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Zhang Z, Guo Q, Yang Z, Sun Y, Jiang S, He Y, Li J, Zhang J. Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia. Cell Rep 2025; 44:115265. [PMID: 39908139 DOI: 10.1016/j.celrep.2025.115265] [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: 08/16/2024] [Revised: 11/29/2024] [Accepted: 01/13/2025] [Indexed: 02/07/2025] Open
Abstract
Sarcopenia significantly diminishes quality of life and increases mortality risk in older adults. While the connection between the gut microbiome and muscle health is recognized, the underlying mechanisms are poorly understood. In this study, shotgun metagenomics revealed that Bifidobacterium adolescentis is notably depleted in individuals with sarcopenia, correlating with reduced muscle mass and function. This finding was validated in aged mice. Metabolomics analysis identified nicotinic acid as a key metabolite produced by B. adolescentis, linked to improvements in muscle mass and functionality in individuals with sarcopenia. Mechanistically, nicotinic acid restores nicotinamide adenine dinucleotide (NAD+) levels in muscle, inhibits the FoxO3/Atrogin-1/Murf-1 axis, and promotes satellite cell proliferation, reducing muscle atrophy. Additionally, NAD+ activation enhances the silent-information-regulator 1 (SIRT1)/peroxisome-proliferator-activated-receptor-γ-coactivator 1-alpha (PGC-1α) axis, stimulating mitochondrial biogenesis and promoting oxidative metabolism in slow-twitch fibers, ultimately improving muscle function. Our findings suggest that B. adolescentis-derived nicotinic acid could be a promising therapeutic strategy for individuals with sarcopenia.
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Affiliation(s)
- Zeng Zhang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, Hainan, China
| | - Quan Guo
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, Hainan, China
| | - Zhihan Yang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, Hainan, China
| | - Yukai Sun
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, Hainan, China
| | - Shuaiming Jiang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, Hainan, China
| | - Yangli He
- Department of Health Center, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, China
| | - Jiahe Li
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, Hainan, China
| | - Jiachao Zhang
- School of Food Science and Engineering, Key Laboratory of Food Nutrition and Functional Food of Hainan Province, Hainan University, Haikou 570228, Hainan, China; Collaborative Innovation Center of One Health, Hainan University, Haikou 570228, Hainan, China.
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2
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Cai A, Shen D, Xiong Q, Ding J, Ding Y, Lin X, Chen L, Yao Q, Lin G, Chen R, Ganapathy V, Kou L. α-methyltryptophan-mediated protection against diabetic nephropathy in db/db mice as studied with a metabolomics approach. Front Pharmacol 2025; 15:1463673. [PMID: 39902076 PMCID: PMC11788373 DOI: 10.3389/fphar.2024.1463673] [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: 07/12/2024] [Accepted: 12/31/2024] [Indexed: 02/05/2025] Open
Abstract
Introduction Diabetic nephropathy (DN), a major complication of diabetes, presents with poor clinical outcomes and affects patients throughout their lifetime. α-Methyltryptophan (α-MT) is a blocker of the amino acid transporter. SLC6A14 and also an inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1). Methods In this study, we employed a nuclear magnetic resonance-based metabolomic approach to investigate the therapeutic effects of α-MT in a db/db mouse model of DN and explore the underlying molecular mechanisms. Results The results of the study demonstrated that α-MT significantly reduced the urinary excretion of albumin and creatinine, improved kidney function, and decreased renal fibrosis in db/db mice. Metabolomic analyses of kidney tissues and urine samples indicated that db/db mice displayed increased activity of the enzyme IDO1, and alongside pronounced metabolic disturbances. These disturbances are chiefly characterized by alterations in amino acid metabolism, energy production pathways, membrane biochemical features, and nicotinamide metabolism, all of which have been implicated in mTOR signaling and apoptotic pathways. Discussion Administration of α-MT to db/db mice showed evidence of IDO1 inhibition and rectification of metabolic dysfunctions with concurrent suppression of mTOR signaling and apoptosis. These findings highlight the potential of α-MT as a promising therapeutic agent for diabetic nephropathy.
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Affiliation(s)
- Aimin Cai
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dingchao Shen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qiushuang Xiong
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jie Ding
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yang Ding
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xinlu Lin
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lijia Chen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qing Yao
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Guangyong Lin
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ruijie Chen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Vadivel Ganapathy
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Longfa Kou
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
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3
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Bauset C, Carda-Diéguez M, Cejudo-Garcés A, Buetas E, Seco-Cervera M, Macias-Ceja DC, Navarro-Vicente F, Esplugues JV, Calatayud S, Mira Á, Ortiz-Masiá D, Barrachina MD, Cosín-Roger J. A disturbed metabolite-GPCR axis is associated with microbial dysbiosis in IBD patients: Potential role of GPR109A in macrophages. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167489. [PMID: 39233260 DOI: 10.1016/j.bbadis.2024.167489] [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: 01/31/2024] [Revised: 06/20/2024] [Accepted: 08/26/2024] [Indexed: 09/06/2024]
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by disrupted immune function. Indeed, gut microbiota dysbiosis and metabolomic profile alterations, are hallmarks of IBD. In this scenario, metabolite-sensing G-protein coupled receptors (GPCRs), involved in several biological processes, have emerged as pivotal players in the pathophysiology of IBD. The aim of this study was to characterize the axis microbiota-metabolite-GPCR in intestinal surgical resections from IBD patients. Results showed that UC patients had a lower microbiota richness and bacterial load, with a higher proportion of the genus Cellulosimicrobium and a reduced proportion of Escherichia, whereas CD patients showed a decreased abundance of Enterococcus. Furthermore, metabolomic analysis revealed alterations in carboxylic acids, fatty acids, and amino acids in UC and CD samples. These patients also exhibited upregulated expression of most metabolite-sensing GPCRs analysed, which positively correlated with pro-inflammatory and pro-fibrotic markers. The role of GPR109A was studied in depth and increased expression of this receptor was detected in epithelial cells and cells from lamina propria, including CD68+ macrophages, in IBD patients. The treatment with β-hydroxybutyrate increased gene expression of GPR109A, CD86, IL1B and NOS2 in U937-derived macrophages. Besides, when GPR109A was transiently silenced, the mRNA expression and secretion of IL-1β, IL-6 and TNF-α were impaired in M1 macrophages. Finally, the secretome from siGPR109A M1 macrophages reduced the gene and protein expression of COL1A1 and COL3A1 in intestinal fibroblasts. A better understanding of metabolite-sensing GPCRs, such as GPR109A, could establish their potential as therapeutic targets for managing IBD.
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Affiliation(s)
- Cristina Bauset
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | | | - Andrea Cejudo-Garcés
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Elena Buetas
- Genomics & Health Department, FISABIO Foundation, Valencia, Spain
| | | | | | | | - Juan Vicente Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain
| | - Sara Calatayud
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain
| | - Álex Mira
- Genomics & Health Department, FISABIO Foundation, Valencia, Spain; CIBER Center for Epidemiology and Public Health, Madrid, Spain
| | - Dolores Ortiz-Masiá
- CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain; Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | - María Dolores Barrachina
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain.
| | - Jesús Cosín-Roger
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd (Centro de Investigaciones en Red Enfermedad Hepática y Digestiva), Madrid, Spain
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Richardson JC, Higgins GA, Upton N, Massey P, Cunningham M, Wilson S, Holenz J, Taylor C, Lavrov A, Lin H, Matsuoka Y, Brown AJ. The hydroxycarboxylic acid receptor HCA2 is required for the protective effect of ketogenic diet in epilepsy. Pharmacol Res Perspect 2024; 12:e70026. [PMID: 39439218 PMCID: PMC11496569 DOI: 10.1002/prp2.70026] [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: 02/19/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
One third of epilepsy patients are resistant to treatment with current anti-seizure medications. The ketogenic diet is used to treat some forms of refractory epilepsy, but the mechanism of its action has not yet been elucidated. In this study, we aimed to investigate whether the hydroxycarboxylic acid receptor 2 (HCA2), a known immunomodulatory receptor, plays a role in mediating the protective effect of this diet. We demonstrate for the first time that selective agonists at this receptor can directly reduce seizures in animal models. Agonists also reduce network activity in rodent and human brain slices. Ketogenic diet is known to increase circulating levels of endogenous HCA2 agonists, and we show that the effect of ketogenic diet in reducing seizures in the 6 Hz seizure model is negated in HCA2-deficient mice. Our data support the potential of HCA2 as a target for the treatment of epilepsy and potentially for neurodegenerative diseases.
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Affiliation(s)
| | | | | | - Peter Massey
- Institute of NeuroscienceUniversity of NewcastleNewcastleUK
| | - Mark Cunningham
- Institute of NeuroscienceUniversity of NewcastleNewcastleUK
- Discipline of Physiology, School of MedicineTrinity College DublinDublin 2Ireland
| | - Steve Wilson
- In vitro and in vivo TranslationGlaxoSmithKline R&D LtdStevenageUK
| | - Joerg Holenz
- Neurosciences Therapeutic Area UnitGlaxoSmithKline R&D LtdUpper ProvidencePennsylvaniaUSA
| | | | - Arseniy Lavrov
- Neurosciences Therapeutic Area UnitGlaxoSmithKline R&D LtdStockley ParkUK
| | - Hong Lin
- Neurosciences Therapeutic Area UnitGlaxoSmithKline R&D LtdUpper ProvidencePennsylvaniaUSA
| | - Yasuji Matsuoka
- Neurosciences Therapeutic Area UnitGlaxoSmithKline R&D LtdUpper ProvidencePennsylvaniaUSA
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Marín-Blázquez M, Rovira J, Ramírez-Bajo MJ, Zapata-Pérez R, Rabadán-Ros R. NAD + enhancers as therapeutic agents in the cardiorenal axis. Cell Commun Signal 2024; 22:537. [PMID: 39516787 PMCID: PMC11546376 DOI: 10.1186/s12964-024-01903-4] [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: 08/01/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Cardiorenal diseases represent a complex interplay between heart failure and renal dysfunction, being clinically classified as cardiorenal syndromes (CRS). Recently, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism, through deficient NAD+ synthesis and/or elevated consumption, have proved to be decisive in the onset and progress of cardiorenal disease. NAD+ is a pivotal coenzyme in cellular metabolism, being significant in various signaling pathways, such as energy metabolism, DNA damage repair, gene expression, and stress response. Convincing evidence suggests that strategies designed to boost cellular NAD+ levels are a promising therapeutic option to address cardiovascular and renal disorders. Here, we review and discuss the implications of NAD+ metabolism in cardiorenal diseases, focusing on the propitious NAD+ boosting therapeutic strategies, based on the use of NAD+ precursors, poly(ADP-ribose) polymerase inhibitors, sirtuin activators, and other alternative approaches, such as CD38 blockade, nicotinamide phosphoribosyltransferase activation and combined interventions.
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Affiliation(s)
- Mariano Marín-Blázquez
- Group of Metabolism and Genetic Regulation of Disease, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, 30107 Guadalupe de Maciascoque, Murcia, Spain
| | - Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova 143 CRB CELLEX sector 2B, Barcelona, 08036, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - María José Ramírez-Bajo
- Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova 143 CRB CELLEX sector 2B, Barcelona, 08036, Spain
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS 2040), Madrid, Spain
| | - Rubén Zapata-Pérez
- Group of Metabolism and Genetic Regulation of Disease, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, 30107 Guadalupe de Maciascoque, Murcia, Spain.
| | - Rubén Rabadán-Ros
- Group of Metabolism and Genetic Regulation of Disease, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, 30107 Guadalupe de Maciascoque, Murcia, Spain.
