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Du W, Zou ZP, Ye BC, Zhou Y. Gut microbiota and associated metabolites: key players in high-fat diet-induced chronic diseases. Gut Microbes 2025; 17:2494703. [PMID: 40260760 PMCID: PMC12026090 DOI: 10.1080/19490976.2025.2494703] [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: 01/03/2025] [Revised: 02/26/2025] [Accepted: 04/11/2025] [Indexed: 04/24/2025] Open
Abstract
Excessive intake of dietary fats is strongly associated with an increased risk of various chronic diseases, such as obesity, diabetes, hepatic metabolic disorders, cardiovascular disease, chronic intestinal inflammation, and certain cancers. A significant portion of the adverse effects of high-fat diet on disease risk is mediated through modifications in the gut microbiota. Specifically, high-fat diets are linked to reduced microbial diversity, an overgrowth of gram-negative bacteria, an elevated Firmicutes-to-Bacteroidetes ratio, and alterations at various taxonomic levels. These microbial alterations influence the intestinal metabolism of small molecules, which subsequently increases intestinal permeability, exacerbates inflammatory responses, disrupts metabolic functions, and impairs signal transduction pathways in the host. Consequently, diet-induced changes in the gut microbiota play a crucial role in the initiation and progression of chronic diseases. This review explores the relationship between high-fat diets and gut microbiota, highlighting their roles and underlying mechanisms in the development of chronic metabolic diseases. Additionally, we propose probiotic interventions may serve as a promising adjunctive therapy to counteract the negative effects of high-fat diet-induced alterations in gut microbiota composition.
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Affiliation(s)
- Wei Du
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Zhen-Ping Zou
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Bang-Ce Ye
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Ying Zhou
- Laboratory of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
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Huang R, Zhou G, Cai J, Cao C, Zhu Z, Wu Q, Zhang F, Ding Y. Maternal consumption of urbanized diet compromises early-life health in association with gut microbiota. Gut Microbes 2025; 17:2483783. [PMID: 40176259 PMCID: PMC11988223 DOI: 10.1080/19490976.2025.2483783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/09/2025] [Accepted: 03/18/2025] [Indexed: 04/04/2025] Open
Abstract
Urbanization has significantly transformed dietary habits worldwide, contributing to a globally increased burden of non-communicable diseases and altered gut microbiota landscape. However, it is often overlooked that the adverse effects of these dietary changes can be transmitted from the mother to offspring during early developmental stages, subsequently influencing the predisposition to various diseases later in life. This review aims to delineate the detrimental effects of maternal urban-lifestyle diet (urbanized diet) on early-life health and gut microbiota assembly, provide mechanistic insights on how urbanized diet mediates mother-to-offspring transfer of bioactive substances in both intrauterine and extrauterine and thus affects fetal and neonatal development. Moreover, we also further propose a framework for developing microbiome-targeted precision nutrition and diet strategies specifically for pregnant and lactating women. The establishment of such knowledge can help develop proactive preventive measures from the beginning of life, ultimately reducing the long-term risk of disease and improving public health outcomes.
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Affiliation(s)
- Rong Huang
- Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Guicheng Zhou
- Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Jie Cai
- Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Cha Cao
- Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zhenjun Zhu
- Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Qingping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Fen Zhang
- Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yu Ding
- Department of Food Science and Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
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Zhang H, Zhao S, Fang R, Wang X, Chen H, Cai Z, Liu Y, Tu J, Zhang F, Zhang W, Zhang M, Xu B, Zhuge Y, Xiao J. FMO3 exacerbates hepatic endoplasmic reticulum stress in drug-induced liver injury by inhibiting CREB3/P4HB axis and activating TMAO-mediated PERK pathway. Life Sci 2025; 374:123699. [PMID: 40345485 DOI: 10.1016/j.lfs.2025.123699] [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: 02/18/2025] [Revised: 04/21/2025] [Accepted: 05/01/2025] [Indexed: 05/11/2025]
Abstract
AIMS The primary objective of this study is to elucidate the role of FMO3, an important enzyme in drug metabolism, and its metabolites in Drug-induced liver injury (DILI). MATERIALS AND METHODS We overexpressed hepatic FMO3 in mice by injecting AAV8 to examine their liver morphology under acetaminophen (APAP) or monocrotaline (MCT) treatment. We also detected the metabolite TMAO of FMO3 in patients and mice with DILI, and further verified its regulatory effects on the endoplasmic reticulum stress pathway in hepatocytes through in vivo and in vitro experiments. KEY FINDINGS We found that FMO3 is upregulated in patients and male mice with DILI and overexpression of hepatic FMO3 exacerbates APAP or MCT-induced acute liver injury in mice. Mechanistically, FMO3 binds to endoplasmic reticulum (ER) stress-related transcription factor CREB3 (cAMP response element-binding protein 3) and inhibits its nuclear transcription. The decreased activity of CREB3 reduces the expression of the downstream gene P4HB(prolyl 4-hydroxylase subunit beta), subsequently inducing ER stress and apoptosis. Trimethylamine N-Oxide (TMAO), as a metabolite of FMO3, is also significantly elevated in patients with pyrrolizidine alkaloids-induced acute liver injury and APAP or MCT-induced liver injury in male mice. TMAO triggers ER stress by activating the PERK signaling pathway, and inhibiting TMAO production in DILI mice mitigates liver injury. SIGNIFICANCE Overall, the above findings identify FMO3 as a potential enzyme that facilitates the progression of DILI and exerts ER stress by CREB3/P4HB axis and its metabolites TMAO, which presents new therapeutic targets for DILI.
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Affiliation(s)
- Han Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Si Zhao
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Rui Fang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xue Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Huan Chen
- Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zihao Cai
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yan Liu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jingjing Tu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Feng Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Wei Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Ming Zhang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Bing Xu
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Yuzheng Zhuge
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
| | - Jiangqiang Xiao
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
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Din AU, Sweet MG, McAmis AM, Ratliff JG, Anandh Babu PV, Neilson AP. Establishing reliable blood biomarkers for trimethylamine N-oxide status in rodents: Effects of oral choline challenge, dietary choline and fasting conditions. J Nutr Biochem 2025; 141:109905. [PMID: 40120776 DOI: 10.1016/j.jnutbio.2025.109905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 03/13/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
Circulating concentrations of the gut microbial-mammalian metabolite trimethylamine N-oxide (TMAO) are linked to atherosclerosis risk. TMAO biosynthesis begins when dietary choline is converted to trimethylamine (TMA) by gut microbial TMA lyase. TMA is transported to the liver, where flavin-containing monooxygenases convert it to TMAO. While dietary modifications regulate TMAO production, the impact of different intake methods, including oral gavage, dietary supplementation, and conditions such as fasting versus nonfasting, has not been fully explored. Twelve female Sprague-Dawley rats were divided into three diet groups (n = 4 per group): no-choline (0% choline), low-choline (0.08% choline), and high-choline (1% choline). Choline and TMAO fasting and nonfasting blood concentrations, and their kinetics following an acute choline challenge, were assessed before and after a 2-week dietary intervention with the distinct choline dietary levels. Fasting choline was under tight control, with little effect of dietary choline. Nonfasting choline was more variable, with high dietary choline reflected in higher blood choline. Greater levels of dietary choline were reflected in significantly greater levels of TMAO, particularly for nonfasting levels. Kinetic profiling demonstrated additional information regarding the appearance and clearance of these compounds from blood. These results suggest that acute oral choline gavage is likely most suitable for studies targeting acute (direct) inhibitors, whereas a choline-rich diet with assessment of fasting and nonfasting blood levels is more suitable for studying alterations to TMAO production capacity. Future research should examine the impact on atherosclerosis biomarkers and microbiome diversity to deepen the understanding of TMAO regulation and its cardiovascular implications.
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Affiliation(s)
- Ahmad Ud Din
- Plants for Human Health Institute, North Carolina State University, Kannapolis, North Carolina, USA
| | - Michael G Sweet
- Plants for Human Health Institute, North Carolina State University, Kannapolis, North Carolina, USA
| | - Ashley M McAmis
- Plants for Human Health Institute, North Carolina State University, Kannapolis, North Carolina, USA
| | - Juanita G Ratliff
- Plants for Human Health Institute, North Carolina State University, Kannapolis, North Carolina, USA
| | - Pon Velayutham Anandh Babu
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah, USA
| | - Andrew P Neilson
- Plants for Human Health Institute, North Carolina State University, Kannapolis, North Carolina, USA; Department of Food, Bioprocessing, and Nutrition Sciences, North Carolina State University, Raleigh, North Carolina, USA.
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Gao ZK, Fan CY, Zhang BW, Geng JX, Han X, Xu DQ, Arshad M, Sun HX, Li JY, Jin X, Mu XQ. Cardiac function of colorectal cancer mice is remotely controlled by gut microbiota: regulating serum metabolites and myocardial cytokines. Anim Microbiome 2025; 7:53. [PMID: 40448218 PMCID: PMC12123981 DOI: 10.1186/s42523-025-00405-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 04/06/2025] [Indexed: 06/02/2025] Open
Abstract
Several studies have indicated that the dysregulation of microbial metabolites and the inflammatory environment resulting from microbial dysbiosis may contribute to the occurrence and progression of cardiovascular diseases. Therefore, restoring the disordered gut microbiota in patients with colorectal cancer by fecal microbiota transplantation (FMT) has the potential to reduce the incidence of cardiac disease. In this study, we identified cardiac dysfunction in azomethane and dextran sodium sulfate-induced colorectal cancer mice. Intestinal microbes from healthy mice were transferred to colorectal cancer mice, which vastly reversed the disorder of the gut microbiota and effectively alleviated cardiac dysfunction. Moreover, FMT regulated the expression of serum metabolites such as uridine triphosphate (UTP), tiamulin, andrographolide, and N-Acetyl-D-glucosamine, as well as cytokines like TGF-β, IRF5, and β-MHC in the heart. These findings uncover that the disturbed gut microbiota causes cardiac dysfunction in colorectal cancer mice by modulating the expression of serum metabolites and cytokines, which could be alleviated by treatment with FMT.
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Affiliation(s)
- Zhan-Kui Gao
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Chao-Yuan Fan
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Bo-Wen Zhang
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Jia-Xin Geng
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Xing Han
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Dan-Qi Xu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Muhammad Arshad
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China
| | - Hao-Xuan Sun
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Jiong-Yi Li
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
| | - Xiangyuan Jin
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
| | - Xiao-Qin Mu
- Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
- National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, 150081, China.
- HMU-UCCSM Centre for Infection and Genomics, Harbin Medical University, Harbin, 150081, China.
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150081, China.
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Zhang Y, Wu H, Jin M, Feng G, Wang S. The gut-heart axis: unveiling the roles of gut microbiota in cardiovascular diseases. Front Cardiovasc Med 2025; 12:1572948. [PMID: 40491716 PMCID: PMC12146390 DOI: 10.3389/fcvm.2025.1572948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 05/05/2025] [Indexed: 06/11/2025] Open
Abstract
The gut microbiome refers to the collective genomes of the approximately 1,000-1,150 microbial species found in the human gut, called the gut microbiota. Changing the gut microbiota composition has been shown to affect cardiovascular health significantly. Numerous studies have demonstrated the part that gut microbiota and its metabolites play in the development and course of several illnesses, including colon cancer, heart failure, stroke, hypertension, and inflammatory bowel disease. With cardiovascular diseases responsible for more than 31% of all fatalities globally, conditions like hypertension, atherosclerosis, and heart failure are serious global health issues. Developing preventive measures to fight cardiovascular diseases requires understanding how the gut microbiota interacts with the cardiovascular system. Understanding the distinctive gut microbiota linked to cardiovascular diseases has been made possible by microbial sequencing analysis. The gut microbiota and cardiovascular diseases are closely related, and more profound knowledge of this association may result in treatment strategies and broad guidelines for enhancing cardiovascular health through gut microbiome modification. This review summarizes the role of gut microbiota in cardiovascular diseases, highlighting their influence on disease progression and potential therapeutic implications.
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Affiliation(s)
- Yuan Zhang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Department of Anesthesiology, International Mongolian Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China
| | - Huimin Wu
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Mu Jin
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Guirong Feng
- Department of Anesthesiology, International Mongolian Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China
| | - Sheng Wang
- Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Linzhi People’s Hospital, Linzhi, Tibet, China
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Snelson M, Muralitharan RR, Liu CF, Markó L, Forslund SK, Marques FZ, Tang WHW. Gut-Heart Axis: The Role of Gut Microbiota and Metabolites in Heart Failure. Circ Res 2025; 136:1382-1406. [PMID: 40403109 PMCID: PMC12101525 DOI: 10.1161/circresaha.125.325516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/03/2025] [Accepted: 04/06/2025] [Indexed: 05/24/2025]
Abstract
Heart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N-oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes.
