, as well as drug metabolism and detoxification. Over the past 10 years, there has been advancement in comprehending the biology and processes of BA receptors in the kidney, as well as in the creation of targeted BA receptor agonists. In this review, we discuss the role of BA receptors, FXR, PXR, VDR, and TGR5 in DN and their role in renal physiology, as well as the development and application of agonists that activate BA receptors for the treatment of kidney diseases.
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Affiliation(s)
- Yuanyuan Fang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Minjing Qin
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qitong Zheng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kuilong Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xin Han
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiao Yang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xia'nan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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6
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Ronen D, Rokach Y, Abedat S, Qadan A, Daana S, Amir O, Asleh R. Human Gut Microbiota in Cardiovascular Disease. Compr Physiol 2024; 14:5449-5490. [PMID: 39109979 DOI: 10.1002/cphy.c230012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The gut ecosystem, termed microbiota, is composed of bacteria, archaea, viruses, protozoa, and fungi and is estimated to outnumber human cells. Microbiota can affect the host by multiple mechanisms, including the synthesis of metabolites and toxins, modulating inflammation and interaction with other organisms. Advances in understanding commensal organisms' effect on human conditions have also elucidated the importance of this community for cardiovascular disease (CVD). This effect is driven by both direct CV effects and conditions known to increase CV risk, such as obesity, diabetes mellitus (DM), hypertension, and renal and liver diseases. Cardioactive metabolites, such as trimethylamine N -oxide (TMAO), short-chain fatty acids (SCFA), lipopolysaccharides, bile acids, and uremic toxins, can affect atherosclerosis, platelet activation, and inflammation, resulting in increased CV incidence. Interestingly, this interaction is bidirectional with microbiota affected by multiple host conditions including diet, bile acid secretion, and multiple diseases affecting the gut barrier. This interdependence makes manipulating microbiota an attractive option to reduce CV risk. Indeed, evolving data suggest that the benefits observed from low red meat and Mediterranean diet consumption can be explained, at least partially, by the changes that these diets may have on the gut microbiota. In this article, we depict the current epidemiological and mechanistic understanding of the role of microbiota and CVD. Finally, we discuss the potential therapeutic approaches aimed at manipulating gut microbiota to improve CV outcomes. © 2024 American Physiological Society. Compr Physiol 14:5449-5490, 2024.
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Affiliation(s)
- Daniel Ronen
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yair Rokach
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Suzan Abedat
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Abed Qadan
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Samar Daana
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Offer Amir
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rabea Asleh
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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7
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Mao Y, Kong C, Zang T, You L, Wang L, Shen L, Ge J. Impact of the gut microbiome on atherosclerosis. MLIFE 2024; 3:167-175. [PMID: 38948150 PMCID: PMC11211673 DOI: 10.1002/mlf2.12110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 11/25/2023] [Accepted: 12/12/2023] [Indexed: 07/02/2024]
Abstract
Atherosclerosis is a chronic inflammatory metabolic disease with a complex pathogenesis. However, the exact details of its pathogenesis are still unclear, which limits effective clinical treatment of atherosclerosis. Recently, multiple studies have demonstrated that the gut microbiota plays a pivotal role in the onset and progression of atherosclerosis. This review discusses possible treatments for atherosclerosis using the gut microbiome as an intervention target and summarizes the role of the gut microbiome and its metabolites in the development of atherosclerosis. New strategies for the treatment of atherosclerosis are needed. This review provides clues for further research on the mechanisms of the relationship between the gut microbiota and atherosclerosis.
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Affiliation(s)
- Yuqin Mao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
- National Clinical Research Center for Interventional MedicineShanghaiChina
- Center for Traditional Chinese Medicine and Gut Microbiota, Minhang HospitalFudan UniversityShanghaiChina
| | - Chao Kong
- Center for Traditional Chinese Medicine and Gut Microbiota, Minhang HospitalFudan UniversityShanghaiChina
| | - Tongtong Zang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
- National Clinical Research Center for Interventional MedicineShanghaiChina
| | - Lingsen You
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
- National Clinical Research Center for Interventional MedicineShanghaiChina
| | - Li‐Shun Wang
- Center for Traditional Chinese Medicine and Gut Microbiota, Minhang HospitalFudan UniversityShanghaiChina
| | - Li Shen
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
- National Clinical Research Center for Interventional MedicineShanghaiChina
| | - Jun‐Bo Ge
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
- National Clinical Research Center for Interventional MedicineShanghaiChina
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8
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Zhang Z, Lv T, Wang X, Wu M, Zhang R, Yang X, Fu Y, Liu Z. Role of the microbiota-gut-heart axis between bile acids and cardiovascular disease. Biomed Pharmacother 2024; 174:116567. [PMID: 38583340 DOI: 10.1016/j.biopha.2024.116567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024] Open
Abstract
Bile acid (BA) receptors (e.g., farnesoid X-activated receptor, muscarinic receptor) are expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells, indicating the relevance of BAs to cardiovascular disease (CVD). Hydrophobic BAs are cardiotoxic, while hydrophilic BAs are cardioprotective. For example, fetal cardiac insufficiency in maternal intrahepatic cholestasis during pregnancy, and the degree of fetal cardiac abnormality, is closely related to the level of hydrophobic BAs in maternal blood and infant blood. However, ursodeoxycholic acid (the most hydrophilic BA) can reverse/prevent these detrimental effects of increased levels of hydrophobic BAs on the heart. The gut microbiota (GM) and GM metabolites (especially secondary BAs) have crucial roles in hypertension, atherosclerosis, unstable angina, and heart failure. Herein, we describe the relationship between CVD and the GM at the BA level. We combine the concept of the "microbiota-gut-heart axis" (MGHA) and postulate the role and mechanism of BAs in CVD development. In addition, the strategies for treating CVD with BAs under the MGHA are proposed.
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Affiliation(s)
- Ziyi Zhang
- Department of Cardiovascular Medicine, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, PR China; Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Tingting Lv
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China; Department of Cardiology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang, PR China
| | - Xiang Wang
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Menglu Wu
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Ruolin Zhang
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Xiaopeng Yang
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Yongping Fu
- Department of Cardiovascular Medicine, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, PR China.
| | - Zheng Liu
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China.
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [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: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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Salvadori M, Rosso G. Update on the gut microbiome in health and diseases. World J Methodol 2024; 14:89196. [PMID: 38577200 PMCID: PMC10989414 DOI: 10.5662/wjm.v14.i1.89196] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/18/2023] [Accepted: 01/27/2024] [Indexed: 03/07/2024] Open
Abstract
The Human Microbiome Project, Earth Microbiome Project, and next-generation sequencing have advanced novel genome association, host genetic linkages, and pathogen identification. The microbiome is the sum of the microbes, their genetic information, and their ecological niche. This study will describe how millions of bacteria in the gut affect the human body in health and disease. The gut microbiome changes in relation with age, with an increase in Bacteroidetes and Firmicutes. Host and environmental factors affecting the gut microbiome are diet, drugs, age, smoking, exercise, and host genetics. In addition, changes in the gut microbiome may affect the local gut immune system and systemic immune system. In this study, we discuss how the microbiome may affect the metabolism of healthy subjects or may affect the pathogenesis of metabolism-generating metabolic diseases. Due to the high number of publications on the argument, from a methodologically point of view, we decided to select the best papers published in referred journals in the last 3 years. Then we selected the previously published papers. The major goals of our study were to elucidate which microbiome and by which pathways are related to healthy and disease conditions.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Tuscany, Italy
| | - Giuseppina Rosso
- Division of Nephrology, San Giovanni di Dio Hospital, Florence 50143, Toscana, Italy
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11
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Shi M, Wei J, Yuan H, Li Y, Guo Z. The role of the gut microbiota and bile acids in heart failure: A review. Medicine (Baltimore) 2023; 102:e35795. [PMID: 37960774 PMCID: PMC10637566 DOI: 10.1097/md.0000000000035795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 10/04/2023] [Indexed: 11/15/2023] Open
Abstract
Heart failure (HF) is the terminal manifestation of various cardiovascular diseases. Recently, accumulating evidence has demonstrated that gut microbiota are involved in the development of various cardiovascular diseases. Gut microbiota and their metabolites might play a pivotal role in the development of HF. However, previous studies have rarely described the complex role of gut microbiota and their metabolites in HF. In this review, we mainly discussed bile acids (BAs), the metabolites of gut microbiota. We explained the mechanisms by which BAs are involved in the pathogenesis of HF. We also discussed the use of gut microbiota and BAs for treating HF in Chinese medicine, highlighting the advantages of Chinese medicine in treating HF.
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Affiliation(s)
- Min Shi
- Hunan University of Chinese Medicine, Changsha, China
- Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan, Changsha, China
| | - Jiaming Wei
- Hunan University of Chinese Medicine, Changsha, China
- Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan, Changsha, China
| | - Hui Yuan
- Hunan University of Chinese Medicine, Changsha, China
| | - Ya Li
- Hunan University of Chinese Medicine, Changsha, China
| | - Zhihua Guo
- Hunan University of Chinese Medicine, Changsha, China
- Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan, Changsha, China
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12
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Sanyal AJ, Ratziu V, Loomba R, Anstee QM, Kowdley KV, Rinella ME, Sheikh MY, Trotter JF, Knapple W, Lawitz EJ, Abdelmalek MF, Newsome PN, Boursier J, Mathurin P, Dufour JF, Berrey MM, Shiff SJ, Sawhney S, Capozza T, Leyva R, Harrison SA, Younossi ZM. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2023; 79:1110-1120. [PMID: 37517454 DOI: 10.1016/j.jhep.2023.07.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/30/2023] [Accepted: 07/06/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND & AIMS Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.
