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Liu Y, Kang W, Liu S, Li J, Liu J, Chen X, Gan F, Huang K. Gut microbiota-bile acid-intestinal Farnesoid X receptor signaling axis orchestrates cadmium-induced liver injury. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 849:157861. [PMID: 35934034 DOI: 10.1016/j.scitotenv.2022.157861] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/02/2022] [Accepted: 08/02/2022] [Indexed: 06/15/2023]
Abstract
Cadmium (Cd) is a widely prevalent environmental pollutant that accumulates in the liver and induces liver injury. The mechanism of Cd-induced liver injury remains elusive. Our study aimed to clarify the mechanism by which changes in the gut microbiota contribute to Cd-induced liver injury. Here, a murine model of liver injury induced by chronic Cd exposure was used. Liver injury was assessed by biochemistry and histopathology. Expression profiles of genes involved in bile acid (BA) homeostasis, inflammation and injury were assessed via Realtime-PCR and Western-blot. 16S rRNA gene sequencing and mass spectrometry-based metabolomics were used to investigate changes in the gut microbiota and its metabolites in the regulation of Cd-induced liver injury. Here, we showed that Cd exposure induced hepatic ductular proliferation, hepatocellular damage and inflammatory infiltration in mice. Cd exposure induced gut microbiota dysbiosis and reduced the fecal bile salt hydrolase activity leading to an increase of tauro-β-muricholic acid levels in the intestine. Cd exposure decreased intestine FXR/FGF-15 signaling and promoted hepatic BA synthesis. Furthermore, the mice receiving fecal microbiota transplantation from Cd-treated mice showed reduced intestinal FXR/FGF-15 signaling, increased hepatic BA synthesis, and liver injury. However, the depletion of the commensal microbiota by antibiotics failed to change these indices in Cd-treated mice. Finally, the administration of the intestine-restricted FXR agonist fexaramine attenuated the liver injury, improved the intestinal barrier, and decreased hepatic BA synthesis in the Cd-treated mice. Our study identified a new mechanism of Cd-induced liver injury. Cd-induced gut microbiota dysbiosis, decreased feces BSH activity, and increased intestinal T-βMCA levels led to an inhibition of intestinal FXR/FGF-15 signaling and an increase in hepatic BA synthesis, ultimately facilitating the development of hepatic ductular proliferation, inflammation, and injury in mice. This study expands our understanding of the health hazards caused by environmental Cd pollution.
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Affiliation(s)
- Yunhuan Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Weili Kang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Shuiping Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Jinyan Li
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Jinyan Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Xingxiang Chen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Fang Gan
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China
| | - Kehe Huang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.
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Neurohormonal Changes in the Gut–Brain Axis and Underlying Neuroendocrine Mechanisms following Bariatric Surgery. Int J Mol Sci 2022; 23:ijms23063339. [PMID: 35328759 PMCID: PMC8954280 DOI: 10.3390/ijms23063339] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 02/05/2023] Open
Abstract
Obesity is a complex, multifactorial disease that is a major public health issue worldwide. Currently approved anti-obesity medications and lifestyle interventions lack the efficacy and durability needed to combat obesity, especially in individuals with more severe forms or coexisting metabolic disorders, such as poorly controlled type 2 diabetes. Bariatric surgery is considered an effective therapeutic modality with sustained weight loss and metabolic benefits. Numerous genetic and environmental factors have been associated with the pathogenesis of obesity, while cumulative evidence has highlighted the gut–brain axis as a complex bidirectional communication axis that plays a crucial role in energy homeostasis. This has led to increased research on the roles of neuroendocrine signaling pathways and various gastrointestinal peptides as key mediators of the beneficial effects following weight-loss surgery. The accumulate evidence suggests that the development of gut-peptide-based agents can mimic the effects of bariatric surgery and thus is a highly promising treatment strategy that could be explored in future research. This article aims to elucidate the potential underlying neuroendocrine mechanisms of the gut–brain axis and comprehensively review the observed changes of gut hormones associated with bariatric surgery. Moreover, the emerging role of post-bariatric gut microbiota modulation is briefly discussed.
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Camastra S, Palumbo M, Santini F. Nutrients handling after bariatric surgery, the role of gastrointestinal adaptation. Eat Weight Disord 2022; 27:449-461. [PMID: 33895917 PMCID: PMC8933374 DOI: 10.1007/s40519-021-01194-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/10/2021] [Indexed: 01/19/2023] Open
Abstract
Bariatric surgery determines a rearrangement of the gastrointestinal tract that influences nutrient handling and plays a role in the metabolic changes observed after surgery. Most of the changes depend on the accelerated gastric emptying observed in Roux-en-Y gastric bypass (RYGB) and, to a lesser extent, in sleeve gastrectomy (SG). The rapid delivery of meal into the jejunum, particularly after RYGB, contributes to the prompt appearance of glucose in peripheral circulation. Glucose increase is the principal determinant of GLP-1 increase with the consequent stimulation of insulin secretion, the latter balanced by a paradoxical glucagon increase that stimulates EGP to prevent hypoglycaemia. Protein digestion and amino acid absorption appear accelerated after RYGB but not after SG. After RYGB, the adaptation of the gut to the new condition participates to the metabolic change. The intestinal transit is delayed, the gut microbioma is changed, the epithelium becomes hypertrophic and increases the expression of glucose transporter and of the number of cell secreting hormones. These changes are not observed after SG. After RYGB-less after SG-bile acids (BA) increase, influencing glucose metabolism probably modulating FXR and TGR5 with an effect on insulin sensitivity. Muscle, hepatic and adipose tissue insulin sensitivity improve, and the gut reinforces the recovery of IS by enhancing glucose uptake and through the effect of the BA. The intestinal changes observed after RYGB result in a light malabsorption of lipid but not of carbohydrate and protein. In conclusion, functional and morphological adaptations of the gut after RYGB and SG activate inter-organs cross-talk that modulates the metabolic changes observed after surgery.Level of evidence Level V, narrative literature review.
