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Wei M, Tu W, Huang G. Regulating bile acids signaling for NAFLD: molecular insights and novel therapeutic interventions. Front Microbiol 2024; 15:1341938. [PMID: 38887706 PMCID: PMC11180741 DOI: 10.3389/fmicb.2024.1341938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 05/14/2024] [Indexed: 06/20/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) emerges as the most predominant cause of liver disease, tightly linked to metabolic dysfunction. Bile acids (BAs), initially synthesized from cholesterol in the liver, undergo further metabolism by gut bacteria. Increasingly acknowledged as critical modulators of metabolic processes, BAs have been implicated as important signaling molecules. In this review, we will focus on the mechanism of BAs signaling involved in glucose homeostasis, lipid metabolism, energy expenditure, and immune regulation and summarize their roles in the pathogenesis of NAFLD. Furthermore, gut microbiota dysbiosis plays a key role in the development of NAFLD, and the interactions between BAs and intestinal microbiota is elucidated. In addition, we also discuss potential therapeutic strategies for NAFLD, including drugs targeting BA receptors, modulation of intestinal microbiota, and metabolic surgery.
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Affiliation(s)
- Meilin Wei
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wei Tu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Genhua Huang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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2
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Pérez-Rubio Á, Soluyanova P, Moro E, Quintás G, Rienda I, Periañez MD, Painel A, Vizuete J, Pérez-Rojas J, Castell JV, Trullenque-Juan R, Pareja E, Jover R. Gut Microbiota and Plasma Bile Acids Associated with Non-Alcoholic Fatty Liver Disease Resolution in Bariatric Surgery Patients. Nutrients 2023; 15:3187. [PMID: 37513605 PMCID: PMC10385764 DOI: 10.3390/nu15143187] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/29/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Bariatric surgery (BS) has several benefits, including resolution of non-alcoholic fatty liver disease (NAFLD) in many patients. However, a significant percentage of patients do not experience improvement in fatty liver after BS, and more than 10% develop new or worsening NAFLD features. Therefore, a question that remains unanswered is why some patients experience resolved NAFLD after BS and others do not. In this study, we investigated the fecal microbiota and plasma bile acids associated with NAFLD resolution in twelve morbidly obese patients undergoing BS, of whom six resolved their steatosis one year after surgery and another six did not. Results indicate that the hallmark of the gut microbiota in responder patients is a greater abundance of Bacteroides, Akkermansia, and several species of the Clostridia class (genera: Blautia, Faecalibacterium, Roseburia, Butyricicoccusa, and Clostridium), along with a decreased abundance of Actinomycetes/Bifidobacterium and Faecalicatena. NAFLD resolution was also associated with a sustained increase in primary bile acids (particularly non-conjugated), which likely results from a reduction in bacterial gut species capable of generating secondary bile acids. We conclude that there are specific changes in gut microbiota and plasma bile acids that could contribute to resolving NAFLD in BS patients. The knowledge acquired can help to design interventions with prebiotics and/or probiotics to promote a gut microbiome that favors NAFLD resolution.
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Affiliation(s)
- Álvaro Pérez-Rubio
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Polina Soluyanova
- Experimental Hepatology Joint Unit, Health Research Institute La Fe-University of Valencia, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universitat de València, 46010 Valencia, Spain
| | - Erika Moro
- Experimental Hepatology Joint Unit, Health Research Institute La Fe-University of Valencia, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universitat de València, 46010 Valencia, Spain
| | - Guillermo Quintás
- Health and Biomedicine, Leitat Technological Center, 08225 Terrassa, Spain
| | - Iván Rienda
- Pathology Department, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain
| | - María Dolores Periañez
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Andrés Painel
- Section of Abdominal Imaging, Radiology Department, Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - José Vizuete
- Section of Abdominal Imaging, Radiology Department, Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Judith Pérez-Rojas
- Pathology Department, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain
| | - José V Castell
- Experimental Hepatology Joint Unit, Health Research Institute La Fe-University of Valencia, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universitat de València, 46010 Valencia, Spain
- CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ramón Trullenque-Juan
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Dr. Peset, 46017 Valencia, Spain
| | - Eugenia Pareja
- Servicio de Cirugía General y Aparato Digestivo, Hospital Universitario Dr. Peset, 46017 Valencia, Spain
- Experimental Hepatology Joint Unit, Health Research Institute La Fe-University of Valencia, 46026 Valencia, Spain
| | - Ramiro Jover
- Experimental Hepatology Joint Unit, Health Research Institute La Fe-University of Valencia, 46026 Valencia, Spain
- Departamento de Bioquímica y Biología Molecular, Universitat de València, 46010 Valencia, Spain
- CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
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Feris F, McRae A, Kellogg TA, McKenzie T, Ghanem O, Acosta A. Mucosal and hormonal adaptations after Roux-en-Y gastric bypass. Surg Obes Relat Dis 2023; 19:37-49. [PMID: 36243547 PMCID: PMC9797451 DOI: 10.1016/j.soard.2022.08.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 01/12/2023]
Abstract
The aim of this study was to perform a comprehensive literature review regarding the relevant hormonal and histologic changes observed after Roux-en-Y gastric bypass (RYGB). We aimed to describe the relevant hormonal (glucagon-like peptides 1 and 2 [GLP-1 and GLP-2], peptide YY [PYY], oxyntomodulin [OXM], bile acids [BA], cholecystokinin [CCK], ghrelin, glucagon, gastric inhibitory polypeptide [GIP], and amylin) profiles, as well as the histologic (mucosal cellular) adaptations happening after patients undergo RYGB. Our review compiles the current evidence and furthers the understanding of the rationale behind the food intake regulatory adaptations occurring after RYGB surgery. We identify gaps in the literature where the potential for future investigations and therapeutics may lie. We performed a comprehensive database search without language restrictions looking for RYGB bariatric surgery outcomes in patients with pre- and postoperative blood work hormonal profiling and/or gut mucosal biopsies. We gathered the relevant study results and describe them in this review. Where human findings were lacking, we included animal model studies. The amalgamation of physiologic, metabolic, and cellular adaptations following RYGB is yet to be fully characterized. This constitutes a fundamental aspiration for enhancing and individualizing obesity therapy.
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Affiliation(s)
- Fauzi Feris
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Alison McRae
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Todd A Kellogg
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Travis McKenzie
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Omar Ghanem
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Andres Acosta
- Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
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The intestinal clock drives the microbiome to maintain gastrointestinal homeostasis. Nat Commun 2022; 13:6068. [PMID: 36241650 PMCID: PMC9568547 DOI: 10.1038/s41467-022-33609-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 09/23/2022] [Indexed: 12/24/2022] Open
Abstract
Diurnal (i.e., 24-hour) oscillations of the gut microbiome have been described in various species including mice and humans. However, the driving force behind these rhythms remains less clear. In this study, we differentiate between endogenous and exogenous time cues driving microbial rhythms. Our results demonstrate that fecal microbial oscillations are maintained in mice kept in the absence of light, supporting a role of the host's circadian system rather than representing a diurnal response to environmental changes. Intestinal epithelial cell-specific ablation of the core clock gene Bmal1 disrupts rhythmicity of microbiota. Targeted metabolomics functionally link intestinal clock-controlled bacteria to microbial-derived products, in particular branched-chain fatty acids and secondary bile acids. Microbiota transfer from intestinal clock-deficient mice into germ-free mice altered intestinal gene expression, enhanced lymphoid organ weights and suppressed immune cell recruitment. These results highlight the importance of functional intestinal clocks for microbiota composition and function, which is required to balance the host's gastrointestinal homeostasis.
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Reversal of NAFLD After VSG Is Independent of Weight-Loss but RYGB Offers More Efficacy When Maintained on a High-Fat Diet. Obes Surg 2022; 32:2010-2022. [PMID: 35419698 DOI: 10.1007/s11695-022-06053-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/28/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022]
Abstract
PURPOSE Bariatric surgery is emerging as an effective treatment for obesity and the metabolic syndrome. Recently, we demonstrated that Roux-en-Y gastric bypass (RYGB), but not vertical sleeve gastrectomy (VSG), resulted in improvements to white adipose physiology and enhanced brown adipose functioning. Since beneficial alterations to liver health are also expected after bariatric surgery, comparing the post-operative effects of RYGB and VSG on liver physiology is essential to their application in the treatment of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS The effects of RYGB and VSG on liver physiology were compared using diet induced mouse model of obesity. High-fat diet (HFD) was administered for 12 weeks after surgery and alterations to liver physiology were assessed. RESULTS Both RYGB and VSG showed decreased liver weight as well as reductions to hepatic cholesterol and triglyceride levels. There were demonstrable improvements to NAFLD activity score (NAS) and fibrosis stage scoring after both surgeries. In RYGB, these beneficial changes to liver function resulted from the downregulation of pro-fibrotic and upregulation anti-fibrotic genes, as well as increased fatty acid oxidation and bile acid flux. For VSG, though similar alterations were observed, they were less potent. However, VSG did significantly downregulate pro-fibrotic genes and showed increased glycogen content paralleled by decreased glycogenolysis which may have contributed to the resolution of NAFLD. CONCLUSION RYGB and VSG improve liver physiology and function, but RYGB is more efficacious. Resolutions of NAFLD in RYGB and VSG are achieved through different processes, independent of weight loss.
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Lo T, Lee Y, Tseng CY, Hu Y, Connelly MA, Mantzoros CS, Karp JM, Tavakkoli A. Daily transient coating of the intestine leads to weight loss and improved glucose tolerance. Metabolism 2022; 126:154917. [PMID: 34687727 PMCID: PMC8666968 DOI: 10.1016/j.metabol.2021.154917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/13/2021] [Accepted: 10/19/2021] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Roux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis. METHODS Sprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry. RESULTS At 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ± 3.8 mg/dl vs. 99.1 ± 2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption. CONCLUSION We demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.
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Affiliation(s)
- Tammy Lo
- Laboratory for Surgical and Metabolic Research, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Yuhan Lee
- Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Nanomedicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT, Division of Health Sciences and Technology, Boston, MA, USA
| | - Chung-Yi Tseng
- Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Nanomedicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT, Division of Health Sciences and Technology, Boston, MA, USA
| | - Yangshuo Hu
- Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Nanomedicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT, Division of Health Sciences and Technology, Boston, MA, USA
| | - Margery A Connelly
- Laboratory Corporation of America Holdings (Labcorp), Morrisville, NC, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
| | - Jeffrey M Karp
- Department of Anesthesiology, Perioperative, and Pain Medicine, Center for Nanomedicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT, Division of Health Sciences and Technology, Boston, MA, USA.
| | - Ali Tavakkoli
- Laboratory for Surgical and Metabolic Research, Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of General and GI Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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Dang JT, Mocanu V, Park H, Laffin M, Tran C, Hotte N, Karmali S, Birch DW, Madsen K. Ileal microbial shifts after Roux-en-Y gastric bypass orchestrate changes in glucose metabolism through modulation of bile acids and L-cell adaptation. Sci Rep 2021; 11:23813. [PMID: 34893681 PMCID: PMC8664817 DOI: 10.1038/s41598-021-03396-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 11/29/2021] [Indexed: 01/03/2023] Open
Abstract
Roux-en-Y gastric bypass (RYGB)-induced glycemic improvement is associated with increases in glucagon-like-peptide-1 (GLP-1) secreted from ileal L-cells. We analyzed changes in ileal bile acids and ileal microbial composition in diet-induced-obesity rats after RYGB or sham surgery to elucidate the early and late effects on L-cells and glucose homeostasis. In early cohorts, there were no significant changes in L-cell density, GLP-1 or glucose tolerance. In late cohorts, RYGB demonstrated less weight regain, improved glucose tolerance, increased L-cell density, and increased villi height. No difference in the expression of GLP-1 genes was observed. There were lower concentrations of ileal bile acids in the late RYGB cohort. Microbial analysis demonstrated decreased alpha diversity in early RYGB cohorts which normalized in the late group. The early RYGB cohorts had higher abundances of Escherichia-Shigella but lower abundances of Lactobacillus, Adlercreutzia, and Proteus while the late cohorts demonstrated higher abundances of Escherichia-Shigella and lower abundances of Lactobacillus. Shifts in Lactobacillus and Escherichia-Shigella correlated with decreases in multiple conjugated bile acids. In conclusion, RYGB caused a late and substantial increase in L-cell quantity with associated changes in bile acids which correlated to shifts in Escherichia-Shigella and Lactobacillus. This proliferation of L-cells contributed to improved glucose homeostasis.