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Affiliation(s)
- Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute for Cardiometabolism and Nutrition, Paris, France
| | - Rohit Loomba
- University of California, San Diego, La Jolla, CA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | | | - Mary E Rinella
- University of Chicago, Pritzker School of Medicine, Chicago, IL, USA
| | | | | | | | - Eric J Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Philip N Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | - Jérôme Boursier
- Angers University Hospital, Angers University, Angers, France
| | | | | | | | | | | | | | - Rina Leyva
- Intercept Pharmaceuticals, Morristown, NJ, USA
| | | | - Zobair M Younossi
- Beatty Liver and Obesity Research Program, Center for Liver Diseases, Inova Medicine, Falls Church, VA, USA
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13
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Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol 2023; 79:1317-1331. [PMID: 37562746 DOI: 10.1016/j.jhep.2023.07.034] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/19/2023] [Accepted: 07/16/2023] [Indexed: 08/12/2023]
Abstract
The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor highly expressed in the liver and intestine, regulates the expression of genes involved in cholesterol and bile acid homeostasis, hepatic gluconeogenesis, lipogenesis, inflammation and fibrosis, in addition to controlling intestinal barrier integrity, preventing bacterial translocation and maintaining gut microbiota eubiosis. Non-alcoholic steatohepatitis (NASH), an advanced stage of non-alcoholic fatty liver disease, is characterized by hepatic steatosis, hepatocyte damage (ballooning) and inflammation, leading to fibrosis, cirrhosis and hepatocellular carcinoma. NASH represents a major unmet medical need, but no pharmacological treatments have yet been approved. The pleiotropic mechanisms involved in NASH development offer a range of therapeutic opportunities and among them FXR activation has emerged as an established pharmacological target. Various FXR agonists with different physicochemical properties, which can be broadly classified as BA derivatives, non-BA-derived steroidal FXR agonists, non-steroidal FXR agonists, and partial FXR agonists, are in advanced clinical development. In this review we will summarize key preclinical and clinical features of the most advanced FXR agonists and critically evaluate their potential in NASH treatment.
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Affiliation(s)
- Luciano Adorini
- Intercept Pharmaceuticals Inc., 305 Madison Ave., Morristown, NJ 07960, USA.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
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14
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Wang C, Ma Q, Yu X. Bile Acid Network and Vascular Calcification-Associated Diseases: Unraveling the Intricate Connections and Therapeutic Potential. Clin Interv Aging 2023; 18:1749-1767. [PMID: 37885621 PMCID: PMC10599251 DOI: 10.2147/cia.s431220] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Bile acids play a crucial role in promoting intestinal nutrient absorption and biliary cholesterol excretion, thereby protecting the liver from cholesterol accumulation and bile acid toxicity. Additionally, bile acids can bind to specific nuclear and membrane receptors to regulate energy expenditure and specific functions of particular tissues. Vascular calcification refers to the pathological process of calcium-phosphate deposition in blood vessel walls, which serves as an independent predictor for cardiovascular adverse events. In addition to aging, this pathological change is associated with aging-related diseases such as atherosclerosis, hypertension, chronic kidney disease, diabetes mellitus, and osteoporosis. Emerging evidence suggests a close association between the bile acid network and these aforementioned vascular calcification-associated conditions. Several bile acids have been proven to participate in calcium-phosphate metabolism, affecting the transdifferentiation of vascular smooth muscle cells and thus influencing vascular calcification. Targeting the bile acid network shows potential for ameliorating these diseases and their concomitant vascular calcification by regulating pathways such as energy metabolism, inflammatory response, oxidative stress, and cell differentiation. Here, we present a summary of the metabolism and functions of the bile acid network and aim to provide insights into the current research on the profound connections between the bile acid network and these vascular calcification-associated diseases, as well as the therapeutic potential.
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Affiliation(s)
- Cui Wang
- Laboratory of Endocrinology & Metabolism/Department of Endocrinology & Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China
| | - Qing Ma
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China
| | - Xijie Yu
- Laboratory of Endocrinology & Metabolism/Department of Endocrinology & Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China
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15
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Paraskevaidis I, Xanthopoulos A, Tsougos E, Triposkiadis F. Human Gut Microbiota in Heart Failure: Trying to Unmask an Emerging Organ. Biomedicines 2023; 11:2574. [PMID: 37761015 PMCID: PMC10526035 DOI: 10.3390/biomedicines11092574] [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: 08/01/2023] [Revised: 09/08/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
There is a bidirectional relationship between the heart and the gut. The gut microbiota, the community of gut micro-organisms themselves, is an excellent gut-homeostasis keeper since it controls the growth of potentially harmful bacteria and protects the microbiota environment. There is evidence suggesting that a diet rich in fatty acids can be metabolized and converted by gut microbiota and hepatic enzymes to trimethyl-amine N-oxide (TMAO), a product that is associated with atherogenesis, platelet dysfunction, thrombotic events, coronary artery disease, stroke, heart failure (HF), and, ultimately, death. HF, by inducing gut ischemia, congestion, and, consequently, gut barrier dysfunction, promotes the intestinal leaking of micro-organisms and their products, facilitating their entrance into circulation and thus stimulating a low-grade inflammation associated with an immune response. Drugs used for HF may alter the gut microbiota, and, conversely, gut microbiota may modify the pharmacokinetic properties of the drugs. The modification of lifestyle based mainly on exercise and a Mediterranean diet, along with the use of pre- or probiotics, may be beneficial for the gut microbiota environment. The potential role of gut microbiota in HF development and progression is the subject of this review.
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Affiliation(s)
| | - Andrew Xanthopoulos
- Department of Cardiology, University Hospital of Larissa, 41110 Larissa, Greece; (A.X.); (F.T.)
| | - Elias Tsougos
- 6th Department of Cardiology, Hygeia Hospital, 15123 Athens, Greece
| | - Filippos Triposkiadis
- Department of Cardiology, University Hospital of Larissa, 41110 Larissa, Greece; (A.X.); (F.T.)
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16
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Jing J, Guo J, Dai R, Zhu C, Zhang Z. Targeting gut microbiota and immune crosstalk: potential mechanisms of natural products in the treatment of atherosclerosis. Front Pharmacol 2023; 14:1252907. [PMID: 37719851 PMCID: PMC10504665 DOI: 10.3389/fphar.2023.1252907] [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: 07/04/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
Atherosclerosis (AS) is a chronic inflammatory reaction that primarily affects large and medium-sized arteries. It is a major cause of cardiovascular disease and peripheral arterial occlusive disease. The pathogenesis of AS involves specific structural and functional alterations in various populations of vascular cells at different stages of the disease. The immune response is involved throughout the entire developmental stage of AS, and targeting immune cells presents a promising avenue for its treatment. Over the past 2 decades, studies have shown that gut microbiota (GM) and its metabolites, such as trimethylamine-N-oxide, have a significant impact on the progression of AS. Interestingly, it has also been reported that there are complex mechanisms of action between GM and their metabolites, immune responses, and natural products that can have an impact on AS. GM and its metabolites regulate the functional expression of immune cells and have potential impacts on AS. Natural products have a wide range of health properties, and researchers are increasingly focusing on their role in AS. Now, there is compelling evidence that natural products provide an alternative approach to improving immune function in the AS microenvironment by modulating the GM. Natural product metabolites such as resveratrol, berberine, curcumin, and quercetin may improve the intestinal microenvironment by modulating the relative abundance of GM, which in turn influences the accumulation of GM metabolites. Natural products can delay the progression of AS by regulating the metabolism of GM, inhibiting the migration of monocytes and macrophages, promoting the polarization of the M2 phenotype of macrophages, down-regulating the level of inflammatory factors, regulating the balance of Treg/Th17, and inhibiting the formation of foam cells. Based on the above, we describe recent advances in the use of natural products that target GM and immune cells crosstalk to treat AS, which may bring some insights to guide the treatment of AS.
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Affiliation(s)
- Jinpeng Jing
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jing Guo
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Rui Dai
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chaojun Zhu
- Institute of TCM Ulcers, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Surgical Department of Traditional Chinese Medicine, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhaohui Zhang
- Institute of TCM Ulcers, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Surgical Department of Traditional Chinese Medicine, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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17
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Guiducci L, Nicolini G, Forini F. Dietary Patterns, Gut Microbiota Remodeling, and Cardiometabolic Disease. Metabolites 2023; 13:760. [PMID: 37367916 DOI: 10.3390/metabo13060760] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
The cardiovascular and metabolic disorders, collectively known as cardiometabolic disease (CMD), are high morbidity and mortality pathologies associated with lower quality of life and increasing health-care costs. The influence of the gut microbiota (GM) in dictating the interpersonal variability in CMD susceptibility, progression and treatment response is beginning to be deciphered, as is the mutualistic relation established between the GM and diet. In particular, dietary factors emerge as pivotal determinants shaping the architecture and function of resident microorganisms in the human gut. In turn, intestinal microbes influence the absorption, metabolism, and storage of ingested nutrients, with potentially profound effects on host physiology. Herein, we present an updated overview on major effects of dietary components on the GM, highlighting the beneficial and detrimental consequences of diet-microbiota crosstalk in the setting of CMD. We also discuss the promises and challenges of integrating microbiome data in dietary planning aimed at restraining CMD onset and progression with a more personalized nutritional approach.