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6
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Dong Y, Gai Z, Han M, Zhao Y. Lacticaseibacillus rhamnosus LRa05 mediates dynamic regulation of intestinal microbiota in mice with low-dose DSS-induced chronic mild inflammation. Front Microbiol 2024; 15:1483104. [PMID: 39444683 PMCID: PMC11496787 DOI: 10.3389/fmicb.2024.1483104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/20/2024] [Indexed: 10/25/2024] Open
Abstract
Aim This study aimed to investigate the effects of low-dose dextran sulfate sodium (DSS) on the induction of chronic mild inflammation in mice and to evaluate the therapeutic potential of Lacticaseibacillus rhamnosus LRa05 (LRa05) to ameliorate the associated effects. The focus was on investigating changes in inflammatory, gut microbiota, serum lipopolysaccharide (LPS) and inflammatory cytokines. Methods Mice were exposed to a low-dose of DSS to induce chronic mild inflammation and LRa05 was administered as a probiotic intervention. The experiment included determination of body weight, colon length, histological examinations, and analysis of LPS and inflammatory cytokines in serum over 12 weeks. In addition, liver function, oxidative stress and intestinal microbiota were examined to understand the comprehensive effects of DSS and LRa05. Results Low-dose DSS did not lead to significant changes in body weight, colon length or histologic signs of inflammation. However, it led to a significant increase in serum levels of LPS, tumor necrosis factor-alpha (TNFα) and interleukin-6 (IL6). Intervention with LRa05 effectively attenuated these changes, particularly by lowering LPS levels and normalizing inflammatory cytokines. In addition, LRa05 protected against DSS-induced liver function damage and attenuated oxidative stress in the liver. Analysis of the gut microbiota demonstrated dynamic regulatory effects, where LRa05 intervention led to significant shifts in microbial populations, promoting a balanced microbiota profile. These changes are indicative of dynamic regulation by LRa05 in response to chronic mild inflammation, highlighting the probiotic's role in modulating the gut environment. Conclusion The LRa05 intervention showed multi-layered regulation in the chronic mild inflammation model by reducing inflammatory cytokines, maintaining liver function and restoring the balance of the gut microbiota. This provides experimental support for the potential use of LRa05 in chronic inflammation-related diseases and emphasizes the importance of probiotics for overall health. The study suggests that LRa05 is a potential therapeutic agent for the treatment of chronic inflammation associated with gut dysbiosis.
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Affiliation(s)
- Yao Dong
- Department of Research and Development, Wecare Probiotics Co., Ltd., Suzhou, China
| | - Zhonghui Gai
- Department of Research and Development, Wecare Probiotics Co., Ltd., Suzhou, China
| | - Mei Han
- Department of Food Quality and Safety, Shanghai Business School, Shanghai, China
| | - Yunjiao Zhao
- Department of Research and Development, Wecare Probiotics Co., Ltd., Suzhou, China
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
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7
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Datta S, Pasham S, Inavolu S, Boini KM, Koka S. Role of Gut Microbial Metabolites in Cardiovascular Diseases-Current Insights and the Road Ahead. Int J Mol Sci 2024; 25:10208. [PMID: 39337693 PMCID: PMC11432476 DOI: 10.3390/ijms251810208] [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: 08/19/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Sindhura Pasham
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Sriram Inavolu
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
| | - Krishna M Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA
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8
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Certo M, Rahimzadeh M, Mauro C. Immunometabolism in atherosclerosis: a new understanding of an old disease. Trends Biochem Sci 2024; 49:791-803. [PMID: 38937222 DOI: 10.1016/j.tibs.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/27/2024] [Accepted: 06/06/2024] [Indexed: 06/29/2024]
Abstract
Atherosclerosis, a chronic inflammatory condition, remains a leading cause of death globally, necessitating innovative approaches to target pro-atherogenic pathways. Recent advancements in the field of immunometabolism have highlighted the crucial interplay between metabolic pathways and immune cell function in atherogenic milieus. Macrophages and T cells undergo dynamic metabolic reprogramming to meet the demands of activation and differentiation, influencing plaque progression. Furthermore, metabolic intermediates intricately regulate immune cell responses and atherosclerosis development. Understanding the metabolic control of immune responses in atherosclerosis, known as athero-immunometabolism, offers new avenues for preventive and therapeutic interventions. This review elucidates the emerging intricate interplay between metabolism and immunity in atherosclerosis, underscoring the significance of metabolic enzymes and metabolites as key regulators of disease pathogenesis and therapeutic targets.
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Affiliation(s)
- Michelangelo Certo
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
| | - Mahsa Rahimzadeh
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran; Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Claudio Mauro
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
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Archana, Gupta AK, Noumani A, Panday DK, Zaidi F, Sahu GK, Joshi G, Yadav M, Borah SJ, Susmitha V, Mohan A, Kumar A, Solanki PR. Gut microbiota derived short-chain fatty acids in physiology and pathology: An update. Cell Biochem Funct 2024; 42:e4108. [PMID: 39228159 DOI: 10.1002/cbf.4108] [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: 06/10/2024] [Revised: 07/28/2024] [Accepted: 08/09/2024] [Indexed: 09/05/2024]
Abstract
Short-chain fatty acids (SCFAs) are essential molecules produced by gut bacteria that fuel intestinal cells and may also influence overall health. An imbalance of SCFAs can result in various acute and chronic diseases, including diabetes, obesity and colorectal cancer (CRC). This review delves into the multifaceted roles of SCFAs, including a brief discussion on their source and various gut-residing bacteria. Primary techniques used for detection of SCFAs, including gas chromatography, high-performance gas chromatography, nuclear magnetic resonance and capillary electrophoresis are also discussed through this article. This review study also compiles various synthesis pathways of SCFAs from diverse substrates such as sugar, acetone, ethanol and amino acids. The different pathways through which SCFAs enter cells for immune response regulation are also highlighted. A major emphasis is the discussion on diseases associated with SCFA dysregulation, such as anaemia, brain development, CRC, depression, obesity and diabetes. This includes exploring the relationship between SCFA levels across ethnicities and their connection with blood pressure and CRC. In conclusion, this review highlights the critical role of SCFAs in maintaining gut health and their implications in various diseases, emphasizing the need for further research on SCFA detection, synthesis and their potential as diagnostic biomarkers. Future studies of SCFAs will pave the way for the development of novel diagnostic tools and therapeutic strategies for optimizing gut health and preventing diseases associated with SCFA dysregulation.
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Affiliation(s)
- Archana
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Abhijeet Kumar Gupta
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Ashab Noumani
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Dharmendra Kumar Panday
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Fareen Zaidi
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Gaurav Kumar Sahu
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Gunjan Joshi
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Manisha Yadav
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Shikha Jyoti Borah
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Vanne Susmitha
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
| | - Anand Mohan
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India
| | - Anil Kumar
- National Institute of Immunology, New Delhi, India
| | - Pratima R Solanki
- Nano-Bio Laboratory, Special Centre for Nanoscience, Jawaharlal Nehru University, New Delhi, India
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10
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Lui DTW, Tan KCB. High-density lipoprotein in diabetes: Structural and functional relevance. J Diabetes Investig 2024; 15:805-816. [PMID: 38416054 PMCID: PMC11215696 DOI: 10.1111/jdi.14172] [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: 01/27/2024] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 02/29/2024] Open
Abstract
Low levels of high-density lipoprotein-cholesterol (HDL-C) is considered a major cardiovascular risk factor. However, recent studies have suggested a more U-shaped association between HDL-C and cardiovascular disease. It has been shown that the cardioprotective effect of HDL is related to the functions of HDL particles rather than their cholesterol content. HDL particles are highly heterogeneous and have multiple functions relevant to cardiometabolic conditions including cholesterol efflux capacity, anti-oxidative, anti-inflammatory, and vasoactive properties. There are quantitative and qualitative changes in HDL as well as functional abnormalities in both type 1 and type 2 diabetes. Non-enzymatic glycation, carbamylation, oxidative stress, and systemic inflammation can modify the HDL composition and therefore the functions, especially in situations of poor glycemic control. Studies of HDL proteomics and lipidomics have provided further insights into the structure-function relationship of HDL in diabetes. Interestingly, HDL also has a pleiotropic anti-diabetic effect, improving glycemic control through improvement in insulin sensitivity and β-cell function. Given the important role of HDL in cardiometabolic health, HDL-based therapeutics are being developed to enhance HDL functions rather than to increase HDL-C levels. Among these, recombinant HDL and small synthetic apolipoprotein A-I mimetic peptides may hold promise for preventing and treating diabetes and cardiovascular disease.
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Affiliation(s)
- David Tak Wai Lui
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
| | - Kathryn Choon Beng Tan
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
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11
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Pedro MP, Lund K, Kang SWS, Chen T, Stuelten CH, Porat-Shliom N, Iglesias-Bartolome R. GPCR Screening Reveals that the Metabolite Receptor HCAR3 Regulates Epithelial Proliferation, Migration, and Cellular Respiration. J Invest Dermatol 2024; 144:1311-1321.e7. [PMID: 38103827 PMCID: PMC11116076 DOI: 10.1016/j.jid.2023.12.002] [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: 10/12/2023] [Revised: 11/24/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
Epithelial cells in the skin and other tissues rely on signals from their environment to maintain homeostasis and respond to injury, and GPCRs play a critical role in this communication. A better understanding of the GPCRs expressed in epithelial cells will contribute to understanding the relationship between cells and their niche and could lead to developing new therapies to modulate cell fate. This study used human primary keratinocytes as a model to investigate the specific GPCRs regulating epithelial cell proliferation and differentiation. We identified 3 key receptors-HCAR3, LTB4R, and GPR137-and found that knockdown of these receptors led to changes in numerous gene networks that are important for maintaining cell identity and promoting proliferation while inhibiting differentiation. Our study also revealed that the metabolite receptor HCAR3 regulates keratinocyte migration and cellular metabolism. Knockdown of HCAR3 led to reduced keratinocyte migration and respiration, which could be attributed to altered metabolite use and aberrant mitochondrial morphology caused by the absence of the receptor. This study contributes to understanding the complex interplay between GPCR signaling and epithelial cell fate decisions.
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Affiliation(s)
- M Pilar Pedro
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Katherine Lund
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Sun Woo Sophie Kang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ting Chen
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Christina H Stuelten
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Natalie Porat-Shliom
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ramiro Iglesias-Bartolome
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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12
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Jang J, Kim SR, Lee JE, Lee S, Son HJ, Choe W, Yoon KS, Kim SS, Yeo EJ, Kang I. Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases. Int J Mol Sci 2023; 25:124. [PMID: 38203294 PMCID: PMC10779133 DOI: 10.3390/ijms25010124] [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: 11/20/2023] [Revised: 12/18/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.
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Affiliation(s)
- Jiwon Jang
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Su Rim Kim
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jo Eun Lee
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seoyeon Lee
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Hyeong Jig Son
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wonchae Choe
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Kyung-Sik Yoon
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung Soo Kim
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Eui-Ju Yeo
- Department of Biochemistry, College of Medicine, Gachon University, Incheon 21999, Republic of Korea
| | - Insug Kang
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (J.J.); (S.R.K.); (J.E.L.); (S.L.); (H.J.S.); (W.C.); (K.-S.Y.); (S.S.K.)
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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13
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Yaku K, Nakagawa T. NAD + Precursors in Human Health and Disease: Current Status and Future Prospects. Antioxid Redox Signal 2023; 39:1133-1149. [PMID: 37335049 DOI: 10.1089/ars.2023.0354] [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] [Indexed: 06/21/2023]
Abstract
Significance: Nicotinamide adenine dinucleotide (NAD+) acts as a cofactor in many important biological processes. The administration of NAD+ precursors increases the intracellular NAD+ pool and has beneficial effects on physiological changes and diseases associated with aging in various organisms, including rodents and humans. Recent Advances: Evidence from preclinical studies demonstrating the beneficial effects of NAD+ precursors has rapidly increased in the last decade. The results of these studies have prompted the development of clinical trials using NAD+ precursors, particularly nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). In addition, in vivo studies of NAD+ metabolism have rapidly progressed. Critical Issues: Several studies have demonstrated that the oral administration of NAD+ precursors, such as NR and NMN, is safe and significantly increases NAD+ levels in humans. However, the efficacy of these NAD+ precursors is lower than expected from the results of preclinical studies. In addition, the identification of the contribution of the host-gut microbiota interactions to NR and NMN metabolism has added to the complexity of NAD+ metabolism. Future Directions: Further studies are required to determine the efficacy of NAD+ precursors in humans. Further in vivo studies of NAD+ metabolism are required to optimize the effects of NAD+ supplementation. There is also a need for methods of delivering NAD+ precursors to target organs or tissues to increase the outcomes of clinical trials. Antioxid. Redox Signal. 39, 1133-1149.