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Affiliation(s)
- Matthew Snelson
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Rikeish R. Muralitharan
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
| | - Chia-Feng Liu
- Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH, USA
| | - Lajos Markó
- Charité – Universitätsmedizin Berlin, Germany
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Experimental and Clinical Research Center ( ECRC), Berlin, Germany
| | - Sofia K. Forslund
- Charité – Universitätsmedizin Berlin, Germany
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Experimental and Clinical Research Center ( ECRC), Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany
| | - Francine Z. Marques
- Hypertension Research Laboratory, Department of Pharmacology, Biomedical Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
- Victorian Heart Institute, Monash University, Melbourne, Australia
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - W. H. Wilson Tang
- Center for Microbiome and Human Health, Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland OH, USA
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland OH, USA
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8
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Yamashita T. The role of gut microbiota in cardiovascular diseases and their potential as novel therapeutic targets. J Cardiol 2025:S0914-5087(25)00126-1. [PMID: 40409712 DOI: 10.1016/j.jjcc.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 04/27/2025] [Accepted: 05/07/2025] [Indexed: 05/25/2025]
Abstract
Cardiovascular diseases (CVDs) including heart failure (HF) is a major health, medical and social issue that needs to be resolved in Japan's super-aged society. Recent clinical and basic studies suggest that the gut microbiota and their metabolites play critical roles in the onset and progression of CVDs. We explored changes in gut microbiota composition and metabolite levels among Japanese patients to investigate their association with CVDs. Changes in specific bacteria were observed, with a decrease in phylum Bacteroidetes and increases in order Lactobacillus or genus Streptococcus in coronary artery disease patients. For HF patients, a reduction in phylum Bacteroidetes and increases in phylum Actinobacteria (e.g. Bifidobacterium) and Proteobacteria (e.g. Escherichia, Shigella, and Klebsiella) were noted. Elevated levels of gut microbiota-associated metabolites, such as trimethylamine N-oxide (TMAO) and indoxyl sulfate, were observed in CVD patients, suggesting potential effects on organ functions. Many studies have linked higher plasma TMAO levels to worse prognoses in CVDs, including HF and renal failure. However, the clinical significance and therapeutic potential of these findings require further investigation. In this manuscript, the author aims to review the current status of research on gut microbiota in CVDs, with a primary focus on the microbes themselves and their related metabolites. Further research is essential to comprehensively understand these intricacies and establish clear cause-and-effect relationships, ultimately paving the way for the development of innovative therapies for CVDs.
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Affiliation(s)
- Tomoya Yamashita
- Division of Advanced Medical and Pharmaceutical Sciences, Graduate School of Science, Technology and Innovation, Kobe University, Japan.
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9
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Zheng Y, Ren Y, You L, Liu J, Xue J. Elevated Trimethylamine-N-oxide (TMAO) Is Associated with Vascular Access Dysfunction in Maintenance Hemodialysis Patients. Hemodial Int 2025. [PMID: 40394908 DOI: 10.1111/hdi.13255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/21/2025] [Accepted: 05/06/2025] [Indexed: 05/22/2025]
Abstract
INTRODUCTION Elevated levels of trimethylamine-N-oxide (TMAO), a metabolite produced by gut microbiota, have been associated with cardiovascular diseases and complications in various populations. However, its role in vascular access dysfunction in hemodialysis patients remains underexplored. This study investigates the potential relationship between TMAO levels and vascular access dysfunction in maintenance hemodialysis patients. METHODS This study included 80 hemodialysis patients. The baseline serum TMAO levels were measured, and clinical characteristics and dialysis-related data were collected. They were followed up on vascular access dysfunction events over a period of 1 year. The association between serum TMAO levels and vascular access dysfunction events were investigated. FINDINGS In our cohort, we observed a wide distribution of serum concentrations, with a median concentration of 15.2 μmol/L and a maximum concentration of 245.3 μmol/L. Patients were stratified into a low-TMAO group and a high-TMAO group according to the median value of TMAO concentrations. Those in the high-TMAO group had a significantly higher incidence of vascular access dysfunction events (p = 0.023). TMAO was independently associated with vascular access dysfunction events after adjusting for some potential vascular access dysfunction risk factors. DISCUSSION This study suggests that elevated serum TMAO levels may serve as an independent risk factor for vascular access dysfunction in hemodialysis patients. Reducing TMAO levels may potentially decrease the incidence of vascular access dysfunction, warranting further investigation into this therapeutic approach.
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Affiliation(s)
- Yin Zheng
- Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuan Ren
- Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Li You
- Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Junfeng Liu
- Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jun Xue
- Department of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
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10
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Yao F, Liu C, Luo D, Zhou Y, Li Q, Huang H, Xu H. Metabolites of Microbiota: A Novel Therapy for Heart Disease. FOOD REVIEWS INTERNATIONAL 2025; 41:1099-1115. [DOI: 10.1080/87559129.2024.2437410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Fei Yao
- The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou Medical University
| | | | - Duo Luo
- Guangzhou Medical University
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11
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Abavisani M, Tafti P, Khoshroo N, Ebadpour N, Khoshrou A, Kesharwani P, Sahebkar A. The heart of the matter: How gut microbiota-targeted interventions influence cardiovascular diseases. Pathol Res Pract 2025; 269:155931. [PMID: 40174272 DOI: 10.1016/j.prp.2025.155931] [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: 09/27/2024] [Revised: 03/10/2025] [Accepted: 03/26/2025] [Indexed: 04/04/2025]
Abstract
The human body is habitat to a wide spectrum of microbial populations known as microbiota, which play an important role in overall health. The considerable research has mostly focused on the gut microbiota due to its potential to impact numerous physiological functions and its correlation with a variety of disorders, such as cardiovascular diseases (CVDs). Imbalances in the gut microbiota, known as dysbiosis, have been linked to the development and progression of CVDs through various processes, including the generation of metabolites like trimethylamine-N-oxide and short-chain fatty acids. Studies have also looked at the idea of using therapeutic interventions, like changing your diet, taking probiotics or prebiotics, or even fecal microbiota transplantation (FMT), to change the gut microbiota's make-up and how it works in order to prevent or treat CVDs. Exploring the cause-and-effect connection between the gut microbiota and CVDs offers a hopeful path for creating innovative microbiome-centered strategies to prevent and cure CVDs. This review presents an in-depth review of the correlation between the gut microbiota and CVDs, as well as potential therapeutic approaches for manipulating the gut microbiota to enhance cardiovascular health.
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Affiliation(s)
- Mohammad Abavisani
- Student research committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Pourya Tafti
- Student research committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Niloofar Khoshroo
- Student research committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negar Ebadpour
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Khoshrou
- Student research committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pardesh, India; University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Wang X, Hui R, Li Q, Lu Y, Wang M, Shi Y, Xie B, Cong B, Ma C, Wen D. Gut microbiota-derived trimethylamine N-oxide involved in methamphetamine-induced depression-like behaviors of male mice. Neuropharmacology 2025; 268:110339. [PMID: 39894298 DOI: 10.1016/j.neuropharm.2025.110339] [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: 10/18/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 02/04/2025]
Abstract
Methamphetamine (METH)-provoked psychiatric symptoms are a major health concern, with depression being a prevalent symptom among METH abusers. Recently, gut microbiota-derived metabolites have been involved in various psychosis pathogenesis, but their roles in METH-induced depression remain unclear. This study investigates the implication of gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) in METH-induced depressive-like behaviors (DLBs). We examined the circulating TMAO levels post-METH exposure besides exploring the impacts of TMAO on METH-triggered DLBs. Then, potential causes of TMAO alterations were explored, along with its effects on hippocampal neuronal damage and neuroinflammation. The findings showcased that METH-treated mice displayed DLBs accompanied by increased serum TMAO levels. Similarly, introducing TMAO to the drinking water elevated serum TMAO levels and induced DLBs. Although METH exposure did not notably alter the abundance of the gut microbiota, antibiotic (ABX) therapy suppressed the increased serum TMAO levels and the onset of DLBs. Additionally, choline and L-carnitine levels were elevated following METH exposure, which may be a potential mechanism for TMAO metabolic dysregulation. Elevated TMAO levels resulted in an elevation in Nissl-positive dead cells, the number of microglia, TNF-α, and IL-1β levels, along with TLR-4, NF-κB, and MyD88 expression in the hippocampal CA3 region. Inhibition of TMAO synthesis mitigated METH-provoked neuronal damage and neuroinflammation.
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Affiliation(s)
- Xintao Wang
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China; Hebei Medical University Postdoctoral Research Station in Biology, Hebei, Shijiazhuang, 050017, PR China
| | - Rongji Hui
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China
| | - Qing Li
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China
| | - Yun Lu
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China
| | - Mengmeng Wang
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China
| | - Yan Shi
- Shanghai Key Laboratory of Forensic Medicine, Shanghai Forensic Science Platform, Key Laboratory of Judicial Expertise, Department of Forensic Toxicology, Academy of Forensic Science, Ministry of Justice, Shanghai, 200063, PR China
| | - Bing Xie
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China
| | - Bin Cong
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China
| | - Chunling Ma
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei, Shijiazhuang, 050017, PR China.
| | - Di Wen
- College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Hebei, Shijiazhuang, 050017, PR China; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei, Shijiazhuang, 050017, PR China.
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Nageswaran V, Carreras A, Reinshagen L, Beck KR, Steinfeldt J, Henricsson M, Ramezani Rad P, Peters L, Strässler ET, Lim J, Verhaar BJ, Döring Y, Weber C, König M, Steinhagen-Thiessen E, Demuth I, Kränkel N, Leistner DM, Potente M, Nieuwdorp M, Knaus P, Kuebler WM, Ferrell M, Nemet I, Hazen SL, Landmesser U, Bäckhed F, Haghikia A. Gut Microbial Metabolite Imidazole Propionate Impairs Endothelial Cell Function and Promotes the Development of Atherosclerosis. Arterioscler Thromb Vasc Biol 2025; 45:823-839. [PMID: 40143816 PMCID: PMC12017598 DOI: 10.1161/atvbaha.124.322346] [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: 12/18/2024] [Accepted: 03/05/2025] [Indexed: 03/28/2025]
Abstract
BACKGROUND The microbially produced amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effects of ImP on endothelial cell (EC) physiology and its role in atherosclerotic coronary artery disease are unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis. METHODS Plasma levels of ImP were measured in patients undergoing elective cardiac angiography (n=831) by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios and corresponding 95% confidence intervals for coronary artery disease were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. The effects of ImP on functional properties of ECs were assessed using HAECs (human aortic endothelial cells). In a mouse model of carotid artery injury, the impact of ImP on vascular regeneration was examined. Additionally, atheroprone Apoe-/- mice fed a high-fat diet were treated with and without ImP (800 µg), and aortic atherosclerotic lesion area was evaluated after 12 weeks. Next-generation sequencing, Western blot analysis, small interfering RNA-based gene knockdown, and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms. RESULTS Plasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk of prevalent coronary artery disease. We found that ImP dose dependently impaired migratory and angiogenic properties of human ECs and promoted an increased inflammatory response. Long-term exposure to ImP compromised the repair potential of the endothelium after an arterial insult. In atheroprone Apoe-/- (apolipoprotein E-/-) mice, ImP increased atherosclerotic lesion size. Mechanistically, ImP attenuated insulin receptor signaling by suppressing the PI3K (phosphoinositide 3-kinase)/AKT pathway leading to sustained activation of the FOXO1 (forkhead box protein O1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of ECs after carotid injury. CONCLUSIONS Our findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.
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Affiliation(s)
- Vanasa Nageswaran
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- Friede Springe-Cardiovascular Prevention Center at Charité, Charité-Universitätsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany (V.N., P.K.)
- University Hospital St. Josef-Hospital Bochum, Cardiology and Rhythmology, Ruhr University Bochum, Germany (V.N., L.R., A.H.)
| | - Alba Carreras
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Sweden (A.C., K.R.B., M.H., F.B.)
| | - Leander Reinshagen
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- University Hospital St. Josef-Hospital Bochum, Cardiology and Rhythmology, Ruhr University Bochum, Germany (V.N., L.R., A.H.)
| | - Katharina R. Beck
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Sweden (A.C., K.R.B., M.H., F.B.)
| | - Jakob Steinfeldt
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- Friede Springe-Cardiovascular Prevention Center at Charité, Charité-Universitätsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany (J.S., U.L., A.H.)
| | - Marcus Henricsson
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Sweden (A.C., K.R.B., M.H., F.B.)
| | - Pegah Ramezani Rad
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
| | - Lisa Peters
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- Institute of Physiology, Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (L.P., W.M.K.)
- Institute of Biology, Freie Universität Berlin, Germany (L.P.)
| | - Elisabeth T. Strässler
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
| | - Joseph Lim
- Angiogenesis and Metabolism Laboratory, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany (J.L., M.P.)
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (J.L., M.P.)
| | - Barbara J.H. Verhaar
- Department of Internal Medicine-Geriatrics, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center (UMC), the Netherlands (B.J.H.V., M.N.)
- Department of Vascular Medicine, Amsterdam UMC, the Netherlands (B.J.H.V., M.N.)
| | - Yvonne Döring
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Germany (Y.D., C.W.)
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Switzerland (Y.D.)
- Department for BioMedical Research (DBMR), University of Bern, Switzerland (Y.D.)
- German Center for Cardiovascular Research (DZHK), Partner Site Munich, Germany (Y.D., C.W.)
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Germany (Y.D., C.W.)
- German Center for Cardiovascular Research (DZHK), Partner Site Munich, Germany (Y.D., C.W.)
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, the Netherlands (C.W.)
- Munich Cluster for Systems Neurology, Germany (C.W.)
| | - Maximilian König
- Department of Internal Medicine D–Geriatrics, University Medicine Greifswald, Germany (M.K.)
| | - Elisabeth Steinhagen-Thiessen
- Friede Springe-Cardiovascular Prevention Center at Charité, Charité-Universitätsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)
- Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (E.S.-T., I.D.)
| | - Ilja Demuth
- Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (E.S.-T., I.D.)