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Affiliation(s)
- Letizia Guiducci
- CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa, Italy
| | | | - Francesca Forini
- CNR Institute of Clinical Physiology, Via Moruzzi 1, 56124 Pisa, Italy
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18
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Yntema T, Koonen DPY, Kuipers F. Emerging Roles of Gut Microbial Modulation of Bile Acid Composition in the Etiology of Cardiovascular Diseases. Nutrients 2023; 15:nu15081850. [PMID: 37111068 PMCID: PMC10141989 DOI: 10.3390/nu15081850] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Despite advances in preventive measures and treatment options, cardiovascular disease (CVD) remains the number one cause of death globally. Recent research has challenged the traditional risk factor profile and highlights the potential contribution of non-traditional factors in CVD, such as the gut microbiota and its metabolites. Disturbances in the gut microbiota have been repeatedly associated with CVD, including atherosclerosis and hypertension. Mechanistic studies support a causal role of microbiota-derived metabolites in disease development, such as short-chain fatty acids, trimethylamine-N-oxide, and bile acids, with the latter being elaborately discussed in this review. Bile acids represent a class of cholesterol derivatives that is essential for intestinal absorption of lipids and fat-soluble vitamins, plays an important role in cholesterol turnover and, as more recently discovered, acts as a group of signaling molecules that exerts hormonal functions throughout the body. Studies have shown mediating roles of bile acids in the control of lipid metabolism, immunity, and heart function. Consequently, a picture has emerged of bile acids acting as integrators and modulators of cardiometabolic pathways, highlighting their potential as therapeutic targets in CVD. In this review, we provide an overview of alterations in the gut microbiota and bile acid metabolism found in CVD patients, describe the molecular mechanisms through which bile acids may modulate CVD risk, and discuss potential bile-acid-based treatment strategies in relation to CVD.
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Affiliation(s)
- Tess Yntema
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Debby P Y Koonen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
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19
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Bettiol A, Emmi G, Low L, Sofi F, Wallace GR. Microbiome in Behcet's syndrome. Clin Immunol 2023; 250:109304. [PMID: 37003591 DOI: 10.1016/j.clim.2023.109304] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023]
Abstract
This review will discuss the current understanding of the role of microbiomes in Behcet's Syndrome, their influence on immune response and disease and potential future studies.
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Affiliation(s)
- Alessandra Bettiol
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Giacomo Emmi
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Liying Low
- Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Francesco Sofi
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Graham R Wallace
- Academic Unit of Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.
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20
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Tonelli A, Lumngwena EN, Ntusi NAB. The oral microbiome in the pathophysiology of cardiovascular disease. Nat Rev Cardiol 2023; 20:386-403. [PMID: 36624275 DOI: 10.1038/s41569-022-00825-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/01/2022] [Indexed: 01/11/2023]
Abstract
Despite advances in our understanding of the pathophysiology of many cardiovascular diseases (CVDs) and expansion of available therapies, the global burden of CVD-associated morbidity and mortality remains unacceptably high. Important gaps remain in our understanding of the mechanisms of CVD and determinants of disease progression. In the past decade, much research has been conducted on the human microbiome and its potential role in modulating CVD. With the advent of high-throughput technologies and multiomics analyses, the complex and dynamic relationship between the microbiota, their 'theatre of activity' and the host is gradually being elucidated. The relationship between the gut microbiome and CVD is well established. Much less is known about the role of disruption (dysbiosis) of the oral microbiome; however, interest in the field is growing, as is the body of literature from basic science and animal and human investigations. In this Review, we examine the link between the oral microbiome and CVD, specifically coronary artery disease, stroke, peripheral artery disease, heart failure, infective endocarditis and rheumatic heart disease. We discuss the various mechanisms by which oral dysbiosis contributes to CVD pathogenesis and potential strategies for prevention and treatment.
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Affiliation(s)
- Andrea Tonelli
- Division of Cardiology, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.,Cardiovascular Research Unit, Christiaan Barnard Division of Cardiothoracic Surgery, Department of Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.,Cape Heart Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Extramural Research Unit on the Intersection of Noncommunicable Diseases and Infectious Disease, South African Medical Research Council, Cape Town, South Africa
| | - Evelyn N Lumngwena
- Cape Heart Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.,Centre for the Study of Emerging and Re-emerging Infections, Institute for Medical Research and Medicinal Plant Studies, Ministry of Scientific Research and Innovation, Yaoundé, Cameroon
| | - Ntobeko A B Ntusi
- Division of Cardiology, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa. .,Cape Heart Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. .,Extramural Research Unit on the Intersection of Noncommunicable Diseases and Infectious Disease, South African Medical Research Council, Cape Town, South Africa. .,Cape Universities Body Imaging Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. .,Wellcome Centre for Infectious Disease Research, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
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21
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Martín Giménez VM, Rukavina Mikusic NL, Lee HJ, García Menéndez S, Choi MR, Manucha W. Physiopathological mechanisms involved in the development of hypertension associated with gut dysbiosis and the effect of nutritional/pharmacological interventions. Biochem Pharmacol 2022; 204:115213. [PMID: 35985404 DOI: 10.1016/j.bcp.2022.115213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/27/2022]
Abstract
The gut microbiota dysbiosis represents a triggering factor for cardiovascular diseases, including hypertension. In addition to the harmful impact caused by hypertension on different target organs, gut dysbiosis is capable of causing direct damage to critical organs such as the brain, heart, blood vessels, and kidneys. In this sense, it should be noted that pharmacological and nutritional interventions may influence gut microbiota composition, either inducing or preventing the development of hypertension. Some of the most important nutritional interventions at this level are represented by pro-, pre-, post- and/or syn-biotics, as well as polysaccharides, polyunsaturated fatty acids ω-3, polyphenols and fiber contained in different foods. Meanwhile, certain natural and synthetic active pharmaceutical ingredients, including antibiotics, antihypertensive and immunosuppressive drugs, vegetable extracts and vitamins, may also have a key role in the modulation of both gut microbiota and cardiovascular health. Additionally, gut microbiota may influence drugs and food-derived bioactive compounds metabolism, positively or negatively affecting their biological behavior facing established hypertension. The understanding of the complex interactions between gut microbiome and drug/food response results of great importance to developing improved pharmacological therapies for hypertension prevention and treatment. The purpose of this review is to critically outline the most relevant and recent findings on cardiovascular, renal and brain physiopathological mechanisms involved in the development of hypertension associated with changes in gut microbiota, besides the nutritional and pharmacological interventions potentially valuable for the prevention and treatment of this prevalent pathology. Finally, harmful food/drug interventions on gut microbiota are also described.
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Affiliation(s)
- Virna Margarita Martín Giménez
- Instituto de Investigaciones en Ciencias Químicas, Facultad de Ciencias Químicas y Tecnológicas, Universidad Católica de Cuyo, Sede San Juan, Argentina
| | - Natalia Lucía Rukavina Mikusic
- Universidad de Buenos Aires. CONICET. Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Anatomía e Histología, Buenos Aires, Argentina
| | - Hyun Jin Lee
- Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Anatomía e Histología, Buenos Aires, Argentina
| | - Sebastián García Menéndez
- Laboratorio de Farmacología Experimental Básica y Traslacional. Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina; Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Argentina
| | - Marcelo Roberto Choi
- Universidad de Buenos Aires. CONICET. Instituto Alberto C. Taquini de Investigaciones en Medicina Traslacional (IATIMET), Buenos Aires, Argentina; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Anatomía e Histología, Buenos Aires, Argentina
| | - Walter Manucha
- Laboratorio de Farmacología Experimental Básica y Traslacional. Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina; Instituto de Medicina y Biología Experimental de Cuyo, Consejo Nacional de Investigación Científica y Tecnológica (IMBECU-CONICET), Argentina.
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22
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Cao Y, Aquino-Martinez R, Hutchison E, Allayee H, Lusis AJ, Rey FE. Role of gut microbe-derived metabolites in cardiometabolic diseases: Systems based approach. Mol Metab 2022; 64:101557. [PMID: 35870705 PMCID: PMC9399267 DOI: 10.1016/j.molmet.2022.101557] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/30/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The gut microbiome influences host physiology and cardiometabolic diseases by interacting directly with intestinal cells or by producing molecules that enter the host circulation. Given the large number of microbial species present in the gut and the numerous factors that influence gut bacterial composition, it has been challenging to understand the underlying biological mechanisms that modulate risk of cardiometabolic disease. SCOPE OF THE REVIEW Here we discuss a systems-based approach that involves simultaneously examining individuals in populations for gut microbiome composition, molecular traits using "omics" technologies, such as circulating metabolites quantified by mass spectrometry, and clinical traits. We summarize findings from landmark studies using this approach and discuss future applications. MAJOR CONCLUSIONS Population-based integrative approaches have identified a large number of microbe-derived or microbe-modified metabolites that are associated with cardiometabolic traits. The knowledge gained from these studies provide new opportunities for understanding the mechanisms involved in gut microbiome-host interactions and may have potentially important implications for developing novel therapeutic approaches.