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Affiliation(s)
- Stefania Camastra
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy. .,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy.
| | - Maria Palumbo
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy
| | - Ferruccio Santini
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy.,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
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FXR in liver physiology: Multiple faces to regulate liver metabolism. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166133. [PMID: 33771667 DOI: 10.1016/j.bbadis.2021.166133] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022]
Abstract
The liver is the central metabolic hub which coordinates nutritional inputs and metabolic outputs. Food intake releases bile acids which can be sensed by the bile acid receptor FXR in the liver and the intestine. Hepatic and intestinal FXR coordinately regulate postprandial nutrient disposal in a network of interacting metabolic nuclear receptors. In this review we summarize and update the "classical roles" of FXR as a central integrator of the feeding state response, which orchestrates the metabolic processing of carbohydrates, lipids, proteins and bile acids. We also discuss more recent and less well studied FXR effects on amino acid, protein metabolism, autophagic turnover and inflammation. In addition, we summarize the recent understanding of how FXR signaling is affected by posttranslational modifications and by different FXR isoforms. These modifications and variations in FXR signaling might be considered when FXR is targeted pharmaceutically in clinical applications.
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Zhang C, Zhang J, Zhou Z. Changes in fasting bile acid profiles after Roux-en-Y gastric bypass and sleeve gastrectomy. Medicine (Baltimore) 2021; 100:e23939. [PMID: 33545968 PMCID: PMC7837931 DOI: 10.1097/md.0000000000023939] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/01/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Bile acid is an essential factor that plays a role in metabolic regulation, but how bile acid is regulated after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) remains unclear. This meta-analysis aimed to investigate changes in the levels of fasting bile acids following RYGB and SG. METHODS A systematic literature search of the PubMed, EMBASE, Cochrane Library and Web of Science databases through July 2020 was performed in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The concentrations of bile acids were evaluated. RESULTS Thirteen studies with 289 patients were included. Our results showed that patients who underwent RYGB had increased levels of fasting total bile acids, primary bile acids, secondary bile acids, conjugated bile acids, and unconjugated bile acids, but no significant differences in all these bile acid levels were observed in patients who underwent SG. Furthermore, 12a-hydroxylated bile acid levels and the 12a-hydroxylated/non-12a-hydroxylated bile acid ratio also increased following RYGB. CONCLUSION In this study, we found that fasting bile acid levels, especially 12a-hydroxylated bile acids levels, were increased after RYGB. However, no differences in fasting bile acid levels were observed following SG.
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Affiliation(s)
- Chunlan Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Metabolic Syndrome Research Center, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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Naumann S, Haller D, Eisner P, Schweiggert-Weisz U. Mechanisms of Interactions between Bile Acids and Plant Compounds-A Review. Int J Mol Sci 2020; 21:E6495. [PMID: 32899482 PMCID: PMC7555273 DOI: 10.3390/ijms21186495] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 02/06/2023] Open
Abstract
Plant compounds are described to interact with bile acids during small intestinal digestion. This review will summarise mechanisms of interaction between bile acids and plant compounds, challenges in in vivo and in vitro analyses, and possible consequences on health. The main mechanisms of interaction assume that increased viscosity during digestion results in reduced micellar mobility of bile acids, or that bile acids and plant compounds are associated or complexed at the molecular level. Increasing viscosity during digestion due to specific dietary fibres is considered a central reason for bile acid retention. Furthermore, hydrophobic interactions are proposed to contribute to bile acid retention in the small intestine. Although frequently hypothesised, no mechanism of permanent binding of bile acids by dietary fibres or indigestible protein fractions has yet been demonstrated. Otherwise, various polyphenolic structures were recently associated with reduced micellar solubility and modification of steroid and bile acid excretion but underlying molecular mechanisms of interaction are not yet fully understood. Therefore, future research activities need to consider the complex composition and cell-wall structures as influenced by processing when investigating bile acid interactions. Furthermore, influences of bile acid interactions on gut microbiota need to be addressed to clarify their role in bile acid metabolism.
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Affiliation(s)
- Susanne Naumann
- ZIEL-Institute for Food & Health, TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany; (D.H.); (P.E.)