- Charité–Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies, Germany (I.D.)
| | - Nicolle Kränkel
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- Friede Springe-Cardiovascular Prevention Center at Charité, Charité-Universitätsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)
| | - David M. Leistner
- German Center for Cardiovascular Research (DZHK), Partner Site Frankfurt Rhine-Main, Germany (D.M.L.)
- Department of Medicine, Cardiology and Angiology, Goethe University Hospital, Frankfurt, Germany (D.M.L.)
| | - Michael Potente
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- Angiogenesis and Metabolism Laboratory, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany (J.L., M.P.)
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany (J.L., M.P.)
| | - Max Nieuwdorp
- Department of Internal Medicine-Geriatrics, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center (UMC), the Netherlands (B.J.H.V., M.N.)
- Department of Vascular Medicine, Amsterdam UMC, the Netherlands (B.J.H.V., M.N.)
| | - Petra Knaus
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany (V.N., P.K.)
- Berlin-Brandenburg School for Regenerative Therapies, Germany (P.K.)
- International Max-Planck Research School for Biology and Computation, Berlin, Germany (P.K.)
| | - Wolfgang M. Kuebler
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- Institute of Physiology, Charité-Universitätsmedizin Berlin, corporate member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (L.P., W.M.K.)
- German Center for Lung Research (DZL), Berlin, Germany (W.M.K.)
- Keenan Research Centre for Biomedical Science at St. Michael’s, Toronto, Canada (W.M.K.)
- Departments of Surgery and Physiology, University of Toronto, Canada (W.M.K.)
| | - Marc Ferrell
- Departments of Cardiovascular and Metabolic Sciences, and Cardiovascular Medicine, Cleveland Clinic, OH (M.F., I.N., S.L.H.)
| | - Ina Nemet
- Departments of Cardiovascular and Metabolic Sciences, and Cardiovascular Medicine, Cleveland Clinic, OH (M.F., I.N., S.L.H.)
| | - Stanley L. Hazen
- Departments of Cardiovascular and Metabolic Sciences, and Cardiovascular Medicine, Cleveland Clinic, OH (M.F., I.N., S.L.H.)
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, OH (S.L.H.)
| | - Ulf Landmesser
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- Friede Springe-Cardiovascular Prevention Center at Charité, Charité-Universitätsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany (J.S., U.L., A.H.)
| | - Fredrik Bäckhed
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Sweden (A.C., K.R.B., M.H., F.B.)
- Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden (F.B.)
| | - Arash Haghikia
- Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin, Berlin, Germany (V.N., L.R., J.S., P.R.R., E.T.S., N.K., U.L., A.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (V.N., L.R., P.R.R., L.P., E.T.S., N.K., M.P., W.M.K., U.L., A.H.)
- Friede Springe-Cardiovascular Prevention Center at Charité, Charité-Universitätsmedizin Berlin, Germany (V.N., J.S., E.S.-T., N.K., U.L., A.H.)
- University Hospital St. Josef-Hospital Bochum, Cardiology and Rhythmology, Ruhr University Bochum, Germany (V.N., L.R., A.H.)
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Germany (J.S., U.L., A.H.)
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Tahmasebi A, Beheshti R, Mahmoudi M, Jalilzadeh M, Salehi-Pourmehr H. Alterations in gut microbial community structure in obstructive sleep apnea /hypopnea syndrome (OSAHS): A systematic review and meta-analysis. Respir Med 2025; 241:108077. [PMID: 40158663 DOI: 10.1016/j.rmed.2025.108077] [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: 11/23/2024] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/02/2025]
Abstract
OBJECTIVES This systematic review investigates gut bacterial diversity and composition in patients with Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) and examines how these changes may contribute to cardiovascular complications. METHODS A comprehensive search was conducted in PubMed, Web of Science, and Scopus up to March 2025. After removing duplicates, titles and abstracts were screened by two reviewers, and full texts were assessed for inclusion. Data extraction on study characteristics and outcomes was performed. Methodological quality was evaluated using the Joanna Briggs Institute checklist. α-diversity was assessed using richness and diversity indices, while β-diversity examined community structure differences. Meta-analysis was conducted using standardized mean differences (SMD) and confidence intervals (CIs), and heterogeneity was assessed with the Cochrane I2 test. RESULTS The review included 18 studies (16 adults, 2 pediatrics) examining the gut microbiome in OSAHS. Meta-analysis revealed significant reductions in α-diversity indices (Shannon, Chao1, observed species, ACE) in OSAHS patients, while Simpson's index showed no difference. β-diversity analyses showed distinct gut microbiome differences in OSA. Key differential bacteria included Bacteroides, Proteobacteria, Faecalibacterium, Ruminococcaceae, Megamonas, Oscillibacter, Dialister, Roseburia, and Lachnospira. Study quality was medium to high. CONCLUSION OSAHS is associated with significant gut microbiome alterations, including a reduction in beneficial bacteria and an increase in LPS-producing bacteria, leading to intestinal barrier dysfunction. These changes may contribute to systemic inflammation and elevate the risk of cardiovascular diseases.
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Affiliation(s)
- Ali Tahmasebi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Evidence-Based Medicine, Iranian EBM Center: A Joanna Briggs Institute Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rasa Beheshti
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Evidence-Based Medicine, Iranian EBM Center: A Joanna Briggs Institute Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadsina Mahmoudi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Evidence-Based Medicine, Iranian EBM Center: A Joanna Briggs Institute Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahan Jalilzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Research Center for Evidence-Based Medicine, Iranian EBM Center: A Joanna Briggs Institute Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hanieh Salehi-Pourmehr
- Research Center for Evidence-Based Medicine, Iranian EBM Center: A Joanna Briggs Institute Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran; Medical Philosophy and History Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Martelli A, Abate F, Roggia M, Benedetti G, Caradonna E, Calderone V, Tenore GC, Cosconati S, Novellino E, Stornaiuolo M. Trimethylamine N-Oxide (TMAO) Acts as Inhibitor of Endothelial Nitric Oxide Synthase (eNOS) and Hampers NO Production and Acetylcholine-Mediated Vasorelaxation in Rat Aortas. Antioxidants (Basel) 2025; 14:517. [PMID: 40427399 PMCID: PMC12108457 DOI: 10.3390/antiox14050517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/29/2025] Open
Abstract
Trimethylamine N-oxide (TMAO) is an endogenous osmolyte produced by enzymatic reactions starting in the human gut, where microbiota release trimethylamine (TMA) from foods, and ending in the liver, where TMA is oxidized to TMAO by flavin-containing monooxygenase 3 (FMO3). While physiological concentrations of TMAO help proteins preserve their folding, high levels of this metabolite are harmful and promote oxidative stress, inflammation, and atherosclerosis. In humans, elevated levels of circulating TMAO predispose individuals to cardiovascular diseases and chronic kidney disease and increase mortality risk, especially in the elderly. How TMAO exerts its negative effects has been only partially elucidated. In hypertensive rats, the eNOS substrate L-arginine and Taurisolo®, a nutraceutical endowed with TMAO-reducing activity, act synergistically to reduce arterial blood pressure. Here, we investigate the molecular mechanisms underpinning this synergism and prove that TMAO, the target of Taurisolo®, acts as direct inhibitor of endothelial nitric oxide synthase (eNOS) and competes with L-arginine at its catalytic site, ultimately inhibiting NO production and acetylcholine (Ach)-induced relaxation in murine aortas.
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Affiliation(s)
- Alma Martelli
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy; (A.M.); (G.B.); (V.C.)
| | - Federico Abate
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy; (F.A.); (M.R.); (S.C.)
| | - Michele Roggia
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy; (F.A.); (M.R.); (S.C.)
| | - Giada Benedetti
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy; (A.M.); (G.B.); (V.C.)
| | - Eugenio Caradonna
- Centro Diagnostico Italiano, Department of Clinical Laboratory, 20100 Milan, Italy;
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56120 Pisa, Italy; (A.M.); (G.B.); (V.C.)
| | - Gian Carlo Tenore
- Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy;
| | - Sandro Cosconati
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy; (F.A.); (M.R.); (S.C.)
| | - Ettore Novellino
- Department of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Mariano Stornaiuolo
- Department of Pharmacy, School of Medicine and Surgery, University of Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy;
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16
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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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17
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Oami T, Yamamoto A, Ishida S, Kondo K, Hata N, Oshima T. Critical Care Nutrition from a Metabolic Point of View: A Narrative Review. Nutrients 2025; 17:1352. [PMID: 40284216 PMCID: PMC12029973 DOI: 10.3390/nu17081352] [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: 03/05/2025] [Revised: 04/08/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Critical illness induces profound metabolic alterations, characterized by a hypermetabolic state, insulin resistance, protein catabolism, and gut barrier dysfunction, which contribute to increased morbidity and mortality. Emerging evidence highlights the role of the gut microbiome and its metabolites in modulating systemic inflammation and immune responses during critical illness. This narrative review explores the metabolic evolution of critically ill patients, the impact of gut dysbiosis on disease progression, and the potential role of nutrition in modulating metabolism and improving patient outcomes. Methods: A comprehensive literature search was conducted across PubMed and Google Scholar for articles published up to February 2025. Search terms included "critical illness", "metabolism", "gut microbiota", "nutrition", and related keywords. Articles published in English addressing metabolic alterations, microbiome changes, and nutritional strategies in critically ill patients were included. After screening for eligibility, relevant articles were synthesized to outline current knowledge and identify gaps. Results: Metabolic changes in critical illness progress through distinct phases, from catabolism-driven hypermetabolism to gradual recovery. Gut dysbiosis, characterized by a loss of microbial diversity and increased gut permeability, contributes to systemic inflammation and organ dysfunction. Nutritional strategies, including enteral nutrition, probiotics, prebiotics, and metabolomics-driven interventions, may help restore microbial balance, preserve gut barrier integrity, and modulate immune and metabolic responses. Future nutrition therapy should focus on metabolic modulation rather than solely addressing nutrient deficits. Conclusions: Advances in gut microbiome research and metabolomics offer new avenues for personalized nutrition strategies tailored to the metabolic demands of critically ill patients. Integrating these approaches may improve clinical and functional recovery while mitigating the long-term consequences of critical illness.
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Affiliation(s)
- Takehiko Oami
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan; (T.O.)
| | - Akiyuki Yamamoto
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan; (T.O.)
| | - Shigenobu Ishida
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan; (T.O.)
| | - Kengo Kondo
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan; (T.O.)
| | - Nanami Hata
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan; (T.O.)
| | - Taku Oshima
- Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba 260-8677, Japan; (T.O.)
- Institute for Advanced Academic Research, Chiba University, Chiba 263-8522, Japan
- Research Institute of Disaster Medicine, Chiba University, Chiba 263-8522, Japan
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18
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Lei D, Liu Y, Liu Y, Jiang Y, Lei Y, Zhao F, Li W, Ouyang Z, Chen L, Tang S, Ouyang D, Li X, Li Y. The gut microbiota metabolite trimethylamine N-oxide promotes cardiac hypertrophy by activating the autophagic degradation of SERCA2a. Commun Biol 2025; 8:596. [PMID: 40210720 PMCID: PMC11986001 DOI: 10.1038/s42003-025-08016-9] [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: 09/07/2022] [Accepted: 03/28/2025] [Indexed: 04/12/2025] Open
Abstract
Trimethylamine oxide (TMAO) is a newly found intestinal microbiota metabolite. Here, we aimed to explore the effects of TMAO on calcium homeostasis and its implication in cardiac hypertrophy, especially focusing on the regulatory mechanism of TMAO on the key calcium transporter SERCA2a. Echocardiography and histological assessment showed that mice fed with TMAO or Choline for 8 weeks exhibited significant pathological changes of cardiac hypertrophy, which is accompanied by increased plasma levels of TMAO. The results indicated that TMAO could increase the intracellular Ca2+ level, up-regulate the expression of ANP and MYH7, and down-regulate SERCA2a expression, which could be reversed by overexpressing of SERCA2a and BAPTA-AM. Meanwhile, TMAO treatment promotes autophagy in vitro and in vivo. By employing immunofluorescence staining and immunoprecipitation assay, it was found that SERCA2a bound to ATG5 and transported to autophagosomes via the ATG5 complex for degradation under TMAO conditions. Furthermore, either 3MA or siATG5 could ameliorate TMAO-induced cardiomyocyte hypertrophy and SERCA2a degradation. Finally, in vivo intervention showed that 3MA could relieve cardiac hypertrophy and rescue the down-regulation of SERCA2a in TMAO-fed mice. The current study identifies a mechanism in which TMAO promotes cardiac hypertrophy via elevated intracellular Ca2+ levels and enhanced autophagy degradation of SERCA2a.