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Affiliation(s)
- Yang Cao
- Departments of Medicine, Human Genetics, and Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA
| | - Ruben Aquino-Martinez
- Department of Bacteriology, University of Wisconsin, Madison, Madison, WI 53706, USA
| | - Evan Hutchison
- Department of Bacteriology, University of Wisconsin, Madison, Madison, WI 53706, USA
| | - Hooman Allayee
- Departments of Population & Public Health Sciences and Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Aldons J Lusis
- Departments of Medicine, Human Genetics, and Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine of UCLA, Los Angeles, CA 90095, USA.
| | - Federico E Rey
- Department of Bacteriology, University of Wisconsin, Madison, Madison, WI 53706, USA
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23
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Panzitt K, Zollner G, Marschall HU, Wagner M. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol 2022; 552:111678. [PMID: 35605722 DOI: 10.1016/j.mce.2022.111678] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/25/2022]
Abstract
The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
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Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
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24
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Bertolini A, Fiorotto R, Strazzabosco M. Bile acids and their receptors: modulators and therapeutic targets in liver inflammation. Semin Immunopathol 2022; 44:547-564. [PMID: 35415765 PMCID: PMC9256560 DOI: 10.1007/s00281-022-00935-7] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/25/2022] [Indexed: 12/11/2022]
Abstract
Bile acids participate in the intestinal emulsion, digestion, and absorption of lipids and fat-soluble vitamins. When present in high concentrations, as in cholestatic liver diseases, bile acids can damage cells and cause inflammation. After the discovery of bile acids receptors about two decades ago, bile acids are considered signaling molecules. Besides regulating bile acid, xenobiotic, and nutrient metabolism, bile acids and their receptors have shown immunomodulatory properties and have been proposed as therapeutic targets for inflammatory diseases of the liver. This review focuses on bile acid-related signaling pathways that affect inflammation in the liver and provides an overview of the preclinical and clinical applications of modulators of these pathways for the treatment of cholestatic and autoimmune liver diseases.
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Affiliation(s)
- Anna Bertolini
- Section of Digestive Diseases, Yale Liver Center, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA
- Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, Groningen, The Netherlands
| | - Romina Fiorotto
- Section of Digestive Diseases, Yale Liver Center, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA
| | - Mario Strazzabosco
- Section of Digestive Diseases, Yale Liver Center, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA.
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Ma W, Zhang P, Yiming A, Amuti S, Ruze A. iTRAQ-based identification of differentially expressed proteins in ED rat model induced by cold stress combined with environmental oestrogen. Andrologia 2022; 54:e14382. [PMID: 35092079 DOI: 10.1111/and.14382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 11/27/2022] Open
Abstract
We aim to identify serum biomarkers and key proteins of erectile dysfunction (ED) induced by cold stress combined with environmental oestrogen through iTRAQ combined with LC-MS/MS. ED rat model was established by using oestrogen-like feed and cold stimulation. Differentially expressed proteins in serum were screened and analysed with iTRAQ combined with LC-MS/MS and IPA bioanalysis platform. We found that 35 proteins were differentially expressed in the ED group, including 31 upregulated and four downregulated proteins. The molecular functions of differential proteins mainly involved the activation of endopeptidase inhibitor and regulator. The main pathways involved were the FXR/RXR activation signalling pathway and the acute phase response signalling pathway. Furthermore, three protein markers related to ED were obtained, namely C-reactive protein (CRP), T-kininogen 1 and apolipoprotein Protein H (APOH). ELISA results showed that compared with the control group, proteins of HPX, TTR, APOH, RBP4, CRP and ORM1 were significantly upregulated, but ANGPT1 protein was significantly downregulated in the serum of the ED group (p < 0.05). Conclusively, the candidate serum markers for ED induced by cold stress combined with environmental hormones were obtained. Our results indicate that inflammation and vascular endothelial function changes may play a key role in the occurrence and development of ED.
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Affiliation(s)
- Wenjing Ma
- School of Pharmacy, Central Laboratory, Xinjiang Medical University, Urumqi, 830017, P.R. China
| | - Panpan Zhang
- Department of Human Anatomy, Basic Medical College, Xinjiang Medical University, Urumqi, 830017, P.R. China
| | - Adilijiang Yiming
- Department of Human Anatomy, Basic Medical College, Xinjiang Medical University, Urumqi, 830017, P.R. China
| | - Siyiti Amuti
- Department of Human Anatomy, Basic Medical College, Xinjiang Medical University, Urumqi, 830017, P.R. China
| | - Abudureyimujiang Ruze
- Department of Human Anatomy, Basic Medical College, Xinjiang Medical University, Urumqi, 830017, P.R. China
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26
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Kaur H, Premkumar M. Diagnosis and Management of Cirrhotic Cardiomyopathy. J Clin Exp Hepatol 2022; 12:186-199. [PMID: 35068798 PMCID: PMC8766707 DOI: 10.1016/j.jceh.2021.08.016] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/13/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Cirrhotic cardiomyopathy refers to the structural and functional changes in the heart leading to either impaired systolic, diastolic, electrocardiographic, and neurohormonal changes associated with cirrhosis and portal hypertension. Cirrhotic cardiomyopathy is present in 50% of patients with cirrhosis and is clinically seen as impaired contractility, diastolic dysfunction, hyperdynamic circulation, and electromechanical desynchrony such as QT prolongation. In this review, we will discuss the cardiac physiology principles underlying cirrhotic cardiomyopathy, imaging techniques such as cardiac magnetic resonance imaging and scintigraphy, cardiac biomarkers, and newer echocardiographic techniques such as tissue Doppler imaging and speckle tracking, and emerging treatments to improve outcomes. METHODS We reviewed available literature from MEDLINE for randomized controlled trials, cohort studies, cross-sectional studies, and real-world outcomes using the search terms "cirrhotic cardiomyopathy," "left ventricular diastolic dysfunction," "heart failure in cirrhosis," "liver transplantation," and "coronary artery disease". RESULTS Cirrhotic cardiomyopathy is associated with increased risk of complications such as hepatorenal syndrome, refractory ascites, impaired response to stressors including sepsis, bleeding or transplantation, poor health-related quality of life and increased morbidity and mortality. The evaluation of cirrhotic cardiomyopathy should also guide the feasibility of procedures such as transjugular intrahepatic portosystemic shunt, dose titration protocol of betablockers, and liver transplantation. The use of targeted heart rate reduction is of interest to improve cardiac filling and improve the cardiac output using repurposed heart failure drugs such as ivabradine. Liver transplantation may also reverse the cirrhotic cardiomyopathy; however, careful cardiac evaluation is necessary to rule out coronary artery disease and improve cardiac outcomes in the perioperative period. CONCLUSION More data are needed on the new diagnostic criteria, molecular and biochemical changes, and repurposed drugs in cirrhotic cardiomyopathy. The use of advanced imaging techniques should be incorporated in clinical practice.
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Key Words
- 2-AG, 2-arachidonylglycerol
- 2D, two-dimensional
- AEA, Anandamide
- ANP, Atrial Natriuretic Peptide
- ASE, the American Society of Echocardiography
- AUC, area under the curve
- BA, bile acid
- BNP, Brain natriuretic peptide
- CAD, coronary artery disease
- CB-1, cannabinoid −1
- CCM, Cirrhotic Cardiomyopathy
- CMR, cardiovascular magnetic resonance imaging
- CO, cardiac output
- CT, computed tomography
- CTP, Child–Turcotte–Pugh
- CVP, central venous pressure
- DT, deceleration Time
- ECG, electrocardiogram
- ECV, extracellular volume
- EF, Ejection fraction
- EMD, electromechanical desynchrony
- ESLD, end-stage liver disease
- FXR, Farnesoid X receptor
- GI, gastrointestinal
- GLS, Global Longitudinal strain
- HCN, Hyperpolarization-activated cyclic nucleotide–gated
- HE, hepatic encephalopathy
- HF, heart failure
- HO, Heme oxygenase
- HPS, hepatopulmonary syndrome
- HR, heart rate
- HRS, hepatorenal syndrome
- HVPG, hepatic venous pressure gradient
- HfmrEF, heart failure with mid-range ejection fraction
- HfrEF, heart failure with reduced ejection fraction
- IVC, Inferior Vena Cava
- IVCD, IVC Diameter
- IVS, intravascular volume status
- L-NAME, NG-nitro-L-arginine methyl ester
- LA, left atrium
- LAVI, LA volume index
- LGE, late gadolinium enhancement
- LT, liver transplant
- LV, left ventricle
- LVDD, left ventricular diastolic dysfunction
- LVEDP, left ventricular end-diastolic pressure
- LVEDV, LV end diastolic volume
- LVEF, left ventricular ejection fraction
- LVESV, LV end systolic volume
- LVOT, left ventricular outflow tract
- MAP, mean arterial pressure
- MELD, Model for End-Stage Liver Disease
- MR, mitral regurgitation
- MRI, Magnetic resonance imaging
- MV, mitral valve
- NAFLD, Nonalcoholic fatty liver disease
- NO, nitric oxide
- NOS, Nitric oxide synthases
- NTProBNP, N-terminal proBNP
- PAP, pulmonary artery pressure
- PCWP, pulmonary capillary wedged pressure
- PHT, portal hypertension
- PWD, Pulsed-wave Doppler
- RV, right ventricle
- RVOT, right ventricular outflow tract
- SA, sinoatrial
- SD, standard deviation
- SV, stroke volume
- SVR, Systemic vascular resistance
- TDI, tissue Doppler imaging
- TIPS, transjugular intrahepatic portosystemic shunt
- TR, Tricuspid valve
- TRPV1, transient receptor potential cation channel subfamily V member 1
- TTE, transthoracic echocardiography
- USG, ultrasonography
- VTI, velocity time integral
- beta blocker
- cirrhotic cardiomyopathy
- hemodynamics in cirrhosis
- left ventricular diastolic dysfunction
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Affiliation(s)
| | - Madhumita Premkumar
- Address for correspondence: Dr. Madhumita Premkumar, M.D., D.M., Department of Hepatology, Postgraduate Institute of Medical Education and Research, 60012, Chandigarh, India. Tel.: ++91-9540951061 (mobile)
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Radun R, Trauner M. Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities. Semin Liver Dis 2021; 41:461-475. [PMID: 34289507 PMCID: PMC8492195 DOI: 10.1055/s-0041-1731707] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.
