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da Silva RS, de Paiva IHR, Mendonça IP, de Souza JRB, Lucena-Silva N, Peixoto CA. Anorexigenic and anti-inflammatory signaling pathways of semaglutide via the microbiota-gut--brain axis in obese mice. Inflammopharmacology 2025; 33:845-864. [PMID: 39586940 DOI: 10.1007/s10787-024-01603-y] [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: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 11/27/2024]
Abstract
Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®-0.05 mg/Kg-translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake.
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Affiliation(s)
- Rodrigo Soares da Silva
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Igor Henrique Rodrigues de Paiva
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Ingrid Prata Mendonça
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil
- Postgraduate Program in Biological Sciences/Center of Biosciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | | | - Norma Lucena-Silva
- Laboratory of Immunogenetics, Aggeu Magalhães Institute (IAM), Recife, PE, Brazil
| | - Christina Alves Peixoto
- Laboratory of Ultrastructure, Laboratório de Ultraestrutura, Aggeu Magalhães Institute (IAM), FIOCRUZ, Av. Moraes Rego S/N, Recife, PE, CEP 50670-420, Brazil.
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He K, An F, Zhang H, Yan D, Li T, Wu J, Wu R. Akkermansia muciniphila: A Potential Target for the Prevention of Diabetes. Foods 2024; 14:23. [PMID: 39796314 PMCID: PMC11720440 DOI: 10.3390/foods14010023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/11/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Akkermansia muciniphila, a Gram-negative anaerobic bacterium colonizing the intestinal mucus layer, is regarded as a promising "next-generation probiotic". There is mounting evidence that diabetes and its complications are associated with disorders of A. muciniphila abundance. Thus, A. muciniphil and its components, including the outer membrane protein Amuc_1100, A. muciniphila-derived extracellular vesicles (AmEVs), and the secreted proteins P9 and Amuc_1409, are systematically summarized with respect to mechanisms of action in diabetes mellitus. Diabetes treatments that rely on altering changes in A. muciniphila abundance are also reviewed, including the identification of A. muciniphila active ingredients, and dietary and pharmacological interventions for A. mucinihila abundance. The potential and challenges of using A. muciniphila are also highlighted, and it is anticipated that this work will serve as a reference for more in-depth studies on A. muciniphila and diabetes development, as well as the creation of new therapeutic targets by colleagues domestically and internationally.
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Affiliation(s)
- Kairu He
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (K.H.)
- Shenyang Key Laboratory of Microbial Fermentation Technology Innovation, Shenyang 110866, China
- Liaoning Engineering Research Center of Food Fermentation Technology, Shenyang 110866, China
| | - Feiyu An
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (K.H.)
- Shenyang Key Laboratory of Microbial Fermentation Technology Innovation, Shenyang 110866, China
- Liaoning Engineering Research Center of Food Fermentation Technology, Shenyang 110866, China
| | - Henan Zhang
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (K.H.)
- Shenyang Key Laboratory of Microbial Fermentation Technology Innovation, Shenyang 110866, China
- Liaoning Engineering Research Center of Food Fermentation Technology, Shenyang 110866, China
| | - Danli Yan
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (K.H.)
- Shenyang Key Laboratory of Microbial Fermentation Technology Innovation, Shenyang 110866, China
- Liaoning Engineering Research Center of Food Fermentation Technology, Shenyang 110866, China
| | - Tong Li
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (K.H.)
- Shenyang Key Laboratory of Microbial Fermentation Technology Innovation, Shenyang 110866, China
- Liaoning Engineering Research Center of Food Fermentation Technology, Shenyang 110866, China
| | - Junrui Wu
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (K.H.)
- Shenyang Key Laboratory of Microbial Fermentation Technology Innovation, Shenyang 110866, China
- Liaoning Engineering Research Center of Food Fermentation Technology, Shenyang 110866, China
| | - Rina Wu
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China; (K.H.)
- Shenyang Key Laboratory of Microbial Fermentation Technology Innovation, Shenyang 110866, China
- Liaoning Engineering Research Center of Food Fermentation Technology, Shenyang 110866, China
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Wunderlich M, Miller M, Ritter B, Le Gleut R, Marchi H, Majzoub-Altweck M, Knerr PJ, Douros JD, Müller TD, Brielmeier M. Experimental colonization with H. hepaticus, S. aureus and R. pneumotropicus does not influence the metabolic response to high-fat diet or incretin-analogues in wildtype SOPF mice. Mol Metab 2024; 87:101992. [PMID: 39019114 PMCID: PMC11338133 DOI: 10.1016/j.molmet.2024.101992] [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: 04/10/2024] [Revised: 07/08/2024] [Accepted: 07/12/2024] [Indexed: 07/19/2024] Open
Abstract
OBJECTIVES We here assessed whether typical pathogens of laboratory mice affect the development of diet-induced obesity and glucose intolerance, and whether colonization affects the efficacy of the GLP-1R agonist liraglutide and of the GLP-1/GIP co-agonist MAR709 to treat obesity and diabetes. METHODS Male C57BL/6J mice were experimentally infected with Helicobacter hepaticus, Rodentibacter pneumotropicus and Staphylococcus aureus and compared to a group of uninfected specific and opportunistic pathogen free (SOPF) mice. The development of diet-induced obesity and glucose intolerance was monitored over a period of 26 weeks. To study the influence of pathogens on drug treatment, mice were then subjected for 6 days daily treatment with either the GLP-1 receptor agonist liraglutide or the GLP-1/GIP co-agonist MAR709. RESULTS Colonized mice did not differ from SOPF controls regarding HFD-induced body weight gain, food intake, body composition, glycemic control, or responsiveness to treatment with liraglutide or the GLP-1/GIP co-agonist MAR709. CONCLUSIONS We conclude that the occurrence of H. hepaticus, R. pneumotropicus and S. aureus does neither affect the development of diet-induced obesity or type 2 diabetes, nor the efficacy of GLP-1-based drugs to decrease body weight and to improve glucose control in mice.
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Affiliation(s)
| | - Manuel Miller
- Core Facility Laboratory Animal Services, Helmholtz Munich, Germany.
| | - Bärbel Ritter
- Core Facility Laboratory Animal Services, Helmholtz Munich, Germany
| | - Ronan Le Gleut
- Core Facility Statistical Consulting, Helmholtz Munich, Germany
| | - Hannah Marchi
- Core Facility Statistical Consulting, Helmholtz Munich, Germany; Faculty of Business Administration and Economics, Bielefeld University, Germany
| | - Monir Majzoub-Altweck
- Institute of Veterinary Pathology, Ludwig-Maximilians-University Munich (LMU), Germany
| | - Patrick J Knerr
- Indiana Biosciences Research Institute, Indianapolis, IN, USA
| | | | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Munich, Germany, and German Center for Diabetes Research, DZD, and Walther-Straub Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University Munich (LMU), Germany
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Xu M, Chen B, Qiao K, Liu S, Su Y, Cai S, Liu Z, Li L, Li Q. Mechanism of Takifugu bimaculatus Skin Peptides in Alleviating Hyperglycemia in Rats with Type 2 Diabetic Mellitus Based on Microbiome and Metabolome Analyses. Mar Drugs 2024; 22:377. [PMID: 39195493 DOI: 10.3390/md22080377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/09/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024] Open
Abstract
In this study, we aimed to explore the hypoglycemic effects of a hydrolysate on Takifugu bimaculatus skin (TBSH). The effect of the dipeptidyl peptidase-IV (DPP-IV) inhibitory activities from different TBSH fractions was investigated on basic indexes, gut hormones, blood lipid indexes, viscera, and the gut microbiota and its metabolites in rats with type 2 diabetes mellitus (T2DM). The results showed that the <1 kDa peptide fraction from TBSH (TBP) exhibited a more potent DPP-IV inhibitory effect (IC50 = 0.45 ± 0.01 mg/mL). T2DM rats were induced with streptozocin, followed by the administration of TBP. The 200 mg/kg TBP mitigated weight loss, lowered fasting blood glucose levels, and increased insulin secretion by 20.47%, 25.23%, and 34.55%, respectively, rectified irregular hormonal fluctuations, lipid metabolism, and tissue injuries, and effectively remedied gut microbiota imbalance. In conclusion, TBP exerts a hypoglycemic effect in rats with T2DM. This study offers the potential to develop nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus. It will provide information for developing nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus.
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Affiliation(s)
- Min Xu
- College of Ocean Food and Bioengineering, Jimei University, Xiamen 361021, China
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen 361013, China
| | - Bei Chen
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen 361013, China
| | - Kun Qiao
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen 361013, China
| | - Shuji Liu
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen 361013, China
| | - Yongchang Su
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen 361013, China
| | - Shuilin Cai
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen 361013, China
| | - Zhiyu Liu
- Key Laboratory of Cultivation and High-Value Utilization of Marine Organisms in Fujian Province, Fisheries Research Institute of Fujian, Xiamen 361013, China
| | - Lijun Li
- College of Ocean Food and Bioengineering, Jimei University, Xiamen 361021, China
| | - Qingbiao Li
- College of Ocean Food and Bioengineering, Jimei University, Xiamen 361021, China
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Angelini G, Russo S, Mingrone G. Incretin hormones, obesity and gut microbiota. Peptides 2024; 178:171216. [PMID: 38636809 DOI: 10.1016/j.peptides.2024.171216] [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: 01/17/2024] [Revised: 04/08/2024] [Accepted: 04/10/2024] [Indexed: 04/20/2024]
Abstract
Over the past 40 years, the prevalence of obesity has risen dramatically, reaching epidemic proportions. By 2030 the number of people affected by obesity will reach 1.12 billion worldwide. Gastrointestinal hormones, namely incretins, play a vital role in the pathogenesis of obesity and its comorbidities. GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1), which are secreted from the intestine after nutrient intake and stimulate insulin secretion from pancreatic β cells, influence lipid metabolism, gastric empting, appetite and body weight. The gut microbiota plays an important role in various metabolic conditions, including obesity and type 2 diabetes and influences host metabolism through the interaction with enteroendocrine cells that modulate incretins secretion. Gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and indole, directly stimulate the release of incretins from colonic enteroendocrine cells influencing host satiety and food intake. Moreover, bariatric surgery and incretin-based therapies are associated with increase gut bacterial richness and diversity. Understanding the role of incretins, gut microbiota, and their metabolites in regulating metabolic processes is crucial to develop effective strategies for the management of obesity and its associated comorbidities.
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Affiliation(s)
| | - Sara Russo
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Geltrude Mingrone
- Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, United Kingdom.
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Niu H, Zhou M, Ji A, Zogona D, Wu T, Xu X. Molecular Mechanism of Pasteurized Akkermansia muciniphila in Alleviating Type 2 Diabetes Symptoms. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:13083-13098. [PMID: 38829529 DOI: 10.1021/acs.jafc.4c01188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Type 2 diabetes (T2DM) significantly diminishes people's quality of life and imposes a substantial economic burden. This pathological progression is intimately linked with specific gut microbiota, such as Akkermansia muciniphila. Pasteurized A. muciniphila (P-AKK) has been defined as a novel food by the European Food Safety Authority and exhibited significant hypoglycemic activity. However, current research on the hypoglycemic activity of P-AKK is limited to the metabolic level, neglecting systematic exploration at the pathological level. Consequently, its material basis and mechanism of action for hypoglycemia remain unclear. Drawing upon this foundation, we utilized high-temperature killed A. muciniphila (H-K-AKK) with insignificant hypoglycemic activity as the control research object. Assessments were conducted at pathological levels to evaluate the hypoglycemic functions of both P-AKK and H-K-AKK separately. Our study unveiled for the first time that P-AKK ameliorated symptoms of T2DM by enhancing the generation of glucagon-Like Peptide 1 (GLP-1), with pasteurized A. muciniphila total proteins (PP) being a pivotal component responsible for this activity. Utilizing SDS-PAGE, proteomics, and molecular docking techniques, we deeply analyzed the material foundation of PP. We scientifically screened and identified a protein weighing 77.85 kDa, designated as P5. P5 enhanced GLP-1 synthesis and secretion by activating the G protein-coupled receptor (GPCR) signaling pathway, with free fatty acid receptor 2 (FFAR-2) being identified as the pivotal target protein for P5's physiological activity. These findings further promote the widespread application of P-AKK in the food industry, laying a solid theoretical foundation for its utilization as a beneficial food ingredient or functional component.