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Affiliation(s)
- Dongyu Lei
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Department of Physiology, School of Basic Medicine, Xinjiang Medical University, Urumqi, 830017, China
| | - Yi Liu
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Yuan Liu
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, 410013, China
- Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yujie Jiang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Yuyan Lei
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Phase I Clinical Trial Laboratory, the Second Nanning People's Hospital, Guangxi, China
| | - Feilong Zhao
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Wenqun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Zhonghua Ouyang
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, 411000, China
| | - Lulu Chen
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, 411000, China
| | - Siyuan Tang
- Xiangya Nursing School, Central South University, Changsha, 410000, China
| | - Dongsheng Ouyang
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, 411000, China
| | - Xiaohui Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, 411000, China.
| | - Ying Li
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
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19
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Li X, Xue C, Yang Y, Zhao L, Chen L, Wang J, Yan L, Meng Z, Qiao X, Liang S, Yang X. Therapeutic effects of Isaria felina on postmenopausal osteoporosis: modulation of gut microbiota, metabolites, and immune responses. Front Immunol 2025; 16:1508634. [PMID: 40270955 PMCID: PMC12015163 DOI: 10.3389/fimmu.2025.1508634] [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: 10/09/2024] [Accepted: 02/12/2025] [Indexed: 04/25/2025] Open
Abstract
Background The intricate relationship between human health and gut microecology has emerged as a central theme in contemporary medical research. Postmenopausal osteoporosis, primarily driven by estrogen deficiency, remains a major health concern. Traditional Chinese herbal medicines have attracted significant interest for their promising role in osteoporosis treatment. Methods The effects of Isaria felina, derived from Cordyceps sinensis, on postmenopausal osteoporosis in rats are the focus of this study. Adult female Sprague-Dawley rats were categorized into control, postmenopausal osteoporosis (OVX), and Isaria felina-treated (IF+OVX) groups. Following a 12-week treatment period, various analyses, including micro-CT, histological assessments, 16S rDNA sequencing, untargeted metabolomics, flow cytometry, and ELISA, were performed. Results Micro-CT and histological assessments indicated significant improvements in bone loss and obesity control in OVX rats treated with Isaria felina. 16S rDNA sequencing revealed that Isaria felina corrected gut microbiota dysbiosis, particularly in the Bacteroides and Ruminococcus genera. Untargeted metabolomics highlighted alterations in nucleotide and lipid metabolism. Flow cytometry and ELISA analyses demonstrated that Isaria felina modulated the Th17/Treg immune balance, resulting in reduced levels of inflammatory cytokines IL-17 and TNF-α. Conclusions These findings indicate that Isaria felina mitigates bone loss in postmenopausal osteoporosis through modulation of gut microbiota and immune responses, underscoring its potential as a therapeutic agent for osteoporosis treatment.
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Affiliation(s)
- Xiaoyan Li
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chenhui Xue
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, Shanxi, China
| | - Yongming Yang
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lili Zhao
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lixia Chen
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jing Wang
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Lei Yan
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zan Meng
- Department of Orthopedics, Hospital of Shaanxi Provincial Armed Police Corps, Xi’an, Shaanxi, China
| | - Xiaochen Qiao
- Department of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sujiao Liang
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xihua Yang
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, China
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20
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Huang Z, Liu C, Zhao X, Guo Y. The effect of elevated levels of the gut metabolite TMAO on glucose metabolism after sleeve gastrectomy. Arch Physiol Biochem 2025:1-10. [PMID: 40202719 DOI: 10.1080/13813455.2025.2489721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 08/04/2024] [Accepted: 03/04/2025] [Indexed: 04/10/2025]
Abstract
Purpose:Bariatric surgery can effectively alleviate obesity and diabetes by regulation of the gut microbiota. This study aimed to investigate the change in the gut microbiota metabolite TMAO and to explore its effect on glucose metabolism after sleeve gastrectomy (SG). Materials and methods:Diet-induced obesity mouse models were established, and the mice were randomly divided into four groups: an SG group, a sham-operated group pair-fed with the SG group (PF), a sham-operated group fed ad libitum (AL), and a lean control group (C). At 10 weeks post-surgery, the changes in glycogen content of liver, gut microbiota and the level of FMO3 in the liver were evaluated, and their correlation with TMAO production was analysed. The expression levels of the TMAO/PERK/FOXO1 pathway and the gluconeogenic genes G6PC and PCK1 were measured. Results:At 10 weeks post-surgery, hepatocyte glycogen levels were restored, and serum TMA and TMAO levels were significantly increased. Faecal metagenomic sequencing results showed that the abundances of Ruminococcaceae and Lachnospiraceae, which were positively correlated with TMAO production, were significantly increased after surgery. While the changes in FMO3, the key enzyme producing TMAO in the liver was found decreased significantly after SG. The expression levels of the TMAO/PERK/FOXO1 pathway and the gluconeogenic genes G6PC and PCK1 were measured. Inconsistent with the changing trend of TMAO, the expression of PERK, FOXO1, PCK, and G6PC significantly decreased after SG. Conclusions:SG can significantly reduce obesity and restore glucose metabolism. After surgery, TMAO metabolites increased in a microbiota-dependent manner.
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Affiliation(s)
- Zhiping Huang
- Department of Hepatobiliary Surgery, Department of Organ Transplantation, General Hospital of Southern Theatre Command, Guangzhou, China
| | - Chaoqian Liu
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiang Zhao
- Department of General Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yan Guo
- Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China
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21
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Roessler J, Zimmermann F, Heidecker B, Landmesser U, Haghikia A. Gut microbiota-related modulation of immune mechanisms in post-infarction remodelling and heart failure. ESC Heart Fail 2025; 12:942-954. [PMID: 39385474 PMCID: PMC11911630 DOI: 10.1002/ehf2.14991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/28/2024] [Accepted: 07/08/2024] [Indexed: 10/12/2024] Open
Abstract
The immune system has long been recognized as a key driver in the progression of heart failure (HF). However, clinical trials targeting immune effectors have consistently failed to improve patient outcome across different HF aetiologies. The activation of the immune system in HF is complex, involving a broad network of pro-inflammatory and immune-modulating components, which complicates the identification of specific immune pathways suitable for therapeutic targeting. Increasing attention has been devoted to identifying gut microbial pathways that affect cardiac remodelling and metabolism and, thereby impacting the development of HF. In particular, gut microbiota-derived metabolites, absorbed by the host and transported to the peripheral circulation, can act as signalling molecules, influencing metabolism and immune homeostasis. Recent reports suggest that the gut microbiota plays a crucial role in modulating immune processes involved in HF. Here, we summarize recent advances in understanding the contributory role of gut microbiota in (auto-)immune pathways that critically determine the progression or alleviation of HF. We also thoroughly discuss potential gut microbiota-based intervention strategies to treat or decelerate HF progression.
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Affiliation(s)
- Johann Roessler
- University Hospital St Josef‐Hospital Bochum, Cardiology and RhythmologyRuhr University BochumBochumGermany
- Department of Cardiology, Angiology and Intensive CareDeutsches Herzzentrum der Charité (DHZC), Campus Benjamin FranklinBerlinGermany
- DZHK (German Centre for Cardiovascular Research), Partner site BerlinBerlinGermany
| | - Friederike Zimmermann
- Department of Cardiology, Angiology and Intensive CareDeutsches Herzzentrum der Charité (DHZC), Campus Benjamin FranklinBerlinGermany
- DZHK (German Centre for Cardiovascular Research), Partner site BerlinBerlinGermany
| | - Bettina Heidecker
- Department of Cardiology, Angiology and Intensive CareDeutsches Herzzentrum der Charité (DHZC), Campus Benjamin FranklinBerlinGermany
- DZHK (German Centre for Cardiovascular Research), Partner site BerlinBerlinGermany
- Berlin Institute of Health at Charité – Universitätsmedizin BerlinBerlinGermany
| | - Ulf Landmesser
- Department of Cardiology, Angiology and Intensive CareDeutsches Herzzentrum der Charité (DHZC), Campus Benjamin FranklinBerlinGermany
- DZHK (German Centre for Cardiovascular Research), Partner site BerlinBerlinGermany
- Berlin Institute of Health at Charité – Universitätsmedizin BerlinBerlinGermany
- Friede Springe‐Cardiovascular Prevention Center at Charité, Charité‐Universitätsmedizin, Berlin Institute of Health (BIH)BerlinGermany
| | - Arash Haghikia
- University Hospital St Josef‐Hospital Bochum, Cardiology and RhythmologyRuhr University BochumBochumGermany
- Department of Cardiology, Angiology and Intensive CareDeutsches Herzzentrum der Charité (DHZC), Campus Benjamin FranklinBerlinGermany
- DZHK (German Centre for Cardiovascular Research), Partner site BerlinBerlinGermany
- Berlin Institute of Health at Charité – Universitätsmedizin BerlinBerlinGermany
- Friede Springe‐Cardiovascular Prevention Center at Charité, Charité‐Universitätsmedizin, Berlin Institute of Health (BIH)BerlinGermany
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22
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Yao W, Li J, Zhu X, Ma R, Xu Y, Ma R, Guo Z, Mu G, Zhu X. GABA-Enriched Lactiplantibacillus plantarum DPUL-F233 Powder and Its Effect on Blood Pressure in Spontaneously Hypertensive Rats. J Food Sci 2025; 90:e70208. [PMID: 40271906 DOI: 10.1111/1750-3841.70208] [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: 12/31/2024] [Revised: 03/26/2025] [Accepted: 03/31/2025] [Indexed: 04/25/2025]
Abstract
Hypertension is a common chronic disease driven by multiple physiological mechanisms, primarily the overactivation of the renin-angiotensin system (RAS). Gamma-aminobutyric acid (GABA), a nonprotein amino acid, has well-documented health benefits, including antihypertensive and calming effects. This study evaluates the blood pressure-lowering effects of Lactiplantibacillus plantarum DPUL-F233 bacterial powder in spontaneously hypertensive rats (SHRs). The bacterial powder was produced using optimized fermentation and freeze-drying techniques. In the oral administration experiment on SHRs, the group treated with a high dose of bacterial powder via long-term gavage showed a significant reduction in blood pressure compared to the untreated group. Specifically, the final measurements of diastolic and systolic blood pressure were reduced to 206.0 ± 2.35 mm Hg and 145.0 ± 6.78 mm Hg, respectively. The angiotensin-converting enzyme I/Angiotensin II/AT1R axis was downregulated, while the angiotensin-converting enzyme II/Angiotensin 1-7/MasR axis was upregulated, rebalancing the RAS signaling pathway. The high-dose group also demonstrated protective effects on the heart and kidneys, with significant improvements observed in reducing cardiac hypertrophy and kidney damage. Additionally, molecular simulation studies indicated potential inhibition of ACE I by GABA. The results suggest that GABA-rich L. plantarum DPUL-F233 powder has significant potential as a natural antihypertensive supplement, particularly for use in functional food development.
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Affiliation(s)
- Wenpu Yao
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, PR China
| | - Junyi Li
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, PR China
| | - Xiaoyan Zhu
- Shandong Yu Wang Ecological Food Co., Ltd., Yucheng, PR China
| | - Ruiyang Ma
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, PR China
| | - Yunpeng Xu
- College of Life Sciences, Dalian Minzu University, Dalian, PR China
| | - Ruida Ma
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, PR China
| | - Zihao Guo
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, PR China
| | - Guangqing Mu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, PR China
| | - Xuemei Zhu
- School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, PR China
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23
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Su JQ, Wu XQ, Wang Q, Xie BY, Xiao CY, Su HY, Tang JX, Yao CW. The microbial metabolite trimethylamine N-oxide and the kidney diseases. Front Cell Infect Microbiol 2025; 15:1488264. [PMID: 40134790 PMCID: PMC11933022 DOI: 10.3389/fcimb.2025.1488264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 02/24/2025] [Indexed: 03/27/2025] Open
Abstract
Trimethylamine N-oxide (TMAO), a metabolite, is a co-metabolite produced by both gut microbiota and livers, originating from foods rich in choline or carnitine. Emerging evidence suggests that TMAO may play a role in the pathogenesis of various kidney diseases, including acute kidney injury and chronic kidney disease. Research has demonstrated that heightened levels of TMAO are correlated with a heightened likelihood of kidney disease advancement and cardiovascular incidents among individuals with chronic kidney disease. Furthermore, TMAO has been observed to stimulate inflammation, oxidative stress, and fibrosis in animal models of kidney disease. Mechanistically, TMAO may contribute to kidney disease pathogenesis by inhibiting autophagy, activating the NLRP3 inflammasome, and inducing mitochondrial dysfunction. Therefore, targeting TMAO may represent a promising therapeutic strategy for the treatment of kidney diseases. Future studies are needed to further investigate the role of TMAO in kidney disease pathogenesis and to develop TMAO-targeted therapies for the prevention and treatment of kidney diseases.
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Affiliation(s)
- Jin-Qi Su
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Xiang-Qi Wu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Qi Wang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Bo-Yang Xie
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Cui-Yan Xiao
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Hong-Yong Su
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Ji-Xin Tang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Cui-Wei Yao
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
- Key Laboratory of Prevention and Management of Chronic Kidney Diseases of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
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Hatamnejad MR, Medzikovic L, Dehghanitafti A, Rahman B, Vadgama A, Eghbali M. Role of Gut Microbial Metabolites in Ischemic and Non-Ischemic Heart Failure. Int J Mol Sci 2025; 26:2242. [PMID: 40076864 PMCID: PMC11900495 DOI: 10.3390/ijms26052242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
The effect of the gut microbiota extends beyond their habitant place from the gastrointestinal tract to distant organs, including the cardiovascular system. Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (H2S), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, H2S by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, H2S, and PAGln.
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Affiliation(s)
| | | | | | | | | | - Mansoureh Eghbali
- Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, BH-550 CHS, Los Angeles, CA 90095-7115, USA; (M.R.H.); (L.M.); (A.D.); (B.R.); (A.V.)