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Affiliation(s)
- Keisuke Yaku
- Department of Molecular and Medical Pharmacology, Faculty of Medicine; Toyama, Japan
| | - Takashi Nakagawa
- Department of Molecular and Medical Pharmacology, Faculty of Medicine; Toyama, Japan
- Research Center for Pre-Disease Science; University of Toyama, Toyama, Japan
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14
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Pan X, Ye F, Ning P, Zhang Z, Li X, Zhang B, Wang Q, Chen G, Gao W, Qiu C, Wu Z, Li J, Zhu L, Xia J, Gong K, Du Y. Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2. Cell Discov 2023; 9:118. [PMID: 38012147 PMCID: PMC10682194 DOI: 10.1038/s41421-023-00610-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 09/28/2023] [Indexed: 11/29/2023] Open
Abstract
Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.
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Affiliation(s)
- Xin Pan
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
- Department of Cardiology, Central Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Fang Ye
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Peiruo Ning
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Zhiyi Zhang
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Xinyu Li
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Binghao Zhang
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Qian Wang
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Geng Chen
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Wei Gao
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Chen Qiu
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Zhangsong Wu
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Jiancheng Li
- Instrumental Analysis Center, Shenzhen University, Shenzhen, Guangdong, China
| | - Lizhe Zhu
- Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
| | - Jiang Xia
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
| | - Kaizheng Gong
- Department of Cardiology, Central Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
| | - Yang Du
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
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15
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Wan T, Wang Y, He K, Zhu S. Microbial sensing in the intestine. Protein Cell 2023; 14:824-860. [PMID: 37191444 PMCID: PMC10636641 DOI: 10.1093/procel/pwad028] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/04/2023] [Indexed: 05/17/2023] Open
Abstract
The gut microbiota plays a key role in host health and disease, particularly through their interactions with the immune system. Intestinal homeostasis is dependent on the symbiotic relationships between the host and the diverse gut microbiota, which is influenced by the highly co-evolved immune-microbiota interactions. The first step of the interaction between the host and the gut microbiota is the sensing of the gut microbes by the host immune system. In this review, we describe the cells of the host immune system and the proteins that sense the components and metabolites of the gut microbes. We further highlight the essential roles of pattern recognition receptors (PRRs), the G protein-coupled receptors (GPCRs), aryl hydrocarbon receptor (AHR) and the nuclear receptors expressed in the intestinal epithelial cells (IECs) and the intestine-resident immune cells. We also discuss the mechanisms by which the disruption of microbial sensing because of genetic or environmental factors causes human diseases such as the inflammatory bowel disease (IBD).
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Affiliation(s)
- Tingting Wan
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Yalong Wang
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Kaixin He
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
| | - Shu Zhu
- Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Institute of Immunology, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China
- Department of Digestive Disease, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
- Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China
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16
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Griepke S, Trauelsen M, Nilsson MD, Hansen J, Steffensen LB, Schwartz TW, Ketelhuth DFJ. G-Protein-Coupled Receptor 91-Dependent Signalling Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidaemic Mice. Cells 2023; 12:2580. [PMID: 37947659 PMCID: PMC10647868 DOI: 10.3390/cells12212580] [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: 09/28/2023] [Revised: 10/31/2023] [Accepted: 11/03/2023] [Indexed: 11/12/2023] Open
Abstract
The TCA cycle intermediate metabolite 'succinate' has been proposed as an inflammatory mediator, influencing autoimmunity and allergic reactions, through ligation to its sensing receptor SUCNR1/GPR91. Whether GPR91-mediated signalling influences the chronic inflammatory process of atherosclerosis has never been investigated. The examination of publicly available datasets revealed that the SUCNR1 gene is expressed in human atherosclerotic plaques, especially in vascular smooth muscle cells. Using GPR91 knockout (Gpr91-/-) and wildtype (WT) littermates, made hyperlipidaemic with the overexpression of the gain-of-function mutated Pcsk9 and Western diet feeding, we showed that the full ablation of GPR91 did not accelerate atherosclerosis-lesions in the aortic arch 2.18 ± 0.48% vs. 1.64 ± 0.31%, and in the aortic roots 10.06 ± 0.91% vs. 10.67 ± 1.53% for Gpr91-/- and WT mice, respectively. In line with this, no differences between groups were observed for macrophage and T-cell infiltration in the plaque, as well as the polarization towards M1- or M2-like macrophages in the aorta, spleen and liver of Gpr91-/- and WT control mice. In conclusion, our study indicates that the global ablation of GPR91 signalling does not influence vascular inflammation or atherogenesis.
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Affiliation(s)
- Silke Griepke
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.G.); (M.D.N.); (J.H.); (L.B.S.)
| | - Mette Trauelsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; (M.T.); (T.W.S.)
| | - Michelle D. Nilsson
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.G.); (M.D.N.); (J.H.); (L.B.S.)
| | - Jakob Hansen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.G.); (M.D.N.); (J.H.); (L.B.S.)
| | - Lasse B. Steffensen
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.G.); (M.D.N.); (J.H.); (L.B.S.)
| | - Thue W. Schwartz
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; (M.T.); (T.W.S.)
| | - Daniel F. J. Ketelhuth
- Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark; (S.G.); (M.D.N.); (J.H.); (L.B.S.)
- Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Bioclinicum, Solna, 171 64 Stockholm, Sweden
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17
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Pividori M, Lu S, Li B, Su C, Johnson ME, Wei WQ, Feng Q, Namjou B, Kiryluk K, Kullo IJ, Luo Y, Sullivan BD, Voight BF, Skarke C, Ritchie MD, Grant SFA, Greene CS. Projecting genetic associations through gene expression patterns highlights disease etiology and drug mechanisms. Nat Commun 2023; 14:5562. [PMID: 37689782 PMCID: PMC10492839 DOI: 10.1038/s41467-023-41057-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 08/18/2023] [Indexed: 09/11/2023] Open
Abstract
Genes act in concert with each other in specific contexts to perform their functions. Determining how these genes influence complex traits requires a mechanistic understanding of expression regulation across different conditions. It has been shown that this insight is critical for developing new therapies. Transcriptome-wide association studies have helped uncover the role of individual genes in disease-relevant mechanisms. However, modern models of the architecture of complex traits predict that gene-gene interactions play a crucial role in disease origin and progression. Here we introduce PhenoPLIER, a computational approach that maps gene-trait associations and pharmacological perturbation data into a common latent representation for a joint analysis. This representation is based on modules of genes with similar expression patterns across the same conditions. We observe that diseases are significantly associated with gene modules expressed in relevant cell types, and our approach is accurate in predicting known drug-disease pairs and inferring mechanisms of action. Furthermore, using a CRISPR screen to analyze lipid regulation, we find that functionally important players lack associations but are prioritized in trait-associated modules by PhenoPLIER. By incorporating groups of co-expressed genes, PhenoPLIER can contextualize genetic associations and reveal potential targets missed by single-gene strategies.
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Affiliation(s)
- Milton Pividori
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, 80045, USA
| | - Sumei Lu
- Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Binglan Li
- Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA
| | - Chun Su
- Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Matthew E Johnson
- Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Wei-Qi Wei
- Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Qiping Feng
- Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Bahram Namjou
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Krzysztof Kiryluk
- Department of Medicine, Division of Nephrology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, 10032, USA
| | | | - Yuan Luo
- Northwestern University, Chicago, IL, 60611, USA
| | - Blair D Sullivan
- Kahlert School of Computing, University of Utah, Salt Lake City, UT, 84112, USA
| | - Benjamin F Voight
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Carsten Skarke
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Marylyn D Ritchie
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Struan F A Grant
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Casey S Greene
- Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
- Center for Health AI, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
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18
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Ye C, Gao ZH, Chen KQ, Lu FG, Wei K. Research on Pachymaran to Ameliorate CsA-Induced Immunosuppressive Lung Injury by Regulating Microflora Metabolism. Microorganisms 2023; 11:2249. [PMID: 37764093 PMCID: PMC10537689 DOI: 10.3390/microorganisms11092249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Pachymaran (PCP), the major medicinal constituent of Poria cocos, has a regulatory effect on immunosuppressive lung injury, but its mechanism of action with respect to gut microorganisms and their metabolites is not clear. The aim of this study was to investigate the protective effect of PCP against immunosuppressive lung injury caused by cyclosporine A (CsA), and to reveal its possible mechanism of action via the comprehensive analysis of 16S rRNA and LC-MS. We demonstrated that PCP was effective at alleviating CsA-induced immunosuppressive lung injury by restoring the organ indices and lung tissue morphology and structure. PCP significantly altered the composition of the gut and lung microbiota in mice with CsA-induced immunosuppressive lung injury by increasing the number of beneficial bacteria from the Eubacterium nodatum group, Eubacterium ventriosum group, Akkermansia, and Ruminococcus, and reducing the pathogenic Rikenellaceae RC9 gut group to fulfill its immunomodulatory role. In lung tissue microecology, PCP intervention significantly reduced the abundance of Chryseobacterium, Lawsonella, Paracoccus, and Sediminibacterium and increased the abundance of Alloprevotella. The LC-MS results showed that PCP alleviated the CsA-induced immunosuppression of lung tissue injury. The model serum metabolite Americine decreased the expression of PC(O-18:1(4Z)/0:0). Our results suggest that PCP may be involved in regulating the composition, function, and metabolism of the gut and lung microbiota to reverse CsA-induced immunosuppressive lung injury.
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Affiliation(s)
| | | | | | | | - Ke Wei
- Medicine School, Hunan University of Chinese Medicine, Changsha 410208, China; (C.Y.); (Z.-H.G.); (K.-Q.C.); (F.-G.L.)
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19
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Zhang F, Yang J, Zhan Q, Shi H, Li Y, Li D, Li Y, Yang X. Dietary oregano aqueous extract improves growth performance and intestinal health of broilers through modulating gut microbial compositions. J Anim Sci Biotechnol 2023; 14:77. [PMID: 37653529 PMCID: PMC10472629 DOI: 10.1186/s40104-023-00857-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 03/01/2023] [Indexed: 09/02/2023] Open
Abstract
BACKGROUND Intestinal health plays a pivotal role in broiler chicken growth. Oregano aqueous extract (OAE) effectively exerts anti-inflammatory and antibacterial effects. However, the protective effects of OAE on intestinal health in broilers and the underlying mechanism remain unclear. This study aimed to investigate the potential effects of OAE on growth performance, the gut microbiota and intestinal health. A total of 840 1-d-old male and female broilers (Arbor Acres) were randomly allocated into 6 groups as follows: basal diet (Con), Con + antibiotics (Anti, colistin sulfate 7 g/kg, roxarsone 35 g/kg), Con + 400, 500, 600 and 700 mg/kg OAE (OAE400, OAE500, OAE600 and OAE700). Subsequently, fermentation in vitro together with oral administration trials were carried out to further assess the function of OAE on intestinal health of broilers. RESULTS Dietary 700 mg/kg OAE supplementation resulted in an increase (P < 0.05) in body weight and a decrease (P < 0.05) in feed conversion ratio when compared with the control during d 22 to 42 of the trial. OAE addition resulted in lower (P < 0.05) jejunal crypt depth and mRNA expression of IL-4 and IL-10 at d 42. In addition, dietary OAE addition increased the abundance of Firmicutes (P = 0.087) and Lactobacillus (P < 0.05) in the cecum, and increased (P < 0.05) the content of acetic acid and butyric acid. In the in vitro fermentation test, OAE significantly increased (P < 0.05) the abundance of Lactobacillus, decreased (P < 0.05) the abundance of unspecified_Enterobacteriaceae, and increased the content of acetic acid (P < 0.05). In the oral administration trial, higher (P < 0.05) IL-4 expression was found in broilers when oral inoculation with oregano fermentation microorganisms at d 42. And SIgA content in the ileum was significantly increased (P = 0.073) when giving OAE fermentation supernatant. CONCLUSIONS Dietary OAE addition could maintain intestinal health and improve growth performance through enhancing intestinal mucosal immunity and barrier function mediated by gut microbiota changes.