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Affiliation(s)
- Huifang Niu
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit Vegetable Processing Quality Control (Huazhong Agricultural University), School of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Minfeng Zhou
- Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, PR China
| | - Anying Ji
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit Vegetable Processing Quality Control (Huazhong Agricultural University), School of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Daniel Zogona
- Department of Food & Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada
| | - Ting Wu
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit Vegetable Processing Quality Control (Huazhong Agricultural University), School of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | - Xiaoyun Xu
- Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit Vegetable Processing Quality Control (Huazhong Agricultural University), School of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
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Morrow NM, Morissette A, Mulvihill EE. Immunomodulation and inflammation: Role of GLP-1R and GIPR expressing cells within the gut. Peptides 2024; 176:171200. [PMID: 38555054 DOI: 10.1016/j.peptides.2024.171200] [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: 01/26/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/02/2024]
Abstract
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones produced by enteroendocrine cells in the small intestine. Despite being produced in the gut, the leveraging of their role in potentiating glucose-stimulated insulin secretion, also known as the incretin effect, has distracted from discernment of direct intestinal signaling circuits. Both preclinical and clinical evidence have highlighted a role for the incretins in inflammation. In this review, we highlight the discoveries of GLP-1 receptor (GLP-1R)+ natural (TCRαβ and TCRγδ) and induced (TCRαβ+CD4+ cells and TCRαβ+CD8αβ+) intraepithelial lymphocytes. Both endogenous signaling and pharmacological activation of GLP-1R impact local and systemic inflammation, the gut microbiota, whole-body metabolism, as well as the control of GLP-1 bioavailability. While GIPR signaling has been documented to impact hematopoiesis, the impact of these bone marrow-derived cells in gut immunology is not well understood. We uncover gaps in the literature of the evaluation of the impact of sex in these GLP-1R and GIP receptor (GIPR) signaling circuits and provide speculations of the maintenance roles these hormones play within the gut in the fasting-refeeding cycles. GLP-1R agonists and GLP-1R/GIPR agonists are widely used as treatments for diabetes and weight loss, respectively; however, their impact on gut homeostasis has not been fully explored. Advancing our understanding of the roles of GLP-1R and GIPR signaling within the gut at homeostasis as well as metabolic and inflammatory diseases may provide targets to improve disease management.
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Affiliation(s)
- Nadya M Morrow
- The University of Ottawa Heart Institute, 40 Ruskin Street, H-3229A, Ottawa, Ontario KIY 4W7, Canada; Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, 451 Smyth Rd, Ottawa, Ontario K1H 8L1, Canada
| | - Arianne Morissette
- The University of Ottawa Heart Institute, 40 Ruskin Street, H-3229A, Ottawa, Ontario KIY 4W7, Canada
| | - Erin E Mulvihill
- The University of Ottawa Heart Institute, 40 Ruskin Street, H-3229A, Ottawa, Ontario KIY 4W7, Canada; Department of Biochemistry, Microbiology and Immunology, The University of Ottawa, Faculty of Medicine, 451 Smyth Rd, Ottawa, Ontario K1H 8L1, Canada; Centre for Infection, Immunity and Inflammation, Ottawa, Ontario, Canada; Montreal Diabetes Research Group, Montreal, Quebec, Canada; Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada.
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Wang Y, Jia X, Cong B. Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota. Front Microbiol 2024; 15:1396031. [PMID: 38855769 PMCID: PMC11157079 DOI: 10.3389/fmicb.2024.1396031] [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: 03/05/2024] [Accepted: 04/29/2024] [Indexed: 06/11/2024] Open
Abstract
Metformin is of great focus because of its high safety, low side effects, and various effects other than lowering blood sugar, such as anti-inflammation, anti-tumor, and anti-aging. Studies have shown that metformin has a modulating effect on the composition and function of the intestinal microbiota other than acting on the liver. However, the composition of microbiota is complex and varies to some extent between species and individuals, and the experimental design of each study is also different. Multiple factors present a major obstacle to better comprehending the effects of metformin on the gut microbiota. This paper reviews the regulatory effects of metformin on the gut microbiota, such as increasing the abundance of genus Akkermansia, enriching short-chain fatty acids (SCFAs)-producing bacterial genus, and regulating gene expression of certain genera. The intestinal microbiota is a large and vital ecosystem in the human body and is considered to be the equivalent of an "organ" of the human body, which is highly relevant to human health and disease status. There are a lot of evidences that the gut microbiota is responsible for metformin's widespread effects. However, there are only a few systematic studies on this mechanism, and the specific mechanism is still unclear. This paper aims to summarize the possible mechanism of metformin in relation to gut microbiota.
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Affiliation(s)
- Yue Wang
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Beijing, China
| | - Xianxian Jia
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Beijing, China
- Department of Pathogen Biology, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Bin Cong
- College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
- Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Beijing, China
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Niu X, Lu P, Huang L, Sun Y, Jin M, Liu J, Li X. The effect of metformin combined with liraglutide on gut microbiota of Chinese patients with type 2 diabetes. Int Microbiol 2024; 27:265-276. [PMID: 37316616 DOI: 10.1007/s10123-023-00380-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/17/2022] [Accepted: 05/18/2023] [Indexed: 06/16/2023]
Abstract
BACKGROUND Metformin (MET) is a first-line therapy for type-2 diabetes mellitus (T2DM). Liraglutide (LRG) is a glucagon-like peptide-1 receptor agonist used as a second-line therapy in combination with MET. METHODS We performed a longitudinal analysis comparing the gut microbiota of overweight and/or pre-diabetic participants (NCP group) with that of each following their progression to T2DM diagnosis (UNT group) using 16S ribosomal RNA gene sequencing of fecal bacteria samples. We also examined the effects of MET (MET group) and MET plus LRG (MET+LRG group) on the gut microbiota of these participants following 60 days of anti-diabetic drug therapy in two parallel treatment arms. RESULTS In the UNT group, the relative abundances of Paraprevotella (P = 0.002) and Megamonas (P = 0.029) were greater, and that of Lachnospira (P = 0.003) was lower, compared with the NCP group. In the MET group, the relative abundance of Bacteroides (P = 0.039) was greater, and those of Paraprevotella (P = 0.018), Blautia (P = 0.001), and Faecalibacterium (P = 0.005) were lower, compared with the UNT group. In the MET+LRG group, the relative abundances of Blautia (P = 0.005) and Dialister (P = 0.045) were significantly lower than in the UNT group. The relative abundance of Megasphaera in the MET group was significantly greater than in the MET+LRG group (P = 0.041). CONCLUSIONS Treatment with MET and MET+LRG results in significant alterations in gut microbiota, compared with the profiles of patients at the time of T2DM diagnosis. These alterations differed significantly between the MET and MET+LRG groups, which suggests that LRG exerted an additive effect on the composition of gut microbiota.
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Affiliation(s)
- Xiaohong Niu
- Department of Endocrinology, Changzhi Medical College Affiliated Heji Hospital, Changzhi, 046011, China
| | - Panpan Lu
- Department of Endocrinology, Changzhi Medical College, Changzhi, 046013, China
| | - Linqing Huang
- Department of Endocrinology, Changzhi Medical College, Changzhi, 046013, China
| | - Yan Sun
- Department of Endocrinology, Changzhi Medical College Affiliated Heji Hospital, Changzhi, 046011, China
| | - Miaomiao Jin
- Department of Endocrinology, Changzhi Medical College Affiliated Heji Hospital, Changzhi, 046011, China
| | - Jing Liu
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Xing Li
- Department of Endocrinology, Second Hospital of Shanxi Medical University, Taiyuan, 030001, China.
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Horvath A, Zukauskaite K, Hazia O, Balazs I, Stadlbauer V. Human gut microbiome: Therapeutic opportunities for metabolic syndrome-Hype or hope? Endocrinol Diabetes Metab 2024; 7:e436. [PMID: 37771199 PMCID: PMC10781898 DOI: 10.1002/edm2.436] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/01/2023] [Accepted: 06/11/2023] [Indexed: 09/30/2023] Open
Abstract
Shifts in gut microbiome composition and metabolic disorders are associated with one another. Clinical studies and experimental data suggest a causal relationship, making the gut microbiome an attractive therapeutic goal. Diet, intake of probiotics or prebiotics and faecal microbiome transplantation (FMT) are methods to alter a person's microbiome composition. Although FMT may allow establishing a proof of concept to use microbiome modulation to treat metabolic disorders, studies show mixed results regarding the effects on metabolic parameters as well as on the composition of the microbiome. This review summarizes the current knowledge on diet, probiotics, prebiotics and FMT to treat metabolic diseases, focusing on studies that also report alterations in microbiome composition. Furthermore, clinical trial results on the effects of common drugs used to treat metabolic diseases are synopsized to highlight the bidirectional relationship between the microbiome and metabolic diseases. In conclusion, there is clear evidence that microbiome modulation has the potential to influence metabolic diseases; however, it is not possible to distinguish which intervention is the most successful. In addition, a clear commitment from all stakeholders is necessary to move forward in the direction of developing targeted interventions for microbiome modulation.
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Affiliation(s)
- Angela Horvath
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Kristina Zukauskaite
- Medical University of GrazGrazAustria
- Life Sciences CentreVilnius UniversityVilniusLithuania
| | - Olha Hazia
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Irina Balazs
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
| | - Vanessa Stadlbauer
- Medical University of GrazGrazAustria
- Center for Biomarker Research in Medicine (CBmed)GrazAustria
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11
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Wang L, Yang L, Cheng XL, Qin XM, Chai Z, Li ZY. The Beneficial Effects of Dietary Astragali Radix Are Related to the Regulation of Gut Microbiota and Its Metabolites. J Med Food 2024; 27:22-34. [PMID: 38236693 DOI: 10.1089/jmf.2023.k.0091] [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] [Indexed: 01/23/2024] Open
Abstract
Astragali Radix (AR) or its extract has been used as an herbal medicine and dietary supplement in China, Europe, and the United States. The gut microbiota could provide new insights for exploring dietary supplements' underlying mechanism on organisms. However, no reports have focused on the regulatory effect of AR on the gut microbiota as a dietary supplement. In this study, healthy ICR mice of either sex were divided into AR and control (CON) groups and given AR water extract (4.55 mg/kg·day-1) or saline by gavage for 14 days, respectively. Then 16S rRNA gene sequencing and ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry-based fecal metabolomics were integrated to investigate the benefits of dietary AR. Weighted gene coexpression network analysis was also introduced to investigate the metabolites with highly synergistic changes. AR supplementation influenced the structure of intestinal microflora, especially enriching short-chain fatty acid-producing bacteria g_Coprobacillus, g_Prevotella, and g_Parabacteroides. AR also significantly altered the fecal metabolome, mainly related to amino acid metabolism, nucleotide metabolism, and bile acid (BA) metabolism. Moreover, the increased secondary BAs and BA-sulfates might closely relate to intestinal microflora. These findings provide valuable insights for future research of dietary AR as a functional food.
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Affiliation(s)
- Ling Wang
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, Shanxi, China
| | - Lan Yang
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, Shanxi, China
| | - Xiao-Ling Cheng
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, Shanxi, China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, Shanxi, China
| | - Zhi Chai
- College of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong, China
| | - Zhen-Yu Li
- Modern Research Center for Traditional Chinese Medicine, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan, Shanxi, China
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12
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Soeda K, Sasako T, Enooku K, Kubota N, Kobayashi N, Ikushima YM, Awazawa M, Bouchi R, Toda G, Yamada T, Nakatsuka T, Tateishi R, Kakiuchi M, Yamamoto S, Tatsuno K, Atarashi K, Suda W, Honda K, Aburatani H, Yamauchi T, Fujishiro M, Noda T, Koike K, Kadowaki T, Ueki K. Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis. Nat Commun 2023; 14:6584. [PMID: 37852976 PMCID: PMC10584811 DOI: 10.1038/s41467-023-42334-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.