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25
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Shukla A, Sharma C, Malik MZ, Singh AK, Aditya AK, Mago P, Shalimar, Ray AK. Deciphering the tripartite interaction of urbanized environment, gut microbiome and cardio-metabolic disease. JOURNAL OF ENVIRONMENTAL MANAGEMENT 2025; 377:124693. [PMID: 40022791 DOI: 10.1016/j.jenvman.2025.124693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/13/2025] [Accepted: 02/21/2025] [Indexed: 03/04/2025]
Abstract
The world is experiencing a sudden surge in urban population, especially in developing Asian and African countries. Consequently, the global burden of cardio-metabolic disease (CMD) is also rising owing to gut microbiome dysbiosis due to urbanization factors such as mode of birth, breastfeeding, diet, environmental pollutants, and soil exposure. Dysbiotic gut microbiome indicated by altered Firmicutes to Bacteroides ratio and loss of beneficial short-chain fatty acids-producing bacteria such as Prevotella, and Ruminococcus may disrupt host-intestinal homeostasis by altering host immune response, gut barrier integrity, and microbial metabolism through altered T-regulatory cells/T-helper cells balance, activation of pattern recognition receptors and toll-like receptors, decreased mucus production, elevated level of trimethylamine-oxide and primary bile acids. This leads to a pro-inflammatory gut characterized by increased pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin-2, Interferon-ϒ and elevated levels of metabolites or metabolic endotoxemia due to leaky gut formation. These pathophysiological characteristics are associated with an increased risk of cardio-metabolic disease. This review aims to comprehensively elucidate the effect of urbanization on gut microbiome-driven cardio-metabolic disease. Additionally, it discusses targeting the gut microbiome and its associated pathways via strategies such as diet and lifestyle modulation, probiotics, prebiotics intake, etc., for the prevention and treatment of disease which can potentially be integrated into clinical and professional healthcare settings.
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Affiliation(s)
- Avaneesh Shukla
- Department of Environmental Studies, University of Delhi, New Delhi, India
| | - Chanchal Sharma
- Department of Environmental Studies, University of Delhi, New Delhi, India
| | - Md Zubbair Malik
- Department of Translational Medicine, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Alok Kumar Singh
- Department of Zoology, Ramjas College, University of Delhi, New Delhi, India
| | - Abhishek Kumar Aditya
- Department of Medicine, K.D. Medical College, Hospital and Research Center, Mathura, India
| | - Payal Mago
- Shaheed Rajguru College of Applied Sciences for Women, University of Delhi, New Delhi, India; Campus of Open Learning, University of Delhi, New Delhi, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Ashwini Kumar Ray
- Department of Environmental Studies, University of Delhi, New Delhi, India.
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26
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Sampson T. Microbial amyloids in neurodegenerative amyloid diseases. FEBS J 2025; 292:1265-1281. [PMID: 38041542 PMCID: PMC11144261 DOI: 10.1111/febs.17023] [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: 09/05/2023] [Revised: 11/13/2023] [Accepted: 11/30/2023] [Indexed: 12/03/2023]
Abstract
Human-disease associated amyloidogenic proteins are not unique in their ability to form amyloid fibrillar structures. Numerous microbes produce amyloidogenic proteins that have distinct functions for their physiology in their amyloid form, rather than solely detrimental. Emerging data indicate associations between various microbial organisms, including those which produce functional amyloids, with neurodegenerative diseases. Here, we review some of the evidence suggesting that microbial amyloids impact amyloid disease in host organisms. Experimental data are building a foundation for continued lines of enquiry and suggest that that direct or indirect interactions between microbial and host amyloids may be a contributor to amyloid pathologies. Inhibiting microbial amyloids or their interactions with the host may therefore represent a tangible target to limit various amyloid pathologies.
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Affiliation(s)
- Timothy Sampson
- Department of Cell BiologyEmory University School of MedicineAtlantaGAUSA
- Aligning Science Across Parkinson's (ASAP) Collaborative Research NetworkChevy ChaseMDUSA
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27
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Liu H, Ma X, Yang X, Xiao S, Ouyang S, Hu Z, Zhou Z, Jiang Z. E. coli Nissle 1917 improves gut microbiota composition and serum metabolites to counteract atherosclerosis via the homocitrulline/Caspase 1/NLRP3/GSDMD axis. Int J Med Microbiol 2025; 318:151642. [PMID: 39742694 DOI: 10.1016/j.ijmm.2024.151642] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND The probiotic E. coli Nissle 1917 (EcN) alleviates the progression of various diseases, including colitis and tumors. However, EcN has not been studied in atherosclerosis. The study investigated the effects of EcN on atherosclerosis model mice and the potential mechanisms. METHODS Mice in the high-fat diet (HFD) model were given EcN (1 × 109 CFU/g) or homocitrulline (150 mg/L) by oral administration for 12 weeks. The EcN + antibiotic group was set up to investigate the effects of EcN combined with antibiotics on gut microbiota. The control group was utilized as the negative control. Atherosclerosis status, pyroptosis, gut microbiota, and serum metabolites of mice were examined. RESULTS EcN treatment alleviated HFD-caused atherosclerotic plaque and lipid droplet production. EcN treatment reversed HFD-induced increases in total cholesterol, triglycerides, and low-density lipoprotein levels and decreases in high-density lipoprotein levels. EcN inhibited the HFD-caused rise in the expression of pyroptosis-related indicators (cleaved Caspase 1, GSDMD-N, NLRP3, IL-18, and IL-1β). The antibiotics partially reversed the effects of EcN on the model mice, suggesting that EcN regulated pyroptosis in the model mice through gut microbiota. Probiotic bacteria, such as Lactobacillus and Muribaculum, were mainly enriched in the EcN and EcN + antibiotic groups, while Helicobacter, Alistipes, and Rikenella were depleted, suggesting that EcN and EcN + antibiotics could alleviate disorders of gut microbiota in the model mice. EcN reversed the trend of HFD-induced decrease of some metabolites, such as 2-methyl-5-nitroimidazole-1-ethanol, methionine sulfoxide, and shikimate 3-phosphate, and inhibited the increase of some metabolites, such as kynurenine, oxoadipate, and homocitrulline. In addition, homocitrulline showed the opposite effects of EcN in the model mice. Homocitrulline could bind to pyroptosis-related proteins to aggravate ox-LDL-induced endothelial cell pyroptosis. CONCLUSION EcN could alleviate atherosclerosis development by ameliorating HFD-induced disorders of gut microbiota and serum metabolites (such as homocitrulline) to alleviate pyroptosis, which may be associated with homocitrulline/Caspase 1/NLRP3/GSDMD axis. Our study lays the foundation for the development of promising drugs for atherosclerosis in the future.
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Affiliation(s)
- Huan Liu
- Insititute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, Hunan 421001, China; Department of Cardiology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xiaofeng Ma
- Department of Cardiology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Xuefeng Yang
- Department of Gastroenterology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Hunan Provincial Clinical Research Center for Metabolic Associated Fatty Liver Disease, University of South China, Hengyang, Hunan 421001, China
| | - Sujun Xiao
- Department of Cardiology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Shao Ouyang
- Department of Cardiology, the Second Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhihao Hu
- Department of Cardiology, the Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhixiang Zhou
- Insititute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, Hunan 421001, China
| | - Zhisheng Jiang
- Insititute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, International Joint Laboratory for Arteriosclerotic Disease Research of Hunan Province, University of South China, Hengyang, Hunan 421001, China.
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28
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Zhang L, Yin Y, Jin S. Gut microbial metabolites: The bridge connecting diet and atherosclerosis, and next-generation targets for dietary interventions. Microbiol Res 2025; 292:128037. [PMID: 39752807 DOI: 10.1016/j.micres.2024.128037] [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: 10/08/2024] [Revised: 12/05/2024] [Accepted: 12/19/2024] [Indexed: 01/19/2025]
Abstract
Mounting evidence indicates that gut microbial metabolites are central hubs linking the gut microbiota to atherosclerosis (AS). Gut microbiota enriched with pathobiont bacteria responsible for producing metabolites like trimethylamine N-oxide and phenylacetylglutamine are related to an increased risk of cardiovascular events. Furthermore, gut microbiota enriched with bacteria responsible for producing short-chain fatty acids, indole, and its derivatives, such as indole-3-propionic acid, have demonstrated AS-protective effects. This study described AS-related gut microbial composition and how microbial metabolites affect AS. Summary findings revealed gut microbiota and their metabolites-targeted diets could benefit AS treatment. In conclusion, dietary interventions centered on the gut microbiota represent a promising strategy for AS treatment, and understanding diet-microbiota interactions could potentially be devoted to developing novel anti-AS therapies.
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Affiliation(s)
- Liyin Zhang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, 39 Lake Road, East Lake Ecological Scenic, Wuhan, Hubei 430077, China
| | - Yao Yin
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, 39 Lake Road, East Lake Ecological Scenic, Wuhan, Hubei 430077, China
| | - Si Jin
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, 39 Lake Road, East Lake Ecological Scenic, Wuhan, Hubei 430077, China.
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29
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Milena E, Maurizio M. Exploring the Cardiovascular Benefits of Extra Virgin Olive Oil: Insights into Mechanisms and Therapeutic Potential. Biomolecules 2025; 15:284. [PMID: 40001586 PMCID: PMC11852600 DOI: 10.3390/biom15020284] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/01/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, driven by complex interactions among genetic, environmental, and lifestyle factors, with diet playing a pivotal role. Extra Virgin Olive Oil (EVOO), a cornerstone of the Mediterranean diet (MedDiet), is a plant-based fat that has garnered attention for its robust cardiovascular benefits, which are attributed to its unique composition of monounsaturated fatty acids (MUFAs), particularly oleic acid (OA); and bioactive polyphenols, such as Hydroxytyrosol (HT) and oleocanthal. These compounds collectively exert antioxidant, anti-inflammatory, vasodilatory, and lipid-modulating effects. Numerous clinical and preclinical studies have demonstrated that EVOO's properties reduce major modifiable cardiovascular risk factors, including hypertension, dyslipidemia, obesity, and type 2 diabetes. EVOO also promotes endothelial function by increasing nitric oxide (NO) bioavailability, thus favoring vasodilation, lowering blood pressure (BP), and supporting vascular integrity. Furthermore, it modulates biomarkers of cardiovascular health, such as C-reactive protein, low-density lipoprotein (LDL) cholesterol, and NT-proBNP, aligning with improved hemostatic balance and reduced arterial vulnerability. Emerging evidence highlights its interaction with gut microbiota, further augmenting its cardioprotective effects. This review synthesizes current evidence, elucidating EVOO's multifaceted mechanisms of action and therapeutic potential. Future directions emphasize the need for advanced extraction techniques, nutraceutical formulations, and personalized dietary recommendations to maximize its health benefits. EVOO represents a valuable addition to dietary strategies aimed at reducing the global burden of cardiovascular diseases.
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Affiliation(s)
- Esposito Milena
- Department of Biology, Ecology & Earth Sciences, University of Calabria, 87036 Rende, Italy;
| | - Mandalà Maurizio
- Department of Biology, Ecology & Earth Sciences, University of Calabria, 87036 Rende, Italy;
- Department of Obstetrics, Gynecology and Reproductive Sciences, Larner College of Medicine, University of Vermont, Burlington, VT 05401, USA
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30
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Wu H, Forslund S, Wang Z, Zhao G. Human Gut Microbiome Researches Over the Last Decade: Current Challenges and Future Directions. PHENOMICS (CHAM, SWITZERLAND) 2025; 5:1-7. [PMID: 40313604 PMCID: PMC12040780 DOI: 10.1007/s43657-023-00131-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Affiliation(s)
- Hao Wu
- Fudan Microbiome Center, Human Phenome Institute, and State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 201203 China
- Department of Bariatric and Metabolic Surgery, Huashan Hospital, Fudan University, Shanghai, 201203 China
| | - Sofia Forslund
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, 13092 Germany
| | - Zeneng Wang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 USA
| | - Guoping Zhao
- Fudan Microbiome Center, Human Phenome Institute, and State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 201203 China
- Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200032 China
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31
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Khuu MP, Paeslack N, Dremova O, Benakis C, Kiouptsi K, Reinhardt C. The gut microbiota in thrombosis. Nat Rev Cardiol 2025; 22:121-137. [PMID: 39289543 DOI: 10.1038/s41569-024-01070-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2024] [Indexed: 09/19/2024]
Abstract
The gut microbiota has emerged as an environmental risk factor that affects thrombotic phenotypes in several cardiovascular diseases. Evidence includes the identification of marker species by sequencing studies of the gut microbiomes of patients with thrombotic disease, the influence of antithrombotic therapies on gut microbial diversity, and preclinical studies in mouse models of thrombosis that have demonstrated the functional effects of the gut microbiota on vascular inflammatory phenotypes and thrombus formation. In addition to impaired gut barrier function promoting low-grade inflammation, gut microbiota-derived metabolites have been shown to act on vascular cell types and promote thrombus formation. Therefore, these meta-organismal pathways that link the metabolic capacities of gut microorganisms with host immune functions have emerged as potential diagnostic markers and novel drug targets. In this Review, we discuss the link between the gut microbiota, its metabolites and thromboembolic diseases.