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Affiliation(s)
- Jerry T Dang
- Division of General Surgery, Department of Surgery, University of Alberta Hospital, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada.
| | - Valentin Mocanu
- Division of General Surgery, Department of Surgery, University of Alberta Hospital, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada
| | - Heekuk Park
- Department of Medicine, Columbia University, New York City, NY, USA
| | - Michael Laffin
- Division of General Surgery, Department of Surgery, University of Alberta Hospital, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada
| | - Caroline Tran
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
| | - Naomi Hotte
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Shahzeer Karmali
- Division of General Surgery, Department of Surgery, University of Alberta Hospital, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada
| | - Daniel W Birch
- Division of General Surgery, Department of Surgery, University of Alberta Hospital, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada
| | - Karen Madsen
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Yang C, Brecht J, Weiß C, Reissfelder C, Otto M, Buchwald JN, Vassilev G. Serum Glucagon, Bile Acids, and FGF-19: Metabolic Behavior Patterns After Roux-en-Y Gastric Bypass and Vertical Sleeve Gastrectomy. Obes Surg 2021; 31:4939-4946. [PMID: 34471996 DOI: 10.1007/s11695-021-05677-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/14/2021] [Accepted: 08/19/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Metabolic/bariatric surgery is a highly effective treatment for obesity and metabolic diseases. Serum glucagon, bile acids, and FGF-19 are key effectors of various metabolic processes and may play central roles in bariatric surgical outcomes. It is unclear whether these factors behave similarly after Roux-en-Y gastric bypass (RYGB) vs vertical sleeve gastrectomy (VSG). METHODS Serum glucagon, bile acids (cholic acid [CA], chenodeoxycholic acid [CDCA], deoxycholic acid [DCA]), and FGF-19 were analyzed in samples of fasting blood collected before bariatric surgery, on postoperative days 2 and 10, and at 3- and 6-month follow-up. RESULTS From September 2016 to July 2017, patients with obesity underwent RYGB or VSG; 42 patients (RYGB n = 21; VSG n = 21) were included in the analysis. In the RYGB group, glucagon, CA, and CDCA increased continuously after surgery (p = 0.0003, p = 0.0009, p = 0.0001, respectively); after an initial decrease (p = 0.04), DCA increased significantly (p = 0.0386). Serum FGF-19 was unchanged. In the VSG group, glucagon increased on day 2 (p = 0.0080), but decreased over the 6-month study course (p = 0.0025). Primary BAs (CA and CDCA) decreased immediately after surgery (p = 0.0016, p = 0.0091) and then rose (p = 0.0350, p = 0.0350); DCA followed the curve of the primary BAs until it fell off at 6 months (p = 0.0005). VSG group serum FGF-19 trended upward. CONCLUSION RYGB and VSG involve different surgical techniques and final anatomical configurations. Between postoperative day 2 and 6-month follow-up, RYGB and VSG resulted in divergent patterns of change in serum glucagon, bile acids, and FGF-19.
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Affiliation(s)
- Cui Yang
- Department of Surgery, University Medicine Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Julia Brecht
- Department of Surgery, University Medicine Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Christel Weiß
- Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
| | - Christoph Reissfelder
- Department of Surgery, University Medicine Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Mirko Otto
- Department of Surgery, University Medicine Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Jane N Buchwald
- Division of Scientific Research Writing, Medwrite Medical Communications, Maiden Rock, WI, 54750, USA
| | - Georgi Vassilev
- Department of Surgery, University Medicine Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
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Xue H, Huang L, Tu J, Ding L, Huang W. Bile acids and metabolic surgery. LIVER RESEARCH 2021; 5:164-170. [PMID: 39957846 PMCID: PMC11791848 DOI: 10.1016/j.livres.2021.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/04/2021] [Accepted: 05/05/2021] [Indexed: 02/16/2023]
Abstract
The epidemic of obesity and its co-mortalities has reached an alarming level worldwide. Currently, metabolic surgeries, especially the Roux-en-Y gastric bypass and vertical sleeve gastrectomy, are the most effective and sustainable treatments for obesity, type 2 diabetes, non-alcoholic steatohepatitis, as well as other metabolic diseases. However, the invasive nature of the surgeries limits their broad applications to the general public. Therefore, developing alternative non-invasive approaches to mimic metabolic surgery is an important direction of the field. Recent studies have identified several potential metabolic surgery-induced downstream endocrine mediators, among which bile acids are key candidate signaling molecules. Bile acids are profoundly altered by metabolic surgery, which contributes to the metabolic effects of the surgery. In this review, we focus on the most recent studies on the roles of bile acids and bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor 5 in mediating the metabolic effects of metabolic surgery. We conclude that targeting bile acid pathways may be a promising pharmacological approach to mimic the beneficial effects of metabolic surgery.
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Affiliation(s)
- Hui Xue
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Luyao Huang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jui Tu
- Department of Diabetes Complications and Metabolism, Institute of Diabetes and Metabolism Research Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Institute of Diabetes and Metabolism Research Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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Leptin Receptors Are Not Required for Roux-en-Y Gastric Bypass Surgery to Normalize Energy and Glucose Homeostasis in Rats. Nutrients 2021; 13:nu13051544. [PMID: 34064308 PMCID: PMC8147759 DOI: 10.3390/nu13051544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 12/29/2022] Open
Abstract
Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.
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Ueno T, Tanaka N, Imoto H, Maekawa M, Kohyama A, Watanabe K, Motoi F, Kamei T, Unno M, Naitoh T. Mechanism of Bile Acid Reabsorption in the Biliopancreatic Limb After Duodenal-Jejunal Bypass in Rats. Obes Surg 2021; 30:2528-2537. [PMID: 32291708 DOI: 10.1007/s11695-020-04506-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bile acids (BAs) are important in the metabolic effects of bariatric surgery. Most BAs are reabsorbed in the ileum and recycled back to the liver. We have reported that this enterohepatic circulation was shortened by duodenal-jejunal bypass (DJB), and the biliopancreatic (BP)-limb plays an important role in reabsorption of BAs. However, the mechanism of BA reabsorption in BP-limb remains uncertain. We aimed to investigate the mechanisms of BA reabsorption after DJB, especially focusing on carrier-mediated transport of BAs and the impact of the presence or absence of lipids on BA reabsorption. METHODS Otsuka-Long-Evans-Tokushima fatty rats or Sprague-Dawley rats were assigned to a control group and DJB group. BA levels in the divided small intestine were quantified with liquid chromatography-mass spectrometry. Labeled BA was injected and perfused with BA transporter inhibitors or mixture of lipids in the isolated BP-limb, and bile was sampled and analyzed. RESULTS Conjugated BA levels in the BP-limb were significantly higher than that of the control group. BA absorption tended to decrease by the apical sodium-dependent BA transporter inhibitor and was significantly decreased by the organic anion-transporting peptide (OATP) inhibitor. BA absorption tended to increase in the absence of lipid solutions compared with that in the presence of lipid solutions. CONCLUSION We attributed the increased BA reabsorption in the BP-limb to lack of food in the BP-limb, which contains concentrated BAs and no lipids. OATP played an important role in BA reabsorption in the BP-limb. Therefore, BAs would be reabsorbed in different manners after DJB.
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Affiliation(s)
- Tomotaka Ueno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Naoki Tanaka
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
| | - Hirofumi Imoto
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Masamitsu Maekawa
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Atsushi Kohyama
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Kazuhiro Watanabe
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Fuyuhiko Motoi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Takeshi Naitoh
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
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Hankir MK, Langseder T, Bankoglu EE, Ghoreishi Y, Dischinger U, Kurlbaum M, Kroiss M, Otto C, le Roux CW, Arora T, Seyfried F, Schlegel N. Simulating the Post-gastric Bypass Intestinal Microenvironment Uncovers a Barrier-Stabilizing Role for FXR. iScience 2020; 23:101777. [PMID: 33294786 PMCID: PMC7689555 DOI: 10.1016/j.isci.2020.101777] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/12/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
Regional changes to the intestinal microenvironment brought about by Roux-en-Y gastric bypass (RYGB) surgery may contribute to some of its potent systemic metabolic benefits through favorably regulating various local cellular processes. Here, we show that the intestinal contents of RYGB-operated compared with sham-operated rats region-dependently confer superior glycemic control to recipient germ-free mice in association with suppression of endotoxemia. Correspondingly, they had direct barrier-stabilizing effects on an intestinal epithelial cell line which, bile-exposed intestinal contents, were partly farnesoid X receptor (FXR)-dependent. Further, circulating fibroblast growth factor 19 levels, a readout of intestinal FXR activation, negatively correlated with endotoxemia severity in longitudinal cohort of RYGB patients. These findings suggest that various host- and/or microbiota-derived luminal factors region-specifically and synergistically stabilize the intestinal epithelial barrier following RYGB through FXR signaling, which could potentially be leveraged to better treat endotoxemia-induced insulin resistance in obesity in a non-invasive and more targeted manner.
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Affiliation(s)
- Mohammed K. Hankir
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
| | - Theresa Langseder
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
| | - Ezgi Eyluel Bankoglu
- Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Bavaria 97080, Germany
| | - Yalda Ghoreishi
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
| | - Ulrich Dischinger
- Department of Endocrinology and Diabetology, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany
| | - Max Kurlbaum
- Department of Endocrinology and Diabetology, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany
| | - Matthias Kroiss
- Department of Endocrinology and Diabetology, University Hospital Wuerzburg, Wuerzburg, Bavaria 97080, Germany
| | - Christoph Otto
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
| | - Carel W. le Roux
- Diabetes Complications Research Centre, University College Dublin, Dublin 4, Ireland
| | - Tulika Arora
- Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark
| | - Florian Seyfried
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany
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Yang H, Liu H, Jiao Y, Qian J. Roux-en-Y Gastrointestinal Bypass Promotes Activation of TGR5 and Peptide YY. Endocr Metab Immune Disord Drug Targets 2020; 20:1262-1267. [PMID: 32600238 DOI: 10.2174/1871530320666200628024500] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 04/26/2020] [Accepted: 05/04/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND G protein-coupled bile acid receptor (TGR5) is involved in a number of metabolic diseases. The aim of this study was to identify the role of TGR5 after Roux-en-Y gastric bypass (GBP). METHODS Wild type and TGR5 knockout mice (tgr5-/-) were fed a high-fat diet (HFD) to establish the obesity model. GBP was performed. The changes in body weight and food intake were measured. The levels of TGR5 and peptide YY (PYY) were evaluated by RT-PCR, Western blot, and ELISA. Moreover, the L-cells were separated from wild type and tgr5-/- mice. The levels of PYY in L-cells were evaluated by ELISA. RESULTS The body weights were significantly decreased after GBP in wild type mice (p<0.05), but not tgr5-/- mice (p>0.05). Food intake was reduced after GBP in wild type mice, but also not significantly affected in tgr5-/- mice (p>0.05). The levels of PYY were significantly increased after GBP compared with the sham group (p<0.05); however, in tgr5-/- mice the expression of PYY was not significantly affected (p>0.05). After INT-777 stimulation in L-cells obtained from murine intestines, the levels of PYY were significantly increased in L-cells tgr5+/+ (p<0.05). CONCLUSION Our study suggests that GBP up-regulated the expression of TGR5 in murine intestines, and increased the levels of PYY, which further reduced food intake and decreased the body weight.