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Affiliation(s)
- Kotaro Soeda
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takayoshi Sasako
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenichiro Enooku
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoki Kobayashi
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshiko Matsumoto Ikushima
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Motoharu Awazawa
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Ryotaro Bouchi
- Diabetes and Metabolism Information Center, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Gotaro Toda
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomoharu Yamada
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Takuma Nakatsuka
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Miwako Kakiuchi
- Genome Science Division, The University of Tokyo, Tokyo, Japan
| | - Shogo Yamamoto
- Genome Science Division, The University of Tokyo, Tokyo, Japan
| | - Kenji Tatsuno
- Genome Science Division, The University of Tokyo, Tokyo, Japan
| | - Koji Atarashi
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | - Wataru Suda
- RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | - Kenya Honda
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
- RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | | | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Tetsuo Noda
- Department of Cell Biology, Cancer Institute, Japanese Foundation of Cancer Research, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Toranomon Hospital, Tokyo, Japan
| | - Kohjiro Ueki
- Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
- Department of Molecular Diabetology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
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13
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Li R, Shokri F, Rincon AL, Rivadeneira F, Medina-Gomez C, Ahmadizar F. Bi-Directional Interactions between Glucose-Lowering Medications and Gut Microbiome in Patients with Type 2 Diabetes Mellitus: A Systematic Review. Genes (Basel) 2023; 14:1572. [PMID: 37628624 PMCID: PMC10454120 DOI: 10.3390/genes14081572] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Background: Although common drugs for treating type 2 diabetes (T2D) are widely used, their therapeutic effects vary greatly. The interaction between the gut microbiome and glucose-lowering drugs is one of the main contributors to the variability in T2D progression and response to therapy. On the one hand, glucose-lowering drugs can alter gut microbiome components. On the other hand, specific gut microbiota can influence glycemic control as the therapeutic effects of these drugs. Therefore, this systematic review assesses the bi-directional relationships between common glucose-lowering drugs and gut microbiome profiles. Methods: A systematic search of Embase, Web of Science, PubMed, and Google Scholar databases was performed. Observational studies and randomised controlled trials (RCTs), published from inception to July 2023, comprising T2D patients and investigating bi-directional interactions between glucose-lowering drugs and gut microbiome, were included. Results: Summarised findings indicated that glucose-lowering drugs could increase metabolic-healthy promoting taxa (e.g., Bifidobacterium) and decrease harmful taxa (e.g., Bacteroides and Intestinibacter). Our findings also showed a significantly different abundance of gut microbiome taxa (e.g., Enterococcus faecium (i.e., E. faecium)) in T2D patients with poor compared to optimal glycemic control. Conclusions: This review provides evidence for glucose-lowering drug and gut microbiome interactions, highlighting the potential of gut microbiome modulators as co-adjuvants for T2D treatment.
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Affiliation(s)
- Ruolin Li
- Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands; (R.L.); (F.R.); (C.M.-G.)
| | - Fereshteh Shokri
- Department of Epidemiology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
| | - Alejandro Lopez Rincon
- Department of Data Science & Biostatistics, Julius Global Health, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands;
| | - Fernando Rivadeneira
- Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands; (R.L.); (F.R.); (C.M.-G.)
| | - Carolina Medina-Gomez
- Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands; (R.L.); (F.R.); (C.M.-G.)
| | - Fariba Ahmadizar
- Department of Epidemiology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
- Department of Data Science & Biostatistics, Julius Global Health, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands;
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14
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Zhang F, Wang D. Potential of Akkermansia muciniphila and its outer membrane proteins as therapeutic targets for neuropsychological diseases. Front Microbiol 2023; 14:1191445. [PMID: 37440890 PMCID: PMC10333588 DOI: 10.3389/fmicb.2023.1191445] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/25/2023] [Indexed: 07/15/2023] Open
Abstract
The gut microbiota varies dramatically among individuals, and changes over time within the same individual, due to diversities in genetic backgrounds, diet, nutrient supplementations and use of antibiotics. Up until now, studies on dysbiosis of microbiota have expanded to a wider range of diseases, with Akkermansia muciniphila at the cross spot of many of these diseases. A. muciniphila is a Gram-negative bacterium that produces short-chain fatty acids (SCFAs), and Amuc_1100 is one of its most highly expressed outer membrane proteins. This review aims to summarize current knowledge on correlations between A. muciniphila and involved neuropsychological diseases published in the last decade, with a focus on the potential of this bacterium and its outer membrane proteins as therapeutic targets for these diseases, on the basis of evidence accumulated from animal and clinical studies, as well as mechanisms of action from peripheral to central nervous system (CNS).
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Affiliation(s)
- Fenghua Zhang
- Department of Laboratory Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Dali Wang
- Center for Clinical and Translational Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China
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15
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Thomas MC, Coughlan MT, Cooper ME. The postprandial actions of GLP-1 receptor agonists: The missing link for cardiovascular and kidney protection in type 2 diabetes. Cell Metab 2023; 35:253-273. [PMID: 36754019 DOI: 10.1016/j.cmet.2023.01.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Recent clinical trials in people with type 2 diabetes have demonstrated beneficial actions on heart and kidney outcomes following treatment with GLP-1RAs. In part, these actions are consistent with improved glucose control and significant weight loss. But GLP-1RAs may also have additive benefits by improving postprandial dysmetabolism. In diabetes, dysregulated postprandial nutrient excursions trigger inflammation, oxidative stress, endothelial dysfunction, thrombogenicity, and endotoxemia; alter hormone levels; and modulate cardiac output and regional blood and lymphatic flow. In this perspective, we explore the actions of GLP-1RAs on the postprandial state and their potential role in end-organ benefits observed in recent trials.
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Affiliation(s)
- Merlin C Thomas
- Department of Diabetes, Monash University, Central Clinical School, 99 Commercial Road, Melbourne, Australia; Department of Biochemistry, Monash University, Melbourne, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Monash University, Central Clinical School, 99 Commercial Road, Melbourne, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University Parkville Campus, 381 Royal Parade, Parkville, 3052 VIC, Australia
| | - Mark E Cooper
- Department of Diabetes, Monash University, Central Clinical School, 99 Commercial Road, Melbourne, Australia.
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16
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Ying X, Rongjiong Z, Kahaer M, Chunhui J, Wulasihan M. Therapeutic efficacy of liraglutide versus metformin in modulating the gut microbiota for treating type 2 diabetes mellitus complicated with nonalcoholic fatty liver disease. Front Microbiol 2023; 14:1088187. [PMID: 36778868 PMCID: PMC9909237 DOI: 10.3389/fmicb.2023.1088187] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/09/2023] [Indexed: 01/27/2023] Open
Abstract
Metformin and liraglutide are used in the treatment of type 2 diabetes mellitus (T2DM) complicated with nonalcoholic fatty liver disease (NAFLD). Although these drugs can alter the intestinal microbiome, clinical data are required to explore their mechanisms of action. Using 16S sequencing technology, we analyzed and compared the intestinal bacterial community structure and function between patients before and after treatment (12 weeks) with the two drugs (metformin or liraglutide, n = 15) and healthy controls (n = 15). Moreover, combined with 19 clinical indices, the potential therapeutic mechanisms of the two drugs were compared. The studied clinical indices included those associated with islet β-cell function (FPG, FINS, HbA1c, and HOMA-IR), inflammation (TNF-α, IL-6, and APN), lipid metabolism (TC, TG, and LDL-C), and liver function (ALT, AST, and GGT); the values of all indices changed significantly after treatment (p < 0.01). In addition, the effect of the two drugs on the intestinal bacterial community varied. Liraglutide treatment significantly increased the diversity and richness of the intestinal bacterial community (p < 0.05); it significantly increased the relative abundances of Bacteroidetes, Proteobacteria, and Bacilli, whereas metformin treatment significantly increased the relative abundance of Fusobacteria and Actinobacteria (p < 0.05). Metformin treatment increased the complexity and stability of the intestinal bacterial network. However, liraglutide treatment had a weaker effect on the intestinal bacterial network, and the network after treatment was similar to that in healthy controls. Correlation matrix analysis between dominant genera and clinical indicators showed that the correlation between the bacterial community and islet β-cell function was stronger after liraglutide treatment, whereas the correlation between the bacterial community and inflammation-related factors was stronger after metformin treatment. Functional prediction showed that liraglutide could significantly affect the abundance of functional genes related to T2DM and NAFLD (p < 0.05), but the effect of metformin was not significant. This study is the first to report the changes in the intestinal bacterial community in patients treated with metformin or liraglutide and the differences between the mechanisms of action of metformin and liraglutide. Metformin or liraglutide has a therapeutic value in T2DM complicated with NAFLD, with liraglutide having a weaker effect on the intestinal bacterial community but a better therapeutic efficacy.
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Affiliation(s)
- Xing Ying
- Department of Comprehensive Internal Medicine Department 4, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Zheng Rongjiong
- Department of Infectious Disease, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Mayila Kahaer
- Department of Comprehensive Internal Medicine Department 4, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jiang Chunhui
- Department of Comprehensive Internal Medicine Department 4, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Muhuyati Wulasihan
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China,*Correspondence: Muhuyati Wulasihan, ✉
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17
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Van Hul M, Cani PD. The gut microbiota in obesity and weight management: microbes as friends or foe? Nat Rev Endocrinol 2023; 19:258-271. [PMID: 36650295 DOI: 10.1038/s41574-022-00794-0] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2022] [Indexed: 01/18/2023]
Abstract
Obesity is caused by a long-term difference between energy intake and expenditure - an imbalance that is seemingly easily restored by increasing exercise and reducing caloric consumption. However, as simple as this solution appears, for many people, losing excess weight is difficult to achieve and even more difficult to maintain. The reason for this difficulty is that energy intake and expenditure, and by extension body weight, are regulated through complex hormonal, neural and metabolic mechanisms that are under the influence of many environmental factors and internal responses. Adding to this complexity, the microorganisms (microbes) that comprise the gut microbiota exert direct effects on the digestion, absorption and metabolism of food. Furthermore, the gut microbiota exerts a miscellany of protective, structural and metabolic effects both on the intestinal milieu and peripheral tissues, thus affecting body weight by modulating metabolism, appetite, bile acid metabolism, and the hormonal and immune systems. In this Review, we outline historical and recent advances in understanding how the gut microbiota is involved in regulating body weight homeostasis. We also discuss the opportunities, limitations and challenges of using gut microbiota-related approaches as a means to achieve and maintain a healthy body weight.
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Affiliation(s)
- Matthias Van Hul
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain (Université catholique de Louvain), Brussels, Belgium
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO Department, WEL Research Institute, Wavre, Belgium
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain (Université catholique de Louvain), Brussels, Belgium.
- Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), WELBIO Department, WEL Research Institute, Wavre, Belgium.
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18
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Abstract
Diabetes represents one of the most significant, and rapidly escalating, global healthcare crises we face today. Diabetes already affects one-tenth of the world's adults-more than 537 million people, numbers that have tripled since 2000 and are estimated to reach 643 million by 2030. Type 2 diabetes (T2D), the most prevalent form, is a complex disease with numerous contributing factors, including genetics, epigenetics, diet, lifestyle, medication use, and socioeconomic factors. In addition, the gut microbiome has emerged as a significant potential contributing factor in T2D development and progression. Gut microbes and their metabolites strongly influence host metabolism and immune function, and are now known to contribute to vitamin biosynthesis, gut hormone production, satiety, maintenance of gut barrier integrity, and protection against pathogens, as well as digestion and nutrient absorption. In turn, gut microbes are influenced by diet and lifestyle factors such as alcohol and medication use, including antibiotic use and the consumption of probiotics and prebiotics. Here we review current evidence regarding changes in microbial populations in T2D and the mechanisms by which gut microbes influence glucose metabolism and insulin resistance, including inflammation, gut permeability, and bile acid production. We also explore the interrelationships between gut microbes and different T2D medications and other interventions, including prebiotics, probiotics, and bariatric surgery. Lastly, we explore the particular role of the small bowel in digestion and metabolism and the importance of studying small bowel microbes directly in our search to find metabolically relevant biomarkers and therapeutic targets for T2D.
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Affiliation(s)
- Gillian M Barlow
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA
| | - Ruchi Mathur
- Correspondence: Ruchi Mathur, MD, FRCPC, Director, Clinical Diabetes, Cedars-Sinai, 700 N San Vicente, Ste G271, West Hollywood, CA 90069, USA.