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Affiliation(s)
- My Phung Khuu
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Nadja Paeslack
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Olga Dremova
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Corinne Benakis
- Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
| | - Klytaimnistra Kiouptsi
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Christoph Reinhardt
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.
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32
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Zhang S, Tang S, Liu Y, Xue B, Xie Q, Zhao L, Yuan H. Protein-bound uremic toxins as therapeutic targets for cardiovascular, kidney, and metabolic disorders. Front Endocrinol (Lausanne) 2025; 16:1500336. [PMID: 39931238 PMCID: PMC11808018 DOI: 10.3389/fendo.2025.1500336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 01/02/2025] [Indexed: 02/13/2025] Open
Abstract
Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic clinical condition characterized by pathological and physiological interactions among metabolic abnormalities, chronic kidney disease, and cardiovascular diseases, leading to multi-organ dysfunction and a higher incidence of cardiovascular endpoints. Traditional approaches to managing CKM syndrome risk are inadequate in these patients, necessitating strategies targeting specific CKM syndrome risk factors. Increasing evidence suggests that addressing uremic toxins and/or pathways induced by uremic toxins may reduce CKM syndrome risk and treat the disease. This review explores the interactions among heart, kidney, and metabolic pathways in the context of uremic toxins and underscores the significant role of uremic toxins as potential therapeutic targets in the pathophysiology of these diseases. Strategies aimed at regulating these uremic toxins offer potential avenues for reversing and managing CKM syndrome, providing new insights for its clinical diagnosis and treatment.
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Affiliation(s)
| | | | | | | | | | | | - Huijuan Yuan
- Department of Endocrinology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Henan Provincial Key Medicine Laboratory of Intestinal Microecology and Diabetes, Zhengzhou, China
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33
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Tain YL, Hsu CN. Does maternal consumption of nutritive and non-nutritive sweeteners result in offspring hypertension? Front Nutr 2025; 12:1464269. [PMID: 39911806 PMCID: PMC11794092 DOI: 10.3389/fnut.2025.1464269] [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: 07/13/2024] [Accepted: 01/10/2025] [Indexed: 02/07/2025] Open
Abstract
The consumption of nutritive and non-nutritive sweeteners (NNS) has increased significantly in recent decades. The nutritional status of pregnant women plays a crucial role in determining the likelihood of their offspring developing hypertension in adulthood. While NNSs provide a sweet taste without adding to sugar intake, emerging evidence suggests that maternal consumption of not only nutritive sweeteners (such as fructose) but also NNS may lead to adverse outcomes in offspring, including hypertension. This review provides an overview of the latest research connecting maternal intake of sweeteners to the long-term risk of hypertension in offspring. We examine proposed mechanisms underlying the programming of offspring hypertension by sweeteners, encompassing oxidative stress, dysregulated nutrient sensing signals, abnormal renin-angiotensin system, transcriptome changes, and dysbiotic gut microbiota. Additionally, we outline preventive strategies that can help alleviate offspring hypertension programmed by maternal diets high in sweeteners. Recent advancements in understanding the mechanisms through which maternal consumption of nutritive and non-nutritive sweeteners contributes to offspring hypertension offer promise for addressing this widespread health concern at its developmental roots. Nonetheless, further research is needed to educate the public about the safety of sweetener consumption during pregnancy and lactation.
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Affiliation(s)
- You-Lin Tain
- Division of Pediatric Nephrology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
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34
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Zha X, Liu X, Wei M, Huang H, Cao J, Liu S, Bian X, Zhang Y, Xiao F, Xie Y, Wang W, Zhang C. Microbiota-derived lysophosphatidylcholine alleviates Alzheimer's disease pathology via suppressing ferroptosis. Cell Metab 2025; 37:169-186.e9. [PMID: 39510074 DOI: 10.1016/j.cmet.2024.10.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 04/16/2024] [Accepted: 10/04/2024] [Indexed: 11/15/2024]
Abstract
Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.
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Affiliation(s)
- Xu Zha
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China
| | - Xicheng Liu
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China.
| | - Mengping Wei
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China
| | - Huanwei Huang
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China
| | - Jiaqi Cao
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China
| | - Shuo Liu
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China
| | - Xiaomei Bian
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China
| | - Yuting Zhang
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China
| | - Fenyan Xiao
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China
| | - Yuping Xie
- National Center for Protein Sciences Beijing, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China
| | - Wei Wang
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China.
| | - Chen Zhang
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair & Beijing Key Laboratory for Tumor Invasion and Metastasis, Beijing Laboratory of Oral Health, Capital Medical University, Beijing, China; State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Chinese Institute for Brain Research, Beijing, China.
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35
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Leng X, Wei X, Wang J, Yao X, Zhang M, Sun D, Liang J, Chi L, Cheng Y. Impacts of intestinal microbiota metabolite trimethylamine N-oxide on cardiovascular disease: a bibliometric analysis. Front Microbiol 2025; 15:1491731. [PMID: 39834376 PMCID: PMC11743947 DOI: 10.3389/fmicb.2024.1491731] [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: 11/05/2024] [Accepted: 12/16/2024] [Indexed: 01/22/2025] Open
Abstract
Background Trimethylamine N-oxide (TMAO), a metabolite dependent on intestinal microbiota, is closely related to the emergence, progression, and prognosis of cardiovascular disease (CVD), and has received increasing attention in recent years. Objective The current research hotspots and future development trends in TMAO and CVD field are found through bibliometrics analysis, which provides reference for further study. Methods The bibliometrics tools VOSviewer and CiteSpace were used to analyze the publications from the Web of Science Core Collection (WOSCC) database. The articles published from 2004 to 2024 about the relationship between TMAO and CVD were retrieved. Bibliometric analysis includes annual publications, countries/regions, institutions, authors and co-cited authors, journals and cited-journals, references and keywords. Results After searching and screening, 1,466 publications were included for subsequent bibliometric analysis. Since 2014, the number of publications exposing the relationship between TMAO and CVD has increased rapidly, as has the frequency of citations. China, USA and Italy are the countries that publish the most relevant research. Cleveland Clinic is the leading institution in this field. Stanley L Hazen, Zeneng Wang and W H Wilson Tang are the most prolific authors in this field, and the latter two have the closest academic cooperation. American Journal of Clinical Nutrition and Journal of the American Heart Association are influential journals that publish research in this field. "Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk" is the most frequently cited article. Keyword analysis shows that gut microbiota, metabolism, phosphatidylcholine and atherosclerosis (AS) are the hotspots in this field. Conclusion This study summarizes the research situation of TMAO and CVD in the past 20 years, focusing on the effect of TMAO on pathogenesis of AS, predictive value of TMAO on CVD risk, and dietary and drug intervention for TMAO. Probiotics and natural products may be the research focus of preventing and treating CVD by intervening TMAO in the future.
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Affiliation(s)
- Xiaohui Leng
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- Yantai Yuhuangding Hospital, Yantai, China
| | - Xiunan Wei
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jun Wang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaodong Yao
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Miaomiao Zhang
- First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dajuan Sun
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Junwei Liang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lili Chi
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yan Cheng
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Kenny TC, Scharenberg S, Abu-Remaileh M, Birsoy K. Cellular and organismal function of choline metabolism. Nat Metab 2025; 7:35-52. [PMID: 39779890 PMCID: PMC11990872 DOI: 10.1038/s42255-024-01203-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 12/09/2024] [Indexed: 01/11/2025]
Abstract
Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.
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Affiliation(s)
- Timothy C Kenny
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA
| | - Samantha Scharenberg
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA
- Department of Genetics, Stanford University, Stanford, CA, USA
- The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA, USA
- Stanford Medical Scientist Training Program, Stanford University, Stanford, CA, USA
- Stanford Biophysics Program, Stanford University, Stanford, CA, USA
| | - Monther Abu-Remaileh
- Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
- Department of Genetics, Stanford University, Stanford, CA, USA.
- The Institute for Chemistry, Engineering and Medicine for Human Health (Sarafan ChEM-H), Stanford University, Stanford, CA, USA.
- The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
| | - Kıvanç Birsoy
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
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Khan TJ, Semenkovich CF, Zayed MA. De novo lipid synthesis in cardiovascular tissue and disease. Atherosclerosis 2025; 400:119066. [PMID: 39616863 DOI: 10.1016/j.atherosclerosis.2024.119066] [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: 06/06/2024] [Revised: 11/14/2024] [Accepted: 11/21/2024] [Indexed: 12/13/2024]
Abstract
Most tissues have the capacity for endogenous lipid synthesis. A crucial foundational pathway for lipid synthesis is de novo lipid synthesis (DNL), a ubiquitous and complex metabolic process that occurs at high levels in the liver, adipose and brain tissue. Under normal physiological conditions, DNL is vital in converting excess carbohydrates into fatty acids. DNL is linked to other pathways, including the endogenous synthesis of phospholipids and sphingolipids. However, abnormal lipid synthesis can contribute to various pathologies and clinical conditions. Experimental studies involving dietary restriction and in vivo genetic modifications provide compelling evidence demonstrating the significance of lipid synthesis in maintaining normal cardiovascular tissue function. Similarly, clinical investigations suggest altered lipid synthesis can harm cardiac and arterial tissues, thereby influencing cardiovascular disease (CVD) development and progression. Consequently, there is increased interest in exploring pharmacological interventions that target lipid synthesis metabolic pathways as potential strategies to alleviate CVD. Here we review the physiological and pathological impact of endogenous lipid synthesis and its implications for CVD. Since lipid synthesis can be targeted pharmacologically, enhancing our understanding of the molecular and biochemical mechanisms underlying lipid generation and cardiovascular function may prompt new insights into CVD and its treatment.
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Affiliation(s)
- Tariq J Khan
- Washington University School of Medicine, Department of Surgery, Section of Vascular Surgery, St. Louis, MO, USA
| | - Clay F Semenkovich
- Washington University School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, St. Louis, MO, USA; Washington University School of Medicine, Department of Cell Biology and Physiology, St. Louis, MO, USA
| | - Mohamed A Zayed
- Washington University School of Medicine, Department of Surgery, Section of Vascular Surgery, St. Louis, MO, USA; Washington University School of Medicine, Department of Surgery, Division of Surgical Sciences, St. Louis, MO, USA; Washington University School of Medicine, Department of Radiology, St. Louis, MO, USA; Washington University School of Medicine, Division of Molecular Cell Biology, St. Louis, MO, USA; Washington University, McKelvey School of Engineering, Department of Biomedical Engineering, St. Louis, MO, USA; Veterans Affairs St. Louis Health Care System, St. Louis, MO, USA.
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Cheng E, Hung SC, Lin TY. Association of trimethylamine N-oxide and metabolites with kidney function decline in patients with chronic kidney disease. Clin Nutr 2025; 44:239-247. [PMID: 39709651 DOI: 10.1016/j.clnu.2024.12.001] [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: 09/11/2024] [Revised: 10/29/2024] [Accepted: 12/01/2024] [Indexed: 12/24/2024]
Abstract
BACKGROUND Trimethylamine N-oxide (TMAO) is a gut microbial metabolite derived from dietary l-carnitine and choline. High plasma TMAO levels are associated with cardiovascular disease and overall mortality, but little is known about the associations of TMAO and related metabolites with the risk of kidney function decline among patients with chronic kidney disease (CKD). METHODS We prospectively followed 152 nondialysis patients with CKD stages 3-5 and measured plasma TMAO and related metabolites (trimethylamine [TMA], choline, carnitine, and γ-butyrobetaine) via liquid chromatography‒mass spectrometry. An estimated glomerular filtration rate (eGFR) slope >3 ml/min/per 1.73 m2 per year was defined as a rapid decline. We performed logistic regression to determine the probability of rapid or slow eGFR decline, with each metabolite as the main predictor. The gut microbiota was profiled via whole metagenomic sequencing. RESULTS The participants had a median age of 66 years, 41.4 % were women, 39.5 % had diabetes, and the median eGFR was 23 mL/min/1.73 m2. A rapid decrease in the eGFR occurred in 65 patients (42.8 %) over a median follow-up of 3.3 years. After adjustment for baseline eGFR, proteinuria, and clinical factors, plasma TMAO levels were independently associated with increased odds of rapid eGFR decline (odds ratio, 2.42; 95 % CI, 1.36-4.32), whereas plasma TMA, choline, carnitine, and γ-butyrobetaine levels were not. Patients who exhibited rapid eGFR decline had a distinct gut microbial composition characterized by increased α-diversity and an abundance of TMA-producing bacteria, including those of the genera Desulfovibrio and Collinsella tanakaei, as well as increased expression of the TMA-producing enzymes bbuA and cutC. CONCLUSION Our findings suggest the relevance of plasma TMAO in the progression of kidney disease among patients with CKD.
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Affiliation(s)
- Evelyn Cheng
- Department of Medical Education, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan; Bellevue Vision Clinic, Bellevue, WA, USA
| | - Szu-Chun Hung
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Ting-Yun Lin
- Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan.