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Affiliation(s)
- Richard Radun
- Department of Internal Medicine III, Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria
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28
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Königshofer P, Brusilovskaya K, Petrenko O, Hofer BS, Schwabl P, Trauner M, Reiberger T. Nuclear Receptors in Liver Fibrosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166235. [PMID: 34339839 DOI: 10.1016/j.bbadis.2021.166235] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/18/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
Nuclear receptors are ligand-activated transcription factors that regulate gene expression of a variety of key molecular signals involved in liver fibrosis. The primary cellular driver of liver fibrogenesis are activated hepatic stellate cells. Different NRs regulate the hepatic expression of pro-inflammatory and pro-fibrogenic cytokines that promote the transformation of hepatic stellate cells into fibrogenic myofibroblasts. Importantly, nuclear receptors regulate gene expression circuits that promote hepatic fibrogenesis and/or allow liver fibrosis regression. In this review, we highlight the direct and indirect influence of nuclear receptors on liver fibrosis, with a focus on hepatic stellate cells, and discuss potential therapeutic effects of nuclear receptor modulation in regard to anti-fibrotic and anti-inflammatory effects. Further research on nuclear receptors-related signaling may lead to the clinical development of effective anti-fibrotic therapies for patients with liver disease.
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Affiliation(s)
- Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Ksenia Brusilovskaya
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Oleksandr Petrenko
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Benedikt Silvester Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
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29
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Fang X, Zhang S, Wang Z, Zhou J, Qi C, Song J. Cigarette smoke extract combined with LPS down-regulates the expression of MRP2 in chronic pulmonary inflammation may be related to FXR. Mol Immunol 2021; 137:174-186. [PMID: 34273652 DOI: 10.1016/j.molimm.2021.06.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/13/2021] [Accepted: 06/25/2021] [Indexed: 01/19/2023]
Abstract
The transporter multidrug resistance protein 2 (MRP2) plays an important role in chronic pulmonary inflammation by transporting cigarette smoke and other related inflammatory mediators. However, it is not completely clear whether pulmonary inflammation caused by cigarette smoke extract (CSE) and lipopolysaccharide (LPS) is related to MRP2 and its signal factors. In this study, CSE combined with LPS was used to establish an inflammation model in vivo and in vitro. We found that compared with the control group, after CSE combined with LPS treatment, the expression of MRP2 in rat lung tissue in vivo and human alveolar cell line in vitro was down-regulated, while the expression of inflammatory factors was up-regulated. Through silencing and overexpression of FXR, it was found that silent FXR could down-regulate MRP2 and up-regulate the expression of inflammatory factors. On the contrary, overexpression of FXR could up-regulate MRP2 and down-regulate the expression of inflammatory factors. Our results show that CSE combined with LPS can down-regulate the expression of MRP2 under inflammatory conditions, and the down-regulation of MRP2 expression may be achieved partly through the FXR signal pathway.
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Affiliation(s)
- Xin Fang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Shuyi Zhang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Zihao Wang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jian Zhou
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Chuanzong Qi
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jue Song
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.
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30
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The pathophysiological function of non-gastrointestinal farnesoid X receptor. Pharmacol Ther 2021; 226:107867. [PMID: 33895191 DOI: 10.1016/j.pharmthera.2021.107867] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Farnesoid X receptor (FXR) influences bile acid homeostasis and the progression of various diseases. While the roles of hepatic and intestinal FXR in enterohepatic transport of bile acids and metabolic diseases were reviewed previously, the pathophysiological functions of FXR in non-gastrointestinal cells and tissues have received little attention. Thus, the roles of FXR in the liver, immune system, nervous system, cardiovascular system, kidney, and pancreas beyond the gastrointestinal system are reviewed herein. Gain of FXR function studies in non-gastrointestinal tissues reveal that FXR signaling improves various experimentally-induced metabolic and immune diseases, including non-alcoholic fatty liver disease, type 2 diabetes, primary biliary cholangitis, sepsis, autoimmune diseases, multiple sclerosis, and diabetic nephropathy, while loss of FXR promotes regulatory T cells production, protects the brain against ischemic injury, atherosclerosis, and inhibits pancreatic tumor progression. The downstream pathways regulated by FXR are diverse and tissue/cell-specific, and FXR has both ligand-dependent and ligand-independent activities, all of which may explain why activation and inhibition of FXR signaling could produce paradoxical or even opposite effects in some experimental disease models. FXR signaling is frequently compromised by diseases, especially during the progressive stage, and rescuing FXR expression may provide a promising strategy for boosting the therapeutic effect of FXR agonists. Tissue/cell-specific modulation of non-gastrointestinal FXR could influence the treatment of various diseases. This review provides a guide for drug discovery and clinical use of FXR modulators.
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31
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Gut Microbiome and Precision Nutrition in Heart Failure: Hype or Hope? Curr Heart Fail Rep 2021; 18:23-32. [DOI: 10.1007/s11897-021-00503-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2021] [Indexed: 02/06/2023]
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32
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Cariello M, Piccinin E, Moschetta A. Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH. Cell Mol Gastroenterol Hepatol 2021; 11:1519-1539. [PMID: 33545430 PMCID: PMC8042405 DOI: 10.1016/j.jcmgh.2021.01.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Elena Piccinin
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro," Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy; National Institute for Biostructures and Biosystems (INBB), Rome, Italy; Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy.
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33
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Zhang R, Ma WQ, Fu MJ, Li J, Hu CH, Chen Y, Zhou MM, Gao ZJ, He YL. Overview of bile acid signaling in the cardiovascular system. World J Clin Cases 2021; 9:308-320. [PMID: 33521099 PMCID: PMC7812903 DOI: 10.12998/wjcc.v9.i2.308] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/28/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.
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Affiliation(s)
- Rou Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Wen-Qi Ma
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Meng-Jun Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Chun-Hua Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Mi-Mi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Zhi-Jie Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Ying-Li He
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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Role of Farnesoid X Receptor in the Pathogenesis of Respiratory Diseases. Can Respir J 2020; 2020:9137251. [PMID: 33294085 PMCID: PMC7714608 DOI: 10.1155/2020/9137251] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 11/02/2020] [Accepted: 11/13/2020] [Indexed: 12/14/2022] Open
Abstract
Farnesoid X receptor (FXR) is a bile acid receptor encoded by the Nr1h4 gene. FXR plays an important role in maintaining the stability of the internal environment and the integrity of many organs, including the liver and intestines. The expression of FXR in nondigestible tissues other than in the liver and small intestine is known as the expression of “nonclassical” bile acid target organs, such as blood vessels and lungs. In recent years, several studies have shown that FXR is widely involved in the pathogenesis of various respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, and idiopathic pulmonary fibrosis. Moreover, a number of works have confirmed that FXR can regulate the bile acid metabolism in the body and exert its anti-inflammatory and antifibrotic effects in the airways and lungs. In addition, FXR may be used as a potential therapeutic target for some respiratory diseases. For example, FXR can regulate the tumor microenvironment by regulating the balance of inflammatory and immune responses in the body to promote the occurrence and development of non-small-cell lung cancer (NSCLC), thereby being considered a potential target for immunotherapy of NSCLC. In this article, we provide an overview of the internal relationship between FXR and respiratory diseases to track the progress that has been achieved thus far in this direction and suggest potential therapeutic prospects of FXR in respiratory diseases.
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Montagnana M, Danese E, Giontella A, Bonafini S, Benati M, Tagetti A, Dalbeni A, Cavarzere P, Gaudino R, Pucci M, Salvagno GL, Antoniazzi F, Lippi G, Maffeis C, Fava C. Circulating Bile Acids Profiles in Obese Children and Adolescents: A Possible Role of Sex, Puberty and Liver Steatosis. Diagnostics (Basel) 2020; 10:diagnostics10110977. [PMID: 33233601 PMCID: PMC7699673 DOI: 10.3390/diagnostics10110977] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 01/04/2023] Open
Abstract
Background. Childhood obesity is becoming a major health issue and contributes to increasing the risk of cardiovascular disease in adulthood. Since dysregulated metabolism of bile acids (BAs) plays a role in progression of obesity-related disorders, including steatosis and hypertension, this study aimed to investigate BAs profiles in obese children with and without steatosis and hypertension, as well as exploring the interplay between BAs profile and vascular function. Methods. BAs concentrations were quantified with liquid chromatography-tandem mass spectrometry in 69 overweight/obese children and adolescents (mean age, 11.6 ± 2.5 years; 30 females). Liver steatosis was defined with abdomen ultrasonography, whilst hypertension was defined according to the current European guidelines. Vascular function was assessed with ultrasound technique, by measuring carotid intima media thickness (cIMT) and common carotid artery distensibility (cDC). Results. Total and individual glycine-conjugated BAs concentrations were found to be significantly higher in males compared to females, as well as in pre-pubertal compared to pubertal stage (p < 0.05 for both). No difference in BAs concentration was observed between hypertensive and normotensive subjects. Total BAs and glycine conjugated BAs were significantly higher in participants with steatosis compared to those without (p = 0.004 for both). The values of total glycine-conjugate acids were positively correlated with cDC and this association remained significant in linear regression after adjusting for sex, age, pubertal stage, body mass index and aspartate aminotransferase. Conclusion. The results suggest a possible role of BAs in the pathogenesis of liver and/or vascular damage in children and adolescent. Further studies are hence needed to validate these preliminary findings.