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19
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Gao Y, Hou L, Hu M, Li D, Tian Z, Wen W, Fan B, Li S, Wang F. Effects of Bacillus subtilis BSNK-5-Fermented Soymilk on the Gut Microbiota by In Vitro Fecal Fermentation. Foods 2022; 11:3501. [PMID: 36360112 PMCID: PMC9654106 DOI: 10.3390/foods11213501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/21/2022] [Accepted: 10/28/2022] [Indexed: 06/13/2024] Open
Abstract
The gut microbiota of soymilk intervention is beneficial to maintaining human health. Bacillus subtilis fermented soymilk has brought much interest, due to its richness of thrombolytic nattokinase and the strain of potential probiotic properties. In this study, soymilk was fermented by B. subtilis BSNK-5, and the BSNK-5-fermented soymilk (SMF) on the production of short chain fatty acids (SCFAs) and the regulation of fecal microbiota was initially evaluated by in vitro fecal fermentation. SMF supplementation obviously increased the levels of SCFAs from 32.23 mM to 49.10 mM, especially acetic acid, propionic acid, and isobutyric acid. Additionally, SMF changed the composition and microbial diversity of gut microbiota. After 24 h of anaerobic incubation in vitro, SMF decreased the Firmicutes/Bacteroidota ratio favoring weight loss, increased Lachnospiraceae_UCG-004 and the other beneficial bacteria producing SCFAs, as well as suppressing pathogenic Streptococcus genus. These results revealed the potential use of BSNK-5-fermented soymilk as a potential candidate to promote gut health.
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Affiliation(s)
- Yaxin Gao
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
| | - Lizhen Hou
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
| | - Miao Hu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
| | - Danfeng Li
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
| | - Zhiliang Tian
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
| | - Wei Wen
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
| | - Bei Fan
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Shuying Li
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, No. 2 Yuan Ming Yuan West Road, Beijing 100193, China
| | - Fengzhong Wang
- Key Laboratory of Agro-Products Quality and Safety Control in Storage and Transport Process, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing 100193, China
- Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing 100193, China
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20
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Abdalqadir N, Adeli K. GLP-1 and GLP-2 Orchestrate Intestine Integrity, Gut Microbiota, and Immune System Crosstalk. Microorganisms 2022; 10:2061. [PMID: 36296337 PMCID: PMC9610230 DOI: 10.3390/microorganisms10102061] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/11/2022] [Accepted: 10/13/2022] [Indexed: 12/15/2022] Open
Abstract
The intestine represents the body's largest interface between internal organs and external environments except for its nutrient and fluid absorption functions. It has the ability to sense numerous endogenous and exogenous signals from both apical and basolateral surfaces and respond through endocrine and neuronal signaling to maintain metabolic homeostasis and energy expenditure. The intestine also harbours the largest population of microbes that interact with the host to maintain human health and diseases. Furthermore, the gut is known as the largest endocrine gland, secreting over 100 peptides and other molecules that act as signaling molecules to regulate human nutrition and physiology. Among these gut-derived hormones, glucagon-like peptide 1 (GLP-1) and -2 have received the most attention due to their critical role in intestinal function and food absorption as well as their application as key drug targets. In this review, we highlight the current state of the literature that has brought into light the importance of GLP-1 and GLP-2 in orchestrating intestine-microbiota-immune system crosstalk to maintain intestinal barrier integrity, inflammation, and metabolic homeostasis.
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Affiliation(s)
- Nyan Abdalqadir
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biology, College of Science, University of Sulaimani, Sulaymaniyah 46001, Iraq
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 1H3, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
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21
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Liang YY, Liu LY, Jia Y, Li Y, Cai JN, Shu Y, Tan JY, Chen PY, Li HW, Cai HH, Cai XS. Correlation between gut microbiota and glucagon-like peptide-1 in patients with gestational diabetes mellitus. World J Diabetes 2022; 13:861-876. [PMID: 36311998 PMCID: PMC9606788 DOI: 10.4239/wjd.v13.i10.861] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 06/25/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) places both the mother and offspring at high risk of complications. Increasing evidence suggests that the gut microbiota plays a role in the pathogenesis of GDM. However, it is still unclear whether the gut microbiota is related to blood biochemical traits, particularly glucagon-like peptide-1 (GLP-1), in GDM patients.
AIM To explore the correlation between the gut microbiota and blood biochemical traits, particularly GLP-1, in GDM patients.
METHODS The V4 region of the 16S ribosomal ribonucleic acid (rRNA) gene was sequenced based on the fecal samples of 35 pregnant women with GDM and was compared to that of 25 pregnant women with normal glucose tolerance (NGT).
RESULTS The results showed that Ruminococcaceae_UCG-002, Ruminococcaceae_UCG-005, Clostri-dium_sensu_stricto_1, and Streptococcus were more abundant in the NGT group than in the GDM group. Bacteroides and Lachnoclostridium were more abundant in the GDM group than in the NGT group. Spearman’s correlation analysis was performed to identify the relationships between microbiota genera and blood biochemical traits. Paraprevotella, Roseburia, Faecalibacterium, and Ruminococcaceae_UCG-002 were significantly negatively correlated with glucose. Ruminococcaceae_UCG-002 was significantly negatively correlated with hemoglobin A1c. Bacteroides was significantly positively correlated with glucose. Sutterella, Oscillibacter, and Bifidobacterium were significantly positively correlated with GLP-1. A random forest model showed that 20 specific genera plus glucose provided the best discriminatory power, as indicated by the area under the receiver operating characteristic curve (0.94).
CONCLUSION The results of this study reveal novel relationships between the gut microbiome, blood bio-chemical traits, particularly GLP-1, and GDM status. These findings suggest that some genera are crucial for controlling blood glucose-related indices and may be beneficial for GDM treatment. Alteration in the microbial composition of the gut may potentially serve as a marker for identifying individuals at risk of GDM.
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Affiliation(s)
- Yun-Yi Liang
- Health Management Center, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528000, Guangdong Province, China
| | - Ling-Yu Liu
- The First Affiliated Hospital, Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
| | - Yan Jia
- Health Management Center, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528000, Guangdong Province, China
| | - Yi Li
- Health Management Center, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528000, Guangdong Province, China
- Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen 518001, Guangdong Province, China
| | - Jie-Na Cai
- Clinical Laboratory, Puning People’s Hospital, Puning 515300, Guangdong Province, China
| | - Yi Shu
- Health Management Center, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528000, Guangdong Province, China
| | - Jing-Yi Tan
- Health Management Center, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528000, Guangdong Province, China
| | - Pei-Yi Chen
- Health Management Center, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan 528000, Guangdong Province, China
| | - Hong-Wei Li
- Institute of Biotherapy, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hui-Hua Cai
- Department of Obstetrics and Gynecology, Guangdong Provincial People's Hospital, Guangzhou 510080, Guangdong Province, China
| | - Xiang-Sheng Cai
- Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen 518001, Guangdong Province, China
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22
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Wong CK, Yusta B, Koehler JA, Baggio LL, McLean BA, Matthews D, Seeley RJ, Drucker DJ. Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation. Cell Metab 2022; 34:1514-1531.e7. [PMID: 36027914 DOI: 10.1016/j.cmet.2022.08.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 05/31/2022] [Accepted: 08/03/2022] [Indexed: 11/03/2022]
Abstract
Gut intraepithelial lymphocytes (IELs) are thought to calibrate glucagon-like peptide 1 (GLP-1) bioavailability, thereby regulating systemic glucose and lipid metabolism. Here, we show that the gut IEL GLP-1 receptor (GLP-1R) is not required for enteroendocrine L cell GLP-1 secretion and glucose homeostasis nor for the metabolic benefits of GLP-1R agonists (GLP-1RAs). Instead, the gut IEL GLP-1R is essential for the full effects of GLP-1RAs on gut microbiota. Moreover, independent of glucose control or weight loss, the anti-inflammatory actions of GLP-1RAs require the gut IEL GLP-1R to selectively restrain local and systemic T cell-induced, but not lipopolysaccharide-induced, inflammation. Such effects are mediated by the suppression of gut IEL effector functions linked to the dampening of proximal T cell receptor signaling in a protein-kinase-A-dependent manner. These data reposition key roles of the L cell-gut IEL GLP-1R axis, revealing mechanisms linking GLP-1R activation in gut IELs to modulation of microbiota composition and control of intestinal and systemic inflammation.
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Affiliation(s)
- Chi Kin Wong
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Bernardo Yusta
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Jacqueline A Koehler
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Laurie L Baggio
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Brent A McLean
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Dianne Matthews
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Daniel J Drucker
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada.
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23
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Kant R, Chandra L, Verma V, Nain P, Bello D, Patel S, Ala S, Chandra R, Antony MA. Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus. World J Methodol 2022; 12:246-257. [PMID: 36159100 PMCID: PMC9350729 DOI: 10.5662/wjm.v12.i4.246] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/03/2022] [Accepted: 06/18/2022] [Indexed: 02/06/2023] Open
Abstract
Microorganisms including bacteria, viruses, protozoa, and fungi living in the gastrointestinal tract are collectively known as the gut microbiota. Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state. Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Pathophysiological mechanisms linking gut dysbiosis, and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids, interaction with gut hormones, increased gut microbial metabolite trimethylamine-N-oxide, bacterial translocation/Leaky gut syndrome, and endotoxin production such as lipopolysaccharides. The association between the gut microbiota and glycemic agents, however, is much less understood and is the growing focus of research and conversation. Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other, meaning that while anti-diabetic medications alter the gut microbiota, the gut microbiota also alters the efficacy of anti-diabetic medications. With increasing evidence regarding the significance of gut microbiota, it is imperative to review the role of gut microbiota in the pathogenesis of T2DM. This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.
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Affiliation(s)
- Ravi Kant
- Department of Endocrinology, Diabetes and Metabolism, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Endocrinology, Diabetes and Metabolism, AnMed Health, Anderson, SC 29621, United States
| | - Lakshya Chandra
- Department of Internal Medicine, St Francis Hospital, Greenville, SC 29601, United States
| | - Vipin Verma
- Department of Internal Medicine, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Internal Medicine, AnMed Health, Anderson, SC 29621, United States
| | - Priyanshu Nain
- Department of Graduate Medical Education, Maulana Azad Medical College, Delhi 110002, India
| | - Diego Bello
- Department of Surgery, AnMed Health, Anderson, SC 29621, United States
| | - Siddharth Patel
- Department of Internal Medicine, Decatur Morgan Hospital, Decatur, AL 35601, United States
| | - Subash Ala
- Department of Internal Medicine, St Francis Hospital, Greenville, SC 29601, United States
| | - Rashmi Chandra
- Department of Internal Medicine, Medical University of South Carolina, Anderson, SC 29621, United States
| | - Mc Anto Antony
- Department of Endocrinology, Diabetes and Metabolism, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Endocrinology, Diabetes and Metabolism, AnMed Health, Anderson, SC 29621, United States
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24
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Bock PM, Martins AF, Ramalho R, Telo GH, Leivas G, Maraschin CK, Schaan BD. The impact of dietary, surgical, and pharmacological interventions on gut microbiota in individuals with diabetes mellitus: A systematic review. Diabetes Res Clin Pract 2022; 189:109944. [PMID: 35697155 DOI: 10.1016/j.diabres.2022.109944] [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: 01/18/2022] [Revised: 05/09/2022] [Accepted: 06/06/2022] [Indexed: 11/03/2022]
Abstract
AIMS To conduct a systematic review assessing the association between dietary, surgical, and pharmacological interventions and changes in the gut microbiota of individuals with diabetes. METHODS The MEDLINE, EMBASE, and Cochrane Library databases were searched focusing on the effects of dietary, bariatric surgery, and pharmacological interventions on gut microbiota in adults with diabetes. Studies were classified based on qualitative changes using a simple vote-counting method, evaluating reduction, no effect, or an increase in the gut microbiota outcomes. RESULTS 6,004 studies were retained to review their titles and abstracts. A total of 149 full-text articles were reassessed, of which 49 were included in the final analysis. This review indicates that dietary, surgical, and pharmacological interventions increase or decrease bacterial populations from more than 60 families, genera, or species. In general, the interventions led to an increase in the bacterial population from phylum Firmicutes, mainly Lactobacillus species, compared to the gram-negative bacterial population from phylum Bacteroidetes. CONCLUSIONS The results of the included studies suggest that interventions aimed at reducing species related to uncontrolled diabetes and increasing species related to the healthy gut are potential adjuvants in treating diabetes; however, well-conducted interventional studies targeting gut microbiota are necessary.