- Fraunhofer Institute for Process Engineering and Packaging (IVV), 85354 Freising, Germany;
| | - Dirk Haller
- ZIEL-Institute for Food & Health, TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany; (D.H.); (P.E.)
- Chair of Nutrition and Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany
| | - Peter Eisner
- ZIEL-Institute for Food & Health, TUM School of Life Sciences Weihenstephan, Technical University of Munich, 85354 Freising, Germany; (D.H.); (P.E.)
- Fraunhofer Institute for Process Engineering and Packaging (IVV), 85354 Freising, Germany;
- Steinbeis-Hochschule, Faculty of Technology and Engineering, George-Bähr-Straße 20, 01069 Dresden, Germany
| | - Ute Schweiggert-Weisz
- Fraunhofer Institute for Process Engineering and Packaging (IVV), 85354 Freising, Germany;
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Cagiltay E, Celik A, Dixon JB, Pouwels S, Santoro S, Gupta A, Ugale S, Abdul-Ghani M. Effects of different metabolic states and surgical models on glucose metabolism and secretion of ileal L-cell peptides: results from the HIPER-1 study. Diabet Med 2020; 37:697-704. [PMID: 31773794 DOI: 10.1111/dme.14191] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/22/2019] [Indexed: 12/13/2022]
Abstract
AIM To compare the impact of four surgical procedures (mini-gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition) vs medical management on gut peptide secretion, β-cell function and resolution of hyperglycaemia in people with type 2 diabetes. RESEARCH DESIGN AND METHODS A mixed-meal tolerance test was administered 6-24 months after each surgical procedure (mini-gastric bypass, sleeve gastrectomy, ileal transposition and transit bipartition; n=30 in each group) and the results were compared with those obtained in matched lean (n=30) and obese (n=30) people with type 2 diabetes undergoing medical management. RESULTS Participants in the mini-gastric bypass and ileal transposition groups had a greater increase in plasma glucose concentration after the mixed-meal tolerance test than those in the sleeve gastrectomy and transit bipartition groups. Participants in the mini-gastric bypass group exhibited the greatest increase in the incremental area under the curve of plasma glucose concentration above baseline (P<0.0001). Insulin sensitivity was similar across surgical groups, and statistically greater in participants in the surgical groups than in obese participants in the non-surgical group (P<0.0001). β-cell responsiveness to glucose was greater in participants in the sleeve gastrectomy and transit bipartition groups than in the mini-gastric bypass and ileal transposition groups (P<0.001) despite a smaller incremental increase above baseline in the area under the plasma glucagon-like peptide-1 concentration curve relative to ileal transposition. Postoperative β-cell function was the strongest predictor of hyperglycaemia resolution. CONCLUSIONS The present study showed that the level of β-cell function after bariatric surgery is the strongest predictor of hyperglycaemia resolution. The study also demonstrates a disconnect between postprandial GLP-1 levels and β-cell function among the studied surgical procedures.
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Affiliation(s)
- E Cagiltay
- Department of Immunology, Faculty of Medicine, Saglik Bilimleri University, Istanbul, Turkey
| | - A Celik
- Metabolic Surgery Clinic, Istanbul, Sisli, Turkey
| | - J B Dixon
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia
- Department of Primary Health Care, Monash University, Melbourne, Vic., Australia
| | - S Pouwels
- Department of Surgery, Haaglanden Medical Centre, The Hague, Netherlands
| | - S Santoro
- Department of Surgery, Albert Einstein Hospital, Sao Paolo, Brazil
| | - A Gupta
- Centre for Medical Weight Loss and Metabolic Control, Rowan University, Stratford, NJ, USA
| | - S Ugale
- Department of Bariatric and Metabolic Surgery, Kirloskar Hospital, Hyderabad, India
| | - M Abdul-Ghani
- Cardio-Metabolic Institute, AHS, HMC, Doha, Qatar
- Diabetes Division, University of Texas Health Science Centre, San Antonio, TX, USA
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Li M, Liu Z, Qian B, Liu W, Horimoto K, Xia J, Shi M, Wang B, Zhou H, Chen L. "Dysfunctions" induced by Roux-en-Y gastric bypass surgery are concomitant with metabolic improvement independent of weight loss. Cell Discov 2020; 6:4. [PMID: 32025334 PMCID: PMC6985254 DOI: 10.1038/s41421-019-0138-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 12/03/2019] [Indexed: 12/19/2022] Open
Abstract
Metabolic surgery has been increasingly recommended for obese diabetic patients, but questions remain as to its molecular mechanism that leads to improved metabolic parameters independently of weight loss from a network viewpoint. We evaluated the role of the Roux limb (RL) in Roux-en-Y gastric bypass (RYGB) surgery in nonobese diabetic rat models. Improvements in metabolic parameters were greater in the long-RL RYGB group. Transcriptome profiles reveal that amelioration of diabetes state following RYGB differs remarkably from both normal and diabetic states. According to functional analysis, RYGB surgery significantly affected a major gene group, i.e., the newly changed group, which represented diabetes-irrelevant genes abnormally expressed after RYGB. We hypothesize that novel "dysfunctions" carried by this newly changed gene group induced by RYGB rebalance diabetic states and contribute to amelioration of metabolic parameters. An unusual increase in cholesterol (CHOL) biosynthesis in RL enriched by the newly changed group was concomitant with ameliorated metabolic parameters, as demonstrated by measurements of physiological parameters and biodistribution analysis using [14C]-labeled glucose. Our findings demonstrate RYGB-induced "dysfunctions" in the newly changed group as a compensatory role contributes to amelioration of diabetes. Rather than attempting to normalize "abnormal" molecules, we suggest a new disease treatment strategy of turning "normal" molecules "abnormal" in order to achieve a new "normal" physiological balance. It further implies a novel strategy for drug discovery, i.e. targeting also on "normal" molecules, which are traditionally ignored in pharmaceutical development.