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Affiliation(s)
- Fan Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi China
| | - Jiantao Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi China
| | - Qinyi Zhan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi China
| | - Hao Shi
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi China
| | - Yanhe Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi China
| | - Dinggang Li
- Baoding Jizhong Pharmaceutical Corporation, LTD, Baoding, Hebei China
| | - Yingge Li
- Shaanxi Province Animal Husbandry Technology Extension Station, Xi’an, Shaanxi China
| | - Xiaojun Yang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi China
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20
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Zhang Y, Li Y, Wang X, Huang J, Feng X, Shi C, Yang W, Jiang Y, Cao X, Wang J, Huang H, Zeng Y, Wang N, Yang G, Wang C. Lactobacillus Plantarum NC8 and its metabolite acetate alleviate type 1 diabetes via inhibiting NLRP3. Microb Pathog 2023; 182:106237. [PMID: 37422174 DOI: 10.1016/j.micpath.2023.106237] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 07/10/2023]
Abstract
A healthy organism is the result of host-microbiome co-evolution. Microbial metabolites can also stimulate immune cells to reduce intestinal inflammation and permeability. Gut dysbiosis will lead to a variety of autoimmune diseases, such as Type 1 diabetes (T1D). Most of probiotics, such as Lactobacillus casei, Lactobacillus reuteri, Bifidobacterium bifidium, and Streptococcus thermophiles, can improve the intestinal flora structure of the host, reduce intestinal permeability, and relieve symptoms of T1D patients if ingested above probiotics in sufficient amounts. Lactobacillus Plantarum NC8, a kind of Lactobacillus, whether it has an effect on T1D, and the mechanism of it regulating T1D is still unclear. As a member of the inflammatory family, NLRP3 inflammasome can enhance inflammatory responses by promoting the production and secretion of proinflammatory cytokines. Many previous studies had shown that NLRP3 also plays an important role in the development of T1D. When the NLRP3 gene is deleted, the disease progression of T1D will be delayed. Therefore, this study investigated whether Lactobacillus Plantarum NC8 can alleviate T1D by regulating NLRP3. The results demonstrated that Lactobacillus Plantarum NC8 and its metabolites acetate play a role in T1D by co-modulating NLRP3. Lactobacillus Plantarum NC8 and acetate can reduce the damage of T1D in the model mice, even if orally administered them in the early stage of T1D. The number of Th1/Th17 cells in the spleen and pancreatic lymph nodes (PLNs) of T1D mice were significantly reduced by oral Lactobacillus Plantarum NC8 or acetate. The expression of NLRP3 in the pancreas of T1D mice or murine macrophages of inflammatory model were significantly inhibited by treatment with Lactobacillus Plantarum NC8 or acetate. In addition, the number of macrophages in the pancreas were significantly reduced by the treatment with Lactobacillus Plantarum NC8 or acetate. In summary, this study indicated that the regulatory mechanism of Lactobacillus Plantarum NC8 and its metabolite acetate to T1D maybe via inhibiting NLRP3 and provides a novel insights into the mechanism of the alleviated role of probiotics to T1D.
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Affiliation(s)
- Yuting Zhang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yanning Li
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xiuquan Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Jingshu Huang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xize Feng
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Chunwei Shi
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Wentao Yang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yanlong Jiang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Xin Cao
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Jianzhong Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Haibin Huang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Yan Zeng
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Nan Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China.
| | - Guilian Yang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China.
| | - Chunfeng Wang
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, China; Jilin Provincial Engineering Research Center of Animal Probiotics, Jilin Provincial Key Laboratory of Animal Microecology and Healthy Breeding, Jilin Agricultural University, Changchun, China; Engineering Research Center of Microecological Vaccines (Drugs) for Major Animal Diseases, Ministry of Education, Jilin Agricultural University, Changchun, China.
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Kang YM, Kim YJ, Kim K. Significance of traditional herbal medicine for dyslipidemia. Am J Transl Res 2023; 15:5373-5388. [PMID: 37692941 PMCID: PMC10492084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/13/2023] [Indexed: 09/12/2023]
Abstract
Dyslipidemia is a multifactorial disorder that is a causative factor and risk factor for cardiovascular disease. The incidence of dyslipidemia is expected to increase because of the presence of comorbidities. Although several lipid-lowering drugs have been developed and approved, they are not completely effective and are associated with side effects. Traditional herbal medicine (THM) represents an alternative and complementary approach for managing dyslipidemia because of its low toxicity and beneficial effects, such as anti-inflammatory and antioxidant effects. This review focuses on our current understanding of the antidyslipidemic effect of THMs and discusses the associated regulatory mechanisms. The current findings indicate that THM may lead to the development of novel therapeutic regimens for dyslipidemia.
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Affiliation(s)
- Yun-Mi Kang
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM)Daegu 41062, Republic of Korea
| | - Yeon-Ji Kim
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM)Daegu 41062, Republic of Korea
| | - Kyungho Kim
- Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM)Daegu 41062, Republic of Korea
- Korean Convergence Medical Science Major, KIOM School, University of Science and Technology (UST)Daejeon 34054, Republic of Korea
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22
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Niño-Narvión J, Rojo-López MI, Martinez-Santos P, Rossell J, Ruiz-Alcaraz AJ, Alonso N, Ramos-Molina B, Mauricio D, Julve J. NAD+ Precursors and Intestinal Inflammation: Therapeutic Insights Involving Gut Microbiota. Nutrients 2023; 15:2992. [PMID: 37447318 DOI: 10.3390/nu15132992] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/26/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
The oxidized form of nicotinamide adenine dinucleotide (NAD+) is a critical metabolite for living cells. NAD+ may act either as a cofactor for many cellular reactions as well as a coenzyme for different NAD+-consuming enzymes involved in the physiological homeostasis of different organs and systems. In mammals, NAD+ is synthesized from either tryptophan or other vitamin B3 intermediates that act as NAD+ precursors. Recent research suggests that NAD+ precursors play a crucial role in maintaining the integrity of the gut barrier. Indeed, its deficiency has been associated with enhanced gut inflammation and leakage, and dysbiosis. Conversely, NAD+-increasing therapies may confer protection against intestinal inflammation in experimental conditions and human patients, with accumulating evidence indicating that such favorable effects could be, at least in part, mediated by concomitant changes in the composition of intestinal microbiota. However, the mechanisms by which NAD+-based treatments affect the microbiota are still poorly understood. In this context, we have focused specifically on the impact of NAD+ deficiency on intestinal inflammation and dysbiosis in animal and human models. We have further explored the relationship between NAD+ and improved host intestinal metabolism and immunity and the composition of microbiota in vivo. Overall, this comprehensive review aims to provide a new perspective on the effect of NAD+-increasing strategies on host intestinal physiology.
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Affiliation(s)
- Julia Niño-Narvión
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- Grupo de Obesidad y Metabolismo, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain
- Departamento de Bioquímica y Biología Molecular B e Inmunología, Facultad de Medicina, Universidad de Murcia (UMU), 30120 Murcia, Spain
| | | | | | - Joana Rossell
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 08041 Barcelona, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
| | - Antonio J Ruiz-Alcaraz
- Departamento de Bioquímica y Biología Molecular B e Inmunología, Facultad de Medicina, Universidad de Murcia (UMU), 30120 Murcia, Spain
| | - Núria Alonso
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias I Pujol, 08916 Badalona, Spain
| | - Bruno Ramos-Molina
- Grupo de Obesidad y Metabolismo, Instituto Murciano de Investigación Biosanitaria (IMIB), 30120 Murcia, Spain
| | - Didac Mauricio
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 08041 Barcelona, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
- Faculty of Medicine, University of Vic/Central University of Catalonia (UVIC/UCC), 08500 Vic, Spain
| | - Josep Julve
- Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 08041 Barcelona, Spain
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23
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Pedro MP, Lund K, Kang SWS, Chen T, Stuelten CH, Porat-Shliom N, Iglesias-Bartolome R. A GPCR screening in human keratinocytes identifies that the metabolite receptor HCAR3 controls epithelial proliferation, migration, and cellular respiration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.30.542853. [PMID: 37398171 PMCID: PMC10312554 DOI: 10.1101/2023.05.30.542853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Epithelial cells in the skin and other tissues rely on signals from their environment to maintain homeostasis and respond to injury, and G protein-coupled receptors (GPCRs) play a critical role in this communication. A better understanding of the GPCRs expressed in epithelial cells will contribute to understanding the relationship between cells and their niche and could lead to developing new therapies to modulate cell fate. This study used human primary keratinocytes as a model to investigate the specific GPCRs regulating epithelial cell proliferation and differentiation. We identified three key receptors, hydroxycarboxylic acid-receptor 3 (HCAR3), leukotriene B4-receptor 1 (LTB4R), and G Protein-Coupled Receptor 137 (GPR137) and found that knockdown of these receptors led to changes in numerous gene networks that are important for maintaining cell identity and promoting proliferation while inhibiting differentiation. Our study also revealed that the metabolite receptor HCAR3 regulates keratinocyte migration and cellular metabolism. Knockdown of HCAR3 led to reduced keratinocyte migration and respiration, which could be attributed to altered metabolite use and aberrant mitochondrial morphology caused by the absence of the receptor. This study contributes to understanding the complex interplay between GPCR signaling and epithelial cell fate decisions.
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Affiliation(s)
- M. Pilar Pedro
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Katherine Lund
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Sun Woo Sophie Kang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Ting Chen
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Christina H. Stuelten
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Natalie Porat-Shliom
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Ramiro Iglesias-Bartolome
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
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Abstract
The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.
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Affiliation(s)
- Timothy R. Matsuura
- Cardiovascular Institute and Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Patrycja Puchalska
- Department of Medicine, Division of Molecular Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Peter A. Crawford
- Department of Medicine, Division of Molecular Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Daniel P. Kelly
- Cardiovascular Institute and Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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25
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Chen J, Lin T, Zhang S, Yue X, Liu X, Wu C, Liang Y, Zeng X, Ren M, Chen F, Guan W, Zhang S. Niacin/β-hydroxybutyrate regulates milk fat and milk protein synthesis via the GPR109A/G i/mTORC1 pathway. Food Funct 2023; 14:2642-2656. [PMID: 36866679 DOI: 10.1039/d3fo00127j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
As a crucial receptor of BHBA and niacin, GPR109A is largely expressed in the mammary gland. However, the role of GPR109A in milk synthesis and its underlying mechanism is still largely unknown. In this study, we first investigated the effect of GPR109A agonists (niacin/BHBA) on milk fat and milk protein synthesis in a mouse mammary epithelial cell line (HC11) and PMECs (porcine mammary epithelial cells). The results showed that both niacin and BHBA promote milk fat and milk protein synthesis with the activation of mTORC1 signaling. Importantly, knockdown GPR109A attenuated the niacin-induced increase of milk fat and protein synthesis and the niacin-induced activation of mTORC1 signaling. Furthermore, we found that GPR109A downstream G protein-Gαi and -Gβγ participated in the regulation of milk synthesis and the activation of mTORC1 signaling. Consistent with the finding in vitro, dietary supplementation with niacin increases milk fat and protein synthesis in mice with the activation of GPR109A-mTORC1 signaling. Collectively, GPR109A agonists promote the synthesis of milk fat and milk protein through the GPR109A/Gi/mTORC1 signaling pathway.
