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Ke Z, Lu Z, Li F, Zhao Q, Jiang X, Hu Z, Sun F, He Z, Tang Y, Li Q, van Oostendorp S, Chen X, He Q, Wang Y, Zhu Z, Tong W. Gut microbiota alterations induced by Roux-en-Y gastric bypass result in glucose-lowering by enhancing intestinal glucose excretion. Gut Microbes 2025; 17:2473519. [PMID: 40028693 PMCID: PMC11881838 DOI: 10.1080/19490976.2025.2473519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/26/2025] [Accepted: 02/21/2025] [Indexed: 03/05/2025] Open
Abstract
Roux-en-Y gastric bypass (RYGB) results in glucose-lowering in patients with type 2 diabetes mellitus (T2DM) and may be associated with increased intestinal glucose excretion. However, the contribution of intestinal glucose excretion to glycemic control after RYGB and its underlying mechanisms are not fully elucidated. Here, we confirmed that intestinal glucose excretion significantly increased in obese rats after RYGB, which was negatively correlated with postoperative blood glucose levels. Moreover, we also found that the contribution of Biliopancreatic limb length, an important factor affecting glycemic control after RYGB, to the improvement of glucose metabolism after RYGB attributed to the enhancement of intestinal glucose excretion. Subsequently, we further determined through multiple animal models that intestinal glucose excretion is physiological rather than pathological and plays a crucial role in maintaining glucose homeostasis in the body. Finally, we employed germ-free mice colonized with fecal samples from patients and rats to demonstrate that enhanced intestinal glucose excretion after RYGB is directly modulated by the surgery-induced changes in the gut microbiota. These results indicated that the gut microbiota plays a direct causal role in the hypoglycemic effect of RYGB by promoting intestinal glucose excretion, which may provide new insights for developing gut microbiota-based therapies for T2DM.
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Affiliation(s)
- Zhigang Ke
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Zongshi Lu
- Department of Hypertension and Endocrinology, Daping Hospital, Center for Hypertension and Metabolic Diseases, Chongqing Institute of Hypertension, Army Medical University, Chongqing, China
| | - Fan Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Qingyuan Zhao
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Xianhong Jiang
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhihao Hu
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Fang Sun
- Department of Hypertension and Endocrinology, Daping Hospital, Center for Hypertension and Metabolic Diseases, Chongqing Institute of Hypertension, Army Medical University, Chongqing, China
| | - Zongcheng He
- Department of Digestive Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Yi Tang
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Qing Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Stefan van Oostendorp
- Department of Surgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Xiao Chen
- Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Qiuyue He
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Yong Wang
- Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhiming Zhu
- Department of Hypertension and Endocrinology, Daping Hospital, Center for Hypertension and Metabolic Diseases, Chongqing Institute of Hypertension, Army Medical University, Chongqing, China
| | - Weidong Tong
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, China
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Fredrickson G, Florczak K, Barrow F, Mahmud S, Dietsche K, Wang H, Parthiban P, Hakeem A, Almutlaq R, Adeyi O, Herman A, Bartolomucci A, Staley C, Dong X, Jahansouz C, Williams JW, Mashek DG, Ikramuddin S, Revelo XS. TREM2 macrophages mediate the beneficial effects of bariatric surgery against MASH. Hepatology 2025; 81:1776-1791. [PMID: 39292863 PMCID: PMC11913751 DOI: 10.1097/hep.0000000000001098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 09/03/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND AND AIMS For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. APPROACH AND RESULT Using murine models, we report that VSG ameliorates MASH progression in a weight loss-independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) repress inflammation and increase their lysosomal activity in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytic function. CONCLUSIONS Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by TREM2+ macrophages, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.
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Affiliation(s)
- Gavin Fredrickson
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kira Florczak
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Fanta Barrow
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Shamsed Mahmud
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
| | - Katrina Dietsche
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Haiguang Wang
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Preethy Parthiban
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Andrew Hakeem
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Rawan Almutlaq
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Oyedele Adeyi
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Adam Herman
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Alessandro Bartolomucci
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christopher Staley
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiao Dong
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
| | - Cyrus Jahansouz
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jesse W. Williams
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
- Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Douglas G. Mashek
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sayeed Ikramuddin
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xavier S. Revelo
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, Minnesota, USA
- Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
- Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA
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Cook TM, Bethea MM, Sandoval DA. The role of the gut-brain axis in bariatric surgery. Curr Opin Neurobiol 2025; 92:103041. [PMID: 40349608 DOI: 10.1016/j.conb.2025.103041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 04/04/2025] [Accepted: 04/13/2025] [Indexed: 05/14/2025]
Abstract
Bariatric surgery is the gold standard for sustained weight loss. Despite common misconceptions, bariatric surgery remodels gut-brain physiology in more complex ways than simply reducing stomach size or causing nutrient malabsorption. Bariatric surgery induces weight loss primarily by reductions in food intake and alterations in feeding patterns, macronutrient preference, and the rewarding aspects of food. Bariatric surgery also enhances nutrient-induced brain activation, alters nutrient processing, enhances gut hormone secretion, and increases bile acids. However, which of these signals directly link to improved satiety and altered reward pathways remains unclear. While state-of-the-art tools are now available to manipulate specific subpopulations of peripheral sensory neurons, work is needed to apply these tools to obesity and bariatric surgery. This will be critical for advancing the understanding of the role of the gut-brain axis in the success of surgery and allowing for the continued expansion of therapeutic options for obesity.