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Affiliation(s)
- Meiyi Li
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy Sciences, Shanghai, 200031 China
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201199 China
| | - Zhiyuan Liu
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy Sciences, Shanghai, 200031 China
| | - Bangguo Qian
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy Sciences, Shanghai, 200031 China
| | - Weixin Liu
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy Sciences, Shanghai, 200031 China
| | - Katsuhisa Horimoto
- Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan
| | - Jie Xia
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy Sciences, Shanghai, 200031 China
| | - Meilong Shi
- Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011 China
| | - Bing Wang
- Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011 China
| | - Huarong Zhou
- Sherman College of Chiropractic, Boiling Springs, SC 29316 USA
| | - Luonan Chen
- Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy Sciences, Shanghai, 200031 China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223 China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031 China
- Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210 China
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Jain AK, le Roux CW, Puri P, Tavakkoli A, Gletsu-Miller N, Laferrère B, Kellermayer R, DiBaise JK, Martindale RG, Wolfe BM. Proceedings of the 2017 ASPEN Research Workshop-Gastric Bypass: Role of the Gut. JPEN J Parenter Enteral Nutr 2019; 42:279-295. [PMID: 29443403 DOI: 10.1002/jpen.1121] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 11/16/2017] [Indexed: 12/11/2022]
Abstract
The goal of the National Institutes of Health-funded American Society for Parenteral and Enteral Nutrition 2017 research workshop (RW) "Gastric Bypass: Role of the Gut" was to focus on the exciting research evaluating gut-derived signals in modulating outcomes after bariatric surgery. Although gastric bypass surgery has undoubted positive effects, the mechanistic basis of improved outcomes cannot be solely explained by caloric restriction. Emerging data suggest that bile acid metabolic pathways, luminal contents, energy balance, gut mucosal integrity, as well as the gut microbiota are significantly modulated after bariatric surgery and may be responsible for the variable outcomes, each of which was rigorously evaluated. The RW served as a timely and novel academic meeting that brought together clinicians and researchers across the scientific spectrum, fostering a unique venue for interdisciplinary collaboration among investigators. It promoted engaging discussion and evolution of new research hypotheses and ideas, driving the development of novel ameliorative, therapeutic, and nonsurgical interventions targeting obesity and its comorbidities. Importantly, a critical evaluation of the current knowledge regarding gut-modulated signaling after bariatric surgery, potential pitfalls, and lacunae were thoroughly addressed.
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Affiliation(s)
- Ajay Kumar Jain
- Department of Pediatrics, SSM Cardinal Glennon Children's Medical Center, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Carel W le Roux
- Diabetes Complications Research Center, University College Dublin, School of Medicine, Dublin, Ireland
| | - Puneet Puri
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Vieginia, USA
| | - Ali Tavakkoli
- Brigham and Women's Hospital, Center for Weight Management and Metabolic Surgery, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Blandine Laferrère
- Department of Medicine, Division of Endocrinology, Columbia University, New York, New York, USA
| | | | - John K DiBaise
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | | | - Bruce M Wolfe
- Oregon Health and Science University, Portland, Oregon, USA
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10
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Andrew CA, Umashanker D, Aronne LJ, Shukla AP. Intestinal and Gastric Origins for Diabetes Resolution After Bariatric Surgery. Curr Obes Rep 2018; 7:139-146. [PMID: 29637413 DOI: 10.1007/s13679-018-0302-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW This paper will review the intestinal and gastric origins for diabetes resolution after bariatric surgery. RECENT FINDINGS In addition to the known metabolic effects of changes in the gut hormonal milieu, more recent studies investigating the role of the microbiome and bile acids and changes in nutrient sensing mechanisms have been shown to have glycemic effects in human and animal models. Independent of weight loss, there are multiple mechanisms that may lead to amelioration or resolution of diabetes following bariatric surgery. There is abundant evidence pointing to changes in gut hormones, bile acids, gut microbiome, and intestinal nutrient sensing; more research is needed to clearly delineate their role in regulating energy and glucose homeostasis after bariatric surgery.