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Affiliation(s)
- Haojun Yang
- Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou, 213000, China
| | - Hanyang Liu
- Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou, 213000, China
| | - YuWen Jiao
- Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou, 213000, China
| | - Jun Qian
- Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou, 213000, China
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14
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Laessle C, Jin K, Seifert GJ, Timme-Bronsert S, Fichtner-Feigl S, Marjanovic G, Fink JM. Putting the Hindgut Hypothesis to the Test in a Diabetic Zucker Rat Model. Obes Surg 2020; 29:4000-4007. [PMID: 31367988 DOI: 10.1007/s11695-019-04079-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND The hindgut theory hypothesizes a key role of differential hindgut stimulation following metabolic procedures in ameliorating diabetes mellitus. We used two strategies to remove the hindgut from intestinal continuity in order to analyze its impact on diabetes mellitus. METHODS Loop duodeno-jejunostomy (DJOS) with exclusion of one-third of total intestinal length was performed in 3 groups of 9-week-old Zucker diabetic fatty rats. In group 1, no further alteration of the intestinal tract was made. Group 2 received additional ileal exclusion (IE). Group 3 underwent additional resection of 50% of the ileum with side-to-side ileocecal anastomosis (IR). One, 2, and 4 months after surgery, fasting blood glucose levels, oral glucose tolerance tests (OGTT), and glucose-stimulated hormone analyses were conducted, and bile acid blood levels were compared. Body weight was documented weekly. RESULTS In relation to DJOS, glucose control was not impaired in IR or IE. On the contrary, only IR could maintain preOP glucose values until 4 months. There were no significant weight differences between the groups. Confirming effective ileal diversion, bile acid blood levels were significantly higher in the DJOS group compared with both IR and IE (p = 0.0025 and p = 0.0047). Operative interventions had no impact on GLP-1 levels at any time point (ANOVA p > 0.05 for all). Insulin secretion was preserved in all groups. CONCLUSION This data supports the hypothesis that the mechanisms driving amelioration of diabetes mellitus are complex and cannot be reduced to the ileum.
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Affiliation(s)
- Claudia Laessle
- Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.
| | - Ke Jin
- Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany
| | - Gabriel J Seifert
- Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany
| | - Sylvia Timme-Bronsert
- Faculty of Medicine, Institute of Pathology, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany
| | - Stefan Fichtner-Feigl
- Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany
| | - Goran Marjanovic
- Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany
| | - Jodok Matthias Fink
- Department of General and Visceral Surgery, Faculty of Medicine, Medical Center - University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany
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15
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Simoni AH, Ladebo L, Christrup LL, Drewes AM, Johnsen SP, Olesen AE. Chronic abdominal pain and persistent opioid use after bariatric surgery. Scand J Pain 2020; 20:239-251. [PMID: 31756166 DOI: 10.1515/sjpain-2019-0092] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 10/17/2019] [Indexed: 01/03/2025]
Abstract
Background and aims Bariatric surgery remains a mainstay for treatment of morbid obesity. However, long-term adverse outcomes include chronic abdominal pain and persistent opioid use. The aim of this review was to assess the existing data on prevalence, possible mechanisms, risk factors, and outcomes regarding chronic abdominal pain and persistent opioid use after bariatric surgery. Methods PubMed was screened for relevant literature focusing on chronic abdominal pain, persistent opioid use and pharmacokinetic alterations of opioids after bariatric surgery. Relevant papers were cross-referenced to identify publications possibly not located during the ordinary screening. Results Evidence regarding general chronic pain status after bariatric surgery is sparse. However, our literature review revealed that abdominal pain was the most prevalent complication to bariatric surgery, presented in 3-61% of subjects with health care contacts or readmissions 1-5 years after surgery. This could be explained by behavioral, anatomical, and/or functional disorders. Persistent opioid use and doses increased after bariatric surgery, and 4-14% initiated a persistent opioid use 1-7 years after the surgery. Persistent opioid use was associated with severe pain symptoms and was most prevalent among subjects with a lower socioeconomic status. Alteration of absorption and distribution after bariatric surgery may impact opioid effects and increase the risk of adverse events and development of addiction. Changes in absorption have been briefly investigated, but the identified alterations could not be separated from alterations caused solely by excessive weight loss, and medication formulation could influence the findings. Subjects with persistent opioid use after bariatric surgery achieved lower weight loss and less metabolic benefits from the surgery. Thus, remission from comorbidities and cost effectiveness following bariatric surgery may be limited in these subjects. Conclusions Pain, especially chronic abdominal, and persistent opioid use were found to be prevalent after bariatric surgery. Physiological, anatomical, and pharmacokinetic changes are likely to play a role. However, the risk factors for occurrence of chronic abdominal pain and persistent opioid use have only been scarcely examined as have the possible impact of pain and persistent opioid use on clinical outcomes, and health-care costs. This makes it difficult to design targeted preventive interventions, which can identify subjects at risk and prevent persistent opioid use after bariatric surgery. Future studies could imply pharmacokinetic-, pharmacodynamics-, and physiological-based modelling of pain treatment. More attention to social, physiologic, and psychological factors may be warranted in order to identify specific risk profiles of subjects considered for bariatric surgery in order to tailor and optimize current treatment recommendations for this population.
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Affiliation(s)
- Amalie H Simoni
- Danish Center for Clinical Health Service Research (DACS), Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Louise Ladebo
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Lona L Christrup
- Section of Pharmacotherapy, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Asbjørn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Søren P Johnsen
- Danish Center for Clinical Health Service Research (DACS), Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Anne E Olesen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Clinical Pharmacology, Aalborg University Hospital, Gartnerboligen, Ground Floor, Mølleparkvej 8a, 9000 Aalborg, Denmark, Phone: +45 97664376
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16
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Li K, Zou J, Li S, Guo J, Shi W, Wang B, Han X, Zhang H, Zhang P, Miao Z, Li Y. Farnesoid X receptor contributes to body weight-independent improvements in glycemic control after Roux-en-Y gastric bypass surgery in diet-induced obese mice. Mol Metab 2020; 37:100980. [PMID: 32305491 PMCID: PMC7182762 DOI: 10.1016/j.molmet.2020.100980] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/12/2020] [Accepted: 03/12/2020] [Indexed: 02/08/2023] Open
Abstract
Objective Roux-en-Y gastric bypass surgery (RYGB) can achieve long-term remission of type 2 diabetes. However, the specific molecular mechanism through which this occurs has remained largely elusive. Bile acid signaling through the nuclear hormone receptor farnesoid X receptor (FXR) exerts beneficial effects after sleeve gastrectomy (VSG), which has similar effects to RYGB. Therefore, we investigated whether FXR signaling is necessary to mediate glycemic control after RYGB. Methods RYGB or sham surgery was performed in high-fat diet-induced obese FXR−/− (knockout) and FXR+/+ (wild type) littermates. Sham-operated mice were fed ad libitum (S-AL) or by weight matching (S-WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance tests, insulin tolerance tests, and homeostatic model assessment of insulin resistance were performed. Results RYGB surgery decreases body weight and fat mass in WT and FXR-KO mice. RYGB surgery has similar effects on food intake and energy expenditure independent of genotype. In addition, body weight-independent improvements in glucose control were attenuated in FXR −/− relative to FXR +/+ mice after RYGB. Furthermore, pharmacologic blockade of the glucagon-like peptide-1 receptor (GLP-1R) blunts the glucoregulatory effects of RYGB in FXR +/+ but not in FXR −/− mice at 4 weeks after surgery. Conclusions These results suggest that FXR signaling is not required for the weight loss up to 16 weeks after RYGB. Although most of the improvements in glucose homeostasis are secondary to RYGB-induced weight loss in wild type mice, FXR signaling contributes to glycemic control after RYGB in a body weight-independent manner, which might be mediated by an FXR-GLP-1 axis during the early postoperative period.
The reduction in body weight after RYGB is independent of FXR, which is mainly due to a decrease in net energy intake. RYGB prevents the weight loss-induced decrease observed in nonsurgical weight-matched mice in both genotypes. FXR signaling contributes to glycemic control after RYGB in a body weight-independent manner. The early body weight-independent improvements in glucose homeostasis after RYGB might be mediated by an FXR-GLP-1 axis.
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Affiliation(s)
- Kun Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Jianan Zou
- Department of Nephrology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, PR China
| | - Song Li
- School of Basic Medicine, Shandong First Medical University, Tai'an, 271000, PR China
| | - Jing Guo
- Discipline Planning Department, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Wentao Shi
- Clinical Research Center, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Bing Wang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China
| | - Xiaodong Han
- Department of Metabolic & Bariatric Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China
| | - Hongwei Zhang
- Department of Metabolic & Bariatric Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China
| | - Pin Zhang
- Department of Metabolic & Bariatric Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China
| | - Zengmin Miao
- School of Life Sciences, Shandong First Medical University, Tai'an, 271000, PR China.
| | - Yousheng Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, PR China.
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17
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Ilhan ZE, DiBaise JK, Dautel SE, Isern NG, Kim YM, Hoyt DW, Schepmoes AA, Brewer HM, Weitz KK, Metz TO, Crowell MD, Kang DW, Rittmann BE, Krajmalnik-Brown R. Temporospatial shifts in the human gut microbiome and metabolome after gastric bypass surgery. NPJ Biofilms Microbiomes 2020; 6:12. [PMID: 32170068 PMCID: PMC7070067 DOI: 10.1038/s41522-020-0122-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 02/14/2020] [Indexed: 02/08/2023] Open
Abstract
Although the etiology of obesity is not well-understood, genetic, environmental, and microbiome elements are recognized as contributors to this rising pandemic. It is well documented that Roux-en-Y gastric bypass (RYGB) surgery drastically alters the fecal microbiome, but data are sparse on temporal and spatial microbiome and metabolome changes, especially in human populations. We characterized the structure and function (through metabolites) of the microbial communities in the gut lumen and structure of microbial communities on mucosal surfaces in nine morbidly obese individuals before, 6 months, and 12 months after RYGB surgery. Moreover, using a comprehensive multi-omic approach, we compared this longitudinal cohort to a previously studied cross-sectional cohort (n = 24). In addition to the expected weight reduction and improvement in obesity-related comorbidities after RYGB surgery, we observed that the impact of surgery was much greater on fecal communities in comparison to mucosal ones. The changes in the fecal microbiome were linked to increased concentrations of branched-chain fatty acids and an overall decrease in secondary bile acid concentrations. The microbiome and metabolome data sets for this longitudinal cohort strengthen our understanding of the persistent impact of RYGB on the gut microbiome and its metabolism. Our findings highlight the importance of changes in mucosal and fecal microbiomes after RYGB surgery. The spatial modifications in the microbiome after RYGB surgery corresponded to persistent changes in fecal fermentation and bile acid metabolism, both of which are associated with improved metabolic outcomes.
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Affiliation(s)
- Zehra Esra Ilhan
- Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ, USA.
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, USA.
| | - John K DiBaise
- Mayo Clinic, Division of Gastroenterology, Scottsdale, AZ, USA
| | - Sydney E Dautel
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Nancy G Isern
- William R. Wiley Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Young-Mo Kim
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - David W Hoyt
- William R. Wiley Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Athena A Schepmoes
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Heather M Brewer
- William R. Wiley Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Karl K Weitz
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Thomas O Metz
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | | | - Dae-Wook Kang
- Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ, USA
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, USA
- Department of Civil & Environmental Engineering, The University of Toledo, Toledo, OH, USA
| | - Bruce E Rittmann
- Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ, USA
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ, USA
| | - Rosa Krajmalnik-Brown
- Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ, USA.
- Biodesign Center for Fundamental and Applied Microbiomics, Arizona State University, Tempe, AZ, USA.
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ, USA.
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Ahmad TR, Haeusler RA. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nat Rev Endocrinol 2019; 15:701-712. [PMID: 31616073 PMCID: PMC6918475 DOI: 10.1038/s41574-019-0266-7] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/11/2019] [Indexed: 12/12/2022]
Abstract
Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research.
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Affiliation(s)
- Tiara R Ahmad
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA.