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Affiliation(s)
- Tyler M Cook
- Department of Pediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Denver, CO, USA
| | - Maigen M Bethea
- Department of Pediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Denver, CO, USA
| | - Darleen A Sandoval
- Department of Pediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Denver, CO, USA.
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Brial F, Le Lay A, Rouch C, Henrion E, Bourgey M, Bourque G, Lathrop M, Magnan C, Gauguier D. Transcriptome atlases of rat brain regions and their adaptation to diabetes resolution following gastrectomy in the Goto-Kakizaki rat. Mol Brain 2025; 18:9. [PMID: 39920851 PMCID: PMC11806591 DOI: 10.1186/s13041-025-01176-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 01/13/2025] [Indexed: 02/09/2025] Open
Abstract
Brain regions drive multiple physiological functions through specific gene expression patterns that adapt to environmental influences, drug treatments and disease conditions. To generate a detailed atlas of the brain transcriptome in the context of diabetes, we carried out RNA sequencing in hypothalamus, hippocampus, brainstem and striatum of the Goto-Kakizaki (GK) rat model of spontaneous type 2 diabetes, which was applied to identify gene transcription adaptation to improved glycemic control following vertical sleeve gastrectomy (VSG) in the GK. Over 19,000 distinct transcripts were detected in the rat brain, including 2794 which were consistently expressed in the four brain regions. Region-specific gene expression was identified in hypothalamus (n = 477), hippocampus (n = 468), brainstem (n = 1173) and striatum (n = 791), resulting in differential regulation of biological processes between regions. Differentially expressed genes between VSG and sham operated rats were only found in the hypothalamus and were predominantly involved in the regulation of endothelium and extracellular matrix. These results provide a detailed atlas of regional gene expression in the diabetic rat brain and suggest that the long term effects of gastrectomy-promoted diabetes remission involve functional changes in the hypothalamus endothelium.
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Affiliation(s)
- François Brial
- Université Paris Cité, INSERM U1132 Biologie de l'os et du Cartilage (BIOSCAR), 75010, Paris, France
| | - Aurélie Le Lay
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France
| | - Claude Rouch
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France
| | - Edouard Henrion
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Mathieu Bourgey
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Guillaume Bourque
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Mark Lathrop
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Christophe Magnan
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France
| | - Dominique Gauguier
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France.
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.
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Stefater-Richards MA, Panciotti C, Esteva V, Lerner M, Petty CR, Gourash WF, Courcoulas AP. Gastric bypass elicits persistent gut adaptation and unique diabetes remission-related metabolic gene regulation. Obesity (Silver Spring) 2024; 32:2135-2148. [PMID: 39410706 PMCID: PMC11537825 DOI: 10.1002/oby.24135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 06/21/2024] [Accepted: 07/16/2024] [Indexed: 11/06/2024]
Abstract
OBJECTIVE We have previously shown that early intestinal adaptation precedes and relates to metabolic improvement in humans after Roux-en-Y gastric bypass surgery (RYGB). We hypothesized that intestinal adaptation would persist at the 1-year postoperative time point and that gene expression (GE) signatures would relate to type 2 diabetes remission, providing insight into potential mechanisms for intestinally mediated metabolic improvement after RYGB. METHODS We determined GE by RNA sequencing in jejunum (Roux limb [RL]) collected from 28 patients before and 12 months after RYGB. RESULTS Global GE from paired baseline and 1-year jejunal samples did not separate according to clinical phenotype (type 2 diabetes remission, sustained weight loss). In general, GE was consistent with persistent RL remodeling, and microvilli were elongated by 39%. Remodeling was not attenuated in patients with lack of diabetes remission or with weight regain. Patients with diabetes remission demonstrated greater jejunal activation of lipogenesis-related pathways driven by RXR, LXR, and SREBP. CONCLUSIONS RL adaptation is a key feature of RYGB in all patients, likely reflecting the dramatic alterations to gastrointestinal anatomy, but jejunal lipogenesis appears to be more strongly activated in those patients with diabetes remission. Further study is needed to understand whether these pathways may drive metabolic remission after RYGB.