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Affiliation(s)
- Martina Montagnana
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy; (E.D.); (M.B.); (M.P.); (G.L.S.); (G.L.)
- Correspondence:
| | - Elisa Danese
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy; (E.D.); (M.B.); (M.P.); (G.L.S.); (G.L.)
| | - Alice Giontella
- “General Medicine and Hypertension” Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (A.G.); (S.B.); (A.T.); (A.D.); (C.F.)
| | - Sara Bonafini
- “General Medicine and Hypertension” Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (A.G.); (S.B.); (A.T.); (A.D.); (C.F.)
| | - Marco Benati
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy; (E.D.); (M.B.); (M.P.); (G.L.S.); (G.L.)
| | - Angela Tagetti
- “General Medicine and Hypertension” Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (A.G.); (S.B.); (A.T.); (A.D.); (C.F.)
| | - Andrea Dalbeni
- “General Medicine and Hypertension” Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (A.G.); (S.B.); (A.T.); (A.D.); (C.F.)
| | - Paolo Cavarzere
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37126 Verona, Italy; (P.C.); (R.G.); (F.A.); (C.M.)
| | - Rossella Gaudino
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37126 Verona, Italy; (P.C.); (R.G.); (F.A.); (C.M.)
| | - Mairi Pucci
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy; (E.D.); (M.B.); (M.P.); (G.L.S.); (G.L.)
| | - Gian Luca Salvagno
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy; (E.D.); (M.B.); (M.P.); (G.L.S.); (G.L.)
| | - Franco Antoniazzi
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37126 Verona, Italy; (P.C.); (R.G.); (F.A.); (C.M.)
| | - Giuseppe Lippi
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement Science, University of Verona, 37134 Verona, Italy; (E.D.); (M.B.); (M.P.); (G.L.S.); (G.L.)
| | - Claudio Maffeis
- Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37126 Verona, Italy; (P.C.); (R.G.); (F.A.); (C.M.)
| | - Cristiano Fava
- “General Medicine and Hypertension” Unit, Department of Medicine, University of Verona, 37134 Verona, Italy; (A.G.); (S.B.); (A.T.); (A.D.); (C.F.)
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Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging. Physiol Rev 2020; 101:683-731. [PMID: 32790577 DOI: 10.1152/physrev.00049.2019] [Citation(s) in RCA: 249] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Hadrien Demagny
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Laura Velazquez-Villegas
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
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Li C, Zhang S, Chen X, Ji J, Yang W, Gui T, Gai Z, Li Y. Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p. Commun Biol 2020; 3:327. [PMID: 32581266 PMCID: PMC7314757 DOI: 10.1038/s42003-020-1058-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 06/08/2020] [Indexed: 01/06/2023] Open
Abstract
Chronic inflammation plays a crucial role in vascular calcification. However, only a few studies have revealed the mechanisms underlying the development of inflammation under high-phosphate conditions in chronic kidney disease (CKD) patients. Here, we show that inflammation resulting from the activation of the TGFBR1/TAK1 pathway is involved in calcification in CKD rats or osteogenic medium-cultured human aortic smooth muscle cells (HASMCs). Moreover, miR-135a-5p is demonstrated to be a key regulator of the TGFBR1/TAK1 pathway, which has been reported to be decreased in CKD rats. We further reveal that farnesoid X receptor (FXR) activation increases miR-135a-5p expression, thereby inhibiting the activation of the TGFBR1/TAK1 pathway, ultimately resulting in the attenuation of vascular inflammation and calcification in CKD rats. Our findings provide advanced insights into the mechanisms underlying the development of inflammation in vascular calcification, and evidence that FXR activation could serve as a therapeutic strategy for retarding vascular calcification in CKD patients.
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MESH Headings
- Animals
- Aorta/cytology
- Calcinosis/genetics
- Calcinosis/metabolism
- Cells, Cultured
- Female
- Humans
- MAP Kinase Kinase Kinases/genetics
- MAP Kinase Kinase Kinases/metabolism
- Male
- MicroRNAs/genetics
- Muscle, Smooth, Vascular/cytology
- Osteogenesis
- Rats, Wistar
- Receptor, Transforming Growth Factor-beta Type I/genetics
- Receptor, Transforming Growth Factor-beta Type I/metabolism
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Renal Insufficiency, Chronic/etiology
- Renal Insufficiency, Chronic/pathology
- Vasculitis/genetics
- Vasculitis/metabolism
- Vasculitis/pathology
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Affiliation(s)
- Chao Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, 8032, Switzerland
| | - Shijun Zhang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Xiaoqing Chen
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Jingkang Ji
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Wenqing Yang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Ting Gui
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Zhibo Gai
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, 8032, Switzerland.
| | - Yunlun Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250000, China.
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Abstract
Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.
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Affiliation(s)
- W H Wilson Tang
- Center for Microbiome & Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. .,Department for Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. .,Center for Clinical Genomics, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA. .,Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA. .,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.
| | - Daniel Y Li
- Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA
| | - Stanley L Hazen
- Center for Microbiome & Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Department for Cellular & Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA.,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA
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Choucair I, Nemet I, Li L, Cole MA, Skye SM, Kirsop JD, Fischbach MA, Gogonea V, Brown JM, Tang WHW, Hazen SL. Quantification of bile acids: a mass spectrometry platform for studying gut microbe connection to metabolic diseases. J Lipid Res 2019; 61:159-177. [PMID: 31818878 DOI: 10.1194/jlr.ra119000311] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 11/24/2019] [Indexed: 02/07/2023] Open
Abstract
Bile acids (BAs) serve multiple biological functions, ranging from the absorption of lipids and fat-soluble vitamins to serving as signaling molecules through the direct activation of dedicated cellular receptors. Synthesized by both host and microbial pathways, BAs are increasingly understood as participating in the regulation of numerous pathways relevant to metabolic diseases, including lipid and glucose metabolism, energy expenditure, and inflammation. Quantitative analyses of BAs in biological matrices can be problematic due to their unusual and diverse physicochemical properties, making optimization of a method that shows good accuracy, precision, efficiency of extraction, and minimized matrix effects across structurally distinct human and murine BAs challenging. Herein we develop and clinically validate a stable-isotope-dilution LC/MS/MS method for the quantitative analysis of numerous primary and secondary BAs in both human and mouse biological matrices. We also utilize this tool to investigate gut microbiota participation in the generation of structurally specific BAs in both humans and mice. We examine circulating levels of specific BAs and in a clinical case-control study of age- and gender-matched type 2 diabetes mellitus (T2DM) versus nondiabetics. BAs whose circulating levels are associated with T2DM include numerous 12α-hydroxyl BAs (taurocholic acid, taurodeoxycholic acid, glycodeoxycholic acid, deoxycholic acid, and 3-ketodeoxycholic acid), while taurohyodeoxycholic acid was negatively associated with diabetes. The LC/MS/MS-based platform described should serve as a robust, high-throughput investigative tool for studying the potential involvement of structurally specific BAs and the gut microbiome on both physiological and disease processes.
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Affiliation(s)
- Ibrahim Choucair
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195
| | - Ina Nemet
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195 .,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195
| | - Lin Li
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195
| | - Margaret A Cole
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195
| | - Sarah M Skye
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195
| | - Jennifer D Kirsop
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195
| | - Michael A Fischbach
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305
| | - Valentin Gogonea
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195.,Department of Chemistry, Cleveland State University, Cleveland, OH 44115
| | - J Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195
| | - W H Wilson Tang
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195.,Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195
| | - Stanley L Hazen
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH 44195.,Heart and Vascular Institute, and Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44195.,Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195
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Human Postprandial Nutrient Metabolism and Low-Grade Inflammation: A Narrative Review. Nutrients 2019; 11:nu11123000. [PMID: 31817857 PMCID: PMC6950246 DOI: 10.3390/nu11123000] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 12/11/2022] Open
Abstract
The importance of the postprandial state has been acknowledged, since hyperglycemia and hyperlipidemia are linked with several chronic systemic low-grade inflammation conditions. Humans spend more than 16 h per day in the postprandial state and the postprandial state is acknowledged as a complex interplay between nutrients, hormones and diet-derived metabolites. The purpose of this review is to provide insight into the physiology of the postprandial inflammatory response, the role of different nutrients, the pro-inflammatory effects of metabolic endotoxemia and the anti-inflammatory effects of bile acids. Moreover, we discuss nutritional strategies that may be linked to the described pathways to modulate the inflammatory component of the postprandial response.