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
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Cӑtoi AF, Pârvu AE, Mironiuc A, Silaghi H, Pop ID, Andreicuț AD. Ultra-Early and Early Changes in Bile Acids and Insulin After Sleeve Gastrectomy Among Obese Patients. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:E757. [PMID: 31766784 PMCID: PMC6955910 DOI: 10.3390/medicina55120757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/17/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVE In obese patients, sleeve gastrectomy (SG) has shown mixed results on bile acid (BA) values. The aim of our study was to examine the potential ultra-early and early changes of the circulating total BA in relation with the changes of insulin resistance (IR) in obese patients submitted to laparoscopic SG. Materials and Methods: Twenty-four obese subjects were investigated for body mass index (BMI), total fasting BA, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and leptin before and at 7 and 30 d after SG. Results: After surgery, mean BMI decreased at the first (p < 0.001) and at the second time point (p < 0.001) relative to baseline. Total fasting BA values did not change significantly at 7 d (p = 0.938) and at 30 d (p = 0.289) after SG. No significant changes were found at 7 d (p = 0.194, p = 0.34) and 30 d (p = 0.329, p = 0.151) after surgery regarding fasting insulin and HOMA-IR, respectively. However, a trend of increased total fasting BA and decreased fasting insulin and HOMA- after laparoscopic SG has been found. Negative correlations between total fasting BA and insulin (r = -0.807, p = 0.009), HOMA-IR (r = -0.855, p = 0.014), and blood glucose (r = -0.761, p = 0.047), respectively, were observed at one month after SG. Conclusion: In conclusion, here, we found a lack of significant changes in total fasting BA, insulin, and HOMA-IR ultra-early and early after SG, which precluded us to consider a possible relation between the variations of BA and IR. However, the presence of the tendency for total fasting BA to increase and for insulin and HOMA-IR to decrease, as well as of the negative correlations one month after laparoscopic SG, suggest that this surgery brings about some changes that point towards the existence, and possibly towards the restoration, at least to some extent, of the link between BA and glucose metabolism.
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Affiliation(s)
- Adriana Florinela Cӑtoi
- Department of Pathophysiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.E.P.); (A.D.A.)
| | - Alina Elena Pârvu
- Department of Pathophysiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.E.P.); (A.D.A.)
| | - Aurel Mironiuc
- 2nd Surgical Clinic, Department of Surgery, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Horațiu Silaghi
- 5th Surgical Clinic, Department of Surgery, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Ioana Delia Pop
- Department of Exact Sciences, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400372 Cluj-Napoca, Romania;
| | - Andra Diana Andreicuț
- Department of Pathophysiology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (A.E.P.); (A.D.A.)
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Shan CX, Qiu NC, Liu ME, Zha SL, Song X, Du ZP, Rao WS, Jiang DZ, Zhang W, Qiu M. Effects of Diet on Bile Acid Metabolism and Insulin Resistance in Type 2 Diabetic Rats after Roux-en-Y Gastric Bypass. Obes Surg 2019; 28:3044-3053. [PMID: 29721762 DOI: 10.1007/s11695-018-3264-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Roux-en-Y gastric bypass (RYGB) is effective for the treatment of type 2 diabetes mellitus; however, the mechanism remains unclear. METHODS The effects of RYGB on postprandial responses to three different diets (low carbohydrate (CH)-rich diet, high CH-rich diet, and fat-rich diet) of different nutritional composition in a Goto-Kakizaki (GK) diabetic rat model were assessed by measuring glucose tolerance, insulin resistance, incretin responses, and bile acid (BA) metabolism. RESULTS GK-RYGB group rats lost weight and preferred low CH-rich diet, but there were no significant differences in BW among the different diets. Glucose tolerance and insulin resistance were improved in rats who underwent RYGB, together with higher levels of circulating BAs, plasma GLP-1, and PYY levels. GK-RYGB rats fed high CH-rich or fat-rich diet showed increased glucose level and insulin resistance, together with high plasma BA, GIP, and PYY levels compared to those fed a low CH-rich diet. CONCLUSION RYGB improves glucose tolerance and insulin resistance which may be related to BA metabolism and hormone levels, and the nutrient composition of the diet affects the treatment effect of RYGB on T2DM.
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Affiliation(s)
- Cheng-Xiang Shan
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China
| | - Nian-Cun Qiu
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China.,Department of General Surgery, Hainan Branch of Chinese PLA General Hospital, Sanya, 572000, China
| | - Miao-E Liu
- Key Laboratory of Reproductive Genetics, Women's Hospital, Zhejiang University, Zhejiang, 310000, China
| | - Si-Luo Zha
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China
| | - Xin Song
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China
| | - Zhi-Peng Du
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China
| | - Wen-Sheng Rao
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China
| | - Dao-Zhen Jiang
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China
| | - Wei Zhang
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China.
| | - Ming Qiu
- Department of General Surgery, Chang Zheng Hospital affiliated to Second Military Medical University, 440 Chengdu North Road, Shanghai, 200003, China.
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Tsuchiya T, Naitoh T, Nagao M, Tanaka N, Watanabe K, Imoto H, Miyachi T, Motoi F, Unno M. Increased Bile Acid Signals After Duodenal-Jejunal Bypass Improve Non-alcoholic Steatohepatitis (NASH) in a Rodent Model of Diet-Induced NASH. Obes Surg 2019; 28:1643-1652. [PMID: 29235014 DOI: 10.1007/s11695-017-3065-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The increasing incidence of non-alcoholic steatohepatitis (NASH) has resulted in it becoming a common cause of liver-related mortality; however, no efficient treatment has been established. It has been reported that bariatric surgery improves metabolic comorbidities, such as diabetes mellitus and NASH. Although the mechanism is unclear, it is thought that the changes in bile acid (BA) signaling via its nuclear receptor, farnesoid X receptor (FXR), produce various metabolic effects. We sought to investigate the effects and mechanisms of bariatric surgery on NASH improvement. METHODS Male Sprague-Dawley rats were fed by a high-fat and high-fructose diet, which results in obesity, insulin resistance, and NASH. Rats underwent duodenal-jejunal bypass (DJB), which is a main component of bariatric procedures. The liver pathological findings and the expression level of mRNA of FXR were investigated. The plasma BA level was measured in peripheral and portal vein blood. RESULTS DJB suppressed weight gain, improved insulin resistance, and ameliorated NASH mainly in a point of inflammation. The plasma BA level along with the expression of FXR and its target transcriptional factor, small heterodimer partner (SHP), in the liver were elevated. CONCLUSIONS DJB has a direct effect on NASH improvement, and there is a possibility that an anti-inflammatory effect is functioning as a part of the mechanism. The increase of plasma bile acid level followed by the stimulation of FXR signaling may contribute to this phenomenon.
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Affiliation(s)
- Takahiro Tsuchiya
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Takeshi Naitoh
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
| | - Munenori Nagao
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Naoki Tanaka
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Kazuhiro Watanabe
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Hirofumi Imoto
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Tomohiro Miyachi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Fuyuhiko Motoi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
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Kong X, Tu Y, Li B, Zhang L, Feng L, Wang L, Zhang L, Zhou H, Hua X, Ma X. Roux-en-Y gastric bypass enhances insulin secretion in type 2 diabetes via FXR-mediated TRPA1 expression. Mol Metab 2019; 29:1-11. [PMID: 31668381 PMCID: PMC6728758 DOI: 10.1016/j.molmet.2019.08.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/12/2019] [Accepted: 08/12/2019] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVE Roux-en-Y gastric bypass surgery (RYGB) improves the first phase of glucose-stimulated insulin secretion (GSIS) in patients with type 2 diabetes. How it does so remains unclear. Farnesoid X receptor (FXR), the nuclear receptor of bile acids (BAs), is implicated in bariatric surgery. Moreover, the transient receptor potential ankyrin 1 (TRPA1) channel is expressed in pancreatic β-cells and involved in insulin secretion. We aimed to explore the role of BAs/FXR and TRPA1 in improved GSIS in diabetic rats after RYGB. METHODS RYGB or sham surgery was conducted in spontaneous diabetic Goto-Kakizaki (GK) rats, or FXR or TRPA1 transgenic mice. Gene and protein expression of islets were assessed by qPCR and western blotting. Electrophysiological properties of single β-cells were studied using patch-clamp technique. Binding of FXR and histone acetyltransferase steroid receptor coactivator-1 (SRC1) to the TRPA1 promoter, acetylated histone H3 (ACH3) levels at the TRPA1 promoter were determined using ChIP assays. GSIS was measured using enzyme-linked immunosorbent assays or intravenous glucose tolerance test (IVGTT). RESULTS RYGB increases GSIS, particularly the first-phase of GSIS in both intact islets and GK rats in vivo, and ameliorates hyperglycemia of GK rats. Importantly, the effects of RYGB were attenuated in TRPA1-deficient mice. Moreover, GK β-cells displayed significantly decreased TRPA1 expression and current. Patch-clamp recording revealed that TRPA1-/- β-cells displayed a marked hyperpolarization and decreased glucose-evoked action potential firing, which was associated with impaired GSIS. RYGB restored TRPA1 expression and current in GK β-cells. This was accompanied by improved glucose-evoked electrical activity and insulin secretion. Additionally, RYGB-induced TRPA1 expression involved BAs/FXR-mediated recruitment of SRC1, promoting ACH3 at the promoter of TRPA1. CONCLUSIONS The BAs/FXR/SRC1 axis-mediated restoration of TRPA1 expression plays a critical role in the enhanced GSIS and remission of diabetes in GK rats after RYGB.
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Affiliation(s)
- Xiangchen Kong
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Yifan Tu
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Bingfeng Li
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Longmei Zhang
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Linxian Feng
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Lixiang Wang
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Lin Zhang
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Huarong Zhou
- Key laboratory of System Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Xianxin Hua
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China; University of Pennsylvania Perelman School of Medicine, 421 Curie Blvd, Philadelphia, PA 19104, USA
| | - Xiaosong Ma
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China.
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Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP. Systemic bile acids induce insulin resistance in a TGR5-independent manner. Am J Physiol Endocrinol Metab 2019; 316:E782-E793. [PMID: 30779633 PMCID: PMC6732652 DOI: 10.1152/ajpendo.00362.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 02/04/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
Abstract
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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Affiliation(s)
- Kristen E Syring
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
| | - Travis J Cyphert
- Department of Biological Sciences, Marshall University College of Science, Huntington, West Virginia
| | - Thomas C Beck
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center , Nashville, Tennessee
| | - Nicholas A Mignemi
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
| | - Owen P McGuinness
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
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24
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Pal A, Rhoads DB, Tavakkoli A. Portal milieu and the interplay of multiple antidiabetic effects after gastric bypass surgery. Am J Physiol Gastrointest Liver Physiol 2019; 316:G668-G678. [PMID: 30896970 PMCID: PMC6580237 DOI: 10.1152/ajpgi.00389.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Diabetes is a worldwide health problem. Roux-en-Y gastric bypass (RYGB) leads to rapid resolution of type 2 diabetes (T2D). Decreased hepatic insulin resistance is key, but underlying mechanisms are poorly understood. We hypothesized that changes in intestinal function and subsequent changes in portal venous milieu drive some of these postoperative benefits. We therefore aimed to evaluate postoperative changes in portal milieu. Two rat strains, healthy [Sprague-Dawley (SD)] and obese diabetic [Zucker diabetic fatty (ZDF)] rats, underwent RYGB or control surgery. After 4 wk, portal and systemic blood was sampled before and during an intestinal glucose bolus to investigate changes in intestinal glucose absorption (Gabsorp) and utilization (Gutil), and intestinal secretion of incretins and glucagon-like peptide-2 (GLP-2). Hepatic activity of dipeptidyl peptidase-4 (DPP4), which degrades incretins, was also measured. RYGB decreased Gabsorp in both rat strains. Gutil increased in SD rats and decreased in ZDF rats. In both strains, there was increased expression of intestinal hexokinase and gluconeogenesis enzymes. Systemic incretin and GLP-2 levels also increased after RYGB. This occurred without an increase in secretion. Hepatic DPP4 activity and expression were unchanged. RYGB perturbs multiple intestinal pathways, leading to decreased intestinal glucose absorption and increased incretin levels in both healthy and diabetic animals. In diabetic rats, intestinal glucose balance shifts toward glucose release. The portal vein as the gut-liver axis may integrate these intestinal changes to contribute to rapid changes in hepatic glucose and hormone handling. This fresh insight into the surgical physiology of RYGB raises the hope of less invasive alternatives. NEW & NOTEWORTHY Portal milieu after gastric bypass surgery is an underinvestigated area. Roux-en-Y gastric bypass perturbs multiple intestinal pathways, reducing intestinal glucose absorption and increasing incretin levels. In diabetic rats, the intestine becomes a net releaser of glucose, increasing portal glucose levels. The portal vein as the gut-liver axis may integrate these intestinal changes to contribute to changes in hepatic glucose handling. This fresh insight raises the hope of less invasive alternatives.