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MESH Headings
- Animals
- Bariatric Surgery
- Bile Acids and Salts/metabolism
- Biomarkers/blood
- Biomarkers/metabolism
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Diabetes Mellitus, Type 2/therapy
- Diet, Reducing
- Dysbiosis/complications
- Dysbiosis/etiology
- Dysbiosis/microbiology
- Dysbiosis/prevention & control
- Gastrointestinal Microbiome
- Humans
- Insulin Resistance
- Intestinal Mucosa/innervation
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/microbiology
- Intestinal Mucosa/physiopathology
- Intestines/innervation
- Intestines/microbiology
- Intestines/physiopathology
- Neurons, Afferent/metabolism
- Neurons, Efferent/metabolism
- Obesity, Morbid/complications
- Obesity, Morbid/diet therapy
- Obesity, Morbid/physiopathology
- Obesity, Morbid/surgery
- Weight Loss
- Weight Reduction Programs
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Affiliation(s)
- Caroline A Andrew
- Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY, 10065, USA
| | - Devika Umashanker
- Comprehensive Medical Weight Management, Department of Bariatric Surgery, Hartford HealthCare Medical Group, Hartford, CT, USA
| | - Louis J Aronne
- Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY, 10065, USA
| | - Alpana P Shukla
- Comprehensive Weight Control Center, Division of Endocrinology, Diabetes & Metabolism, Weill Cornell Medical College, 1165 York Avenue, New York, NY, 10065, USA.
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Lee WJ, Almalki O. Recent advancements in bariatric/metabolic surgery. Ann Gastroenterol Surg 2017; 1:171-179. [PMID: 29863165 PMCID: PMC5881368 DOI: 10.1002/ags3.12030] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Accepted: 06/27/2017] [Indexed: 12/19/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are currently two pan‐endemic health problems worldwide and are associated with considerable increase in morbidity and mortality. Both diseases are closely related and very difficult to control by current medical treatment, including diet, drug therapy and behavioral modification. Bariatric surgery has proven successful in treating not just obesity but also in significantly decreasing overall obesity‐associated morbidities as well as improving quality of life in severely obese patients (body mass index [BMI] >35 kg/m2). A rapid increase in bariatric surgery started in the 2000s when the laparoscopic surgical technique was introduced into this field. Many new procedures had been developed and changed the face of modern bariatric surgery. Recently, bariatric surgery played as gastrointestinal metabolic surgery has been proposed as a new treatment modality for obesity‐related T2DM for patients with BMI >35 kg/m2. Strong evidence has demonstrated that bariatric/metabolic surgery is an effective and durable treatment for obese T2DM patients. Bariatric/metabolic surgery is now becoming an important surgical division. The present article examines and discusses recent advancements in bariatric/metabolic surgery and covers four major fields: (i) the rapid increase in numbers and better safety; (ii) new procedures with better outcomes; (iii) from bariatric to metabolic surgery; and (iv) understanding the mechanisms and personalized treatment.
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Affiliation(s)
- Wei-Jei Lee
- Department of Surgery Min-Sheng General Hospital National Taiwan University Taoyuan Taiwan
| | - Owaid Almalki
- Department of Surgery Min-Sheng General Hospital National Taiwan University Taoyuan Taiwan.,Department of Surgery College of Medicine Taif University Taif Saudi Arabia
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Abstract
Obesity has become increasingly prevalent, and the number of obese patients in need of liver transplant is expected to continue to increase. In addition, liver disease due to nonalcoholic fatty liver disease is expected to become the leading cause of liver transplantation in the near future. However, obesity remains a relative contraindication in liver transplant. New strategies in managing this patient population are clearly needed. To this end, the authors review the current literature on the efficacy of bariatric surgery in the setting of liver transplantation in obese patients.
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Affiliation(s)
- Duminda Suraweera
- Department of Medicine, Olive-View Medical Center, 14445 Olive View Drive, 2B-182, Sylmar, CA 91342, USA
| | - Erik Dutson
- Department of Surgery, University of California at Los Angeles, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA
| | - Sammy Saab
- Department of Surgery, University of California at Los Angeles, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA; Department of Medicine, University of California at Los Angeles, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA.
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Kaska L, Sledzinski T, Chomiczewska A, Dettlaff-Pokora A, Swierczynski J. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World J Gastroenterol 2016; 22:8698-8719. [PMID: 27818587 PMCID: PMC5075546 DOI: 10.3748/wjg.v22.i39.8698] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 08/23/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission.
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Makaronidis JM, Batterham RL. Potential Mechanisms Mediating Sustained Weight Loss Following Roux-en-Y Gastric Bypass and Sleeve Gastrectomy. Endocrinol Metab Clin North Am 2016; 45:539-52. [PMID: 27519129 DOI: 10.1016/j.ecl.2016.04.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Bariatric surgery is the only effective treatment for severe obesity. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the most commonly performed procedures, lead to sustained weight loss, improvements in obesity-related comorbidities and reduced mortality. In humans, the main driver for weight loss following RYGB and SG is reduced energy intake. Reduced appetite, changes in subjective taste and food preference, and altered neural response to food cues are thought to drive altered eating behavior. The biological mediators underlying these changes remain incompletely understood but changes in gut-derived signals, as a consequence of altered nutrient and/or biliary flow, are key candidates.