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Affiliation(s)
- Jiaming Chen
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - Tongbin Lin
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - Shuchang Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - Xianhuai Yue
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - XingHong Liu
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - Caichi Wu
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - Yunyi Liang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture and Rural Affairs Feed Industry Center, China Agricultural University, Beijing, China
| | - Man Ren
- College of Animal Science, Anhui Science and Technology University, Anhui Provincial Key Laboratory of Animal Nutritional Regulation and Health, Fengyang, China
| | - Fang Chen
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Wutai Guan
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| | - Shihai Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
- College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China
- Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
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26
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Song D, Wang X, Ma Y, Liu NN, Wang H. Beneficial insights into postbiotics against colorectal cancer. Front Nutr 2023; 10:1111872. [PMID: 36969804 PMCID: PMC10036377 DOI: 10.3389/fnut.2023.1111872] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 02/21/2023] [Indexed: 03/12/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and life-threatening cancer types with limited therapeutic options worldwide. Gut microbiota has been recognized as the pivotal determinant in maintaining gastrointestinal (GI) tract homeostasis, while dysbiosis of gut microbiota contributes to CRC development. Recently, the beneficial role of postbiotics, a new concept in describing microorganism derived substances, in CRC has been uncovered by various studies. However, a comprehensive characterization of the molecular identity, mechanism of action, or routes of administration of postbiotics, particularly their role in CRC, is still lacking. In this review, we outline the current state of research toward the beneficial effects of gut microbiota derived postbiotics against CRC, which will represent the key elements of future precision-medicine approaches in the development of novel therapeutic strategies targeting gut microbiota to improve treatment outcomes in CRC.
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Affiliation(s)
| | | | | | - Ning-Ning Liu
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Wang
- State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Ney LM, Wipplinger M, Grossmann M, Engert N, Wegner VD, Mosig AS. Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections. Open Biol 2023; 13:230014. [PMID: 36977462 PMCID: PMC10049789 DOI: 10.1098/rsob.230014] [Citation(s) in RCA: 62] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
Abstract
The human intestinal microbiome substantially affects human health and resistance to infections in its dynamic composition and varying release of microbial-derived metabolites. Short-chain fatty acids (SCFA) produced by commensal bacteria through fermentation of indigestible fibres are considered key regulators in orchestrating the host immune response to microbial colonization by regulating phagocytosis, chemokine and central signalling pathways of cell growth and apoptosis, thereby shaping the composition and functionality of the intestinal epithelial barrier. Although research of the last decades provided valuable insight into the pleiotropic functions of SCFAs and their capability to maintain human health, mechanistic details on how SCFAs act across different cell types and other organs are not fully understood. In this review, we provide an overview of the various functions of SCFAs in regulating cellular metabolism, emphasizing the orchestration of the immune response along the gut-brain, the gut-lung and the gut-liver axes. We discuss their potential pharmacological use in inflammatory diseases and infections and highlight new options of relevant human three-dimensional organ models to investigate and validate their biological functions in more detail.
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Affiliation(s)
- Lisa-Marie Ney
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Maximilian Wipplinger
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Martha Grossmann
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Nicole Engert
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Valentin D Wegner
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
| | - Alexander S Mosig
- Institute of Biochemistry II, Jena University Hospital, Kastanienallee 1, 07747 Jena, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
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Yuan B, Liu M, Luo S, Qu Q, Zhu M, Wang Z, Zhang X, Xie G, Li B, Wang W. ETEC regulates GPR109A expression in intestinal epithelial cells mediated by inflammatory factors secreted by macrophages. Res Vet Sci 2023; 154:15-21. [PMID: 36403332 DOI: 10.1016/j.rvsc.2022.11.005] [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: 07/21/2022] [Revised: 11/08/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022]
Abstract
Gut microbes control host immunity and homeostasis, and their abnormal changes are associated with the occurrence and development of diseases. GPR109A is an essential receptor on intestinal epithelial cells and interacts with gut microbes. Moreover, increased Enterotoxigenic Escherichia coli K88 strain colonization promotes GPR109A expression in vivo. This study evaluated the detailed mechanism of pathogenic bacteria promoting GPR109A expression. The results revealed that ETEC K88 indirectly fosters GPR109A expression in intestinal epithelial cells by stimulating the production of IL-1β and TNF-α through macrophages which are mediated by ERK1/2 pathway. The study explains the molecular mechanisms by which the bacteria regulate the homeostasis of the host intestinal gene expression during ETEC infection.
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Affiliation(s)
- Boyu Yuan
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mingming Liu
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Siyuan Luo
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Qing Qu
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Mingqiang Zhu
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Zifan Wang
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Xue Zhang
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Gaijie Xie
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China
| | - Bai Li
- First clinical hospital of Jilin University, Changchun 130021, China.
| | - Wei Wang
- Innovative Institute of Animal Healthy Breeding, College of Animal Science & Technology, Zhongkai University of Agriculture and Engineering, Guangzhou 510225, China.
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29
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Helman T, Braidy N. Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders. Drugs Aging 2023; 40:33-48. [PMID: 36510042 DOI: 10.1007/s40266-022-00989-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2022] [Indexed: 12/14/2022]
Abstract
The role of nicotinamide adenine dinucleotide (NAD+) in ageing has emerged as a critical factor in understanding links to a wide range of chronic diseases. Depletion of NAD+, a central redox cofactor and substrate of numerous metabolic enzymes, has been detected in many major age-related diseases. However, the mechanisms behind age-associated NAD+ decline remains poorly understood. Despite limited conclusive evidence, supplements aimed at increasing NAD+ levels are becoming increasingly popular. This review provides renewed insights regarding the clinical utility and benefits of NAD+ precursors, namely nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline and phenotypic characterization of age-related disorders, including metabolic, cardiovascular and neurodegenerative diseases. While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD+, whether friend or foe in ageing, should be considered.
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Affiliation(s)
- Tessa Helman
- Centre for Healthy Brain Ageing, School of Psychiatry, NPI, Euroa Centre, Prince of Wales Hospital, University of New South Wales, Barker Street, Randwick, Sydney, NSW, 2031, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, NPI, Euroa Centre, Prince of Wales Hospital, University of New South Wales, Barker Street, Randwick, Sydney, NSW, 2031, Australia.
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30
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Zhang Z, Li J, Zhang M, Li B, Pan X, Dong X, Pan LL, Sun J. GPR109a Regulates Phenotypic and Functional Alterations in Macrophages and the Progression of Type 1 Diabetes. Mol Nutr Food Res 2022; 66:e2200300. [PMID: 36208084 DOI: 10.1002/mnfr.202200300] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 08/27/2022] [Indexed: 01/18/2023]
Abstract
SCOPE Dietary fibers can alter gut microbiota and microbial metabolite profiles. SCFAs are produced by bacterial fermentation of fiber, mediating immune homeostasis through G-protein-coupled receptors (GPCRs). GPR109a, a receptor for niacin and butyrate, expressed by immune cells and non-immune cells, is a key factor regulating immune responses. However, the role and underlying mechanisms of GPR109a in type 1 diabetes (T1D) remain unclear. METHODS AND RESULTS Experimental T1D was induced by streptozotocin in GPR109a-deficient (Gpr109a-/- ) and wild type mice. The study found that Gpr109a-/- mice were more susceptible to T1D with dysregulated immune responses, along with increased M1 macrophage polarization (from 10.55% to 21.48%). Further, an adoptive transfer experiment demonstrated that GPR109a-deficient macrophages promoted the homing of intestine-derived type 1 cytotoxic T cells to pancreas (from 18.91% to 24.24%), thus disturbing the pancreatic immune homeostasis in non-obese diabetic mice. Mechanistically, GPR109a deficiency promoted M1 macrophage polarization associated with the activation of suppressor of cytokine signaling 3-signal transducer and activator of transcription 1 signaling pathway. CONCLUSION The findings reveal that macrophage GPR109a deficiency accelerates the development of T1D. Activation of GPR109a on macrophage by dietary components may provide a new strategy for preventing or treating T1D.
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Affiliation(s)
- Zhaodi Zhang
- Key Laboratory of Food Science and Technology, Department of Food Science and Engineering, Jiangnan University, Wuxi, 214122, China.,School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Jiahong Li
- Key Laboratory of Food Science and Technology, Department of Food Science and Engineering, Jiangnan University, Wuxi, 214122, China.,School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Ming Zhang
- Key Laboratory of Food Science and Technology, Department of Food Science and Engineering, Jiangnan University, Wuxi, 214122, China.,School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Binbin Li
- Key Laboratory of Food Science and Technology, Department of Food Science and Engineering, Jiangnan University, Wuxi, 214122, China.,School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - XiaoHua Pan
- Key Laboratory of Food Science and Technology, Department of Food Science and Engineering, Jiangnan University, Wuxi, 214122, China.,School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Xiaoliang Dong
- Key Laboratory of Food Science and Technology, Department of Food Science and Engineering, Jiangnan University, Wuxi, 214122, China.,School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Li-Long Pan
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Jia Sun
- Key Laboratory of Food Science and Technology, Department of Food Science and Engineering, Jiangnan University, Wuxi, 214122, China.,School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
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31
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Exploring GPR109A Receptor Interaction with Hippuric Acid Using MD Simulations and CD Spectroscopy. Int J Mol Sci 2022; 23:ijms232314778. [PMID: 36499106 PMCID: PMC9741133 DOI: 10.3390/ijms232314778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/17/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Previous research has indicated that various metabolites belonging to phenolic acids (PAs), produced by gut microflora through the breakdown of polyphenols, help in promoting bone development and protecting bone from degeneration. Results have also suggested that G-protein-coupled receptor 109A (GPR109A) functions as a receptor for those specific PAs such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA). Indeed, HA has a molecular structural similarity with nicotinic acid (niacin) which has been shown previously to bind to GPR109A receptor and to mediate antilipolytic effects; however, the binding pocket and the structural nature of the interaction remain to be recognized. In the present study, we employed a computational strategy to elucidate the molecular structural determinants of HA binding to GPR109A and GPR109B homology models in understanding the regulation of osteoclastogenesis. Based on the docking and molecular dynamics simulation studies, HA binds to GPR109A similarly to niacin. Specifically, the transmembrane helices 3, 4 and 6 (TMH3, TMH4 and TMH6) and Extracellular loop 1 and 2 (ECL1 and ECL2) residues of GRP109A; R111 (TMH3), K166 (TMH4), ECL2 residues; S178 and S179, and R251 (TMH6), and residues of GPR109B; Y87, Y86, S91 (ECL1) and C177 (ECL2) contribute for HA binding. Simulations and Molecular Mechanics Poisson-Boltzmann solvent accessible area (MM-PBSA) calculations reveal that HA has higher affinity for GPR109A than for GPR109B. Additionally, in silico mutation analysis of key residues have disrupted the binding and HA exited out from the GPR109A protein. Furthermore, measurements of time-resolved circular dichroism spectra revealed that there are no major conformational changes in the protein secondary structure on HA binding. Taken together, our findings suggest a mechanism of interaction of HA with both GPR109A and GPR109B receptors.