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Affiliation(s)
- Atanu Pal
- 1Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts,2Harvard Medical School, Boston, Massachusetts
| | - David B. Rhoads
- 2Harvard Medical School, Boston, Massachusetts,3Pediatric Endocrinology, MassGeneral Hospital for Children, Boston, Massachusetts
| | - Ali Tavakkoli
- 1Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts,2Harvard Medical School, Boston, Massachusetts,4Center for Weight Management and Metabolic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
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25
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Wang W, Cheng Z, Wang Y, Dai Y, Zhang X, Hu S. Role of Bile Acids in Bariatric Surgery. Front Physiol 2019; 10:374. [PMID: 31001146 PMCID: PMC6454391 DOI: 10.3389/fphys.2019.00374] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 03/18/2019] [Indexed: 12/11/2022] Open
Abstract
Bariatric surgery has been proved to be effective and sustainable in the long-term weight-loss and remission of metabolic disorders. However, the underlying mechanisms are still far from fully elucidated. After bariatric surgery, the gastrointestinal tract is manipulated, either anatomically or functionally, leading to changed bile acid metabolism. Accumulating evidence has shown that bile acids play a role in metabolic regulation as signaling molecules other than digestive juice. And most of the metabolism-beneficial effects are mediated through nuclear receptor FXR and membrane receptor TGR5, as well as reciprocal influence on gut microbiota. Bile diversion procedure is also performed on animals to recapitulate the benefits of bariatric surgery. It appears that bile acid alteration is an important component of bariatric surgery, and represents a promising target for the management of metabolic disorders.
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Affiliation(s)
- Wenting Wang
- Department of Obstetrics and Gynecology, The Second Hospital of Shandong University, Jinan, China
| | - Zhiqiang Cheng
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yanlei Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yong Dai
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiang Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Sanyuan Hu
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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26
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Ise I, Tanaka N, Imoto H, Maekawa M, Kohyama A, Watanabe K, Motoi F, Unno M, Naitoh T. Changes in Enterohepatic Circulation after Duodenal–Jejunal Bypass and Reabsorption of Bile Acids in the Bilio-Pancreatic Limb. Obes Surg 2019; 29:1901-1910. [DOI: 10.1007/s11695-019-03790-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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27
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Guida C, Stephen SD, Watson M, Dempster N, Larraufie P, Marjot T, Cargill T, Rickers L, Pavlides M, Tomlinson J, Cobbold JFL, Zhao CM, Chen D, Gribble F, Reimann F, Gillies R, Sgromo B, Rorsman P, Ryan JD, Ramracheya RD. PYY plays a key role in the resolution of diabetes following bariatric surgery in humans. EBioMedicine 2019; 40:67-76. [PMID: 30639417 PMCID: PMC6413583 DOI: 10.1016/j.ebiom.2018.12.040] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 12/11/2018] [Accepted: 12/18/2018] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Bariatric surgery leads to early and long-lasting remission of type 2 diabetes (T2D). However, the mechanisms behind this phenomenon remain unclear. Among several factors, gut hormones are thought to be crucial mediators of this effect. Unlike GLP-1, the role of the hormone peptide tyrosine tyrosine (PYY) in bariatric surgery in humans has been limited to appetite regulation and its impact on pancreatic islet secretory function and glucose metabolism remains under-studied. METHODS Changes in PYY concentrations were examined in obese patients after bariatric surgery and compared to healthy controls. Human pancreatic islet function was tested upon treatment with sera from patients before and after the surgery, in presence or absence of PYY. Alterations in intra-islet PYY release and insulin secretion were analysed after stimulation with short chain fatty acids (SCFAs), bile acids and the cytokine IL-22. FINDINGS We demonstrate that PYY is a key effector of the early recovery of impaired glucose-mediated insulin and glucagon secretion in bariatric surgery. We establish that the short chain fatty acid propionate and bile acids, which are elevated after surgery, can trigger PYY release not only from enteroendocrine cells but also from human pancreatic islets. In addition, we identify IL-22 as a new factor which is modulated by bariatric surgery in humans and which directly regulates PYY expression and release. INTERPRETATION This study shows that some major metabolic benefits of bariatric surgery can be emulated ex vivo. Our findings are expected to have a direct impact on the development of new non-surgical therapy for T2D correction.
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Affiliation(s)
- Claudia Guida
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK
| | - Sam D Stephen
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK
| | - Michael Watson
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Niall Dempster
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK
| | - Pierre Larraufie
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Thomas Marjot
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Tamsin Cargill
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Lisa Rickers
- Oxford Bariatric Service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Michael Pavlides
- Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, Oxford, UK
| | - Jeremy Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK
| | | | - Chun-Mei Zhao
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Duan Chen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Fiona Gribble
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Frank Reimann
- Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Richard Gillies
- Oxford Bariatric Service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Bruno Sgromo
- Oxford Bariatric Service, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK
| | - John D Ryan
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
| | - Reshma D Ramracheya
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK.
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de Siqueira Cardinelli C, Torrinhas RS, Sala P, Pudenzi MA, Fernando F Angolini C, Marques da Silva M, Machado NM, Ravacci G, Eberlin MN, Waitzberg DL. Fecal bile acid profile after Roux-en-Y gastric bypass and its association with the remission of type 2 diabetes in obese women: A preliminary study. Clin Nutr 2019; 38:2906-2912. [PMID: 30799193 DOI: 10.1016/j.clnu.2018.12.028] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/03/2018] [Accepted: 12/26/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To assess the influence of Roux-en-Y gastric by-pass (RYGB) on fecal bile acid (BA) profile and its relationship with postoperative remission of type 2 diabetes (T2D). METHODS Fecal samples were collected 3 and 12 months after RYGB from diabetic obese women who were responsive (n = 12) and non-responsive (n = 8) to postoperative remission of T2D. Fecal BA profile was accessed by liquid chromatography coupled to tandem mass spectrometry in a targeted approach. RESULTS Relative to pre-operative levels, a total of 10 fecal BA profiles decreased after RYGB (ANOVA, p ≤ 0.05) with significant fold-changes for glycochenodeoxycholic, glycocholic, taurocholic, and taurochenodeoxycholic acids at 3-months postoperatively, and for glycochenodeoxycholic, glycocholic and taurocholic acids at 12 months postoperatively (Benjamini-Hochberg, p ≤ 0.05). Postoperative changes in fecal BA were different between responsive and non-responsive women, with a significant reduction in more sub-fractions of BA in responsive women than in non-responsive women, and a marked difference in the temporal behavior of cholic acid (CA) and chenodeoxycholic acid (CDCA), thus reflecting changes in CA/CDCA ratio, and tauroursodeoxycolic (TUDCA) levels between these responsiveness groups (ANOVA, p ≤ 0.05). CONCLUSION RYGB induces a marked reduction in the concentration of fecal BA, which is heterogeneous according to T2D responsiveness.
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Affiliation(s)
- Camila de Siqueira Cardinelli
- Laboratory of Nutrition and Surgery Metabolic of the Digestive Tract, Metanutri - Lim 35, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil.
| | - Raquel Susana Torrinhas
- Laboratory of Nutrition and Surgery Metabolic of the Digestive Tract, Metanutri - Lim 35, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Priscila Sala
- Laboratory of Nutrition and Surgery Metabolic of the Digestive Tract, Metanutri - Lim 35, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Marcos Albieri Pudenzi
- ThoMSon Mass Spectrometry Laboratory, State University of Campinas (UNICAMP), São Paulo, Brazil
| | | | - Mariane Marques da Silva
- Laboratory of Nutrition and Surgery Metabolic of the Digestive Tract, Metanutri - Lim 35, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Natasha Mendonça Machado
- Laboratory of Nutrition and Surgery Metabolic of the Digestive Tract, Metanutri - Lim 35, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Graziela Ravacci
- Laboratory of Nutrition and Surgery Metabolic of the Digestive Tract, Metanutri - Lim 35, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Marcos N Eberlin
- ThoMSon Mass Spectrometry Laboratory, State University of Campinas (UNICAMP), São Paulo, Brazil
| | - Dan L Waitzberg
- Laboratory of Nutrition and Surgery Metabolic of the Digestive Tract, Metanutri - Lim 35, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
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29
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Ding L, Fang Z, Liu Y, Zhang E, Huang T, Yang L, Wang Z, Huang W. Targeting Bile Acid-Activated Receptors in Bariatric Surgery. Handb Exp Pharmacol 2019; 256:359-378. [PMID: 31144046 DOI: 10.1007/164_2019_229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Bariatric surgical procedures, including Roux-en-Y gastric bypass and vertical sleeve gastrectomy, are currently the most effective clinical approaches to achieve a significant and sustainable weight loss. Bariatric surgery also concomitantly improves type 2 diabetes and other metabolic diseases such as nonalcoholic steatohepatitis, cardiovascular diseases, and hyperlipidemia. However, despite the recent exciting progress in the understanding how bariatric surgery works, the underlying molecular mechanisms of bariatric surgery remain largely unknown. Interestingly, bile acids are emerging as potential signaling molecules to mediate the beneficial effects of bariatric surgery. In this review, we summarize the recent findings on bile acids and their activated receptors in mediating the beneficial metabolic effects of bariatric surgery. We also discuss the potential to target bile acid-activated receptors in order to treat obesity and other metabolic diseases.
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Affiliation(s)
- Lili Ding
- Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute of City of Hope, Beckman Research Institute of City of Hope, Duarte, CA, USA.,Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhipeng Fang
- Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute of City of Hope, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Yanjun Liu
- Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute of City of Hope, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Eryun Zhang
- Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute of City of Hope, Beckman Research Institute of City of Hope, Duarte, CA, USA.,Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tracy Huang
- Eugene and Roth Roberts Summer Student Academy, City of Hope, Duarte, CA, USA
| | - Li Yang
- Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Compound Chinese Medicines and The Ministry of Education (MOE) Key Laboratory of Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Diabetes & Metabolism Research Institute of City of Hope, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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Jönsson TJ, Schäfer HL, Herling AW, Brönstrup M. A metabolome-wide characterization of the diabetic phenotype in ZDF rats and its reversal by pioglitazone. PLoS One 2018; 13:e0207210. [PMID: 30481177 PMCID: PMC6258476 DOI: 10.1371/journal.pone.0207210] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 10/26/2018] [Indexed: 12/19/2022] Open
Abstract
Type 2 diabetes (T2D) is a complex metabolic disease associated with alterations in glucose, lipid and protein metabolism. In order to characterize the biochemical phenotype of the Zucker diabetic fatty (ZDF) rat, the most common animal model for the study of T2D, and the impact of the insulin sensitizer pioglitazone, a global, mass spectrometry-based analysis of the metabolome was conducted. Overall, 420 metabolites in serum, 443 in the liver and 603 in the intestine were identified at study end. In comparison to two control groups, obese diabetic ZDF rats showed characteristic metabolic signatures that included hyperglycemia, elevated β-oxidation, dyslipidemia—featured by an increase in saturated and monounsaturated fatty acids and a decrease of medium chain and of polyunsaturated fatty acids in serum–and decreased amino acid levels, consistent with their utilization in hepatic gluconeogenesis. A 13-week treatment with the PPARγ agonist pioglitazone reversed most of these signatures: Pioglitazone improved glycemic control and the fatty acid profile, elevated amino acid levels in the liver, but decreased branched chain amino acids in serum. The hitherto most comprehensive metabolic profiling study identified a biochemical blueprint for the ZDF diabetic model and captured the impact of genetic, nutritional and pharmacological perturbations. The in-depth characterization on the molecular level deepens the understanding and further validates the ZDF rat as a suitable preclinical model of diabetes in humans.