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Alghanem B, Alamri HS, Barhoumi T, Ali Khan I, Almuhalhil K, Aloyouni E, Shaibah H, Mashhour A, Algheribe S, Islam I, Boudjelal M, Alfadhel M. First Report from Saudi Arabia of Trimethylaminuria Caused by a Premature Stop Codon Mutation in the FMO3 Gene. Appl Clin Genet 2024; 17:215-228. [PMID: 39758160 PMCID: PMC11699836 DOI: 10.2147/tacg.s497959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 12/23/2024] [Indexed: 01/07/2025] Open
Abstract
Background Trimethylaminuria (TMAU) is a rare recessive genetic disorder with limited global prevalence. To date, there have been no official reports of TMAU cases documented in Saudi Arabia. Purpose In this study, we developed a liquid chromatography-mass spectrometry (LC-MS) method for the analysis of trimethylamine (TMA) and Trimethylamine N-Oxide (TMAO) in urine and plasma samples for the first reported case of TMAU in Saudi Arabia. Patients and Methods A 41-year-old Saudi man was diagnosed with TMAU in National Guard Hospital. Blood and urine samples were collected to confirm the diagnosis of TMAU. In this study, we have studied LC-MS, cell culture, flow cytometry, adhesion assay and Sanger sequencing analysis. Additionally, in this study, we have selected 5 healthy controls. Results The results have revealed elevated TMA levels were present in both urine and plasma samples, while TMAO levels were significantly lower compared to control group. Further, we utilized plasma sample from the TMAU patient as novel model to investigate the potential effect of low TMAO on monocyte and endothelial cell function in vitro. DNA sequencing analysis identified a c.622G >T (p.Glu208*) which creates a premature stop codon in FMO3 gene. Conclusion Our findings revealed differential responses in monocytes and endothelial cells stimulated with plasma from the TMAU patient compared to plasma from non-TMAU patients. These distinct responses may be key modulators of endothelial function and contributes to vascular damage.
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Affiliation(s)
- Bandar Alghanem
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Hassan S Alamri
- King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Tlili Barhoumi
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Imran Ali Khan
- Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Khawlah Almuhalhil
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Essra Aloyouni
- Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Hayat Shaibah
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Abdullah Mashhour
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Shatha Algheribe
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Imadul Islam
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Mohamed Boudjelal
- Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Majid Alfadhel
- Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- Genetics and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
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Li Z, Gu M, Zaparte A, Fu X, Mahen K, Mrdjen M, Li XS, Yang Z, Ma J, Thoudam T, Chandler K, Hesler M, Heathers L, Gorse K, Van TT, Wong D, Gibson AM, Wang Z, Taylor CM, Quijada P, Makarewich CA, Hazen SL, Liangpunsakul S, Brown JM, Lefer DJ, Welsh DA, Sharp TE. Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease. Nat Commun 2024; 15:10788. [PMID: 39738016 PMCID: PMC11685538 DOI: 10.1038/s41467-024-55084-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 11/27/2024] [Indexed: 01/01/2025] Open
Abstract
The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology. Fecal microbiota transplantation from pair-/alcohol-fed mice into naïve male mice demonstrates the transmissibility of PAGln production and the CVD phenotype. Independent of alcohol exposure, pharmacological-mediated increases in PAGln elicits direct cardiac and vascular dysfunction. PAGln induced hypercontractility and altered calcium cycling in isolated cardiomyocytes providing evidence of improper relaxation which corresponds to elevated filling pressures observed in vivo. Furthermore, PAGln directly induces vascular endothelial cell activation through induction of oxidative stress leading to endothelial cell dysfunction. We thus reveal that the alcohol-induced microbial reorganization and resultant GMM elevation, specifically PAGln, directly contributes to CVD.
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Affiliation(s)
- Zhen Li
- Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Min Gu
- Section of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Science Center, New Orleans, LA, USA
- International Flavors and Fragrances Health and Bioscience, Shanghai, China
| | - Aline Zaparte
- Section of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Science Center, New Orleans, LA, USA
- Comprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Xiaoming Fu
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Center for Microbiome and Human Health, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Kala Mahen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Center for Microbiome and Human Health, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Northern Ohio Alcohol Center (NOAC), Cleveland Clinic, Cleveland, OH, USA
| | - Marko Mrdjen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Center for Microbiome and Human Health, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Northern Ohio Alcohol Center (NOAC), Cleveland Clinic, Cleveland, OH, USA
| | - Xinmin S Li
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Center for Microbiome and Human Health, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Themis Thoudam
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kristina Chandler
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Maggie Hesler
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Laura Heathers
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kiersten Gorse
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Thanh Trung Van
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - David Wong
- Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Aaron M Gibson
- The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Zeneng Wang
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Christopher M Taylor
- Comprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Science Center, New Orleans, LA, USA
- Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Pearl Quijada
- Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Catherine A Makarewich
- The Heart Institute, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Stanley L Hazen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Center for Microbiome and Human Health, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Heart and Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - J Mark Brown
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Center for Microbiome and Human Health, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Northern Ohio Alcohol Center (NOAC), Cleveland Clinic, Cleveland, OH, USA
| | - David J Lefer
- Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - David A Welsh
- Section of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Science Center, New Orleans, LA, USA
- Comprehensive Alcohol Research Center, School of Medicine, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Thomas E Sharp
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
- Heart Institute, Morsani College of Medicine, USF Health, University South Florida, Tampa, FL, USA.
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Qu J, Meng F, Wang Z, Xu W. Unlocking Cardioprotective Potential of Gut Microbiome: Exploring Therapeutic Strategies. J Microbiol Biotechnol 2024; 34:2413-2424. [PMID: 39467697 PMCID: PMC11729380 DOI: 10.4014/jmb.2405.05019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/05/2024] [Accepted: 06/15/2024] [Indexed: 10/30/2024]
Abstract
The microbial community inhabiting the human gut resembles a bustling metropolis, wherein beneficial bacteria play pivotal roles in regulating our bodily functions. These microorganisms adeptly break down resilient dietary fibers to fuel our energy, synthesize essential vitamins crucial for our well-being, and maintain the delicate balance of our immune system. Recent research indicates a potential correlation between alterations in the composition and activities of these gut microbes and the development of coronary artery disease (CAD). Consequently, scientists are delving into the intriguing realm of manipulating these gut inhabitants to potentially mitigate disease risks. Various promising strategies have emerged in this endeavor. Studies have evidenced that probiotics can mitigate inflammation and enhance the endothelial health of our blood vessels. Notably, strains such as Lactobacilli and Bifidobacteria have garnered substantial attention in both laboratory settings and clinical trials. Conversely, prebiotics exhibit anti-inflammatory properties and hold potential in managing conditions like hypertension and hypercholesterolemia. Synbiotics, which synergistically combine probiotics and prebiotics, show promise in regulating glucose metabolism and abnormal lipid profiles. However, uncertainties persist regarding postbiotics, while antibiotics are deemed unsuitable due to their potential adverse effects. On the other hand, TMAO blockers, such as 3,3-dimethyl-1-butanol, demonstrate encouraging outcomes in laboratory experiments owing to their anti-inflammatory and tissue-protective properties. Moreover, fecal transplantation, despite yielding mixed results, warrants further exploration and refinement. In this comprehensive review, we delve into the intricate interplay between the gut microbiota and CAD, shedding light on the multifaceted approaches researchers are employing to leverage this understanding for therapeutic advancements.
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Affiliation(s)
- Jun Qu
- Department of Internal Medicine-Cardiovascular, YanTai YuHuangDing Hospital, Yantai, Shandong, P.R. China
| | - Fantao Meng
- Department of Internal Medicine-Cardiovascular, LinYi Central Hospital, LinYi, Shandong, P.R. China
| | - Zhen Wang
- Department of Internal Medicine-Cardiovascular, YanTai YuHuangDing Hospital, Yantai, Shandong, P.R. China
| | - Wenhao Xu
- Department of Internal Medicine-Cardiovascular, YanTai YuHuangDing Hospital, Yantai, Shandong, P.R. China
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Wang Y, Weng S, Xia C, Xu T, Song X, Wang F. Effect of physical exercise on metabolism in patients with atrial fibrillation. Front Cardiovasc Med 2024; 11:1502620. [PMID: 39749313 PMCID: PMC11693651 DOI: 10.3389/fcvm.2024.1502620] [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: 09/27/2024] [Accepted: 12/06/2024] [Indexed: 01/04/2025] Open
Abstract
Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is closely linked to metabolic dysfunctions, including obesity, diabetes, and dyslipidemia. These lead to pathological changes in myocardial metabolism and mitochondrial energy metabolism, thereby aggravating AF's incidence and severity. This review introduces the role of metabolic dysfunctions in exacerbating AF, assesses the therapeutic potential of physical exercise and investigates it as a non-pharmacological intervention to alleviate these metabolic disturbances. Evidence suggests that regular physical activity not only enhances metabolic profiles but also reduces the frequency of AF episodes and improves overall cardiovascular health. At the same time, the review emphasizes the need for individualized exercise regimens, individualized to the metabolic and cardiac conditions of each patient to optimize benefits and minimize risks. Additionally, it calls for more basic studies and large-scale clinical trials to establish and refine evidence-based exercise guidelines specific to AF management.
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Affiliation(s)
- Yutong Wang
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Sixian Weng
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Cardiology, Beijing Anzhen Hospital, Affiliated to Capital Medical University, Beijing, China
| | - Chenxi Xia
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Cardiology Department, Beijing Hospital, Peking University Fifth School of Clinical Medicine, Beijing, China
| | - Tao Xu
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Xinyang Song
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Cardiology Department, Beijing Hospital, Peking University Fifth School of Clinical Medicine, Beijing, China
| | - Fang Wang
- Cardiology Department, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Cardiology Department, Beijing Hospital, Peking University Fifth School of Clinical Medicine, Beijing, China
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Ng YH, Koay YC, Marques FZ, Kaye DM, O’Sullivan JF. Leveraging metabolism for better outcomes in heart failure. Cardiovasc Res 2024; 120:1835-1850. [PMID: 39351766 PMCID: PMC11630082 DOI: 10.1093/cvr/cvae216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/26/2024] [Accepted: 08/07/2024] [Indexed: 12/11/2024] Open
Abstract
Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium-glucose cotransporter 2 inhibitor therapy as one of the four 'pillars' of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.
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Affiliation(s)
- Yann Huey Ng
- Cardiometabolic Medicine, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Room 3E71 D17, Camperdown, NSW 2006, Australia
- Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Office 3E72, Camperdown, NSW 2006, Australia
| | - Yen Chin Koay
- Cardiometabolic Medicine, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Room 3E71 D17, Camperdown, NSW 2006, Australia
- Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Office 3E72, Camperdown, NSW 2006, Australia
| | - Francine Z Marques
- Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, Melbourne, VIC 3800, Australia
- Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC 3800, Australia
- Victorian Heart Institute, Monash University, Melbourne, VIC 3800, Australia
| | - David M Kaye
- Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, VIC 3800, Australia
- Department of Cardiology, Alfred Hospital, Melbourne, VIC 3004, Australia
- Monash-Alfred-Baker Centre for Cardiovascular Research, Monash University, Melbourne, VIC 3800, Australia
| | - John F O’Sullivan
- Cardiometabolic Medicine, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Room 3E71 D17, Camperdown, NSW 2006, Australia
- Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Office 3E72, Camperdown, NSW 2006, Australia
- Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
- Department of Medicine, Technische Univeristat Dresden, 01062 Dresden, Germany
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44
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Zhang Y, Huang L, Ou S. Research progress on the association between TMAO and vascular calcification in patients with chronic kidney disease. Ren Fail 2024; 46:2435485. [PMID: 39627031 PMCID: PMC11616764 DOI: 10.1080/0886022x.2024.2435485] [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: 08/08/2024] [Revised: 11/14/2024] [Accepted: 11/23/2024] [Indexed: 12/06/2024] Open
Abstract
Vascular calcification (VC) is a common complication in patients with chronic kidney disease (CKD) and a major risk factor for increased cardiovascular mortality in patients with CKD. Its pathology and pathogenesis are complex and have not been fully elucidated. Trimethylamine N-oxide (TMAO) is an enteric-borne uremic toxin that has been found to play a role in the progression of VC. This article mainly reviews the metabolism of TMAO, the relationship between TMAO and VC in CKD patients, and possible treatments for TMAO, aiming to further explore the mechanism of VC occurrence in CKD patients and provide potential diagnostic and treatment strategies.
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Affiliation(s)
- Yuxin Zhang
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
| | - Liangying Huang
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
| | - Santao Ou
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
- Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, China
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Ge H, Wei Y, Zhang W, Yong C, Chen Y, Zhou E. Suyin Detoxification Granule alleviates trimethylamine N-oxide-induced tubular ferroptosis and renal fibrosis to prevent chronic kidney disease progression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156195. [PMID: 39488871 DOI: 10.1016/j.phymed.2024.156195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 10/15/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, is a risk factor for chronic kidney disease (CKD) progression. Suyin Detoxification Granule (SDG) is a traditional Chinese medicine preparation that has been proven to significantly reduce renal function damage and serum TMAO levels in patients with CKD. However, its specific mechanism remains unclear. PURPOSE This study investigated the role of TMAO-induced ferroptosis in CKD, and further explored the mechanism of SDG in improving TMAO-induced kidney injury. METHODS A TMAO renal tubular epithelial cell injury model was constructed in vitro. After using freeze-dried powder of Suyin Detoxification Prescription (SDP), proteomic analysis, Western blotting, ferroptosis phenotype-related detection, and ELISA were performed to explore its mechanism. In vivo, a adenine-induced CKD model was established, with or without a high-choline diet to observe the impact of TMAO on CKD, and SDG or 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) was used for intervention. The composition of gut microbiota was analyzed using 16SrRNA sequencing, and the effect of SDG on gut-derived TMAO-induced kidney injury under the background of CKD was evaluated by pathological staining, immunoblotting, immunohistochemistry, and fluorescence staining. RESULTS In vitro, TMAO could induce ferroptosis and secrete profibrotic factors in NRK-52E cells. SDP could inhibit TMAO-induced ferroptosis and reduce the secretion of profibrotic factors. The amelioration of ferroptosis by SDP was also verified in RSL3-induced cells. In vivo, our results demonstrated that gut-derived TMAO could promote CKD progression by inducing tubular ferroptosis, profibrotic factors expression and renal fibrosis. In addition, we illustrated that SDG might reduce circulating TMAO levels by down-regulating the gut microbiota related to TMAO (including Muribaculaceae, Bacteroides and Ruminococcaceae_UCG-010). Furthermore, SDG could prevent CKD progression by reducing TMAO-induced renal damage. CONCLUSION SDG reduced circulating TMAO levels by regulating gut microbiota and inhibited TMAO-induced renal tubular ferroptosis, profibrotic factors secretion, and renal fibrosis to prevent CKD progression.