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Xia Y, Zhang F, Zhao S, Li Y, Chen X, Gao E, Xu X, Xiong Z, Zhang X, Zhang J, Zhao H, Wang W, Wang H, Guo Y, Liu Y, Li C, Wang S, Zhang L, Yan W, Tao L. Adiponectin determines farnesoid X receptor agonism-mediated cardioprotection against post-infarction remodelling and dysfunction. Cardiovasc Res 2019; 114:1335-1349. [PMID: 29668847 DOI: 10.1093/cvr/cvy093] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 04/12/2018] [Indexed: 12/16/2022] Open
Abstract
Aims The farnesoid X receptor (FXR) is a member of the metabolic nuclear receptor superfamily that plays a critical regulatory role in cardiovascular physiology/pathology. However, the role of systemic FXR activation in the chronic phase in myocardial infarction (MI)-induced cardiac remodelling and dysfunction remains unclear. In this study, we aimed to elucidate the role of long-term FXR activation on post-MI cardiac remodelling and dysfunction. Methods and results Mice underwent either MI surgery or sham operation. At 1 week after MI, both sham and MI mice were gavaged with 25 mg/kg/d of a synthetic FXR agonist (GW4064) or a vehicle control for 7 weeks, and cardiac performance was assessed by consecutive echocardiography studies. Administration of GW4064 significantly increased left ventricular ejection fraction at 4 weeks and 8 weeks after MI (both P < 0.01). Moreover, GW4064 treatment increased angiogenesis and mitochondrial biogenesis, reduced cardiomyocyte loss and inflammation, and ameliorated cardiac remodelling as evidenced by heart weight, lung weight, atrial natriuretic peptide/brain natriuretic peptide levels, and myocardial fibrosis at 8 weeks post-MI. At the molecular level, GW4064 significantly increased FXR mRNA expression and transcriptional activity in heart tissue. Moreover, over-expression of myocardial FXR failed to exert significant cardioprotection in vivo, indicating that GW4064 improved post-MI heart remodelling and function independent of myocardial FXR expression/activity. Among the four down-stream soluble molecules of FXR, plasma adiponectin was most significantly increased by GW4064. In cultured adipocytes, GW4064 increased mRNA levels and protein expression of adiponectin. Conditioned medium of GW4064-treated adipocytes activated AMPK-PGC-1α signalling and reduced hypoxia-induced cardiomyocyte apoptosis, all of which were attenuated by an adiponectin neutralizing anti-body. More importantly, when knocking-out adiponectin in mice, the cardioprotective effects of GW4064 were attenuated. Conclusions We are the first to show that FXR agonism ameliorated post-MI cardiac dysfunction and remodelling by stimulating adiponectin secretion. Thus, we demonstrated that FXR agonism is a potential therapeutic strategy in post-MI heart failure.
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Affiliation(s)
- Yunlong Xia
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Fuyang Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Shihao Zhao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China.,Department of Cardiology, Hainan Branch of PLA General Hospital, Sanya 572013, China
| | - Yueyang Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Xiyao Chen
- Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Erhe Gao
- Center for Translational Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Xinyue Xu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China
| | - Zhenyu Xiong
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Xiaomeng Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Jinglong Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Huishou Zhao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Wei Wang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Helin Wang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Yanjie Guo
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Yi Liu
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Congye Li
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Shan Wang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Ling Zhang
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Wenjun Yan
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
| | - Ling Tao
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 127 West Changle Road, Xi'an 710032, China
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SAA1 increases NOX4/ROS production to promote LPS-induced inflammation in vascular smooth muscle cells through activating p38MAPK/NF-κB pathway. BMC Mol Cell Biol 2019; 20:15. [PMID: 31216990 PMCID: PMC6582534 DOI: 10.1186/s12860-019-0197-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 05/17/2019] [Indexed: 01/01/2023] Open
Abstract
Background To investigate the effects of serum amyloid A1 (SAA1) on lipopolysaccharide (LPS) -induced inflammation in vascular smooth muscle cells (VSMCs). SAA1 expression was detected in LPS induced VSMCs at different concentrations for different time by using Western blotting. After pre-incubation with recombinant SAA1 protein, VSMCs were treated with 1 μg/ml LPS for 24 h. The VSMCs were then divided into Control, SAA1 siRNA, Nox4 siRNA, LPS, LPS + SAA1 siRNA, LPS + Nox4 siRNA and LPS + SAA1 siRNA + Nox4 groups. MTT was performed to observe the toxicity of VSMCs. Lucigenin-enhanced chemiluminescence method was used to detect superoxide anion (O2−) production and NADPH oxidase activity. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine expressions of inflammatory factors. Western blotting was used to determine expressions of NOX-4 and p38MAPK/NF-κB pathway related proteins. Results LPS promoted SAA1 protein expression in a concentration−/time-dependent manner. Recombinant SAA1 protein could increase NOX4/ROS production and promote the release of inflammatory factors (IL-1β, IL-6, IL-8, IL-17, TNF-α and MCP-1) in LPS (1 μg/ml) - induced VSMCs. Besides, both SAA1 siRNA and NOX-4 siRNA could not only enhance the O2− production and NADPH oxidase activity, but also up-regulate the protein expression of NOX4, the release of inflammatory factors, and the levels of p-p38 and p-NF-κB p65 in LPS-induced VSMCs. However, no significant differences in each index were observed between LPS group and LPS + SAA1 siRNA + Nox4 group. Conclusion SAA1-mediated NOX4/ROS pathway could activate p38MAPK/NF-κB pathway, thereby contributing to the release of inflammatory factors in LPS-induced VSMCs.
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Masaoutis C, Theocharis S. The farnesoid X receptor: a potential target for expanding the therapeutic arsenal against kidney disease. Expert Opin Ther Targets 2018; 23:107-116. [PMID: 30577722 DOI: 10.1080/14728222.2019.1559825] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor widely distributed among tissues, a major sensor of BA levels, primary suppressor of hepatic BA synthesis and secondary regulator of lipid metabolism and inflammation. Chronic kidney disease is a common, multifactorial condition with metabolic and inflammatory causes and implications. An array of natural and synthetic FXR agonists has been developed, but not yet studied clinically in kidney disease. Areas covered: Following a summary of FXR's physiological functions in the kidney, we discuss its effects in renal disease with emphasis on chronic and acute kidney disease, chemotherapy-induced nephrotoxicity, and renal neoplasia. Most information is derived from animal models; no relevant clinical study has been conducted to date. Expert opinion: Most available preclinical data indicates a promising outlook for clinical research in this direction. We believe FXR agonism to be an auspicious approach to treating renal disease, considering that multifactorial diseases call for ideally wide-reaching therapies.
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Affiliation(s)
- Christos Masaoutis
- a First Department of Pathology, Medical School , National and Kapodistrian University of Athens , Athens , Greece
| | - Stamatios Theocharis
- a First Department of Pathology, Medical School , National and Kapodistrian University of Athens , Athens , Greece
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Ðanić M, Stanimirov B, Pavlović N, Goločorbin-Kon S, Al-Salami H, Stankov K, Mikov M. Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome. Front Pharmacol 2018; 9:1382. [PMID: 30559664 PMCID: PMC6287190 DOI: 10.3389/fphar.2018.01382] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 11/09/2018] [Indexed: 12/12/2022] Open
Abstract
Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6α-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives.
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Affiliation(s)
- Maja Ðanić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Bojan Stanimirov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Nebojša Pavlović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Hani Al-Salami
- Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Biosciences Research Precinct, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Karmen Stankov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
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Abenavoli L, Falalyeyeva T, Boccuto L, Tsyryuk O, Kobyliak N. Obeticholic Acid: A New Era in the Treatment of Nonalcoholic Fatty Liver Disease. Pharmaceuticals (Basel) 2018; 11:104. [PMID: 30314377 PMCID: PMC6315965 DOI: 10.3390/ph11040104] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/01/2018] [Accepted: 10/03/2018] [Indexed: 12/13/2022] Open
Abstract
The main treatments for patients with nonalcoholic fatty liver disease (NAFLD) are currently based on lifestyle changes, including ponderal decrease and dietary management. However, a subgroup of patients with nonalcoholic steatohepatitis (NASH), who are unable to modify their lifestyle successfully, may benefit from pharmaceutical support. Several drugs targeting pathogenic mechanisms of NAFLD have been evaluated in clinical trials for the treatment of NASH. Farnesoid X receptor (FXR) is a nuclear key regulator controlling several processes of the hepatic metabolism. NAFLD has been proven to be associated with abnormal FXR activity. Obeticholic acid (OCA) is a first-in-class selective FXR agonist with anticholestatic and hepato-protective properties. Currently, OCA is registered for the treatment of primary biliary cholangitis. However, promising effects of OCA on NASH and its metabolic features have been reported in several studies.
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Affiliation(s)
- Ludovico Abenavoli
- Department of Health Sciences, University "Magna Graecia", Viale Europa-Germaneto, 8810 Catanzaro, Italy.
| | - Tetyana Falalyeyeva
- School of Medicine, Taras Shevchenko National University of Kyiv, Volodymyrska Street 64/13, 01601 Kiev, Ukraine.
| | - Luigi Boccuto
- Greenwood Genetic Center, Greenwood, SC 29646, USA.
- School of Health Research, Clemson University, Clemson, SC 29646, USA.
| | - Olena Tsyryuk
- School of Medicine, Taras Shevchenko National University of Kyiv, Volodymyrska Street 64/13, 01601 Kiev, Ukraine.
| | - Nazarii Kobyliak
- Department of Endocrinology, Bogomolets National Medical University, Pushkinska 22a, 01610 Kiev, Ukraine.