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Affiliation(s)
- Janine M Makaronidis
- Department of Medicine, Centre for Obesity Research, Rayne Institute, University College London, Rayne Building, 5 University Street, London WC1E 6JF, UK; University College London Hospitals (UCLH) Bariatric Centre for Weight Loss, Metabolic and Endocrine Surgery, UCLH, Ground Floor West Wing, 250 Euston Road, London NW1 2PG, UK; National Institute of Health Research University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road, Kings Cross, London W1T 7DN, UK
| | - Rachel L Batterham
- Department of Medicine, Centre for Obesity Research, Rayne Institute, University College London, Rayne Building, 5 University Street, London WC1E 6JF, UK; University College London Hospitals (UCLH) Bariatric Centre for Weight Loss, Metabolic and Endocrine Surgery, UCLH, Ground Floor West Wing, 250 Euston Road, London NW1 2PG, UK; National Institute of Health Research University College London Hospitals Biomedical Research Centre, 149 Tottenham Court Road, Kings Cross, London W1T 7DN, UK.
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Batterham RL, Cummings DE. Mechanisms of Diabetes Improvement Following Bariatric/Metabolic Surgery. Diabetes Care 2016; 39:893-901. [PMID: 27222547 PMCID: PMC5864134 DOI: 10.2337/dc16-0145] [Citation(s) in RCA: 258] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 03/21/2016] [Indexed: 02/03/2023]
Abstract
More than 20 years ago, Pories et al. published a seminal article, "Who Would Have Thought It? An Operation Proves to Be the Most Effective Therapy for Adult-Onset Diabetes Mellitus." This was based on their observation that bariatric surgery rapidly normalized blood glucose levels in obese people with type 2 diabetes mellitus (T2DM), and 10 years later, almost 90% remained diabetes free. Pories et al. suggested that caloric restriction played a key role and that the relative contributions of proximal intestinal nutrient exclusion, rapid distal gut nutrient delivery, and the role of gut hormones required further investigation. These findings of T2DM improvement/remission after bariatric surgery have been widely replicated, together with the observation that bariatric surgery prevents or delays incident T2DM. Over the ensuing two decades, important glucoregulatory roles of the gastrointestinal (GI) tract have been firmly established. However, the physiological and molecular mechanisms underlying the beneficial glycemic effects of bariatric surgery remain incompletely understood. In addition to the mechanisms proposed by Pories et al., changes in bile acid metabolism, GI tract nutrient sensing and glucose utilization, incretins, possible anti-incretin(s), and the intestinal microbiome are implicated. These changes, acting through peripheral and/or central pathways, lead to reduced hepatic glucose production, increased tissue glucose uptake, improved insulin sensitivity, and enhanced β-cell function. A constellation of factors, rather than a single overarching mechanism, likely mediate postoperative glycemic improvement, with the contributing factors varying according to the surgical procedure. Thus, different bariatric/metabolic procedures provide us with experimental tools to probe GI tract physiology. Embracing this approach through the application of detailed phenotyping, genomics, metabolomics, and gut microbiome studies will enhance our understanding of metabolic regulation and help identify novel therapeutic targets.
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Affiliation(s)
- Rachel L Batterham
- Centre for Obesity Research, Department of Medicine, University College London, London, U.K. Bariatric Centre for Weight Management and Metabolic Surgery, University College London Hospital, London, U.K. National Institute for Health Research, Biomedical Research Centre, University College London Hospital, London, U.K.
| | - David E Cummings
- VA Puget Sound Health Care System and Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA
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Expedited Biliopancreatic Juice Flow to the Distal Gut Benefits the Diabetes Control After Duodenal-Jejunal Bypass. Obes Surg 2016; 25:1802-9. [PMID: 25726319 DOI: 10.1007/s11695-015-1633-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Serum bile acids (BAs) are elevated after metabolic surgeries including Roux-en-Y gastric bypass (RYGB), ileal transposition (IT), and duodenal-jejunal bypass (DJB). Recently, BAs have emerged as a kind of signaling molecules, which can not only promote glucagon-like peptide-1 (GLP-1) secretion but can also regulate multiple enzymes involved in glucose metabolism. The aim of this study was to investigate whether expedited biliopancreatic juice flow to the distal gut contributes to the increased serum GLP-1 and BAs and benefits the diabetes control after DJB. METHODS DJB, long alimentary limb DJB (LDJB), duodenal-jejunal anastomosis (DJA), and sham operation were performed in diabetic rats induced by high-fat diet (HFD) and low dose of streptozotocin (STZ). Body weight, food intake, oral glucose tolerance, insulin tolerance, glucose-stimulated insulin and GLP-1 secretion, fasting serum total bile acids (TBAs), and lipid profiles were measured at indicated time points. RESULTS Compared with sham operation, DJA, DJB, and LDJB all achieved rapid and dramatic improvements in glucose tolerance and insulin sensitivity independently of food restriction and weight loss. DJB and LDJB-operated rats exhibited even better glucose tolerance, higher fasting serum TBAs, and higher glucose-stimulated GLP-1 secretion than the DJA group postoperatively. No difference was detected in insulin sensitivity and glucose-stimulated insulin secretion between DJA, DJB, and LDJB groups. CONCLUSIONS Expedited biliopancreatic juice flow to the distal gut was associated with augmented GLP-1 secretion and increased fasting serum TBA concentration, which may partly explain the metabolic benefits of DJB.