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Affiliation(s)
- Hongwei Ge
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yuan Wei
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Wentao Zhang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Chen Yong
- Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Jiangsu University Key Laboratory of Tonifying Kidney and Anti-senescence, Nanjing 210036, China.
| | - Yanlin Chen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China; The First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Enchao Zhou
- Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; Jiangsu University Key Laboratory of Tonifying Kidney and Anti-senescence, Nanjing 210036, China; Nanjing University of Chinese Medicine, Nanjing 210023, China; Inheritance Studio of Traditional Chinese Medicine Master Yanqin Zou, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China.
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Luo W, Meng J, Yu XH, Zhang ZZ, Wang G, He J. Indole-3-Carboxaldehyde Inhibits Inflammatory Response and Lipid Accumulation in Macrophages Through the miR-1271-5p/HDAC9 Pathway. J Cell Mol Med 2024; 28:e70263. [PMID: 39698913 DOI: 10.1111/jcmm.70263] [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: 08/10/2024] [Revised: 11/21/2024] [Accepted: 11/23/2024] [Indexed: 12/20/2024] Open
Abstract
Indole-3-carboxaldehyde (ICA), a microbiota-derived tryptophan metabolite, has been reported to protect against atherosclerosis. However, the molecular mechanisms for its atheroprotective effect remain largely unknown. This study aimed to explore the influence of ICA on lipid accumulation and inflammatory response in THP-1 macrophage-derived foam cells. Our results showed that administration of ICA upregulated the expression of miR-1271-5p, ATP binding cassette transporter A1 (ABCA1) and ABCG1, downregulated histone deacetylase 9 (HDAC9) expression and inhibited macrophage lipid accumulation. ICA treatment also facilitated macrophage polarisation to the M2 phenotype and alleviated inflammatory response, as evidenced by decreased IL-6 levels and increased IL-10 levels. HDAC9 was identified as a direct target of miR-1271-5p. HDAC9 overexpression or miR-1271-5p knockdown decreased the effect of ICA on ABCA1 and ABCG1 expression as well as inflammatory response. Taken together, these results suggest that ICA can suppress lipid accumulation and mitigate inflammatory response in macrophages by activating the miR-1271-5p/HDAC9 signalling cascade, thereby providing new explanations for how ICA reduces atherosclerosis.
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Affiliation(s)
- Wei Luo
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jun Meng
- The First Affiliated Hospital, Department of Function, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Zi-Zhen Zhang
- School of Medical and Pharmacological Technology, Hunan Polytechnic of Environment and Biology, Hengyang, Hunan, China
| | - Gang Wang
- The First Affiliated Hospital, Department of Cardiology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jin He
- The First Affiliated Hospital, Department of Function, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Gan G, Zhang R, Zeng Y, Lu B, Luo Y, Chen S, Lei H, Cai Z, Huang X. Fecal microbiota transplantation validates the importance of gut microbiota in an ApoE -/- mouse model of chronic apical periodontitis-induced atherosclerosis. BMC Oral Health 2024; 24:1455. [PMID: 39614243 DOI: 10.1186/s12903-024-05230-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 11/19/2024] [Indexed: 12/01/2024] Open
Abstract
BACKGROUND Chronic apical periodontitis (CAP) has been linked to the development of atherosclerosis, although the underlying mechanisms remain unclear. This study aimed to investigate the role of gut microbiota disruption in CAP-induced atherosclerosis development, focusing on trimethylamine N-oxide (TMAO)-related metabolites. METHODS The study utilized fecal microbiota transplantation (FMT) to transfer gut microbiota from mice with CAP to healthy mice. Atherosclerosis development was assessed by analyzing lesions in the aortic arch and aortic root. Serum lipid and inflammatory factor levels were measured. Composition and diversity of gut microbiota were analyzed using targeted metabolomics, with a focus on the ratio of Firmicutes to Bacteroidetes. The expression of hepatic flavin-containing monooxygenase 3 (FMO3) and serum TMAO levels were also evaluated. RESULTS Mice receiving gut microbiota from CAP mice showed increased atherosclerotic lesions compared to controls, without significant differences in serum lipid or inflammatory factor levels. Alterations in gut microbiota composition were observed, characterized by an increase in the Firmicutes to Bacteroidetes ratio. Peptostreptococcaceae abundance positively correlated with atherosclerosis severity, while Odoribacteraceae showed a negative correlation. No significant differences were found in hepatic FMO3 expression or serum TMAO levels. CONCLUSIONS The study confirms the role of gut microbiota disruption in CAP-mediated atherosclerosis development, independent of serum lipid or TMAO levels. Alterations in gut microbiota composition, particularly increased Firmicutes to Bacteroidetes ratio and specific bacterial families, were associated with atherosclerosis severity. These findings highlight the intricate interplay between gut microbiota and cardiovascular health in the context of CAP.
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Affiliation(s)
- Guowu Gan
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Ren Zhang
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Yu Zeng
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Beibei Lu
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Yufang Luo
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Shuai Chen
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Huaxiang Lei
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China
| | - Zhiyu Cai
- Department of Stomatology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiaojing Huang
- Fujian Key Laboratory of Oral Diseases & Fujian Provincial Engineering Research Center of Oral Biomaterial & Stomatology Key lab of Fujian College and University, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.
- Clinical Research Center for Oral Tissue Deficiency Diseases of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, Fuzhou, China.
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Sidoti A, D’Angelo R, Castagnetti A, Viciani E, Scimone C, Alibrandi S, Giannini G. Exploring Trimethylaminuria: Genetics and Molecular Mechanisms, Epidemiology, and Emerging Therapeutic Strategies. BIOLOGY 2024; 13:961. [PMID: 39765628 PMCID: PMC11726875 DOI: 10.3390/biology13120961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 11/18/2024] [Accepted: 11/20/2024] [Indexed: 01/15/2025]
Abstract
Trimethylaminuria (TMAU) is a rare metabolic syndrome caused by the accumulation of trimethylamine in the body, causing odor emissions similar to rotten fish in affected patients. This condition is determined by both genetic and environmental factors, especially gut dysbiosis. The multifactorial nature of this syndrome makes for a complex and multi-level diagnosis. To date, many aspects of this disease are still unclear. Recent research revealed the FMO3 haplotypes' role on the enzyme's catalytic activity. This could explain why patients showing only combined polymorphisms or heterozygous causative variants also manifest the TMAU phenotype. In addition, another research hypothesized that the behavioral disturbances showed by patients may be linked to gut microbiota alterations. Our review considers current knowledge about TMAU, clarifying its molecular aspects, the therapeutic approaches used to limit this condition, and the new therapies that are under study.
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Affiliation(s)
- Antonina Sidoti
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy; (A.S.); (R.D.); (C.S.)
| | - Rosalia D’Angelo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy; (A.S.); (R.D.); (C.S.)
| | - Andrea Castagnetti
- Wellmicro Srl, Via Antonio Canova, 30, 40138 Bologna, Italy; (A.C.); (E.V.)
| | - Elisa Viciani
- Wellmicro Srl, Via Antonio Canova, 30, 40138 Bologna, Italy; (A.C.); (E.V.)
| | - Concetta Scimone
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy; (A.S.); (R.D.); (C.S.)
- Department of Biomolecular Strategies, Genetics, Cutting-Edge Therapies, I.E.ME.S.T., Via Michele Miraglia, 20, 90139 Palermo, Italy
| | - Simona Alibrandi
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy; (A.S.); (R.D.); (C.S.)
- Department of Biomolecular Strategies, Genetics, Cutting-Edge Therapies, I.E.ME.S.T., Via Michele Miraglia, 20, 90139 Palermo, Italy
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Jaworska K, Kopacz W, Koper M, Ufnal M. Microbiome-Derived Trimethylamine N-Oxide (TMAO) as a Multifaceted Biomarker in Cardiovascular Disease: Challenges and Opportunities. Int J Mol Sci 2024; 25:12511. [PMID: 39684223 DOI: 10.3390/ijms252312511] [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: 10/22/2024] [Revised: 11/19/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Biomarkers play a crucial role in various stages of disease management, including screening, diagnosis, prediction, prognosis, treatment, and safety monitoring. Although they are powerful tools in disease diagnosis, management, and drug development, identifying and validating reliable biomarkers remains a significant challenge. Among potential microbiome-derived biomarkers, trimethylamine N-oxide (TMAO) has gained notable attention for its link to atherosclerosis and cardiovascular risk. However, despite the growing body of research on TMAO, its practical application in clinical settings for disease management and patient outcome enhancement is still not a reality. This paper presents recent data on the utility of TMAO as a cardiovascular biomarker, categorized by its various roles: diagnostic, prognostic, susceptibility/risk, monitoring, pharmacodynamic/response, predictive, and safety. It also briefly discusses research on TMAO's potential role in cardiovascular disease development. While TMAO shows promise, particularly in prognostic applications, its reliability as a biomarker has been inconsistent across studies. These variances may result from several confounding factors that affect TMAO plasma levels, including diet, kidney function, and demographic variables. The review aims to elucidate the specific contexts in which TMAO can be valuable, potentially leading to more personalized and effective management of cardiovascular disease.
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Affiliation(s)
- Kinga Jaworska
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Banacha 1B, 02-091 Warsaw, Poland
| | - Wojciech Kopacz
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Banacha 1B, 02-091 Warsaw, Poland
| | - Mateusz Koper
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Banacha 1B, 02-091 Warsaw, Poland
| | - Marcin Ufnal
- Laboratory of Centre for Preclinical Research, Department of Experimental Physiology and Pathophysiology, Medical University of Warsaw, Banacha 1B, 02-091 Warsaw, Poland
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50
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Khalil M, Di Ciaula A, Mahdi L, Jaber N, Di Palo DM, Graziani A, Baffy G, Portincasa P. Unraveling the Role of the Human Gut Microbiome in Health and Diseases. Microorganisms 2024; 12:2333. [PMID: 39597722 PMCID: PMC11596745 DOI: 10.3390/microorganisms12112333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
The human gut is a complex ecosystem that supports billions of living species, including bacteria, viruses, archaea, phages, fungi, and unicellular eukaryotes. Bacteria give genes and enzymes for microbial and host-produced compounds, establishing a symbiotic link between the external environment and the host at both the gut and systemic levels. The gut microbiome, which is primarily made up of commensal bacteria, is critical for maintaining the healthy host's immune system, aiding digestion, synthesizing essential nutrients, and protecting against pathogenic bacteria, as well as influencing endocrine, neural, humoral, and immunological functions and metabolic pathways. Qualitative, quantitative, and/or topographic shifts can alter the gut microbiome, resulting in dysbiosis and microbial dysfunction, which can contribute to a variety of noncommunicable illnesses, including hypertension, cardiovascular disease, obesity, diabetes, inflammatory bowel disease, cancer, and irritable bowel syndrome. While most evidence to date is observational and does not establish direct causation, ongoing clinical trials and advanced genomic techniques are steadily enhancing our understanding of these intricate interactions. This review will explore key aspects of the relationship between gut microbiota, eubiosis, and dysbiosis in human health and disease, highlighting emerging strategies for microbiome engineering as potential therapeutic approaches for various conditions.
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Affiliation(s)
- Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Medical School, University of Bari Aldo Moro, 70124 Bari, Italy; (M.K.); (A.D.C.); (L.M.); (N.J.)
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Medical School, University of Bari Aldo Moro, 70124 Bari, Italy; (M.K.); (A.D.C.); (L.M.); (N.J.)
| | - Laura Mahdi
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Medical School, University of Bari Aldo Moro, 70124 Bari, Italy; (M.K.); (A.D.C.); (L.M.); (N.J.)
| | - Nour Jaber
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Medical School, University of Bari Aldo Moro, 70124 Bari, Italy; (M.K.); (A.D.C.); (L.M.); (N.J.)
| | - Domenica Maria Di Palo
- Division of Hygiene, Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy;
| | - Annarita Graziani
- Institut AllergoSan Pharmazeutische Produkte Forschungs- und Vertriebs GmbH, 8055 Graz, Austria;
| | - Gyorgy Baffy
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02130, USA;
- Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston, MA 02130, USA
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Medical School, University of Bari Aldo Moro, 70124 Bari, Italy; (M.K.); (A.D.C.); (L.M.); (N.J.)
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