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32
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Wang Z, Yi Z, Wang Q, Yin L, Li J, Xie J, Yang H, Yin Y. Effect of Different Levels of Niacin on Serum Biochemical Parameters, Antioxidant Status, Cytokine Levels, Inflammatory Gene Expression and Colonic Microbial Composition in Weaned Piglets. Animals (Basel) 2022; 12:ani12213018. [PMID: 36359142 PMCID: PMC9695451 DOI: 10.3390/ani12213018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/26/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Niacin plays an important role in regulating the gut health of weaned piglets. In this study, 48 25-day-old weaned piglets (7.9 ± 0.20 kg) produced by 14 sows (3 to 4 piglets per sow) were randomly divided into 4 groups with 6 replicates in each group and 2 piglets in each replicate. Each group was fed diets supplemented with 22.5 (N1), 30 (N2), 45 (N3), and 75 (N4) mg/kg of niacin, respectively. Samples were taken at 7 and 14 d, respectively. The study shows that changes in niacin levels significantly affected the content of IgG and IgM in the serum (p < 0.05). Niacin had a significant effect on antioxidant parameters such as MDA, T-SOD, and CuZn-SOD in the jejunal mucosa of weaned piglets (p < 0.05). Moreover, significant differences were observed in the expression of cytokines such as TGF-β, TNF-α, and COX2 in the jejunal mucosa (p < 0.05). The 16S rRNA sequencing analysis showed that there were significant differences in the colonic species composition, which were also accompanied by changes in the isovaleric acid content (p < 0.05). In conclusion, an appropriate increase in niacin dose based on NRC (2012) has an important role in improving the antioxidant status of weaned piglets, alleviating intestinal inflammation in piglets, improving immunity, and regulating the structure of the microbiota.
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Affiliation(s)
- Zhaobin Wang
- National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Zhenfeng Yi
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Qiye Wang
- National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Lanmei Yin
- National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Jun Li
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Fujian Aonong Biotechnology Group Co., Ltd., Xiamen 361008, China
| | - Junyan Xie
- National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
| | - Huansheng Yang
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- Correspondence: (H.Y.); (Y.Y.)
| | - Yulong Yin
- National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China
- Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
- Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- Correspondence: (H.Y.); (Y.Y.)
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Bioactive components of Laetiporus species and their pharmacological effects. Appl Microbiol Biotechnol 2022; 106:5929-5944. [PMID: 36063176 DOI: 10.1007/s00253-022-12149-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/02/2022]
Abstract
Laetiporus species are brown rot fungi belonging to the order Polyporales in the division Basidiomycota. These species produce a variety of metabolites and provide a great source of natural material for the screening of medicinally active natural products or their derivatives. This review summarizes the research progress on bioactive metabolites of Laetiporus species up to April 2022, including biological macromolecules, for instance, polysaccharides and lectins, as well as 80 reported small molecule chemical components (15 sterols, 29 triterpenes, 10 sesquiterpenes, 5 polyenes, 10 volatile compounds, and 11 other compounds). These metabolites exhibit antimicrobial, anticancer, antioxidant, hepatoprotective, anti-inflammatory, and antidiabetic activities. Genome mining predicted 23 terpene synthases, 7 polyketide synthases, and 9 non-ribosomal peptide synthases involved in bioactive metabolites biosynthesis, which were analyzed by antiSMASH in L. sulphureus genome. This review will provide a basis for the biosynthesis of active components in Laetiporus species and a reference for the research of medical precursors. KEY POINTS: • The mini-review summarized 80 secondary metabolites of Laetiporus spp. • The main pharmacological activities of Laetiporus spp. were summarized. • Biosynthetic genes of terpenoids, polyketides, and non-ribosomal peptides were also summarized.
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Chen JR, Lazarenko OP, Blackburn ML. GPR109A gene deletion ameliorates gonadectomy-induced bone loss in mice. Bone 2022; 161:116422. [PMID: 35489706 DOI: 10.1016/j.bone.2022.116422] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 11/30/2022]
Abstract
Sex steroid deficiency plays critical roles in the pathophysiology of bone as the result of uncertain bone remodeling, i.e., increased bone resorption with equivocal bone formation. We have previously shown that GPR109A, a G protein coupled receptor, controls osteoclastogenesis and bone resorption, where global GPR109A deletion decreased osteoclast bone resorption and increased bone mass. Here, we used global GPR109A gene deletion, ovariectomized (OVX) and orchidectomized (ORX) mouse models to probe the role of GPR109A in gonadectomy-induced bone loss in female and male mice. Six months old GPR109A-/- mice and their wild type littermates were allocated to Sham or gonadectomized groups for six weeks. Using densitometric micro-CT confirmed by peripheral quantitative CT (pQCT) scans on tibia and spine, and three-point bending test on femur ex vivo, we found the bone volume, trabecular number, as well as bone mineral density and content in both trabecular and cortical sites were significantly decreased in wild type OVX and ORX compared with respective Sham groups. While bone mass in both male and female GPR109A-/- Sham groups were significantly higher compared with their respective wild type Sham groups, global GPR109A gene deletion ameliorated gonadectomy-induced bone loss. In GPR109A-/- females, most of bone mass and strength parameters measured by micro-CT, pQCT and three-point bending test were not different between Sham and OVX groups. In wild type but not in GPR109-/- mice, bone remodeling marker measurements indicated that both bone resorption (Cathepsin K) and bone formation (osteocalcin) markers were increased in gonadectomized mice compared to sham, with the exception of bone specific ALP, which was decreased in gonadectomized mice. Expression of bone resorption markers (Cathepsin K) were significantly lower, but β-catenin expression was higher in GPR109A-/- mice compared with their wild type littermates. Collectively, these data indicate that global GPR109A deletion ameliorates gonadectomy-induced bone loss through suppression of bone resorption.
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Affiliation(s)
- Jin-Ran Chen
- Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
| | - Oxana P Lazarenko
- Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
| | - Michael L Blackburn
- Arkansas Children's Nutrition Center, Little Rock, AR 72202, USA; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
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Hughey CC, Puchalska P, Crawford PA. Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159209. [DOI: 10.1016/j.bbalip.2022.159209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/25/2022] [Accepted: 07/27/2022] [Indexed: 11/28/2022]
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Thangaleela S, Sivamaruthi BS, Kesika P, Bharathi M, Chaiyasut C. Role of the Gut-Brain Axis, Gut Microbial Composition, Diet, and Probiotic Intervention in Parkinson's Disease. Microorganisms 2022; 10:1544. [PMID: 36013962 PMCID: PMC9412530 DOI: 10.3390/microorganisms10081544] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/18/2022] [Accepted: 07/26/2022] [Indexed: 02/07/2023] Open
Abstract
Parkinson's disease (PD) is the second-most prevalent neurodegenerative or neuropsychiatric disease, affecting 1% of seniors worldwide. The gut microbiota (GM) is one of the key access controls for most diseases and disorders. Disturbance in the GM creates an imbalance in the function and circulation of metabolites, resulting in unhealthy conditions. Any dysbiosis could affect the function of the gut, consequently disturbing the equilibrium in the intestine, and provoking pro-inflammatory conditions in the gut lumen, which send signals to the central nervous system (CNS) through the vagus enteric nervous system, possibly disturbing the blood-brain barrier. The neuroinflammatory conditions in the brain cause accumulation of α-syn, and progressively develop PD. An important aspect of understanding and treating the disease is access to broad knowledge about the influence of dietary supplements on GM. Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. Probiotic supplementation improves the function of the CNS, and improves the motor and non-motor symptoms of PD. Probiotic supplementation could be an adjuvant therapeutic method to manage PD. This review summarizes the role of GM in health, the GM-brain axis, the pathogenesis of PD, the role of GM and diet in PD, and the influence of probiotic supplementation on PD. The study encourages further detailed clinical trials in PD patients with probiotics, which aids in determining the involvement of GM, intestinal mediators, and neurological mediators in the treatment or management of PD.
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Affiliation(s)
- Subramanian Thangaleela
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand; (S.T.); (P.K.); (M.B.)
| | | | - Periyanaina Kesika
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand; (S.T.); (P.K.); (M.B.)
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Muruganantham Bharathi
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand; (S.T.); (P.K.); (M.B.)
| | - Chaiyavat Chaiyasut
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand; (S.T.); (P.K.); (M.B.)
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Johnson WT, Dorn NC, Ogbonna DA, Bottini N, Shah NJ. Lipid-based regulators of immunity. Bioeng Transl Med 2022; 7:e10288. [PMID: 35600637 PMCID: PMC9115682 DOI: 10.1002/btm2.10288] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/29/2021] [Accepted: 12/14/2021] [Indexed: 11/22/2022] Open
Abstract
Lipids constitute a diverse class of molecular regulators with ubiquitous physiological roles in sustaining life. These carbon-rich compounds are primarily sourced from exogenous sources and may be used directly as structural cellular building blocks or as a substrate for generating signaling mediators to regulate cell behavior. In both of these roles, lipids play a key role in both immune activation and suppression, leading to inflammation and resolution, respectively. The simple yet elegant structural properties of lipids encompassing size, hydrophobicity, and molecular weight enable unique biodistribution profiles that facilitate preferential accumulation in target tissues to modulate relevant immune cell subsets. Thus, the structural and functional properties of lipids can be leveraged to generate new materials as pharmacological agents for potently modulating the immune system. Here, we discuss the properties of three classes of lipids: polyunsaturated fatty acids, short-chain fatty acids, and lipid adjuvants. We describe their immunoregulatory functions in modulating disease pathogenesis in preclinical models and in human clinical trials. We conclude with an outlook on harnessing the diverse and potent immune modulating properties of lipids for immunoregulation.
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Affiliation(s)
- Wade T. Johnson
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Nicholas C. Dorn
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
- Chemical Engineering ProgramUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Dora A. Ogbonna
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
- Chemical Engineering ProgramUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Nunzio Bottini
- Division of Rheumatology, Allergy and Immunology, Department of MedicineUniversity of California, San DiegoLa JollaCaliforniaUSA
- Program in ImmunologyUniversity of California, San DiegoLa JollaCaliforniaUSA
| | - Nisarg J. Shah
- Department of NanoengineeringUniversity of California, San DiegoLa JollaCaliforniaUSA
- Chemical Engineering ProgramUniversity of California, San DiegoLa JollaCaliforniaUSA
- Program in ImmunologyUniversity of California, San DiegoLa JollaCaliforniaUSA
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38
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Docampo MD, da Silva MB, Lazrak A, Nichols KB, Lieberman SR, Slingerland AE, Armijo GK, Shono Y, Nguyen C, Monette S, Dwomoh E, Lee N, Geary CD, Perobelli SM, Smith M, Markey KA, Vardhana SA, Kousa AI, Zamir E, Greenfield I, Sun JC, Cross JR, Peled JU, Jenq RR, Stein-Thoeringer CK, van den Brink MRM. Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease. Blood 2022; 139:2392-2405. [PMID: 34653248 PMCID: PMC9012131 DOI: 10.1182/blood.2021010719] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 08/31/2021] [Indexed: 01/17/2023] Open
Abstract
The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.