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Carino A, Marchianò S, Biagioli M, Bucci M, Vellecco V, Brancaleone V, Fiorucci C, Zampella A, Monti MC, Distrutti E, Fiorucci S. Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis. FASEB J 2018; 33:2809-2822. [PMID: 30303744 DOI: 10.1096/fj.201801373rr] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nonalcoholic steatohepatitis (NASH) is associated with an increased risk of developing cardiovascular complications and mortality, suggesting that treatment of NASH might benefit from combined approaches that target the liver and the cardiovascular components of NASH. Using genetic and pharmacologic approaches, we show that G protein-coupled bile acid-activated receptor 1 (GPBAR1) agonism reverses liver and vascular damage in mouse models of NASH. NASH is associated with accelerated vascular inflammation representing an independent risk factor for development of cardiovascular diseases and cardiovascular-related mortality. GPBAR1, also known as TGR5, is a G protein-coupled receptor for secondary bile acids that reduces inflammation and promotes energy expenditure. Using genetic and pharmacologic approaches, we investigated whether GPBAR1 agonism by 6β-ethyl-3α,7β-dihydroxy-5β-cholan-24-ol (BAR501) reverses liver and vascular damage induced by exposure to a diet enriched in fat and fructose (HFD-F). Treating HFD-F mice with BAR501 reversed liver injury and promoted the browning of white adipose tissue in a Gpbar1-dependent manner. Feeding HFD-F resulted in vascular damage, as shown by the increased aorta intima-media thickness and increased expression of inflammatory genes (IL-6,TNF-α, iNOS, and F4/80) and adhesion molecules (VCAM, intercellular adhesion molecule-1, and endothelial selectin) in the aorta, while reducing the expression of genes involved in NO and hydrogen sulfide generation, severely altering vasomotor activities of aortic rings in an ex vivo assay. BAR501 reversed this pattern in a Gpbar1-dependent manner, highlighting a potential role for GPBAR1 agonism in treating the liver and vascular component of NASH.-Carino, A., Marchianò, S., Biagioli, M., Bucci, M., Vellecco, V., Brancaleone, V., Fiorucci, C., Zampella, A., Monti, M. C., Distrutti, E., Fiorucci, S. Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis.
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Affiliation(s)
- Adriana Carino
- Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy
| | - Michele Biagioli
- Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy
| | | | | | | | - Chiara Fiorucci
- Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Maria Chiara Monti
- Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy; and
| | | | - Stefano Fiorucci
- Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy
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47
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van Niekerk G, Davis T, de Villiers W, Engelbrecht AM. The role of bile acids in nutritional support. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2018; 22:231. [PMID: 30268137 PMCID: PMC6164178 DOI: 10.1186/s13054-018-2160-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 08/13/2018] [Indexed: 12/13/2022]
Abstract
Nutritional support continues to receive much attention as a possible intervention to prevent loss of lean tissue mass, promote recovery and re-establish proper immune function in critical care patients. Yet there remains much controversy regarding the clinical efficacy of such interventions. In addition to the direct effect of nutrition in terms of micro- and macronutrient content, nutritional formulations may exert an effect via the physiological response to feeding. Here, we highlight the key role of postprandial reabsorbed bile acids in attenuating both the inflammatory response and autophagy. These observations suggest that not all patients would benefit from aggressive nutritional support.
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Affiliation(s)
- Gustav van Niekerk
- Stellenbosch University, Stellenbosch Central, Stellenbosch, 7599, South Africa.
| | - Tanja Davis
- Stellenbosch University, Stellenbosch Central, Stellenbosch, 7599, South Africa
| | - Willem de Villiers
- Stellenbosch University, Stellenbosch Central, Stellenbosch, 7599, South Africa
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48
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Xu W, Liu P, Mu YP. Research progress on signaling pathways in cirrhotic portal hypertension. World J Clin Cases 2018; 6:335-343. [PMID: 30283796 PMCID: PMC6163134 DOI: 10.12998/wjcc.v6.i10.335] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/27/2018] [Accepted: 08/04/2018] [Indexed: 02/05/2023] Open
Abstract
Portal hypertension (PHT) is an important consequence of liver cirrhosis, which can lead to complications that adversely affect a patient’s quality of life and survival, such as upper gastrointestinal bleeding, ascites, and portosystemic encephalopathy. In recent years, advances in molecular biology have led to major discoveries in the pathological processes of PHT, including the signaling pathways that may be involved: PI3K-AKT-mTOR, RhoA/Rho-kinase, JAK2/STAT3, and farnesoid X receptor. However, the pathogenesis of PHT is complex and there are numerous pathways involved. Therefore, the targeting of signaling pathways for medical management is lagging. This article summarizes the progress that has been made in understanding the signaling pathways in PHT, and provides ideas for treatment of the disorder.
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Affiliation(s)
- Wen Xu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
| | - Ping Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
| | - Yong-Ping Mu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (TCM), Shanghai 201203, China
- Key Laboratory of Liver and Kidney Disease of the Ministry of Education, Shanghai University of TCM, Shanghai 201203, China
- Clinical key laboratory of TCM of Shanghai, Shanghai 201203, China
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49
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Liu J, Liu Z, Hu X, Zhang Y, Zhang S. Synthetic E-selectin prevents postoperative vascular restenosis by inhibiting nuclear factor κB in rats. Mol Med Rep 2018; 17:5065-5073. [PMID: 29393453 PMCID: PMC5865970 DOI: 10.3892/mmr.2018.8536] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 03/21/2017] [Indexed: 12/31/2022] Open
Abstract
During the development of postoperative vascular restenosis, the aberrant proliferation of vascular smooth muscle cells (VSMCs) is a critical event resulting in intimal hyperplasia. Inflammatory responses involving the activation of nuclear factor (NF)-κB are among the major molecular processes underlying restenosis. The present study aimed to investigate the roles of NF-κB in VSMC proliferation and restenosis following vascular anastomosis, as well as to evaluate the potential of synthetic E-selectin to downregulate NF-κB and thus inhibit vascular hyperplasia. A total of 72 adult male Sprague-Dawley rats were randomly assigned to three groups: Control, operation and treatment groups. Rats in the operation and treatment groups received longitudinal incisions in the right carotid arteries, which were closed using interrupted sutures. Following vascular anastomosis, synthetic E-selectin (10 mg/kg), or an equal volume of saline, was immediately injected into the right femoral vein of rats in the treatment and operation groups, respectively. Following surgery, the mRNA and protein expression levels of NF-κB at the site of anastomosis, the levels of tumor necrosis factor-α and interleukin-6 in the serum, NF-κB binding activity, and the presence of proliferating cell nuclear antigen (PCNA)-positive cells were evaluated by western blotting, reverse transcription-quantitative polymerase chain reaction, ELISA, electrophoretic mobility shift assay and immunofluorescence staining. The present results demonstrated that following treatment with synthetic E-selectin, the levels of NF-κB and the inflammatory response, as well as the presence of PCNA-positive cells, were significantly reduced (P<0.01). In conclusion, the results of the present study suggested that synthetic E-selectin may exert anti-inflammatory and anti-restenotic effects following vascular anastomosis in vivo.
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Affiliation(s)
- Jiangang Liu
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zhongjie Liu
- Department of Neurosurgery, Shiqianxian People's Hospital, Guizhou 555100, P.R. China
| | - Xiaohui Hu
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yuan Zhang
- Department of Radiology, Suzhou Guangji Hospital, Suzhou, Jiangsu 215006, P.R. China
| | - Shiming Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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50
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Roth JD, Feigh M, Veidal SS, Fensholdt LKD, Rigbolt KT, Hansen HH, Chen LC, Petitjean M, Friley W, Vrang N, Jelsing J, Young M. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis. World J Gastroenterol 2018; 24:195-210. [PMID: 29375205 PMCID: PMC5768938 DOI: 10.3748/wjg.v24.i2.195] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 11/24/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis (NASH).
METHODS The effects of INT-767 on histological features of NASH were assessed in two studies using Lepob/ob (ob/ob) NASH mice fed the AMLN diet (high fat with trans-fat, cholesterol and fructose). In a proof-of-concept study, Lepob/ob (ob/ob) NASH mice were first dosed with INT-767 (3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767 (3 and 10 mg/kg) to obeticholic acid (OCA) (10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57Bl/6 mice on standard chow. C57Bl/6 mice were orally dosed with INT-767 or OCA (1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.
RESULTS INT-767 dose-dependently (3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation (assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study (16 wk), the FXR agonists OCA (10 and 30 mg/kg) and INT-767 (3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function.
CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH.
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MESH Headings
- Animals
- Bile Acids and Salts/metabolism
- Bile Acids and Salts/pharmacology
- Chromatography, High Pressure Liquid
- Diet, High-Fat
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Gene Expression Regulation
- Liver/drug effects
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis/etiology
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/pathology
- Liver Cirrhosis/prevention & control
- Mice, Inbred C57BL
- Mice, Obese
- Microscopy, Fluorescence, Multiphoton
- Non-alcoholic Fatty Liver Disease/etiology
- Non-alcoholic Fatty Liver Disease/metabolism
- Non-alcoholic Fatty Liver Disease/pathology
- Non-alcoholic Fatty Liver Disease/prevention & control
- Obesity/drug therapy
- Obesity/etiology
- Obesity/metabolism
- Obesity/pathology
- Proof of Concept Study
- Receptors, Cytoplasmic and Nuclear/agonists
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, G-Protein-Coupled/agonists
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction/drug effects
- Tandem Mass Spectrometry
- Time Factors
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Affiliation(s)
- Jonathan D Roth
- Intercept Pharmaceuticals, Intercept Pharmaceuticals, San Diego, CA 92121, United States
| | | | | | | | | | | | - Li C Chen
- PharmaNest, Genesis Imaging Services, Princeton, NJ 08540, United States
| | - Mathieu Petitjean
- PharmaNest, Genesis Imaging Services, Princeton, NJ 08540, United States
| | - Weslyn Friley
- Qualyst Transporter Solutions, Durham, NC 27713, United States
| | | | | | - Mark Young
- Intercept Pharmaceuticals, Intercept Pharmaceuticals, San Diego, CA 92121, United States
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