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Affiliation(s)
| | | | | | - Mark Brönstrup
- Helmholtz Centre for Infection Research and German Center for Infection Research (DZIF), Braunschweig, Germany
- * E-mail:
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Attenuation of diet-induced hypothalamic inflammation following bariatric surgery in female mice. Mol Med 2018; 24:56. [PMID: 30355312 PMCID: PMC6201532 DOI: 10.1186/s10020-018-0057-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/09/2018] [Indexed: 12/14/2022] Open
Abstract
Background Exposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus. Such hypothalamic inflammation is associated with metabolic dysfunction, central leptin resistance, and maintenance of obesity. Bariatric surgeries result in long-term stable weight loss and improved metabolic function. However, the effects of such surgical procedures on HFD-induced hypothalamic inflammation are unknown. We sought to characterize the effects of two bariatric surgical procedures, Roux-en-Y gastric bypass (RYGB) and biliary diversion (BD-IL), in female mice with particular emphasis on HFD-induced hypothalamic inflammation and microgliosis. Methods RYGB and BD-IL were performed on diet-induced obese (DIO) mice. Quantitative RT-PCR and fluorescent microscopy were used to evaluate hypothalamic inflammatory gene expression and microgliosis. Results were compared to lean (CD), DIO sham-surgerized mice (DIO-SHAM), and dietary weight loss (DIO-Rev) controls. Results In female mice, RYGB and BD-IL result in normalization of hypothalamic inflammatory gene expression and microgliosis within 8 weeks of surgery, despite ongoing exposure to HFD. Paralleling these results, the hypothalamic expression levels of the orexigenic neuropeptide Agrp and the anorexic response of surgical mice to exogenous leptin were comparable to lean controls (CD). In contrast, results from DIO-Rev mice were comparable to DIO-SHAM mice, despite transition back to standard rodent show and normalization of weight. Conclusion Bariatric surgery attenuates HFD-induced hypothalamic inflammation and microgliosis and restores leptin sensitivity, despite ongoing exposure to HFD.
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Gut adaptation after metabolic surgery and its influences on the brain, liver and cancer. Nat Rev Gastroenterol Hepatol 2018; 15:606-624. [PMID: 30181611 DOI: 10.1038/s41575-018-0057-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Metabolic surgery is the best treatment for long-term weight loss maintenance and comorbidity control. Metabolic operations were originally intended to change anatomy to alter behaviour, but we now understand that the anatomical changes can modulate physiology to change behaviour. They are no longer considered only mechanically restrictive and/or malabsorptive procedures; rather, they are considered metabolic procedures involving complex physiological changes, whereby gut adaptation influences signalling pathways in several other organs, including the liver and the brain, regulating hunger, satiation, satiety, body weight, glucose metabolism and immune functions. The integrative physiology of gut adaptation after these operations consists of a complex mechanistic web of communication between gut hormones, bile acids, gut microbiota, the brain and both enteric and central nervous systems. The understanding of nutrient sensing via enteroendocrine cells, the enteric nervous system, hypothalamic peptides and adipose tissue and of the role of inflammation has advanced our knowledge of this integrative physiology. In this Review, we focus on the adaptation of gut physiology to the anatomical alterations from Roux-en-Y gastric bypass and vertical sleeve gastrectomy and the influence of these procedures on food intake, weight loss, nonalcoholic fatty liver disease (NAFLD) and cancer. We also aim to demonstrate the underlying mechanisms that could explain how metabolic surgery could be used as a therapeutic option in NAFLD and certain obesity-related cancers.
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Abstract
PURPOSE OF REVIEW Herein, we review the role of FXR and TGR5 in the regulation of hepatic bile acid metabolism, with a focus on how our understanding of bile acid metabolic regulation by these receptors has evolved in recent years and how this improved understanding may facilitate targeting bile acids for type 2 diabetes treatment. RECENT FINDINGS Bile acid profile is a key regulator of metabolic homeostasis. Inhibition of expression of the enzyme that is required for cholic acid synthesis and thus determines bile acid profile, Cyp8b1, may be an effective target for type 2 diabetes treatment. FXR and, more recently, TGR5 have been shown to regulate bile acid metabolism and Cyp8b1 expression and, therefore, may provide a mechanism with which to target bile acid profile for type 2 diabetes treatment. Inhibition of Cyp8b1 expression is a promising therapeutic modality for type 2 diabetes; however, further work is needed to fully understand the pathways regulating Cyp8b1 expression.
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Affiliation(s)
- Karolina E Zaborska
- Department of Biomedical Sciences, Cornell University, T3 014A Veterinary Research Tower, Ithaca, NY, 14853, USA
| | - Bethany P Cummings
- Department of Biomedical Sciences, Cornell University, T3 014A Veterinary Research Tower, Ithaca, NY, 14853, USA.
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Bozadjieva N, Heppner KM, Seeley RJ. Targeting FXR and FGF19 to Treat Metabolic Diseases-Lessons Learned From Bariatric Surgery. Diabetes 2018; 67:1720-1728. [PMID: 30135133 PMCID: PMC6463577 DOI: 10.2337/dbi17-0007] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 06/08/2018] [Indexed: 12/12/2022]
Abstract
Bariatric surgery procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective interventions available for sustained weight loss and improved glucose metabolism. Bariatric surgery alters the enterohepatic bile acid circulation, resulting in increased plasma bile levels as well as altered bile acid composition. While it remains unclear why both VSG and RYGB can alter bile acids, it is possible that these changes are important mediators of the effects of surgery. Moreover, a molecular target of bile acid synthesis, the bile acid-activated transcription factor FXR, is essential for the positive effects of VSG on weight loss and glycemic control. This Perspective examines the relationship and sequence of events between altered bile acid levels and composition, FXR signaling, and gut microbiota after bariatric surgery. We hypothesize that although bile acids and FXR signaling are potent mediators of metabolic function, unidentified downstream targets are the main mediators behind the benefits of weight-loss surgery. One of these targets, the gut-derived peptide FGF15/19, is a potential molecular and therapeutic marker to explain the positive metabolic effects of bariatric surgery. Focusing research efforts on identifying these complex molecular mechanisms will provide new opportunities for therapeutic strategies to treat obesity and metabolic dysfunction.
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Affiliation(s)
- Nadejda Bozadjieva
- Departments of Surgery and Medicine, University of Michigan, Ann Arbor, MI
| | | | - Randy J Seeley
- Departments of Surgery and Medicine, University of Michigan, Ann Arbor, MI
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Wei M, Shao Y, Liu QR, Wu QZ, Zhang X, Zhong MW, Liu SZ, Zhang GY, Hu SY. Bile acid profiles within the enterohepatic circulation in a diabetic rat model after bariatric surgeries. Am J Physiol Gastrointest Liver Physiol 2018; 314:G537-G546. [PMID: 29351394 DOI: 10.1152/ajpgi.00311.2017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Bile acids (BAs), which are synthesized in the liver and cycled in the enterohepatic circulation, have been recognized as signaling molecules by activating their receptors in the intestine and liver. Serum taurine-conjugated BAs have been shown to be elevated after bariatric surgeries although the postoperative BA profiles within the enterohepatic circulation have not been investigated. Clarification of these profiles could help explain the mechanisms by which bariatric surgery leads to BA profile alterations and subsequent metabolic effects. We performed duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham procedures in an obese diabetic rat model induced by high-fat diet and streptozotocin. The weight loss and antidiabetic effects were evaluated postsurgery. BA profiles in the systemic serum and within the enterohepatic circulation were analyzed, together with the expression of related BA transporters and enzymes at week 12 after surgery. Compared with sham, SG induced sustained weight loss, and both DJB and SG significantly improved glucose tolerance and insulin sensitivity with enhanced glucagon-like peptide 1 secretion. Similar to changes in the serum, BAs, especially taurine-conjugated species, were also elevated in the enterohepatic circulation (bile and portal vein) after DJB and SG. In addition, the expression of key BA transporters and conjugational enzymes was elevated postoperatively, whereas the enzymes responsible for BA synthesis were decreased. In conclusion, DJB and SG elevated BA levels in the systemic serum and enterohepatic circulation, especially taurine-conjugated species, which likely indicates increased ileal reabsorption and hepatic conjugation rather than synthesis. NEW & NOTEWORTHY Bile acids (BAs) have been implicated as potential mediators of the weight-independent effects of bariatric surgery. For the first time, we discovered that duodenal-jejunal bypass and sleeve gastrectomy elevated BAs, particularly the taurine-conjugated species in the enterohepatic circulation, likely through the promotion of ileal reabsorption and hepatic conjugation rather than BA synthesis. These findings will improve our understanding of BA metabolism after bariatric surgery and their subsequent metabolic effects.
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Affiliation(s)
- Meng Wei
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - Yi Shao
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - Qiao-Ran Liu
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - Qun-Zheng Wu
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - Xiang Zhang
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - Ming-Wei Zhong
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - Shao-Zhuang Liu
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - Guang-Yong Zhang
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
| | - San-Yuan Hu
- Department of General Surgery, Qilu Hospital of Shandong University , Jinan , People's Republic of China
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Guida C, McCulloch LJ, Godazgar M, Stephen SD, Baker C, Basco D, Dong J, Chen D, Clark A, Ramracheya RD. Sitagliptin and Roux-en-Y gastric bypass modulate insulin secretion via regulation of intra-islet PYY. Diabetes Obes Metab 2018; 20:571-581. [PMID: 28892258 PMCID: PMC5836881 DOI: 10.1111/dom.13113] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 08/28/2017] [Accepted: 09/05/2017] [Indexed: 12/14/2022]
Abstract
AIMS The gut hormone peptide tyrosine tyrosine (PYY) is critical for maintaining islet integrity and restoring islet function following Roux-en-Y gastric bypass (RYGB). The expression of PYY and its receptors (NPYRs) in islets has been documented but not fully characterized. Modulation of islet PYY by the proteolytic enzyme dipeptidyl peptidase IV (DPP-IV) has not been investigated and the impact of DPP-IV inhibition on islet PYY function remains unexplored. Here we have addressed these gaps and their effects on glucose-stimulated insulin secretion (GSIS). We have also investigated changes in pancreatic PYY in diabetes and following RYGB. METHODS Immunohistochemistry and gene expression analysis were used to assess PYY, NPYRs and DPP-IV expression in rodent and human islets. DPP-IV activity inhibition was achieved by sitagliptin. Secretion studies were used to test PYY and the effects of sitagliptin on insulin release, and the involvement of GLP-1. Radioimmunoassays were used to measure hormone content in islets. RESULTS PYY and DPP-IV localized in different cell types in islets while NPYR expression was confined to the beta-cells. Chronic PYY application enhanced GSIS in rodent and diabetic human islets. DPP-IV inhibition by sitagliptin potentiated GSIS; this was mediated by locally-produced PYY, and not GLP-1. Pancreatic PYY was markedly reduced in diabetes. RYGB strongly increased islet PYY content, but did not lead to full restoration of pancreatic GLP-1 levels. CONCLUSION Local regulation of pancreatic PYY, rather than GLP-1, by DPP-IV inhibition or RYGB can directly modulate the insulin secretory response to glucose, indicating a novel role of pancreatic PYY in diabetes and weight-loss surgery.
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Affiliation(s)
- Claudia Guida
- Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill Hospital, Oxford UniversityOxfordUK
| | - Laura J. McCulloch
- Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill Hospital, Oxford UniversityOxfordUK
| | - Mahdieh Godazgar
- Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill Hospital, Oxford UniversityOxfordUK
| | - Sam D. Stephen
- Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill Hospital, Oxford UniversityOxfordUK
| | - Charlotte Baker
- Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill Hospital, Oxford UniversityOxfordUK
| | - Davide Basco
- Center for Integrative GenomicsUniversity of LausanneLausanneSwitzerland
| | | | - Duan Chen
- Department of Clinical and Molecular MedicineNorwegian University of Science and TechnologyTrondheimNorway
| | - Anne Clark
- Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill Hospital, Oxford UniversityOxfordUK
| | - Reshma D Ramracheya
- Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill Hospital, Oxford UniversityOxfordUK
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Pal A, Rhoads DB, Tavakkoli A. Customization of biliopancreatic limb length to modulate and sustain antidiabetic effect of gastric bypass surgery. Am J Physiol Gastrointest Liver Physiol 2018; 314:G287-G299. [PMID: 29097359 PMCID: PMC5866424 DOI: 10.1152/ajpgi.00276.2017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although Roux-en-Y Gastric Bypass (RYGB) remains the most effective treatment for obesity and type 2 diabetes (T2D), many patients fail to achieve remission, or relapse. Increasing intestinal limb lengths of RYGB may improve outcomes, but the mechanistic basis for this remains unclear. We hypothesize biliopancreatic (BP) limb length modulates the antidiabetic effect of RYGB. Rats underwent RYGB with a 20-cm (RYGB-20cm) or 40-cm (RYGB-40cm) BP limb and were compared with control animals. After 2 and 4 wk, portal and systemic blood was sampled during intestinal glucose infusion. Portosystemic gradient was used to calculate intestinal glucose utilization (Gutil), absorption (Gabsorp), and hormone secretion. Intestinal morphology and gene expression were assessed. At 2 wk, Gabsorp progressively decreased with increasing BP limb length; this pattern persisted at 4 wk. Gutil increased ≈70% in both RYGB-20cm and -40cm groups at 2 wk. At 4 wk, Gutil progressively increased with limb length. Furthermore, Roux limb weight, and expression of hexokinase and preproglucagon, exhibited a similar progressive increase. At 4 wk, glucagon-like peptide-1 and -2 levels were higher after RYGB-40cm, with associated increased secretion. We conclude that BP limb length modulates multiple antidiabetic mechanisms, analogous to the dose-response relationship of a drug. Early postoperatively, a longer BP limb reduces Gabsorp. Later, Gutil, Roux limb hypertrophy, hormone secretion, and hormone levels are increased with longer BP limb. Sustained high incretin levels may prevent weight regain and T2D relapse. These data provide the basis for customizing BP limb length according to patient characteristics and desired metabolic effect. NEW & NOTEWORTHY Biliopancreatic limb length in gastric bypass modulates multiple antidiabetic mechanisms, analogous to the dose-response relationship of a drug. With a longer biliopancreatic limb, Roux limb hypertrophy, increased glucose utilization, reduced glucose absorption, and sustained high incretin levels may prevent weight regain and diabetes relapse.