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Affiliation(s)
- Patricia M Bock
- Universidade Federal do Rio Grande do Sul, Faculty of Medicine, Department of Internal Medicine, Graduate Program in Medical Sciences: Endocrinology, Porto Alegre, Brazil; Faculdades Integradas de Taquara, Taquara, Brazil; National Institute of Science and Technology for Health Technology Assessment (IATS) - CNPq/Brazil, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
| | - Andreza F Martins
- Universidade Federal do Rio Grande do Sul, Department of Microbiology, Immunology, and Parasitology, Porto Alegre, Brazil
| | - Rafaela Ramalho
- Universidade Federal do Rio Grande do Sul, Department of Microbiology, Immunology, and Parasitology, Porto Alegre, Brazil
| | - Gabriela H Telo
- Pontifícia Universidade Católica do Rio Grande do Sul, School of Medicine, Internal Medicine Division, Porto Alegre, Brazil
| | - Gabriel Leivas
- Universidade Federal do Rio Grande do Sul, Faculty of Medicine, Department of Internal Medicine, Graduate Program in Medical Sciences: Endocrinology, Porto Alegre, Brazil
| | - Clara K Maraschin
- Universidade Federal do Rio Grande do Sul, Faculty of Medicine, Department of Internal Medicine, Graduate Program in Medical Sciences: Endocrinology, Porto Alegre, Brazil
| | - Beatriz D Schaan
- Universidade Federal do Rio Grande do Sul, Faculty of Medicine, Department of Internal Medicine, Graduate Program in Medical Sciences: Endocrinology, Porto Alegre, Brazil; National Institute of Science and Technology for Health Technology Assessment (IATS) - CNPq/Brazil, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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25
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Kobyliak N, Falalyeyeva T, Kyriachenko Y, Tseyslyer Y, Kovalchuk O, Hadiliia O, Eslami M, Yousefi B, Abenavoli L, Fagoonee S, Pellicano R. Akkermansia muciniphila as a novel powerful bacterial player in the treatment of metabolic disorders. Minerva Endocrinol (Torino) 2022; 47:242-252. [PMID: 35103461 DOI: 10.23736/s2724-6507.22.03752-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
Akkermansia muciniphila (A. muciniphila) is a mucin-degrading bacterium that commonly lives in the intestinal mucus layer. It is normally detected in human faecal specimens and is one of the few bacteria potentially associated to obesity development. In this narrative review, possible mechanisms that support how A. muciniphila is implicated in the pathogenesis of obesity and metabolic-associated disease are described with the evaluation of its role as an intermediary or independent agent whose manipulation could be useful in the management of metabolic disorders. The ampleness of A. muciniphila is notably diminished in obesity, type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiometabolic diseases and low-grade inflammation. Furthermore, an inverse relationship between A. muciniphila, body weight and insulin sensitivity has been observed in both humans and animals. Antidiabetic drugs, gastric bypass surgery, prebiotics and biologically active compounds, such as polyphenols or saponins, have been shown to be associated with A. muciniphila relative abundance and thus could have favourable effects on metabolic disorders. Furthermore, A. muciniphila supplementation alone has been correlated with weight reduction and improvement of metabolic disorders, including fat mass gain, adipose tissue inflammation, metabolic endotoxaemia, and insulin resistance. Nevertheless, since the primary beneficial impacts of this bacterium have been predominantly investigated in various preclinical models, these results need to be confirmed in randomized clinical trials.
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Affiliation(s)
- Nazarii Kobyliak
- Department of Endocrinology, Bogomolets National Medical University, Kyiv, Ukraine -
- Medical Laboratory, CSD Health Care, Kyiv, Ukraine -
| | - Tetyana Falalyeyeva
- Medical Laboratory, CSD Health Care, Kyiv, Ukraine
- Taras Shevchenko National University, Kyiv, Ukraine
| | | | | | - Oleksandr Kovalchuk
- Taras Shevchenko National University, Kyiv, Ukraine
- Department of Human Anatomy, Bogomolets National Medical University, Kyiv, Ukraine
| | | | - Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Ludovico Abenavoli
- Department of Health Sciences, Magna Graecia University, Catanzaro, Italy
| | - Sharmila Fagoonee
- Institute of Biostructures and Bioimaging (CNR), Molecular Biotechnology Center, Turin, Italy
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette-S. Giovanni Antica Sede Hospital, Turin, Italy
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26
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Aggarwal V, Sunder S, Verma SR. Disease-associated dysbiosis and potential therapeutic role of Akkermansia muciniphila, a mucus degrading bacteria of gut microbiome. Folia Microbiol (Praha) 2022; 67:811-824. [PMID: 35596115 PMCID: PMC9122250 DOI: 10.1007/s12223-022-00973-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/19/2022] [Indexed: 02/08/2023]
Abstract
The unique functionality of Akkermansia muciniphila in gut microbiota indicates it to be an indispensable microbe for human welfare. The importance of A. muciniphila lies in its potential to convert mucin into beneficial by-products, regulate intestinal homeostasis and maintain gut barrier integrity. It is also known to competitively inhibit other mucin-degrading bacteria and improve metabolic functions and immunity responses in the host. It finds a pivotal perspective in various diseases and their treatment. It has future as a promising probiotic, disease biomarker and therapeutic agent for chronic diseases. Disease-associated dysbiosis of A. muciniphila in the gut microbiome makes it a potential candidate as a biomarker for some diseases and can provide future theranostics by suggesting ways of diagnosis for the patients and best treatment method based on the screening results. Manipulation of A. muciniphila in gut microbiome may help in developing a novel personalized therapeutic action and can be a suitable next generation medicine. However, the actual pathway governing A. muciniphila interaction with hosts remains to be investigated. Also, due to the limited availability of products containing A. muciniphila, it is not exploited to its full potential. The present review aims at highlighting the potential of A. muciniphila in mucin degradation, contribution towards the gut health and host immunity and management of metabolic diseases such as obesity and type 2 diabetes, and respiratory diseases such as cystic fibrosis and COVID-19.
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Affiliation(s)
- Vidushi Aggarwal
- Department of Biotechnology, Delhi Technological University, Delhi, 110042, India
| | - Sushant Sunder
- Department of Biotechnology, Delhi Technological University, Delhi, 110042, India
| | - Smita Rastogi Verma
- Department of Biotechnology, Delhi Technological University, Delhi, 110042, India.
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27
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Patel N, Patel N, Pal S, Nathani N, Pandit R, Patel M, Patel N, Joshi C, Parekh B. Distinct gut and vaginal microbiota profile in women with recurrent implantation failure and unexplained infertility. BMC Womens Health 2022; 22:113. [PMID: 35413875 PMCID: PMC9004033 DOI: 10.1186/s12905-022-01681-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 03/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Female reproductive tract dysbiosis impacts implantation. However, whether gut dysbiosis influences implantation failure and whether it accompanies reproductive tract dysbiosis remains scantly explored. Herein, we examined the gut-vaginal microbiota axis in infertile women. METHODS We recruited 11 fertile women as the controls, and a cohort of 20 infertile women, 10 of whom had recurrent implantation failure (RIF), and another 10 had unexplained infertility (UE). Using amplicon sequencing, which employs PCR to create sequences of DNA called amplicon, we compared the diversity, structure, and composition of faecal and vaginal bacteria of the controls with that of the infertile cohort. Of note, we could only sequence 8 vaginal samples in each group (n = 24/31). RESULT Compared with the controls, α-diversity and β-diversity of the gut bacteria among the infertile groups differed significantly (p < 0.05). Taxa analysis revealed enrichment of Gram-positive bacteria in the RIF group, whereas Gram-negative bacteria were relatively abundant in the UE group. Strikingly, mucus-producing genera declined in the infertile cohort (p < 0.05). Hungatella, associated with trimethylamine N-oxide (TMAO) production, were enriched in the infertile cohort (p < 0.05). Vaginal microbiota was dominated by the genus Lactobacillus, with Lactobacillus iners AB-1 being the most abundant species across the groups. Compared with the infertile cohort, overgrowth of anaerobic bacteria, associated with vaginal dysbiosis, such as Leptotrichia and Snethia, occurred in the controls. CONCLUSION The gut microbiota had little influence on the vaginal microbiota. Gut dysbiosis and vaginal eubiosis occurred in the infertile women, whereas the opposite trend occurred in the controls.
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Affiliation(s)
- Nayna Patel
- Akanksha Hospital and Research Institute, Lambhvel Road, Lambhvel, Anand, Gujarat, 387310, India
| | - Nidhi Patel
- Gujarat Biotechnology Research Centre (GBRC), Gandhinagar, Gujarat, 382011, India
| | - Sejal Pal
- Akanksha Hospital and Research Institute, Lambhvel Road, Lambhvel, Anand, Gujarat, 387310, India
| | - Neelam Nathani
- Gujarat Biotechnology Research Centre (GBRC), Gandhinagar, Gujarat, 382011, India.,School of Applied Sciences & Technology (SAST-GTU), Gujarat Technological University, Visat - Gandhinagar Road, Chandkheda, Ahmedabad, Gujarat, 382424, India
| | - Ramesh Pandit
- Gujarat Biotechnology Research Centre (GBRC), Gandhinagar, Gujarat, 382011, India
| | - Molina Patel
- Akanksha Hospital and Research Institute, Lambhvel Road, Lambhvel, Anand, Gujarat, 387310, India
| | - Niket Patel
- Akanksha Hospital and Research Institute, Lambhvel Road, Lambhvel, Anand, Gujarat, 387310, India
| | - Chaitanya Joshi
- Gujarat Biotechnology Research Centre (GBRC), Gandhinagar, Gujarat, 382011, India
| | - Bhavin Parekh
- Akanksha Hospital and Research Institute, Lambhvel Road, Lambhvel, Anand, Gujarat, 387310, India.
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28
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Impact of the Gastrointestinal Tract Microbiota on Cardiovascular Health and Pathophysiology. J Cardiovasc Pharmacol 2022; 80:13-30. [PMID: 35384898 DOI: 10.1097/fjc.0000000000001273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/25/2022] [Indexed: 11/25/2022]
Abstract
ABSTRACT The microbiota of the gastrointestinal tract (GIT) is an extremely diverse community of microorganisms, and their collective genomes (microbiome) provide a vast arsenal of biological activities, in particular enzymatic ones, which are far from being fully elucidated. The study of the microbiota (and the microbiome) is receiving great interest from the biomedical community as it carries the potential to improve risk-prediction models, refine primary and secondary prevention efforts, and also design more appropriate and personalized therapies, including pharmacological ones. A growing body of evidence, though sometimes impaired by the limited number of subjects involved in the studies, suggests that GIT dysbiosis, i.e. the altered microbial composition, has an important role in causing and/or worsening cardiovascular disease (CVD). Bacterial translocation as well as the alteration of levels of microbe-derived metabolites can thus be important to monitor and modulate, because they may lead to initiation and progression of CVD, as well as to its establishment as chronic state. We hereby aim to provide readers with details on available resources and experimental approaches that are used in this fascinating field of biomedical research, and on some novelties on the impact of GIT microbiota on CVD.
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29
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Abstract
The increasing prevalence of metabolic diseases has become a severe public health problem. Gut microbiota play important roles in maintaining human health by modulating the host's metabolism. Recent evidences demonstrate that Akkermansia muciniphila is effective in improving metabolic disorders and is thus considered as a promising "next-generation beneficial microbe". In addition to the live A. muciniphila, similar or even stronger beneficial effects have been observed in pasteurized A. muciniphila and its components, including the outer membrane protein Amuc_1100, A. muciniphila-derived extracellular vesicles (AmEVs), and secreted protein P9. Hence, this paper presents a systemic review of recent progress in the effects and mechanisms of A. muciniphila and its components in the treatment of metabolic diseases, including obesity, type 2 diabetes mellitus, cardiovascular disease, and nonalcoholic fatty liver disease, as well as perspectives on its future study.
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Affiliation(s)
- Juan Yan
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lili Sheng
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China,Lili Sheng
| | - Houkai Li
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China,CONTACT Houkai Li Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai201203, China
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30
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Буйваленко АВ, Покровская ЕВ. [Interaction between the gut microbiota and oral antihyperglycemic drugs]. PROBLEMY ENDOKRINOLOGII 2022; 68:66-71. [PMID: 35488758 PMCID: PMC9764270 DOI: 10.14341/probl12835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/21/2021] [Accepted: 12/27/2021] [Indexed: 06/14/2023]
Abstract
The gut microbiome is the largest microbial habitat in the human body. The main functions include obtaining energy from complex food fibers, maturation and formation of the immune system, intestinal angiogenesis, restoration of epithelial damage to the intestine, development of the nervous system, protection against pathogens, etc. It is also known that a number of drugs can cause changes in the composition of the intestinal microflora, and intestinal bacteria, in turn, produce a number of enzymes and metabolites that can chemically change the structure of drugs, leading to more side effects, and in some cases to positive changes. In this review we present current evidence supporting the effects of microbiota in host-drug interactions, in particular, the reciprocal effects of gut microbiota and oral hypoglycemic drugs on each other. Gaining and evaluating knowledge in this area will help pave the way for the development of new microbiota-based strategies that can be used in the future to improve treatment outcomes for type 2 diabetes mellitus (T2D).