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Affiliation(s)
- Melissa D Docampo
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | | | - Amina Lazrak
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | | | | | | | - Gabriel K Armijo
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | - Yusuke Shono
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | - Chi Nguyen
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | | | - Emmanuel Dwomoh
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | - Nicole Lee
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | - Clair D Geary
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | | | - Melody Smith
- Department of Immunology, Sloan Kettering Institute, New York, NY
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Kate A Markey
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | - Eli Zamir
- German Cancer Research Center (DKFZ), Research Division Microbiome and Cancer, Heidelberg, Germany; and
| | | | - Joseph C Sun
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | - Justin R Cross
- Department of Immunology, Sloan Kettering Institute, New York, NY
| | - Jonathan U Peled
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Robert R Jenq
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Marcel R M van den Brink
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY
- Department of Immunology, Sloan Kettering Institute, New York, NY
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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39
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Thiam M, Wang Q, Barreto Sánchez AL, Zhang J, Ding J, Wang H, Zhang Q, Zhang N, Wang J, Li Q, Wen J, Zhao G. Heterophil/Lymphocyte Ratio Level Modulates Salmonella Resistance, Cecal Microbiota Composition and Functional Capacity in Infected Chicken. Front Immunol 2022; 13:816689. [PMID: 35493492 PMCID: PMC9047862 DOI: 10.3389/fimmu.2022.816689] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/15/2022] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal microbiota plays a vital role in ensuring the maintenance of host health through interactions with the immune system. The Heterophil/Lymphocyte (H/L) ratio reflects poultry’s robustness and immune system status. Chickens with low H/L ratio are superior to the chickens with high H/L ratio in survival, immune response, and resistance to Salmonella infection, but the underlying mechanisms remain unclear. This study aimed to identify microorganisms associated with resistance to Salmonella Enteritidis infection in chickens based on the H/L ratio. The 16S rRNA and metagenomic analysis were conducted to examine microbiome and functional capacity between the 2 groups, and Short Chain Fatty Acids (SCFAs) and histopathology were conducted to explore the potential difference between susceptible and resistant groups at 7 and 21 days post-infection (dpi). The microbiome exploration revealed that low H/L ratio chickens, compared to high H/L ratio chickens, displayed a significantly higher abundance of Proteobacteria (Escherichia coli) and Bacteroidetes (Bacteroides plebeius) at 7 and 21 dpi, respectively. Anaerostipes (r = 0.63) and Lachnoclostridium (r = 0.63) were identified as bacterial genus significantly correlated with H/L (P < 0.001). Interestingly, Bacteroides was significantly and positively correlated with bodyweight post-infection (r = 0.72), propionate (r = 0.78) and valerate (r = 0.82) contents, while Salmonella was significantly and negatively correlated with bodyweight post-infection (r = − 0.67), propionate (r = − 0.61) and valerate (r = − 0.65) contents (P < 0.001). Furthermore, the comparative analysis of the functional capacity of cecal microbiota of the chickens with high and low H/L ratio revealed that the chickens with low H/L ratio possess more enriched immune pathways, lower antibiotic resistance genes and virulence factors compared to the chickens with high H/L ratio. These results suggest that the chickens with low H/L ratio are more resistant to Salmonella Enteritidis, and it is possible that the commensal Proteobacteria and Bacteroidetes are involved in this resistance against Salmonella infection. These findings provide valuable resources for selecting and breeding disease-resistant chickens.
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40
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Yang S, Zhang F, Li Q, Li Q. Niacin promotes the efflux of lysosomal cholesterol from macrophages via the CD38/NAADP signaling pathway. Exp Biol Med (Maywood) 2022; 247:1047-1054. [PMID: 35369785 DOI: 10.1177/15353702221084632] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The accumulation of free cholesterol in macrophage lysosomes significantly enhances atherogenesis. Our recent study demonstrated that the cluster of differentiation 38 (CD38)/nicotinic acid adenine dinucleotide phosphate (NAADP)/Ca2+ signaling pathway plays a critical role in the efflux of lysosomal free cholesterol from macrophages in atherosclerosis. Niacin, known as nicotinic acid, is one of the oldest lipid-lowering medications showing unique anti-atherosclerotic activity. However, it is unknown whether this anti-atherosclerosis activity is associated with the efflux of lysosomal compartmentalized cholesterol in macrophages. In this study, we investigated the anti-atherosclerotic effects of niacin on the reduction of lysosomal free cholesterol via CD38/NAADP signaling in macrophages derived from low-density lipoprotein receptor (LDLr−/−) mice. Fluorescent filipin and Nile red labeling coupled with confocal microscopy demonstrated that niacin reduced free cholesterol accumulation in lysosomes in a concentration-dependent manner. Transmission electron microscopy also showed that niacin markedly decreased cholesterol crystal formation in lysosomes in oxidized LDL-containing LDLr−/− bone marrow–derived macrophages. Enzyme-linked immunosorbent assays showed that niacin increased NAADP production in a concentration-dependent manner, which was inhibited by small interfering RNA interference of CD38. Therefore, niacin may promote the efflux of lysosomal cholesterol from macrophages via the CD38/NAADP signaling pathway.
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Affiliation(s)
- Shenghua Yang
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Fan Zhang
- Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23284-2512, USA
| | - Quanwen Li
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Quanzhong Li
- Department of Cardiology, Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China
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41
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Kong D, Yu Y. Prostaglandin D2 signaling and cardiovascular homeostasis. J Mol Cell Cardiol 2022; 167:97-105. [DOI: 10.1016/j.yjmcc.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 02/25/2022] [Accepted: 03/28/2022] [Indexed: 10/18/2022]
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42
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Moutinho M, Puntambekar SS, Tsai AP, Coronel I, Lin PB, Casali BT, Martinez P, Oblak AL, Lasagna-Reeves CA, Lamb BT, Landreth GE. The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer's disease. Sci Transl Med 2022; 14:eabl7634. [PMID: 35320002 PMCID: PMC10161396 DOI: 10.1126/scitranslmed.abl7634] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Increased dietary intake of niacin has been correlated with reduced risk of Alzheimer's disease (AD). Niacin serves as a high-affinity ligand for the receptor HCAR2 (GPR109A). In the brain, HCAR2 is expressed selectively by microglia and is robustly induced by amyloid pathology in AD. The genetic inactivation of Hcar2 in 5xFAD mice, a model of AD, results in impairment of the microglial response to amyloid deposition, including deficits in gene expression, proliferation, envelopment of amyloid plaques, and uptake of amyloid-β (Aβ), ultimately leading to exacerbation of amyloid burden, neuronal loss, and cognitive deficits. In contrast, activation of HCAR2 with an FDA-approved formulation of niacin (Niaspan) in 5xFAD mice leads to reduced plaque burden and neuronal dystrophy, attenuation of neuronal loss, and rescue of working memory deficits. These data provide direct evidence that HCAR2 is required for an efficient and neuroprotective response of microglia to amyloid pathology. Administration of Niaspan potentiates the HCAR2-mediated microglial protective response and consequently attenuates amyloid-induced pathology, suggesting that its use may be a promising therapeutic approach to AD that specifically targets the neuroimmune response.
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Affiliation(s)
- Miguel Moutinho
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Shweta S Puntambekar
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Andy P Tsai
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Israel Coronel
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Peter B Lin
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Brad T Casali
- Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Pablo Martinez
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Adrian L Oblak
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Cristian A Lasagna-Reeves
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Bruce T Lamb
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Gary E Landreth
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.,Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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43
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Sun X, Wang D, Wei L, Ding L, Guo Y, Wang Z, Kong Y, Yang J, Sun L, Sun L. Gut Microbiota and SCFAs Play Key Roles in QingFei Yin Recipe Anti- Streptococcal Pneumonia Effects. Front Cell Infect Microbiol 2021; 11:791466. [PMID: 34950611 PMCID: PMC8688933 DOI: 10.3389/fcimb.2021.791466] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/12/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging evidence has revealed the presence in animals of a bidirectional regulatory “lung-gut axis” that provides resistance to respiratory infections. Clues to the existence of this system stem from observations that respiratory infections are often accompanied by gastrointestinal symptoms, whereby intestinal microbiota appear to play pivotal roles in combating pathogenic infections. Importantly, short-chain fatty acids (SCFAs) produced by the gut microbiota appear to serve as the biological link between host immune defenses and gut flora. Streptococcus pneumoniae (S.pn), the main cause of lower respiratory tract infections, is involved in more than 1.189 million deaths per year. QingFei Yin (QFY) is known for its excellent therapeutic efficacy in combating bacterial lung infections. In this study, effects of S.pn infection on gut homeostasis were assessed using 16S RNA-based microbiota community profiling analysis. In addition, potential mechanisms underlying QFY recipe beneficial therapeutic effects against bacterial pneumonia were explored using S.pn-infected gut microbiota-depleted mice. Results of data analysis indicated that QFY treatment alleviated lung infection-associated pathogenic processes, while also promoting repair of disordered gut flora and counteracting S.pn infection-associated decreases in levels of SCFAs, particularly of acetate and butyrate. Mechanistically, QFY treatment suppressed inflammatory lung injury through inhibition of the host NF-κB-NLRP3 pathway. These results inspired us to identify precise QFY targets and mechanisms underlying QFY anti-inflammatory effects. In addition, we conducted an in-depth evaluation of QFY as a potential treatment for bacterial pneumonia.
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Affiliation(s)
- Xiaozhou Sun
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Dandan Wang
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China., Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Lina Wei
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China.,Center of Children's Clinic, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Lizhong Ding
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China.,Center of Children's Clinic, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Yinan Guo
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China.,Center of Children's Clinic, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Zhongtian Wang
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yibu Kong
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China.,Center of Children's Clinic, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Jingjing Yang
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China.,Center of Children's Clinic, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Liwei Sun
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China., Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Liping Sun
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China.,Center of Children's Clinic, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
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Rotllan N, Camacho M, Tondo M, Diarte-Añazco EMG, Canyelles M, Méndez-Lara KA, Benitez S, Alonso N, Mauricio D, Escolà-Gil JC, Blanco-Vaca F, Julve J. Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases. Antioxidants (Basel) 2021; 10:1939. [PMID: 34943043 PMCID: PMC8750485 DOI: 10.3390/antiox10121939] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases.
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Affiliation(s)
- Noemi Rotllan
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
| | - Mercedes Camacho
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
- CIBER de Enfermedades Cardiovasculares, CIBERCV, 28029 Madrid, Spain
| | - Mireia Tondo
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
- Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain
| | - Elena M. G. Diarte-Añazco
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
| | - Marina Canyelles
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
| | - Karen Alejandra Méndez-Lara
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
| | - Sonia Benitez
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
| | - Núria Alonso
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, 08916 Barcelona, Spain
| | - Didac Mauricio
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain
| | - Joan Carles Escolà-Gil
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
| | - Francisco Blanco-Vaca
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
- Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain
| | - Josep Julve
- Institut de Recerca i d’Investigació Biomèdica de l’Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, 08041 Barcelona, Spain; (N.R.); (M.C.); (E.M.G.D.-A.); (M.C.); (K.A.M.-L.); (S.B.)
- Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, 28029 Madrid, Spain; (N.A.); (D.M.)
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Strassheim D, Sullivan T, Irwin DC, Gerasimovskaya E, Lahm T, Klemm DJ, Dempsey EC, Stenmark KR, Karoor V. Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases. Cells 2021; 10:3347. [PMID: 34943862 PMCID: PMC8699532 DOI: 10.3390/cells10123347] [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: 10/10/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022] Open
Abstract
G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.
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Affiliation(s)
- Derek Strassheim
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Timothy Sullivan
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - David C. Irwin
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Evgenia Gerasimovskaya
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Tim Lahm
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
| | - Dwight J. Klemm
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Edward C. Dempsey
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kurt R. Stenmark
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Vijaya Karoor
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
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Gao H, Song RJ, Jiang H, Zhang W, Han SF. Oat fiber supplementation alleviates intestinal inflammation and ameliorates intestinal mucosal barrier via acting on gut microbiota-derived metabolites in LDLR -/- mice. Nutrition 2021; 95:111558. [PMID: 34998028 DOI: 10.1016/j.nut.2021.111558] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 09/26/2021] [Accepted: 11/22/2021] [Indexed: 10/19/2022]
Abstract
OBJECTIVE Gut microbiota-derived metabolites are involved in intestinal inflammation, which can affect the development of atherosclerotic plaques. Previous studies have shown that oat fiber can delay the progression of atherosclerosis via improving lipid metabolism. The aim of this study was to evaluate how oat fiber acted on gut microbiota-derived metabolites, inhibited intestinal inflammation, and protected the intestinal mucosal barrier. METHODS Male low-density lipoprotein receptor knock-out (LDLR-/-) mice were fed a high-fat/cholesterol diet with or without oat fiber for 14 wk. Histopathology of the aorta was detected by Oil Red O staining, and the small intestine mucosal pathology was measured through hematoxylin and eosin staining. Non-targeted metabolomics of feces was performed using liquid chromatography-mass spectrometry. Western blot method was used to assess the relative levels of the proteins involved in the toll-like receptor (TLR)4 signal pathway and intestinal mucosal barrier in interest tissues. RESULTS Pathologically, oat fiber reversed the increment of the atherosclerotic lesion and ameliorated intestinal mucosal barrier in LDLR-/- mice. Oat fiber regulated the levels of gut microbiota-derived metabolites along with a decrease in isobutyrylcarnitine, valerylcarnitine, 1-methylguanosine, and 2-methylguanosine, and an increase in l-tyrosine and niacinamide. Notably, oat fiber blocked the TLR4 signal pathway and decreased the expression of nuclear factor-κB p65 in both the aorta and gut tissues. Also, oat fiber raised the expression of tight junction proteins including ZO-1 and occludin. CONCLUSION Taken together, the present study revealed that oat fiber feeding effectively attenuated the development of atherosclerosis, at least partly via affecting gut microbiota-derived metabolites, inhibiting the intestinal inflammatory response, and maintaining the integrity of the intestinal mucosal barrier.