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Affiliation(s)
- A. Pal
- 1Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts,2Harvard Medical School Boston, Massachusetts
| | - D. B. Rhoads
- 2Harvard Medical School Boston, Massachusetts,3Pediatric Endocrinology, Massachusetts General Hospital for Children, Boston, Massachusetts
| | - A. Tavakkoli
- 1Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts,2Harvard Medical School Boston, Massachusetts,4Center for Weight Management and Metabolic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
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Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med 2018; 215:383-396. [PMID: 29339445 PMCID: PMC5789421 DOI: 10.1084/jem.20171965] [Citation(s) in RCA: 308] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/11/2022] Open
Abstract
Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration. Alterations in BA metabolism and signaling are associated with obesity and type 2 diabetes mellitus (T2DM), whereas treatment of T2DM patients with BA sequestrants, or bariatric surgery in morbidly obese patients, results in a significant improvement in glycemic response that is associated with changes in the BA profile and signaling. Herein, we review the roles of BAs in glucose metabolism in health and disease; highlight the limitations, unknowns, and challenges in understanding the impact of BAs on the glycemic response; and discuss how this knowledge may be harnessed to develop innovative therapeutic approaches for the treatment of hyperglycemia and diabetes.
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Affiliation(s)
- Hagit Shapiro
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | | | - Daniel Halstuch
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Eran Elinav
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
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Yan Y, Zhou Z, Kong F, Feng S, Li X, Sha Y, Zhang G, Liu H, Zhang H, Wang S, Hu C, Zhang X. Roux-en-Y Gastric Bypass Surgery Suppresses Hepatic Gluconeogenesis and Increases Intestinal Gluconeogenesis in a T2DM Rat Model. Obes Surg 2017; 26:2683-2690. [PMID: 27038047 DOI: 10.1007/s11695-016-2157-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Roux-en-Y gastric bypass (RYGB) is an effective surgical treatment for type 2 diabetes mellitus (T2DM). The present study aimed to investigate the effects of RYGB on glucose homeostasis, lipid metabolism, and intestinal morphological adaption, as well as hepatic and intestinal gluconeogenesis. METHODS Twenty adult male T2DM rats induced by high-fat diet and low dose of streptozotocin were randomly divided into sham and RYGB groups. The parameters of body weight, food intake, glucose tolerance, insulin sensitivity, and serum lipid profiles were assessed to evaluate metabolic changes. Intestinal sections were stained with hematoxylin and eosin (H&E) for light microscopy examination. The messenger RNA (mRNA) and protein expression levels of key regulatory enzymes of gluconeogenesis [phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase)] were determined through reverse-transcription PCR (RT-PCR) and Western blotting, respectively. RESULTS RYGB induced significant improvements in glucose tolerance and insulin sensitivity, along with weight loss and decreased food intake. RYGB also decreased serum triglyceride (TG) and free fatty acid (FFA) levels. The jejunum and ileum exhibited a marked increase in the length and number of intestinal villi after RYGB. The RYGB group exhibited downregulated mRNA and protein expression levels of PEPCK and G6Pase in the liver and upregulated expression of these enzymes in the jejunum and ileum tissues. CONCLUSIONS RYGB ameliorates glucose and lipid metabolism accompanied by weight loss and calorie restriction. The small intestine shows hyperplasia and hypertrophy after RYGB. Meanwhile, our study demonstrated that the reduced hepatic gluconeogenesis and increased intestinal gluconeogenesis may contribute to improved glucose homeostasis after RYGB.
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Affiliation(s)
- Yong Yan
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Zhou Zhou
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Fanzhi Kong
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Suibin Feng
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Xuzhong Li
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Yanhua Sha
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Guangjun Zhang
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Haijun Liu
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Haiqing Zhang
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Shiguang Wang
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China
| | - Cheng Hu
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Xueli Zhang
- Department of General Surgery, Central Hospital of Fengxian District, Southern Medical University, No.6600, Nan Feng Road, Shanghai, 201499, China.
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40
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Blanchard C, Moreau F, Ayer A, Toque L, Garçon D, Arnaud L, Borel F, Aguesse A, Croyal M, Krempf M, Prieur X, Neunlist M, Cariou B, Le May C. Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption. Int J Obes (Lond) 2017; 42:552-560. [PMID: 29135972 DOI: 10.1038/ijo.2017.232] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 08/10/2017] [Accepted: 08/27/2017] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Bariatric surgery appears as the most efficient therapeutic alternative in morbidly obese patients. In addition to its efficiency to decrease body weight, it also improves metabolic complications associated to morbid obesity, including dyslipidemia. Although the cholesterol-lowering effect varies with the bariatric procedures, the underlying molecular mechanisms remain poorly defined. This study aims to assess the consequence of both restrictive (sleeve gastrectomy; SG) and malabsorptive (Roux-en-Y gastric bypass; RYGB) procedures on cholesterol metabolism in mice. SUBJECTS Ten-week-old C57BL6/J males were fed with a high-fat diet for 8-14 weeks before sleeve or RYGB surgery. RESULTS SG has a modest and transient effect on plasma cholesterol levels, linked to a reduction in food intake. In contrast, modified RYGB led to a sustained ≈35% reduction in plasma cholesterol concentrations with a drastic increase in fecal cholesterol output. Mechanistically, RYGB exerts a synergystic effect on cholesterol metabolism by inducing the trans-intestinal cholesterol efflux and reducing the intestinal cholesterol absorption. CONCLUSIONS In mice, RYGB, but not sleeve, strongly favors plasma cholesterol elimination by concomitantly increasing trans-intestinal cholesterol excretion and by decreasing intestinal cholesterol absorption. Our models open new perspective for deciphering the hypocholesterolemic effects of bariatric procedures.
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Affiliation(s)
- C Blanchard
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.,Service de Clinique de Chirurgie Digestive et Endocrinienne, CHU de Nantes, Nantes, France
| | - F Moreau
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - A Ayer
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - L Toque
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - D Garçon
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - L Arnaud
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - F Borel
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.,Service de Clinique de Chirurgie Digestive et Endocrinienne, CHU de Nantes, Nantes, France
| | - A Aguesse
- Physiologie des Adaptations Nutritionnelles, CHU Hôtel-Dieu, Nantes, France.,CRNHO, West Human Nutrition Research Center, CHU, Nantes, France
| | - M Croyal
- Physiologie des Adaptations Nutritionnelles, CHU Hôtel-Dieu, Nantes, France.,CRNHO, West Human Nutrition Research Center, CHU, Nantes, France
| | - M Krempf
- Physiologie des Adaptations Nutritionnelles, CHU Hôtel-Dieu, Nantes, France.,CRNHO, West Human Nutrition Research Center, CHU, Nantes, France
| | - X Prieur
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - M Neunlist
- 5 INSERM UMR 1235, Nantes France.,CHU Nantes, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - B Cariou
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France.,l'institut du thorax, CHU Nantes, Department of Endocrinology, Nantes, France
| | - C Le May
- l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
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41
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Mulla CM, Middelbeek RJW, Patti ME. Mechanisms of weight loss and improved metabolism following bariatric surgery. Ann N Y Acad Sci 2017; 1411:53-64. [PMID: 28868615 DOI: 10.1111/nyas.13409] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/08/2017] [Accepted: 05/12/2017] [Indexed: 12/13/2022]
Abstract
Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, as well as improved metabolic and overall health. Unfortunately, the cellular and physiological mechanisms by which bariatric surgery achieves weight loss have not been fully elucidated, yet are critical to understanding the central role of the intestinal tract in whole-body metabolism and to developing novel strategies for the treatment of obesity. In this review, we provide an overview of potential mechanisms contributing to weight loss, including effects on regulation of energy balance and both central and peripheral nervous system regulation of appetite and metabolism. Moreover, we highlight the importance of the gastrointestinal tract, including alterations in bile acid physiology, secretion of intestinally derived hormones, and the microbiome, as a potent mediator of improved metabolism in postbariatric patients.
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Affiliation(s)
- Christopher M Mulla
- Research and Clinic Divisions, Joslin Diabetes Center, Boston, Massachusetts.,Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Roeland J W Middelbeek
- Research and Clinic Divisions, Joslin Diabetes Center, Boston, Massachusetts.,Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Mary-Elizabeth Patti
- Research and Clinic Divisions, Joslin Diabetes Center, Boston, Massachusetts.,Department of Medicine, Harvard Medical School, Boston, Massachusetts
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42
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Celiker H. A new proposed mechanism of action for gastric bypass surgery: Air hypothesis. Med Hypotheses 2017; 107:81-89. [PMID: 28915970 DOI: 10.1016/j.mehy.2017.08.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 07/02/2017] [Accepted: 08/08/2017] [Indexed: 02/07/2023]
Abstract
Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatments for obesity and type II diabetes. RYGB was originally believed to work by mechanically restricting caloric intake or causing macronutrient malabsorption. However, such mechanical effects play no role in the remarkable efficacy of gastric bypass. Instead, mounting evidence shows that altered neuroendocrine signaling is responsible for the weight reducing effects of RYGB. The exact mechanism of this surgical response is still a mystery. Here, we propose that RYGB leads to weight loss primarily by inducing a functional shift in the gut microbiome, manifested by a relative expansion of aerobic bacteria numbers in the colon. We point to compelling evidence that gastric bypass changes the function of the microbiome by disrupting intestinal gas homeostasis, causing excessive transit of swallowed air (oxygen) into the colon.
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Affiliation(s)
- Hasan Celiker
- Xeno Biosciences Inc., 12 Mt Auburn St #7, Cambridge, MA, USA.
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43
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Albaugh VL, Banan B, Ajouz H, Abumrad NN, Flynn CR. Bile acids and bariatric surgery. Mol Aspects Med 2017; 56:75-89. [PMID: 28390813 PMCID: PMC5603298 DOI: 10.1016/j.mam.2017.04.001] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 02/27/2017] [Accepted: 04/04/2017] [Indexed: 12/12/2022]
Abstract
Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following these procedures is between 40 and 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood, but has been attributed in part to the altered enterohepatic circulation of bile acids. In this review we highlight how bile acids potentially contribute to improved lipid and glucose homeostasis, insulin sensitivity and energy expenditure after these procedures. The impact of altered bile acid levels in enterohepatic circulation is also associated with changes in gut microflora, which may further contribute to some of these beneficial effects. We highlight the beneficial effects of experimental surgical procedures in rodents that alter bile secretory flow without gastric restriction or altering nutrient flow. This information suggests a role for bile acids beyond dietary fat emulsification in altering whole body glucose and lipid metabolism strongly, and also suggests emerging roles for the activation of the bile acid receptors farnesoid x receptor (FXR) and G-protein coupled bile acid receptor (TGR5) in these improvements. The limitations of rodent studies and the current state of our understanding is reviewed and the potential effects of bile acids mediating the short- and long-term metabolic improvements after bariatric surgery is critically examined.