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Kampmann K, Ueberberg S, Menge BA, Breuer TGK, Uhl W, Tannapfel A, Meier JJ. Abundance and turnover of GLP-1 producing L-cells in ileal mucosa are not different in patients with and without type 2 diabetes. Metabolism 2016; 65:84-91. [PMID: 26892519 DOI: 10.1016/j.metabol.2015.10.025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/01/2015] [Accepted: 10/18/2015] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The gastrointestinal hormone GLP-1 is released from enteroendocrine L-cells and augments postprandial insulin secretion. In patients with type 2 diabetes, the incretin effect is markedly diminished. It is unclear, whether this is due to a reduction in the abundance of L-cells in the intestine. METHODS Ileal tissue samples from 10 patients with and 10 patients without diabetes that underwent surgery for the removal of colon tumors were included. Tissue sections were stained for GLP-1, Ki67, TUNEL and chromogranin A. RESULTS The number of L-cells was not different between patients with and without diabetes in either crypts (1.81±0.21% vs. 1.49±0.24%, respectively; p=0.31) or villi (1.07±0.16% vs. 0.83±0.10%, respectively; p=0.23). L-cell number was higher in crypts than in villi (p<0.0001). L-cell replication was detected rarely and not different between the groups. L-cell apoptosis was similar in patients with and without diabetes in both crypts (7.84±2.77% vs. 8.65±3.77%, p=0.85) and villi (4.48±2.89% vs. 8.62±4.64%, p=0.42). Chromogranin A staining was found in a subset of L-cells only. CONCLUSIONS Intestinal L-cell density is higher in crypts than in villi. Chromogranin A is not a prerequisite for GLP-1 production. L-cell density and turnover are not different between patients with and without diabetes. Thus, alterations in the number of GLP-1 producing cells do not explain the reduced incretin effect in patients with type 2 diabetes.
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Affiliation(s)
- Kirsten Kampmann
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Sandra Ueberberg
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Bjoern A Menge
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Thomas G K Breuer
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Waldemar Uhl
- Department of Surgery, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Ruhr-University Bochum, Bürkle de la Camp-Platz 1, Bochum, 44789, Germany
| | - Juris J Meier
- Diabetes Division, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, Bochum, 44791, Germany.
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.
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Jiang C, Xie C, Lv Y, Li J, Krausz KW, Shi J, Brocker CN, Desai D, Amin SG, Bisson WH, Liu Y, Gavrilova O, Patterson AD, Gonzalez FJ. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 2015; 6:10166. [PMID: 26670557 PMCID: PMC4682112 DOI: 10.1038/ncomms10166] [Citation(s) in RCA: 403] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 11/10/2015] [Indexed: 12/17/2022] Open
Abstract
The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders. The nuclear farnesoid X receptor (FXR) is activated by bile acids and influences energy metabolism. Here, the authors report a small molecule inhibitor of FXR, glycine-ß-muricholic acid, which inhibits FXR in the intestine and improves metabolic homeostasis by repressing intestinal ceramide synthesis.
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Affiliation(s)
- Changtao Jiang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.,Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China
| | - Cen Xie
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Ying Lv
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China
| | - Jing Li
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
| | - Kristopher W Krausz
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Jingmin Shi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Chad N Brocker
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Dhimant Desai
- Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA
| | - Shantu G Amin
- Department of Pharmacology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA
| | - William H Bisson
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA
| | - Yulan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
| | - Oksana Gavrilova
- Mouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
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Zhang X, Liu T, Wang Y, Zhong M, Zhang G, Liu S, Wu T, Rayner CK, Hu S. Comparative Effects of Bile Diversion and Duodenal-Jejunal Bypass on Glucose and Lipid Metabolism in Male Diabetic Rats. Obes Surg 2015; 26:1565-75. [PMID: 26464241 DOI: 10.1007/s11695-015-1925-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Camilleri M, Gores GJ. Therapeutic targeting of bile acids. Am J Physiol Gastrointest Liver Physiol 2015; 309:G209-15. [PMID: 26138466 PMCID: PMC4537926 DOI: 10.1152/ajpgi.00121.2015] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 06/30/2015] [Indexed: 01/31/2023]
Abstract
The first objectives of this article are to review the structure, chemistry, and physiology of bile acids and the types of bile acid malabsorption observed in clinical practice. The second major theme addresses the classical or known properties of bile acids, such as the role of bile acid sequestration in the treatment of hyperlipidemia; the use of ursodeoxycholic acid in therapeutics, from traditional oriental medicine to being, until recently, the drug of choice in cholestatic liver diseases; and the potential for normalizing diverse bowel dysfunctions in irritable bowel syndrome, either by sequestering intraluminal bile acids for diarrhea or by delivering more bile acids to the colon to relieve constipation. The final objective addresses novel concepts and therapeutic opportunities such as the interaction of bile acids and the microbiome to control colonic infections, as in Clostridium difficile-associated colitis, and bile acid targeting of the farnesoid X receptor and G protein-coupled bile acid receptor 1 with consequent effects on energy expenditure, fat metabolism, and glycemic control.