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Affiliation(s)
- Hui Gao
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Rui-Juan Song
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Hui Jiang
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Weiguo Zhang
- Independent scientist, Irving, Texas,United States
| | - Shu-Fen Han
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Disease, School of Public Health, Soochow University, Suzhou, China.
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Gao T, Wang Z, Dong Y, Cao J, Chen Y. Melatonin-Mediated Colonic Microbiota Metabolite Butyrate Prevents Acute Sleep Deprivation-Induced Colitis in Mice. Int J Mol Sci 2021; 22:ijms222111894. [PMID: 34769321 PMCID: PMC8584377 DOI: 10.3390/ijms222111894] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/24/2021] [Accepted: 10/27/2021] [Indexed: 12/13/2022] Open
Abstract
Radical cure colitis is a severe public health threat worldwide. Our previous studies have confirmed that melatonin can effectively improve gut microbiota disorder and mucosal injury caused by sleep deprivation (SD). The present study further explored the mechanism whereby exogenous melatonin prevented SD-induced colitis. 16S rRNA high-throughput sequencing and metabolomics analysis were used to explore the correlation between SD-induced colitis and intestinal microbiota and metabolite composition in mice. Fecal microbiota transplantation (FMT) and melatonin or butyrate supplementation tests verified the core role of gut microbiota in melatonin-alleviating SD-induced colitis. Further, in vitro tests studied the modulatory mechanism of metabolite butyrate. The results demonstrated that SD leads to reductions in plasma melatonin levels and colonic Card9 expression and consequent occurrence of colitis and gut microbiota disorder, especially the downregulation of Faecalibacterium and butyrate levels. The FMT from SD-mice to normal mice could restore SD-like colitis, while butyrate supplementation to SD-mice inhibited the occurrence of colitis, but with no change in the plasma melatonin level in both treatments. However, melatonin supplementation reversed all inductions in SD-mice. In intestinal epithelial cells, the inflammatory ameliorative effect of butyrate was blocked with pretreatments of HDAC3 agonist and HIF-1α antagonist but was mimicked by GSK-3β and p-P65 antagonists. Therefore, the administration of MLT may be a better therapy for SD-induced colitis relative to butyrate. A feasible mechanism would involve that melatonin up-regulated the Faecalibacterium population and production of its metabolite butyrate and MCT1 expression and inhibited HDAC3 in the colon, which would allow p-GSK-3β/β-catenin/HIF-1α activation and NF-κB/NLRP3 suppression to up-regulate Card9 expression and suppress inflammation response.
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Affiliation(s)
- Ting Gao
- Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China; (T.G.); (Z.W.); (Y.D.); (J.C.)
| | - Zixu Wang
- Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China; (T.G.); (Z.W.); (Y.D.); (J.C.)
| | - Yulan Dong
- Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China; (T.G.); (Z.W.); (Y.D.); (J.C.)
| | - Jing Cao
- Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China; (T.G.); (Z.W.); (Y.D.); (J.C.)
| | - Yaoxing Chen
- Laboratory of Anatomy of Domestic Animals, College of Veterinary Medicine, China Agricultural University, Haidian, Beijing 100193, China; (T.G.); (Z.W.); (Y.D.); (J.C.)
- Department of Nutrition and Health, China Agricultural University, Haidian, Beijing 100193, China
- Correspondence: ; Tel.: +86-10-62733778; Fax: +86-10-62733199
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Baradaran Ghavami S, Pourhamzeh M, Farmani M, Keshavarz H, Shahrokh S, Shpichka A, Asadzadeh Aghdaei H, Hakemi-Vala M, Hossein-khannazer N, Timashev P, Vosough M. Cross-talk between immune system and microbiota in COVID-19. Expert Rev Gastroenterol Hepatol 2021; 15:1281-1294. [PMID: 34654347 PMCID: PMC8567289 DOI: 10.1080/17474124.2021.1991311] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 10/06/2021] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Human gut microbiota plays a crucial role in providing protective responses against pathogens, particularly by regulating immune system homeostasis. There is a reciprocal interaction between the gut and lung microbiota, called the gut-lung axis (GLA). Any alteration in the gut microbiota or their metabolites can cause immune dysregulation, which can impair the antiviral activity of the immune system against respiratory viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. AREAS COVERED This narrative review mainly outlines emerging data on the mechanisms underlying the interactions between the immune system and intestinal microbial dysbiosis, which is caused by an imbalance in the levels of essential metabolites. The authors will also discuss the role of probiotics in restoring the balance of the gut microbiota and modulation of cytokine storm. EXPERT OPINION Microbiota-derived signals regulate the immune system and protect different tissues during severe viral respiratory infections. The GLA's equilibration could help manage the mortality and morbidity rates associated with SARS-CoV-2 infection.
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Affiliation(s)
- Shaghayegh Baradaran Ghavami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Thran, Iran
| | - Mahsa Pourhamzeh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Farmani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Thran, Iran
| | - Hediye Keshavarz
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Thran, Iran
| | - Shabnam Shahrokh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Thran, Iran
| | - Anastasia Shpichka
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russia
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Thran, Iran
| | - Mojdeh Hakemi-Vala
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Thran, Iran
| | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, Moscow, Russia
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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De Marchi F, Collo A, Scognamiglio A, Cavaletto M, Bozzi Cionci N, Biroli G, Di Gioia D, Riso S, Mazzini L. Study protocol on the safety and feasibility of a normocaloric ketogenic diet in people with amyotrophic lateral sclerosis. Nutrition 2021; 94:111525. [PMID: 34864433 DOI: 10.1016/j.nut.2021.111525] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/30/2021] [Accepted: 10/14/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVES This study evaluates the safety and feasibility of a normocaloric ketogenic diet (KD) in people with amyotrophic lateral sclerosis (ALS) for reducing hyperexcitability levels and modulating neuroinflammation. METHODS This is a prospective, open-label pilot study involving men and women diagnosed with ALS, ages 18 to 75 y. The primary outcome is the safety and reproducibility of the KD in people with ALS. We will monitor secondary clinical outcomes with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, forced vital capacity, the Amyotrophic Lateral Sclerosis Assessment Questionnaire, blood parameters, and gut microbiota analyses. All participants will follow the KD for 8 wk. During the diet, the clinical status of all participants will be monitored every 15 d through neurologic and nutritional visits and biochemical markers. The research ethics committee approved the study. RESULTS Safety will be assessed by measuring the number and severity of adverse events, including death, and any changes in blood chemistry, vital signs, and clinical exam results. Tolerability will be assessed to complete the proposed 8 wk of treatment while maintaining adequate nutritional status without inducing malnutrition. CONCLUSIONS Adequate caloric intake is essential in ALS, because insufficient intake induces loss of body mass. We hope that the proposed study will provide a positive result in terms of the safety and feasibility of a KD in people ALS, with the purpose of developing a patient-centered diet program to limit disease progression and possibly improve survival.
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Affiliation(s)
- Fabiola De Marchi
- Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
| | - Alessandro Collo
- Clinical Nutrition and Dietetic Unit, Maggiore della Carità Hospital, University of Piemonte Orientale, Novara, Italy
| | - Ada Scognamiglio
- Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Maria Cavaletto
- Department of "Scienze e Innovazione Tecnologica-DiSIT," University of Piemonte Orientale, Vercelli, Italy
| | - Nicole Bozzi Cionci
- Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy
| | - Giampaolo Biroli
- Clinical Nutrition and Dietetic Unit, Maggiore della Carità Hospital, University of Piemonte Orientale, Novara, Italy
| | - Diana Di Gioia
- Department of Agricultural and Food Sciences, University of Bologna, Bologna, Italy
| | - Sergio Riso
- Clinical Nutrition and Dietetic Unit, Maggiore della Carità Hospital, University of Piemonte Orientale, Novara, Italy
| | - Letizia Mazzini
- Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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Schlender J, Behrens F, McParland V, Müller D, Wilck N, Bartolomaeus H, Holle J. Bacterial metabolites and cardiovascular risk in children with chronic kidney disease. Mol Cell Pediatr 2021; 8:17. [PMID: 34677718 PMCID: PMC8536815 DOI: 10.1186/s40348-021-00126-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular complications are the major cause of the marked morbidity and mortality associated with chronic kidney disease (CKD). The classical cardiovascular risk factors such as diabetes and hypertension undoubtedly play a role in the development of cardiovascular disease (CVD) in adult CKD patients; however, CVD is just as prominent in children with CKD who do not have these risk factors. Hence, the CKD-specific pathophysiology of CVD remains incompletely understood. In light of this, studying children with CKD presents a unique opportunity to analyze CKD-associated mechanisms of CVD more specifically and could help to unveil novel therapeutic targets. Here, we comprehensively review the interaction of the human gut microbiome and the microbial metabolism of nutrients with host immunity and cardiovascular end-organ damage. The human gut microbiome is evolutionary conditioned and modified throughout life by endogenous factors as well as environmental factors. Chronic diseases, such as CKD, cause significant disruption to the composition and function of the gut microbiome and lead to disease-associated dysbiosis. This dysbiosis and the accompanying loss of biochemical homeostasis in the epithelial cells of the colon can be the result of poor diet (e.g., low-fiber intake), medications, and underlying disease. As a result of dysbiosis, bacteria promoting proteolytic fermentation increase and those for saccharolytic fermentation decrease and the integrity of the gut barrier is perturbed (leaky gut). These changes disrupt local metabolite homeostasis in the gut and decrease productions of the beneficial short-chain fatty acids (SCFAs). Moreover, the enhanced proteolytic fermentation generates unhealthy levels of microbially derived toxic metabolites, which further accumulate in the systemic circulation as a consequence of impaired kidney function. We describe possible mechanisms involved in the increased systemic inflammation in CKD that is associated with the combined effect of SCFA deficiency and accumulation of uremic toxins. In the future, a more comprehensive and mechanistic understanding of the gut–kidney–heart interaction, mediated largely by immune dysregulation and inflammation, might allow us to target the gut microbiome more specifically in order to attenuate CKD-associated comorbidities.
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Affiliation(s)
- Julia Schlender
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, 13353, Berlin, Germany.,Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine (MDC), 13125, Berlin, Germany
| | - Felix Behrens
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, 13353, Berlin, Germany.,Charité - Universitätsmedizin Berlin and Berlin Institute of Health, 10117, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, 13316, Berlin, Germany.,Institute of Physiology, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany
| | - Victoria McParland
- Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine (MDC), 13125, Berlin, Germany
| | - Dominik Müller
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, 13353, Berlin, Germany
| | - Nicola Wilck
- Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine (MDC), 13125, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, 13316, Berlin, Germany.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Nephrology and Internal Intensive Care Medicine, 10117, Berlin, Germany
| | - Hendrik Bartolomaeus
- Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine (MDC), 13125, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, 13316, Berlin, Germany.,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Nephrology and Internal Intensive Care Medicine, 10117, Berlin, Germany
| | - Johannes Holle
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, 13353, Berlin, Germany. .,Experimental and Clinical Research Center (ECRC), a cooperation of Charité - Universitätsmedizin Berlin and Max Delbruck Center for Molecular Medicine (MDC), 13125, Berlin, Germany. .,DZHK (German Centre for Cardiovascular Research), partner site Berlin, 13316, Berlin, Germany.
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