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31
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Chu N, Chan JCN, Chow E. Pharmacomicrobiomics in Western Medicine and Traditional Chinese Medicine in Type 2 Diabetes. Front Endocrinol (Lausanne) 2022; 13:857090. [PMID: 35600606 PMCID: PMC9114736 DOI: 10.3389/fendo.2022.857090] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/01/2022] [Indexed: 12/13/2022] Open
Abstract
Pharmacomicrobiomics refers to the interactions between foreign compounds and the gut microbiome resulting in heterogeneous efficacy, side effects, and toxicity of the compound concerned. Glucose lowering drugs reduce blood glucose by modulating insulin secretion and its actions as well as redistributing energy disposal. Apart from genetic, ecological, and lifestyle factors, maintaining an equilibrium of the whole gut microbiome has been shown to improve human health. Microbial fingerprinting using faecal samples indicated an 'invisible phenotype' due to different compositions of microbiota which might orchestrate the interactions between patients' phenotypes and their responses to glucose-lowering drugs. In this article, we summarize the current evidence on differences in composition of gut microbiota between individuals with type 2 diabetes (T2D) and healthy individuals, the disruption of the balance of beneficial and pathogenic microbiota was shown in patients with T2D and how Western Medicine (WM) and Traditional Chinese Medicine (TCM) might re-shape the gut microbiota with benefits to the host immunity and metabolic health. We particularly highlighted the effects of both WM and TCM increase the relative abundance of health promoting bacteria, such as, Akkermansia muciniphila, Blautia, and Bifidobacterium adolescentis, and which have been implicated in type 2 diabetes (T2D). Several lines of evidence suggested that TCM might complement the efficacy of WM through alteration of microbiota which warrants further investigation in our pursuit of prevention and control of T2D.
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Affiliation(s)
- Natural Chu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong SAR, China
| | - Juliana C. N. Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong SAR, China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong SAR, China
- Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong SAR, China
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong SAR, China
- Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Hong Kong SAR, China
- *Correspondence: Elaine Chow,
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32
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Effects of type 2 diabetes and metformin on salivary microbiota in patients with chronic periodontitis. Microb Pathog 2021; 161:105277. [PMID: 34740808 DOI: 10.1016/j.micpath.2021.105277] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 10/11/2021] [Accepted: 11/01/2021] [Indexed: 12/28/2022]
Abstract
Diabetes is closely associated with periodontitis, however, the effects of type 2 diabetes and metformin treatment on the salivary microbiota in chronic periodontitis patients are still insufficiently studied. Saliva was collected from ten patients with moderate to severe chronic periodontitis (CP group) and 20 patients with type 2 diabetes mellitus (T2DM) and moderate to severe chronic periodontitis (ten patients were newly diagnosed with diabetes without drug treatment (DM group), and ten patients were treated with metformin (CP-DM-MET group)). Total DNA was extracted. DNA amplicons of the V3-V4 hypervariable regions of the 16S rRNA gene were generated and subjected to high-throughput sequencing. There was no significant difference in the alpha diversity of the salivary microbiota (Observed_Species, Shannon, Simpson, ACE, Chao1 index) among the three groups. The dominant phyla with relative abundances greater than 1% were Firmicutes, Proteobacteria, Bacteroidota, Actinobacteriota, Fusobacteriota, and Spirochaetota, and no significant difference was found among the three groups. Compared with the CP group, the relative abundance of twelve genera was found changed in CP-DM group, for example, Aggregatibacter, Unclassified_f_Neisseriaceae, Parvimonas, Erysipelotrichace_UCG-006, Atopobium, and Endomicrobium et al. Metformin treatment could partly restore the abundance of several genera in CP-DM, such as Acholeplasma and Comamonas. Compared with the CP group, genus Lactobacillus, Parvimonas, Norank_f_norank_o_Absconditabacteriales_SR1, and Acholeplasma changed significantly in CP-DM-MET group. Plaque index (PLI) was positively correlated with Prevotella and Lactobacillus but negatively correlated with Haemophilus, Lautropia, Unclassified_f_Pasteurellaceae, and TM7x. In conclusion, there was a significant difference in the salivary microbiota of patients with chronic periodontitis complicated by T2DM. Treatment with metformin partially alleviated the alteration in salivary microbiota caused by T2DM.
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Cheng CK, Huang Y. The gut-cardiovascular connection: new era for cardiovascular therapy. MEDICAL REVIEW (BERLIN, GERMANY) 2021; 1:23-46. [PMID: 37724079 PMCID: PMC10388818 DOI: 10.1515/mr-2021-0002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/02/2021] [Indexed: 09/20/2023]
Abstract
Our gut microbiome is constituted by trillions of microorganisms including bacteria, archaea and eukaryotic microbes. Nowadays, gut microbiome has been gradually recognized as a new organ system that systemically and biochemically interact with the host. Accumulating evidence suggests that the imbalanced gut microbiome contributes to the dysregulation of immune system and the disruption of cardiovascular homeostasis. Specific microbiome profiles and altered intestinal permeability are often observed in the pathophysiology of cardiovascular diseases. Gut-derived metabolites, toxins, peptides and immune cell-derived cytokines play pivotal roles in the induction of inflammation and the pathogenesis of dysfunction of heart and vasculature. Impaired crosstalk between gut microbiome and multiple organ systems, such as gut-vascular, heart-gut, gut-liver and brain-gut axes, are associated with higher cardiovascular risks. Medications and strategies that restore healthy gut microbiome might therefore represent novel therapeutic options to lower the incidence of cardiovascular and metabolic disorders.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science; The Chinese University of Hong Kong, Hong Kong SAR999077, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR999077, China
| | - Yu Huang
- School of Biomedical Sciences and Li Ka Shing Institute of Health Science; The Chinese University of Hong Kong, Hong Kong SAR999077, China
- Heart and Vascular Institute and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR999077, China
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34
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Cunningham AL, Stephens JW, Harris DA. Gut microbiota influence in type 2 diabetes mellitus (T2DM). Gut Pathog 2021; 13:50. [PMID: 34362432 PMCID: PMC8343927 DOI: 10.1186/s13099-021-00446-0] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 07/25/2021] [Indexed: 12/12/2022] Open
Abstract
A strong and expanding evidence base supports the influence of gut microbiota in human metabolism. Altered glucose homeostasis is associated with altered gut microbiota, and is clearly associated with the development of type 2 diabetes mellitus (T2DM) and associated complications. Understanding the causal association between gut microbiota and metabolic risk has the potential role of identifying susceptible individuals to allow early targeted intervention.
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Affiliation(s)
- A L Cunningham
- Department of Surgery, Swansea Bay University Health Board, Singleton Hospital, Swansea, SA2 8QA, Wales. .,School of Medicine, Swansea University Medical School, Institute of Life Science 2, Swansea, SA2 8QA, Wales.
| | - J W Stephens
- Department of Surgery, Swansea Bay University Health Board, Singleton Hospital, Swansea, SA2 8QA, Wales.,School of Medicine, Swansea University Medical School, Institute of Life Science 2, Swansea, SA2 8QA, Wales
| | - D A Harris
- Department of Surgery, Swansea Bay University Health Board, Singleton Hospital, Swansea, SA2 8QA, Wales.,School of Medicine, Swansea University Medical School, Institute of Life Science 2, Swansea, SA2 8QA, Wales
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35
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Detka J, Głombik K. Insights into a possible role of glucagon-like peptide-1 receptor agonists in the treatment of depression. Pharmacol Rep 2021; 73:1020-1032. [PMID: 34003475 PMCID: PMC8413152 DOI: 10.1007/s43440-021-00274-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/04/2021] [Accepted: 05/06/2021] [Indexed: 01/23/2023]
Abstract
Depression is a highly prevalent mood disorder and one of the major health concerns in modern society. Moreover, it is characterized by a high prevalence of coexistence with many other diseases including metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity. Currently used antidepressant drugs, which mostly target brain monoaminergic neurotransmission, have limited clinical efficacy. Although the etiology of depression has not been fully elucidated, current scientific data emphasize the role of neurotrophic factors deficiencies, disturbed homeostasis between the nervous system and the immune and endocrine systems, as well as disturbances in brain energy metabolism and dysfunctions in the gut-brain axis as important factors in the pathogenesis of this neuropsychiatric disorder. Therefore, therapeutic options that could work in a way other than classic antidepressants are being sought to increase the effectiveness of the treatment. Interestingly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), used in the treatment of T2DM and obesity, are known to show pro-cognitive and neuroprotective properties, and exert modulatory effects on immune, endocrine and metabolic processes in the central nervous system. This review article discusses the potential antidepressant effects of GLP-1RAs, especially in the context of their action on the processes related to neuroprotection, inflammation, stress response, energy metabolism, gut-brain crosstalk and the stability of the gut microbiota.
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Affiliation(s)
- Jan Detka
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Maj Institute of Pharmacology, 12 Smętna Street, 31-343, Cracow, Poland.
| | - Katarzyna Głombik
- Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Polish Academy of Sciences, Maj Institute of Pharmacology, 12 Smętna Street, 31-343, Cracow, Poland
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36
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Liu J, Ting JP, Al-Azzam S, Ding Y, Afshar S. Therapeutic Advances in Diabetes, Autoimmune, and Neurological Diseases. Int J Mol Sci 2021; 22:ijms22062805. [PMID: 33802091 PMCID: PMC8001105 DOI: 10.3390/ijms22062805] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/02/2021] [Accepted: 03/06/2021] [Indexed: 02/08/2023] Open
Abstract
Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.
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Affiliation(s)
- Jinsha Liu
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Joey Paolo Ting
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Shams Al-Azzam
- Professional Scientific Services, Eurofins Lancaster Laboratories, Lancaster, PA 17605, USA;
| | - Yun Ding
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
| | - Sepideh Afshar
- Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; (J.L.); (J.P.T.); (Y.D.)
- Correspondence:
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Balvers M, van den Born BJH, Levin E, Nieuwdorp M. Impact drugs targeting cardiometabolic risk on the gut microbiota. Curr Opin Lipidol 2021; 32:38-54. [PMID: 33332920 DOI: 10.1097/mol.0000000000000727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Alterations in the gut microbiome composition or function are associated with risk factors for cardiometabolic diseases, including hypertension, hyperlipidemia and hyperglycemia. Based on recent evidence that also oral medications used to treat these conditions could alter the gut microbiome composition and function and, vice versa, that the gut microbiome could affect the efficacy of these treatments, we reviewed the literature on these observed interactions. RECENT FINDINGS While the interaction of metformin with the gut microbiome has been studied most, other drugs that target cardiometabolic risk are gaining attention and often showed associations with alterations in microbiome-related features, including alterations in specific microbial taxa or pathways, microbiome composition or microbiome-derived metabolites, while the gut microbiome was also involved in drug metabolism and drug efficacy. As for metformin, for some of them even a potential therapeutic effect via the gut microbiome is postulated. However, exact mechanisms remain to be elucidated. SUMMARY There is growing interest in clarifying the interactions between the gut microbiome and drugs to treat hypertension, hyperlipidemia and hyperglycemia as well as the first pass effect of microbiome on drug efficacy. While mostly analysed in animal models, also human studies are gaining more and more traction. Improving the understanding of the gut microbiome drug interaction can provide clinical directions for therapy by optimizing drug efficacy or providing new targets for drug development.