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Affiliation(s)
- Michael Camilleri
- Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota
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Mazuy C, Helleboid A, Staels B, Lefebvre P. Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci 2015; 72:1631-50. [PMID: 25511198 PMCID: PMC11113650 DOI: 10.1007/s00018-014-1805-y] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 12/04/2014] [Accepted: 12/08/2014] [Indexed: 12/16/2022]
Abstract
Bile acids (BAs) are amphipathic molecules produced from cholesterol by the liver. Expelled from the gallbladder upon meal ingestion, BAs serve as fat solubilizers in the intestine. BAs are reabsorbed in the ileum and return via the portal vein to the liver where, together with nutrients, they provide signals to coordinate metabolic responses. BAs act on energy and metabolic homeostasis through the activation of membrane and nuclear receptors, among which the nuclear receptor farnesoid X receptor (FXR) is an important regulator of several metabolic pathways. Highly expressed in the liver and the small intestine, FXR contributes to BA effects on metabolism, inflammation and cell cycle control. The pharmacological modulation of its activity has emerged as a potential therapeutic strategy for liver and metabolic diseases. This review highlights recent advances regarding the mechanisms by which the BA sensor FXR contributes to global signaling effects of BAs, and how FXR activity may be regulated by nutrient-sensitive signaling pathways.
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Affiliation(s)
- Claire Mazuy
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Audrey Helleboid
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Philippe Lefebvre
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
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Affiliation(s)
- Caroline S Stokes
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
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Nies VJM, Sancar G, Liu W, van Zutphen T, Struik D, Yu RT, Atkins AR, Evans RM, Jonker JW, Downes MR. Fibroblast Growth Factor Signaling in Metabolic Regulation. Front Endocrinol (Lausanne) 2015; 6:193. [PMID: 26834701 PMCID: PMC4718082 DOI: 10.3389/fendo.2015.00193] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 12/25/2015] [Indexed: 12/22/2022] Open
Abstract
The prevalence of obesity is a growing health problem. Obesity is strongly associated with several comorbidities, such as non-alcoholic fatty liver disease, certain cancers, insulin resistance, and type 2 diabetes, which all reduce life expectancy and life quality. Several drugs have been put forward in order to treat these diseases, but many of them have detrimental side effects. The unexpected role of the family of fibroblast growth factors in the regulation of energy metabolism provides new approaches to the treatment of metabolic diseases and offers a valuable tool to gain more insight into metabolic regulation. The known beneficial effects of FGF19 and FGF21 on metabolism, together with recently discovered similar effects of FGF1 suggest that FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. To facilitate the development of new therapies with improved targeting and minimal side effects, a better understanding of the molecular mechanism of action of FGFs is needed. In this review, we will discuss what is currently known about the physiological roles of FGF signaling in tissues important for metabolic homeostasis. In addition, we will discuss current concepts regarding their pharmacological properties and effector tissues in the context of metabolic disease. Also, the recent progress in the development of FGF variants will be reviewed. Our goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease and to provide starting points for the development of FGF-based therapies against metabolic conditions.
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Affiliation(s)
- Vera J. M. Nies
- Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Gencer Sancar
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Weilin Liu
- Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Tim van Zutphen
- Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Dicky Struik
- Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Ruth T. Yu
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Annette R. Atkins
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Ronald M. Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Johan W. Jonker
- Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- *Correspondence: Johan W. Jonker, ; Michael Robert Downes,
| | - Michael Robert Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
- *Correspondence: Johan W. Jonker, ; Michael Robert Downes,
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El Aidy S, van den Bogert B, Kleerebezem M. The small intestine microbiota, nutritional modulation and relevance for health. Curr Opin Biotechnol 2014; 32:14-20. [PMID: 25308830 DOI: 10.1016/j.copbio.2014.09.005] [Citation(s) in RCA: 149] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 09/18/2014] [Accepted: 09/22/2014] [Indexed: 02/08/2023]
Abstract
The intestinal microbiota plays a profound role in human health and extensive research has been dedicated to identify microbiota aberrations that are associated with disease. Most of this work has been targeting the large intestine and fecal microbiota, while the small intestine microbiota may also have a profound impact on various aspects of the host's physiology, including immune, metabolic and endocrine functions. This review highlights the recent advances made in the study of the human small intestine microbiota. In addition, it describes recent human and animal studies that underpin the importance of this part of the intestine for health of the host organism.
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Affiliation(s)
- Sahar El Aidy
- TI Food and Nutrition, Wageningen, The Netherlands; Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Industrial Biotechnology, Genetic Engineering and Biotechnology Research Institute, Sadat City University, Sadat City, Egypt
| | - Bartholomeus van den Bogert
- TI Food and Nutrition, Wageningen, The Netherlands; Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
| | - Michiel Kleerebezem
- TI Food and Nutrition, Wageningen, The Netherlands; Host-Microbe Interactomics Group, Wageningen University, Wageningen, The Netherlands; NIZO Food Research, Ede, The Netherlands.
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