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MESH Headings
- Animals
- Bile Acids and Salts/metabolism
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/microbiology
- Diabetes Mellitus, Type 2/pathology
- Diabetes Mellitus, Type 2/surgery
- Enterohepatic Circulation
- Gastrectomy
- Gastric Bypass
- Gastrointestinal Microbiome/physiology
- Gene Expression Regulation
- Glucose/metabolism
- Homeostasis/physiology
- Humans
- Insulin Resistance
- Obesity, Morbid/metabolism
- Obesity, Morbid/microbiology
- Obesity, Morbid/pathology
- Obesity, Morbid/surgery
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Rodentia
- Signal Transduction
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Affiliation(s)
- Vance L Albaugh
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Babak Banan
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Hana Ajouz
- American University of Beirut, Beirut, Lebanon
| | - Naji N Abumrad
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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44
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Distinctive microbiomes and metabolites linked with weight loss after gastric bypass, but not gastric banding. ISME JOURNAL 2017; 11:2047-2058. [PMID: 28548658 DOI: 10.1038/ismej.2017.71] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 03/19/2017] [Accepted: 03/26/2017] [Indexed: 02/07/2023]
Abstract
Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) are anatomically different bariatric operations. RYGB achieves greater weight loss compared with LAGB. Changes in the gut microbiome have been documented after RYGB, but not LAGB, and the microbial contribution to sustainable surgical weight loss warrants further evaluation. We hypothesized that RYGB imposes greater changes on the microbiota and its metabolism than LAGB, and that the altered microbiota may contribute to greater weight loss. Using multi-omic approaches, we analyzed fecal microbial community structure and metabolites of pre-bariatric surgery morbidly obese (PreB-Ob), normal weight (NW), post-RYGB, and post-LAGB participants. RYGB microbiomes were significantly different from those from NW, LAGB and PreB-Ob. Microbiome differences between RYGB and PreB-Ob populations were mirrored in their metabolomes. Diversity was higher in RYGB compared with LAGB, possibly because of an increase in the abundance of facultative anaerobic, bile-tolerant and acid-sensible microorganisms in the former. Possibly because of lower gastric acid exposure, phylotypes from the oral cavity, such as Escherichia, Veillonella and Streptococcus, were in greater abundance in the RYGB group, and their abundances positively correlated with percent excess weight loss. Many of these post-RYGB microorganisms are capable of amino-acid fermentation. Amino-acid and carbohydrate fermentation products-isovalerate, isobutyrate, butyrate and propionate-were prevalent in RYGB participants, but not in LAGB participants. RYGB resulted in greater alteration of the gut microbiome and metabolome than LAGB, and RYGB group exhibited unique microbiome composed of many amino-acid fermenters, compared with nonsurgical controls.
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45
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Chow MD, Lee YH, Guo GL. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med 2017; 56:34-44. [PMID: 28442273 DOI: 10.1016/j.mam.2017.04.004] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 04/11/2017] [Accepted: 04/20/2017] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is marked by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to dysregulation of energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drug therapies target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies.
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Affiliation(s)
- Monica D Chow
- Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Yi-Horng Lee
- Division of Pediatric Surgery, Department of Surgery, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Grace L Guo
- Department of Pharmacy and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
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46
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Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology 2017; 152:1679-1694.e3. [PMID: 28214524 DOI: 10.1053/j.gastro.2017.01.055] [Citation(s) in RCA: 660] [Impact Index Per Article: 82.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 01/19/2017] [Accepted: 01/20/2017] [Indexed: 02/06/2023]
Abstract
Bile acids are signaling molecules that coordinately regulate metabolism and inflammation via the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation by acting predominantly in enterohepatic tissues, but also in peripheral organs. In this review, we discuss the most recent findings on the inter-organ signaling and interplay with the gut microbiota of bile acids and their receptors in meta-inflammation, with a focus on their pathophysiologic roles in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic steatohepatitis, and their potential therapeutic applications.
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Affiliation(s)
- Oscar Chávez-Talavera
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Anne Tailleux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France.
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47
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Chávez-Talavera O, Baud G, Spinelli V, Daoudi M, Kouach M, Goossens JF, Vallez E, Caiazzo R, Ghunaim M, Hubert T, Lestavel S, Tailleux A, Staels B, Pattou F. Roux-en-Y gastric bypass increases systemic but not portal bile acid concentrations by decreasing hepatic bile acid uptake in minipigs. Int J Obes (Lond) 2017; 41:664-668. [PMID: 28093571 DOI: 10.1038/ijo.2017.7] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 12/14/2016] [Accepted: 12/17/2016] [Indexed: 02/06/2023]
Abstract
Roux-en-Y gastric bypass (RYGB) surgery is widely used in the management of morbid obesity. RYGB improves metabolism independently of weight loss by still unknown mechanisms. Bile acids (BAs) are good candidates to explain this benefit, since they regulate metabolic homeostasis and their systemic concentrations increase upon RYGB. Here we analyzed the mechanisms underlying the increase in systemic BA concentrations after RYGB and the role of the liver therein. To this aim, we used the Göttingen-like minipig, a human-size mammalian model, which allows continuous sampling and simultaneous analysis of pre-hepatic portal and systemic venous blood. BA concentrations and pool composition were measured in portal blood, containing intestinal reabsorbed BAs and compared to systemic blood during a standardized meal test before and after RYGB. Systemic total BA concentrations increased after RYGB, due to an increase in conjugated BAs. Interestingly, the ratio of portal:systemic conjugated BAs decreased after RYGB, indicating a role for the liver in systemic BA concentrations changes. In line, hepatic expression of BA transporter genes decreased after RYGB. Our results show that the increase in systemic BAs after surgery is due to decreased selective hepatic recapture. Thus, alterations in hepatic function contribute to the increase in systemic BAs after RYGB.
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Affiliation(s)
- O Chávez-Talavera
- Université de Lille, U1011 - EGID, Lille, France.,Inserm, U1011, Lille, France.,CHU Lille, Lille, France.,Institut Pasteur de Lille, Lille, France.,PECEM, Faculty of Medicine, UNAM, Mexico City, Mexico
| | - G Baud
- CHU Lille, Lille, France.,Université de Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - V Spinelli
- Université de Lille, U1011 - EGID, Lille, France.,Inserm, U1011, Lille, France.,CHU Lille, Lille, France.,Institut Pasteur de Lille, Lille, France
| | - M Daoudi
- CHU Lille, Lille, France.,Université de Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - M Kouach
- Centre Universitaire de Mesures et d'Analyses, Université de Lille, Lille France
| | - J-F Goossens
- Centre Universitaire de Mesures et d'Analyses, Université de Lille, Lille France
| | - E Vallez
- Université de Lille, U1011 - EGID, Lille, France.,Inserm, U1011, Lille, France.,CHU Lille, Lille, France.,Institut Pasteur de Lille, Lille, France
| | - R Caiazzo
- CHU Lille, Lille, France.,Université de Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - M Ghunaim
- CHU Lille, Lille, France.,Université de Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - T Hubert
- CHU Lille, Lille, France.,Université de Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
| | - S Lestavel
- Université de Lille, U1011 - EGID, Lille, France.,Inserm, U1011, Lille, France.,CHU Lille, Lille, France.,Institut Pasteur de Lille, Lille, France
| | - A Tailleux
- Université de Lille, U1011 - EGID, Lille, France.,Inserm, U1011, Lille, France.,CHU Lille, Lille, France.,Institut Pasteur de Lille, Lille, France
| | - B Staels
- Université de Lille, U1011 - EGID, Lille, France.,Inserm, U1011, Lille, France.,CHU Lille, Lille, France.,Institut Pasteur de Lille, Lille, France
| | - F Pattou
- CHU Lille, Lille, France.,Université de Lille, U1190-EGID, Lille, France.,Inserm, U1190, Lille, France
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48
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Backes CF, Lopes E, Tetelbom A, Heineck I. Medication and nutritional supplement use before and after bariatric surgery. SAO PAULO MED J 2016; 134:0. [PMID: 27812597 PMCID: PMC11448729 DOI: 10.1590/1516-3180.2015.0241030516] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 11/23/2015] [Accepted: 05/03/2016] [Indexed: 01/01/2023] Open
Abstract
CONTEXT AND OBJECTIVE: Bariatric surgery has been an effective alternative treatment for morbid obesity and has resulted in decreased mortality, better control over comorbidities and reduced use of drugs. The objective of this study was to analyze the impact of bariatric surgery on medication drug and nutritional supplement use. DESIGN AND SETTING: Longitudinal study of before-and-after type, on 69 morbidly obese patients in a public hospital in Porto Alegre. METHODS: Through interviews, the presence of comorbidities and use of drugs with and without prescription were evaluated. RESULTS: Among the 69 patients interviewed, 85.5% had comorbidities in the preoperative period, with an average of 2.3 (± 1.5) per patient. The main comorbidities reported were hypertension, diabetes and dyslipidemia. 84.1% of the patients were using prescribed drugs in the preoperative period. The mean drug use per patient was 4.8, which decreased to 4.4 after the procedure. The surgery enabled significant reduction in use of most antidiabetic (84%), antilipemic (77%) and antihypertensive drugs (49.5%). On the other hand, there was a significant increase in use of multivitamins and drugs for disorders of the gastrointestinal tract. The dosages of most of the drugs that continued to be prescribed after surgery were decreased, but not significantly. CONCLUSION: After bariatric surgery, there were increases in the use of vitamins, gastric antisecretory drugs and antianemic drugs. Nevertheless, there was an overall reduction in drug use during this period, caused by suspension of drugs or dose reduction.
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Affiliation(s)
- Charline Fernanda Backes
- Master’s Student in the Postgraduate Pharmaceutical Sciences Program, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
| | - Edyane Lopes
- PhD. Pharmacist, School of Public Health, Health Department of the State of Rio Grande do Sul, Porto Alegre, RS, Brazil.
| | - Airton Tetelbom
- MD. Coordinator of the Health Technology Assessment Center, Grupo Hospitalar Conceição; Head Professor of Public Health, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA); Associate Professor of Public Health, Universidade Luterana do Brasil (ULBRA); and Contributing Professor in the Postgraduate Epidemiology Program, Department of Social Medicine, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
| | - Isabela Heineck
- PhD. Associate Professor, Postgraduate Pharmaceutical Sciences Program and Postgraduate Pharmaceutical Services, School of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
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49
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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: 76] [Impact Index Per Article: 8.4] [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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50
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Soni H. Peptide-based GLP-1/glucagon co-agonists: A double-edged sword to combat diabesity. Med Hypotheses 2016; 95:5-9. [PMID: 27692167 DOI: 10.1016/j.mehy.2016.08.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Accepted: 08/11/2016] [Indexed: 11/25/2022]
Abstract
Diabesity is a new term for obesity-dependent diabetes, which is also associated with cardiovascular and other comorbidities with rising epidemic. Traditional treatments (sulfonylureas and thiazolidinediones) of diabetes are associated with weight gain, except metformin. Newer agents such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and Sodium glucose co-transporter 2 inhibitors (SGLT2i) are causing a modest weight reduction, whereas dipeptidyl peptidase-4 inhibitors (DPP-4i) are weight neutral. Oxyntomodulin, a native GLP-1/glucagon receptor agonist produced a superior weight loss and antihyperglycemic effects in obese mice and humans. Recent findings with synthetic dual GLP-1/glucagon receptor agonists have shown a good weight loss and antihyperglycemic profile in diet-induced obese (DIO) mice. Targeting combinations of GLP-1 receptor and glucagon receptor simultaneously with a single peptide may be the better strategy to achieve marked weight loss and considerable glycemic control in diabesity. Cardiovascular safety is very important with new antidiabetic agents due to rosiglitazone controversy. Current on-going clinical trials will clarify the cardiovascular effects of incretin-based therapies in near future. Based on current knowledge and rapid progress in the field, there is a strong possibility that the GLP-1/glucagon receptor co-agonists will likely be the new therapeutic treatment for diabesity for decades to come.
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Affiliation(s)
- Hitesh Soni
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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