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Affiliation(s)
- Manon Balvers
- Department of Internal and Vascular Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam
- Horaizon BV, Delft
| | - Bert-Jan H van den Born
- Department of Internal and Vascular Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam
- Department of Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Evgeni Levin
- Department of Internal and Vascular Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam
- Horaizon BV, Delft
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam
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D'Marco L, Morillo V, Gorriz JL, Suarez MK, Nava M, Ortega Á, Parra H, Villasmil N, Rojas-Quintero J, Bermúdez V. SGLT2i and GLP-1RA in Cardiometabolic and Renal Diseases: From Glycemic Control to Adipose Tissue Inflammation and Senescence. J Diabetes Res 2021; 2021:9032378. [PMID: 34790827 PMCID: PMC8592766 DOI: 10.1155/2021/9032378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/01/2021] [Accepted: 10/18/2021] [Indexed: 12/16/2022] Open
Abstract
Background. Over the last few years, the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) has increased substantially in medical practice due to their documented benefits in cardiorenal and metabolic health. In this sense, and in addition to being used for glycemic control in diabetic patients, these drugs also have other favorable effects such as weight loss and lowering blood pressure, and more recently, they have been shown to have cardio and renoprotective effects with anti-inflammatory properties. Concerning the latter, the individual or associated use of these antihyperglycemic agents has been linked with a decrease in proinflammatory cytokines and with an improvement in the inflammatory profile in chronic endocrine-metabolic diseases. Hence, these drugs have been positioned as first-line therapy in the management of diabetes and its multiple comorbidities, such as obesity, which has been associated with persistent inflammatory states that induce dysfunction of the adipose tissue. Moreover, other frequent comorbidities in long-standing diabetic patients are chronic complications such as diabetic kidney disease, whose progression can be slowed by SGLT2i and/or GLP-1RA. The neuroendocrine and immunometabolism mechanisms underlying adipose tissue inflammation in individuals with diabetes and cardiometabolic and renal diseases are complex and not fully understood. Summary. This review intends to expose the probable molecular mechanisms and compile evidence of the synergistic or additive anti-inflammatory effects of SGLT2i and GLP-1RA and their potential impact on the management of patients with obesity and cardiorenal compromise.
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Affiliation(s)
- Luis D'Marco
- Hospital Clínico Universitario de Valencia, INCLIVA, Valencia 46010, Spain
- CEU Cardenal Herrera University, Valencia 46115, Spain
| | - Valery Morillo
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - José Luis Gorriz
- Hospital Clínico Universitario de Valencia, INCLIVA, Valencia 46010, Spain
| | - María K. Suarez
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Manuel Nava
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Ángel Ortega
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Heliana Parra
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Nelson Villasmil
- School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Joselyn Rojas-Quintero
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 77054, USA
| | - Valmore Bermúdez
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080002, Colombia
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Tsai CY, Lu HC, Chou YH, Liu PY, Chen HY, Huang MC, Lin CH, Tsai CN. Gut Microbial Signatures for Glycemic Responses of GLP-1 Receptor Agonists in Type 2 Diabetic Patients: A Pilot Study. Front Endocrinol (Lausanne) 2021; 12:814770. [PMID: 35095773 PMCID: PMC8793908 DOI: 10.3389/fendo.2021.814770] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 12/13/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUNDS Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is probably one of more effective antidiabetic agents in treatment of type 2 diabetes mellitus (T2D). However, the heterogenicity in responses to GLP-1 RA may be potentially related to gut microbiota, although no human evidence has been published. This pilot study aims to identify microbial signatures associated with glycemic responses to GLP-1 RA. MATERIALS AND METHODS Microbial compositions of 52 patients with T2D receiving GLP-1 RA were determined by 16S rRNA amplicon sequencing. Bacterial biodiversity was compared between responders versus non-responders. Pearson's correlation and random forest tree algorithm were used to identify microbial features of glycemic responses in T2D patients and multivariable linear regression models were used to validate clinical relevance. RESULTS Beta diversity significantly differed between GLP-1 RA responders (n = 34) and non-responders (n = 18) (ADONIS, P = 0.004). The top 17 features associated with glycohemoglobin reduction had a 0.96 diagnostic ability, based on area under the ROC curve: Bacteroides dorei and Roseburia inulinivorans, the two microbes having immunomodulation effects, along with Lachnoclostridium sp. and Butyricicoccus sp., were positively correlated with glycemic reduction; Prevotella copri, the microbe related to insulin resistance, together with Ruminococcaceae sp., Bacteroidales sp., Eubacterium coprostanoligenes sp., Dialister succinatiphilus, Alistipes obesi, Mitsuokella spp., Butyricimonas virosa, Moryella sp., and Lactobacillus mucosae had negative correlation. Furthermore, Bacteroides dorei, Lachnoclostridium sp. and Mitsuokella multacida were significant after adjusting for baseline glycohemoglobin and C-peptide concentrations, two clinical confounders. CONCLUSIONS Unique gut microbial signatures are associated with glycemic responses to GLP-RA treatment and reflect degrees of dysbiosis in T2D patients.
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Affiliation(s)
- Chih-Yiu Tsai
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - Hsiu-Chen Lu
- Department of Life Science, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yu-Hsien Chou
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Po-Yu Liu
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Pathobiology and Population Sciences, Royal Veterinary College, University of London, Hatfield, United Kingdom
| | - Hsin-Yun Chen
- Department of Medical Nutrition Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Meng-Chuan Huang
- Department of Nutrition and Dietetics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Graduate Institute of Medicine and Department of Public Health and Environmental Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Hung Lin
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- *Correspondence: Chia-Hung Lin, ; Chi-Neu Tsai,
| | - Chi-Neu Tsai
- Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
- Department of Surgery, New Taipei Municipal Tucheng Hospital, New Taipei City, Taiwan
- *Correspondence: Chia-Hung Lin, ; Chi-Neu Tsai,
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40
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Gupta A, Osadchiy V, Mayer EA. Brain-gut-microbiome interactions in obesity and food addiction. Nat Rev Gastroenterol Hepatol 2020; 17:655-672. [PMID: 32855515 PMCID: PMC7841622 DOI: 10.1038/s41575-020-0341-5] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/24/2020] [Indexed: 12/13/2022]
Abstract
Normal eating behaviour is coordinated by the tightly regulated balance between intestinal and extra-intestinal homeostatic and hedonic mechanisms. By contrast, food addiction is a complex, maladaptive eating behaviour that reflects alterations in brain-gut-microbiome (BGM) interactions and a shift of this balance towards hedonic mechanisms. Each component of the BGM axis has been implicated in the development of food addiction, with both brain to gut and gut to brain signalling playing a role. Early-life influences can prime the infant gut microbiome and brain for food addiction, which might be further reinforced by increased antibiotic usage and dietary patterns throughout adulthood. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food can further shift this balance towards hedonic eating through both central (disruptions in dopaminergic signalling) and intestinal (vagal afferent function, metabolic endotoxaemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. In this Review, we propose a systems biology model of BGM interactions, which incorporates published reports on food addiction, and provides novel insights into treatment targets aimed at each level of the BGM axis.
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Affiliation(s)
- Arpana Gupta
- G. Oppenheimer Family Center for Neurobiology of Stress and Resilience, Ingestive Behavior and Obesity Program, University of California Los Angeles, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA, USA
| | - Vadim Osadchiy
- G. Oppenheimer Family Center for Neurobiology of Stress and Resilience, Ingestive Behavior and Obesity Program, University of California Los Angeles, Los Angeles, CA, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Emeran A Mayer
- G. Oppenheimer Family Center for Neurobiology of Stress and Resilience, Ingestive Behavior and Obesity Program, University of California Los Angeles, Los Angeles, CA, USA.
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
- Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA, USA.
- Ahmanson-Lovelace Brain Mapping Center at University of California Los Angeles, University of California Los Angeles, Los Angeles, CA, USA.
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Ding QY, Tian JX, Li M, Lian FM, Zhao LH, Wei XX, Han L, Zheng YJ, Gao ZZ, Yang HY, Fang XY, Tong XL. Interactions Between Therapeutics for Metabolic Disease, Cardiovascular Risk Factors, and Gut Microbiota. Front Cell Infect Microbiol 2020; 10:530160. [PMID: 33194785 PMCID: PMC7644821 DOI: 10.3389/fcimb.2020.530160] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 09/16/2020] [Indexed: 12/11/2022] Open
Abstract
With improved standards of living, the incidence of multiple metabolic disorders has increased year by year, especially major risk factors for cardiovascular disease such as hyperglycemia and hyperlipidemia, continues to increase. Emerging epidemiological data and clinical trials have shown the additional protective effects of some metabolic therapy drugs against cardiovascular diseases. A series of studies have found that these drugs may work by modulating the composition of gut microbiota. In this review, we provide a brief overview of the contribution of the gut microbiota to both metabolic disorders and cardiovascular diseases, as well as the response of gut microbiota to metabolic therapy drugs with cardiovascular benefits. In this manner, we link the recent advances in microbiome studies on metabolic treatment drugs with their cardiovascular protective effects, suggesting that intestinal microorganisms may play a potential role in reducing cardiovascular risk factors. We also discuss the potential of microorganism-targeted therapeutics as treatment strategies for preventing and/or treating cardiovascular disease and highlight the need to establish causal links between therapeutics for metabolic diseases, gut microbiota modulation, and cardiovascular protection.
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Affiliation(s)
- Qi-You Ding
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Jia-Xing Tian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Li
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Feng-Mei Lian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lin-Hua Zhao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiu-Xiu Wei
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Lin Han
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu-Jiao Zheng
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Ze-Zheng Gao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Hao-Yu Yang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xin-Yi Fang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xiao-Lin Tong
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Microbiota and Diabetes Mellitus: Role of Lipid Mediators. Nutrients 2020; 12:nu12103039. [PMID: 33023000 PMCID: PMC7600362 DOI: 10.3390/nu12103039] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/23/2020] [Accepted: 08/27/2020] [Indexed: 12/13/2022] Open
Abstract
Diabetes Mellitus (DM) is an inflammatory clinical entity with different mechanisms involved in its physiopathology. Among these, the dysfunction of the gut microbiota stands out. Currently, it is understood that lipid products derived from the gut microbiota are capable of interacting with cells from the immune system and have an immunomodulatory effect. In the presence of dysbiosis, the concentration of lipopolysaccharides (LPS) increases, favoring damage to the intestinal barrier. Furthermore, a pro-inflammatory environment prevails, and a state of insulin resistance and hyperglycemia is present. Conversely, during eubiosis, the production of short-chain fatty acids (SCFA) is fundamental for the maintenance of the integrity of the intestinal barrier as well as for immunogenic tolerance and appetite/satiety perception, leading to a protective effect. Additionally, it has been demonstrated that alterations or dysregulation of the gut microbiota can be reversed by modifying the eating habits of the patients or with the administration of prebiotics, probiotics, and symbiotics. Similarly, different studies have demonstrated that drugs like Metformin are capable of modifying the composition of the gut microbiota, promoting changes in the biosynthesis of LPS, and the metabolism of SCFA.
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43
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Li X, Huang Y, Song L, Xiao Y, Lu S, Xu J, Li J, Ren Z. Lactobacillus plantarum prevents obesity via modulation of gut microbiota and metabolites in high-fat feeding mice. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104103] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Targher G, Byrne CD, Tilg H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut 2020; 69:1691-1705. [PMID: 32321858 DOI: 10.1136/gutjnl-2020-320622] [Citation(s) in RCA: 467] [Impact Index Per Article: 93.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 03/27/2020] [Accepted: 03/31/2020] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a public health problem, affecting up to a third of the world's adult population. Several cohort studies have consistently documented that NAFLD (especially in its more advanced forms) is associated with a higher risk of all-cause mortality and that the leading causes of death among patients with NAFLD are cardiovascular diseases (CVDs), followed by extrahepatic malignancies and liver-related complications. A growing body of evidence also indicates that NAFLD is strongly associated with an increased risk of major CVD events and other cardiac complications (ie, cardiomyopathy, cardiac valvular calcification and cardiac arrhythmias), independently of traditional cardiovascular risk factors. This narrative review provides an overview of the literature on: (1) the evidence for an association between NAFLD and increased risk of cardiovascular, cardiac and arrhythmic complications, (2) the putative pathophysiological mechanisms linking NAFLD to CVD and other cardiac complications and (3) the current pharmacological treatments for NAFLD that might also benefit or adversely affect risk of CVD.
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Affiliation(s)
- Giovanni Targher
- Endocrinology and Metabolism, University of Verona Department of Medicine, Verona, Veneto, Italy
| | - Christopher D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Tirol, Austria
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Mastrocola R, Collotta D, Gaudioso G, Le Berre M, Cento AS, Ferreira Alves G, Chiazza F, Verta R, Bertocchi I, Manig F, Hellwig M, Fava F, Cifani C, Aragno M, Henle T, Joshi L, Tuohy K, Collino M. Effects of Exogenous Dietary Advanced Glycation End Products on the Cross-Talk Mechanisms Linking Microbiota to Metabolic Inflammation. Nutrients 2020; 12:nu12092497. [PMID: 32824970 PMCID: PMC7551182 DOI: 10.3390/nu12092497] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/15/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022] Open
Abstract
Heat-processed diets contain high amounts of advanced glycation end products (AGEs). Here we explore the impact of an AGE-enriched diet on markers of metabolic and inflammatory disorders as well as on gut microbiota composition and plasma proteins glycosylation pattern. C57BL/6 mice were allocated into control diet (CD, n = 15) and AGE-enriched diet (AGE-D, n = 15) for 22 weeks. AGE-D was prepared replacing casein by methylglyoxal hydroimidazolone-modified casein. AGE-D evoked increased insulin and a significant reduction of GIP/GLP-1 incretins and ghrelin plasma levels, altered glucose tolerance, and impaired insulin signaling transduction in the skeletal muscle. Moreover, AGE-D modified the systemic glycosylation profile, as analyzed by lectin microarray, and increased Nε-carboxymethyllysine immunoreactivity and AGEs receptor levels in ileum and submandibular glands. These effects were associated to increased systemic levels of cytokines and impaired gut microbial composition and homeostasis. Significant correlations were recorded between changes in bacterial population and in incretins and inflammatory markers levels. Overall, our data indicates that chronic exposure to dietary AGEs lead to a significant unbalance in incretins axis, markers of metabolic inflammation, and a reshape of both the intestinal microbiota and plasma protein glycosylation profile, suggesting intriguing pathological mechanisms underlying AGEs-induced metabolic derangements.
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Affiliation(s)
- Raffaella Mastrocola
- Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy; (A.S.C.); (M.A.)
- Correspondence: (R.M.); (M.C.); Tel.: +39-011-6707758 (R.M.); +39-011-6706861 (M.C.)
| | - Debora Collotta
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (D.C.); (G.F.A.); (F.C.); (R.V.)
| | - Giulia Gaudioso
- Fondazione Edmund Mach, 38010 San Michele all’Adige, Italy; (G.G.); (F.F.); (K.T.)
| | - Marie Le Berre
- Biomedical Sciences, National University of Ireland, H91 TK33 Galway, Ireland; (M.L.B.); (L.J.)
| | - Alessia Sofia Cento
- Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy; (A.S.C.); (M.A.)
| | - Gustavo Ferreira Alves
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (D.C.); (G.F.A.); (F.C.); (R.V.)
| | - Fausto Chiazza
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (D.C.); (G.F.A.); (F.C.); (R.V.)
| | - Roberta Verta
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (D.C.); (G.F.A.); (F.C.); (R.V.)
| | - Ilaria Bertocchi
- Department of Neuroscience, University of Turin, 10124 Turin, Italy;
| | - Friederike Manig
- Chair of Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany; (F.M.); (M.H.); (T.H.)
| | - Michael Hellwig
- Chair of Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany; (F.M.); (M.H.); (T.H.)
| | - Francesca Fava
- Fondazione Edmund Mach, 38010 San Michele all’Adige, Italy; (G.G.); (F.F.); (K.T.)
| | - Carlo Cifani
- Pharmacology Unit, School of Pharmacy, University of Camerino, 62032 Camerino, Italy;
| | - Manuela Aragno
- Department of Clinical and Biological Sciences, University of Turin, 10125 Turin, Italy; (A.S.C.); (M.A.)
| | - Thomas Henle
- Chair of Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany; (F.M.); (M.H.); (T.H.)
| | - Lokesh Joshi
- Biomedical Sciences, National University of Ireland, H91 TK33 Galway, Ireland; (M.L.B.); (L.J.)
| | - Kieran Tuohy
- Fondazione Edmund Mach, 38010 San Michele all’Adige, Italy; (G.G.); (F.F.); (K.T.)
| | - Massimo Collino
- Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy; (D.C.); (G.F.A.); (F.C.); (R.V.)
- Correspondence: (R.M.); (M.C.); Tel.: +39-011-6707758 (R.M.); +39-011-6706861 (M.C.)
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Orlistat-Induced Gut Microbiota Modification in Obese Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:9818349. [PMID: 32328145 PMCID: PMC7168719 DOI: 10.1155/2020/9818349] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 02/11/2020] [Accepted: 03/04/2020] [Indexed: 12/28/2022]
Abstract
Introduction Accumulating evidence has indicated that alterations of gut microbiota have been involved in various metabolic diseases. Orlistat, a reversible inhibitor of pancreatic and gastric lipase, has beneficial effects on weight loss and metabolism. However, the effect of orlistat on the composition of gut microbiota remains unclear. Objective We aimed to explore the effect of orlistat on gut microbiota in high-fat diet (HFD) fed C57BL/6J obese mice. Methods C57BL/6J mice were randomly divided into three groups: control (NCD), HFD, and HFD + orlistat (ORL). Mice in the NCD group were fed chow diet, while the other groups were fed HFD for 6 months, and orlistat was added in the final 3 months in the HFD + ORL group. After sacrifice, body weight and metabolic parameters were assessed, and the gut microbial composition was analyzed by 16S rRNA gene sequencing. Results Orlistat treatment exerted beneficial effects on body weight, plasma cholesterol, and glucose tolerance. Meanwhile, orlistat treatment modified the gut microbiota, presenting as reduced total microbial abundance and obvious upregulated bacteria. Moreover, the upregulated bacteria correlated with several metabolic pathways. Conclusions Orlistat may exert beneficial effects on body weight and glucose tolerance through modifying the composition of gut microbiota.
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Skonieczna-Żydecka K, Łoniewski I, Stachowska E, Marlicz W, Correll CU. Current and Novel Approaches to Mitigate Cardiometabolic Adverse Effects of Second-Generation Antipsychotics. Int J Neuropsychopharmacol 2020; 23:491-495. [PMID: 32239144 PMCID: PMC7689205 DOI: 10.1093/ijnp/pyaa026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 03/30/2020] [Indexed: 12/16/2022] Open
Abstract
Second-generation antipsychotic-related weight gain and metabolic disturbances are a major public health issue given the widespread prescribing of these medications. The lack of clearly known mechanisms of cardiometabolic adverse effects and the relevance of cardiometabolic health for survival make this an important area for research. While nonpharmacologic and some pharmacologic treatments have shown benefits vs control conditions or placebo, the effects are modest and long-term benefits are less clear. Therefore, new approaches to mitigate second-generation antipsychotic-associated cardiometabolic burden are sorely needed.
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Affiliation(s)
- Karolina Skonieczna-Żydecka
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Szczecin, Poland,Correspondence: Karolina Skonieczna-Żydecka, PhD, Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Broniewskiego 24, 71-460 Szczecin, Poland ()
| | - Igor Łoniewski
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Szczecin, Poland
| | - Ewa Stachowska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Szczecin, Poland
| | - Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
| | - Christoph U Correll
- Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY,Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY,Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany
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Cao TTB, Wu KC, Hsu JL, Chang CS, Chou C, Lin CY, Liao YM, Lin PC, Yang LY, Lin HW. Effects of Non-insulin Anti-hyperglycemic Agents on Gut Microbiota: A Systematic Review on Human and Animal Studies. Front Endocrinol (Lausanne) 2020; 11:573891. [PMID: 33071980 PMCID: PMC7538596 DOI: 10.3389/fendo.2020.573891] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 08/20/2020] [Indexed: 01/30/2023] Open
Abstract
Background: As growing evidence links gut microbiota with the therapeutic efficacy and side effects of anti-hyperglycemic drugs, this article aims to provide a systematic review of the reciprocal interactions between anti-hyperglycemic drugs and gut microbiota taxa, which underlie the effect of the gut microbiome on diabetic control via bug-host interactions. Method: We followed the PRISMA requirements to perform a systematic review on human vs. animal gut microbiota data in PubMed, SCOPUS, and EMBASE databases, and used Cochrane, ROBIN-I, and SYRCLE tools to assess potential bias risks. The outcomes of assessment were trends on gut microbiota taxa, diversity, and associations with metabolic control (e.g., glucose, lipid) following anti-hyperglycemic treatment. Results: Of 2,804 citations, 64 studies (17/humans; 47/mice) were included. In human studies, seven were randomized trials using metformin or acarbose in obese, pre-diabetes, and type 2 diabetes (T2D) patients. Treatment of pre-diabetes and newly diagnosed T2D patients with metformin or acarbose was associated with decreases in genus of Bacteroides, accompanied by increases in both Bifidobacterium and Lactobacillus. Additionally, T2D patients receiving metformin showed increases in various taxa of the order Enterobacteriales and the species Akkermansia muciniphila. Of seven studies with significant differences in beta-diversity, the incremental specific taxa were associated with the improvement of glucose and lipid profiles. In mice, the effects of metformin on A. muciniphila were similar, but an inverse association with Bacteroides was reported. Animal studies on other anti-hyperglycemic drugs, however, showed substantial variations in results. Conclusions: The changes in specific taxa and β-diversity of gut microbiota were associated with metformin and acarbose in humans while pertinent information for other anti-hyperglycemic drugs could only be obtained in rodent studies. Further human studies on anti-hyperglycemic drugs other than metformin and acarbose are needed to explore gut microbiota's role in their therapeutic efficacies and side effects.
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Affiliation(s)
- Thao T. B. Cao
- School of Pharmacy and Graduate Institute, China Medical University, Taichung City, Taiwan
- Department of Clinical Pharmacy, Hanoi University of Pharmacy, Hanoi, Vietnam
| | - Kun-Chang Wu
- School of Pharmacy and Graduate Institute, China Medical University, Taichung City, Taiwan
| | - Jye-Lin Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung City, Taiwan
| | - Chih-Shiang Chang
- School of Pharmacy and Graduate Institute, China Medical University, Taichung City, Taiwan
| | - Chiahung Chou
- Department of Health Outcomes Research and Policy, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
- Department of Medical Research, China Medical University Hospital, Taichung City, Taiwan
| | - Chen-Yuan Lin
- School of Pharmacy and Graduate Institute, China Medical University, Taichung City, Taiwan
- Division of Hematology and Oncology, China Medical University Hospital, Taichung City, Taiwan
| | - Yu-Min Liao
- Division of Hematology and Oncology, China Medical University Hospital, Taichung City, Taiwan
| | - Pei-Chun Lin
- School of Pharmacy and Graduate Institute, China Medical University, Taichung City, Taiwan
| | - Liang-Yo Yang
- Department of Physiology, School of Medicine, College of Medicine, China Medical University, Taichung City, Taiwan
- Laboratory for Neural Repair, China Medical University Hospital, Taichung City, Taiwan
- Biomedical Technology Research and Development Center, China Medical University Hospital, Taichung City, Taiwan
| | - Hsiang-Wen Lin
- School of Pharmacy and Graduate Institute, China Medical University, Taichung City, Taiwan
- Department of Pharmacy, China Medical University Hospital, Taichung City, Taiwan
- Department of Pharmacy System, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, United States
- *Correspondence: Hsiang-Wen Lin
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Affiliation(s)
- Andrea Nuzzo
- Computational Biology, Human Genetics, R&D, GlaxoSmithKline, Mail Stop UP12-200 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States
| | - James R. Brown
- Computational Biology, Human Genetics, R&D, GlaxoSmithKline, Mail Stop UP12-200 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States
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Metabolic and gut microbiome changes following GLP-1 or dual GLP-1/GLP-2 receptor agonist treatment in diet-induced obese mice. Sci Rep 2019; 9:15582. [PMID: 31666597 PMCID: PMC6821799 DOI: 10.1038/s41598-019-52103-x] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 10/14/2019] [Indexed: 12/12/2022] Open
Abstract
Enteroendocrine L-cell derived peptide hormones, notably glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2), have become important targets in the treatment of type 2 diabetes, obesity and intestinal diseases. As gut microbial imbalances and maladaptive host responses have been implicated in the pathology of obesity and diabetes, this study aimed to determine the effects of pharmacologically stimulated GLP-1 and GLP-2 receptor function on the gut microbiome composition in diet-induced obese (DIO) mice. DIO mice received treatment with a selective GLP-1 receptor agonist (liraglutide, 0.2 mg/kg, BID) or dual GLP-1/GLP-2 receptor agonist (GUB09–145, 0.04 mg/kg, BID) for 4 weeks. Both compounds suppressed caloric intake, promoted a marked weight loss, improved glucose tolerance and reduced plasma cholesterol levels. 16S rDNA sequencing and deep-sequencing shotgun metagenomics was applied for comprehensive within-subject profiling of changes in gut microbiome signatures. Compared to baseline, DIO mice assumed phylogenetically similar gut bacterial compositional changes following liraglutide and GUB09-145 treatment, characterized by discrete shifts in low-abundant species and related bacterial metabolic pathways. The microbiome alterations may potentially associate to the converging biological actions of GLP-1 and GLP-2 receptor signaling on caloric intake, glucose metabolism and lipid handling.
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