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Affiliation(s)
- Margaret A Stefater-Richards
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Courtney Panciotti
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Valerie Esteva
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Miriam Lerner
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Carter R Petty
- Biostatistics and Research Design Center, Boston Children's Hospital, Boston, Massachusetts, USA
| | - William F Gourash
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Anita P Courcoulas
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Sun S, Wang A, Kou R, Xue H, Zhao X, Yang B, Shi M, Wang Y, Yan Q, Qu M, Wang Y, Gao Z. Duodenal-Jejunal Bypass Restores Sweet Taste Receptor-Mediated Glucose Sensing and Absorption in Diabetic Rats. J Diabetes Res 2024; 2024:5544296. [PMID: 39263491 PMCID: PMC11390237 DOI: 10.1155/2024/5544296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 01/04/2024] [Accepted: 08/07/2024] [Indexed: 09/13/2024] Open
Abstract
Aim: The aim of the study is to identify the regulatory role of intestinal sweet taste receptors (STRs) and glucose transporters (SGLT1, GLUT2) and gut peptide secretion in duodenal-jejunal bypass (DJB)-ameliorated glycemic control in Type 2 diabetes. Materials and Methods: DJB and sham surgeries were performed in streptozotocin-induced diabetic male rats. The blood GLP-1 and GLP-2 levels were evaluated under feeding and fasting conditions. The expression of STRs (T1R2, T1R3), sweet taste signaling effector (Gα-gustducin), SGLT1, and GLUT2 was detected in the intestinal alimentary limb (A limb), biliopancreatic limb (BP limb), and common limb (C limb). The effects of STR inhibition on glucose control were measured with lactisole. Results: Glucose tolerance was improved in DJB-operated rats compared with the sham group, similar to that of normal control rats, without significant differences in food intake and body weight. The plasma GLP-1 levels of DJB rats were increased under diet-fed condition, and GLP-2 levels were increased after fasting. The villus height and crypt depth were significantly increased in the A limb of DJB-operated rats. In addition, GLP-1 expression was restored in enterocytes. The expression of T1R2, Gα-gustducin, and SGLT1 was elevated in the A limb after DJB, while GLUT2 was downregulated in the A, BP, and C limbs. The localization of GLUT2 was normalized in the three intestinal limbs after DJB. However, the beneficial effects of DJB on glucose control were abolished in the presence of lactisole in vivo. Conclusion: DJB ameliorates glycemic control probably by restoring STR-mediated glucose sensing and absorption with the responses of GLP-1 and GLP-2 to carbohydrate.
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Affiliation(s)
- Sipeng Sun
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Anping Wang
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Rongguan Kou
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Hantao Xue
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Xiangyu Zhao
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Ben Yang
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Mengqi Shi
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Yubing Wang
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Qingtao Yan
- Department of Pediatric SurgeryWeifang People's HospitalThe First Affiliated Hospital of Shandong Second Medical University, Weifang 261021, China
| | - Meihua Qu
- Translational Medical CenterWeifang Second People's Hospital, Weifang 261021, China
| | - Yi Wang
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
| | - Zhiqin Gao
- School of Life Science and TechnologyShandong Second Medical University, Weifang 261021, China
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Ke Z, Lu Z, Li Q, Tong W. Intestinal glucose excretion: A potential mechanism for glycemic control. Metabolism 2024; 152:155743. [PMID: 38007149 DOI: 10.1016/j.metabol.2023.155743] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/20/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023]
Abstract
The gut has been increasingly recognized in recent years as a pivotal organ in the maintenance of glucose homeostasis. Specifically, the profound and enduring improvement in glucose metabolism achieved through metabolic surgery to modify the anatomy of the gut has prompted scholars to acknowledge that the most effective strategy for treating type 2 diabetes mellitus (T2DM) involves the gut. The mechanisms underlying the regulation of glucose metabolism by the gut encompass gut hormones, bile acids, intestinal gluconeogenesis, gut microbiota, and signaling interactions between the gut and other organs (liver, brain, adipose, etc.). Recent studies have also revealed a novel phenomenon of glucose lowering through the gut: metabolic surgery and metformin promote the excretion of glucose from the circulation into the intestinal lumen by enterocytes. However, there is still limited understanding regarding the underlying mechanisms of intestinal glucose excretion and its contribution to glycemic control. This article reviews current research on intestinal glucose excretion while focusing on its role in T2DM management as well as potential mechanisms.
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Affiliation(s)
- Zhigang Ke
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zongshi Lu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Qing Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Weidong Tong
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China.
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Solanki S, Shah YM. Hypoxia-Induced Signaling in Gut and Liver Pathobiology. ANNUAL REVIEW OF PATHOLOGY 2024; 19:291-317. [PMID: 37832943 DOI: 10.1146/annurev-pathmechdis-051122-094743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2023]
Abstract
Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, the presence of oxygen gradients or physiologic hypoxia is necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets.
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Affiliation(s)
- Sumeet Solanki
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA;
| | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA;
- University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
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Frey S, Ayer A, Sotin T, Lorant V, Louis-Gaubert C, Arnaud L, Billon-Crossouard S, Croyal M, Prieur X, Hadjadj S, Cariou B, Blanchard C, Le May C. Single-anastomosis duodeno-ileal bypass with sleeve gastrectomy improves lipid and glucose homeostasis in ob/ob mice. Obesity (Silver Spring) 2024; 32:91-106. [PMID: 37875256 DOI: 10.1002/oby.23916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 07/27/2023] [Accepted: 08/22/2023] [Indexed: 10/26/2023]
Abstract
OBJECTIVE The objective of this study was to compare the general and metabolic impact of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) with Roux-en-Y gastric bypass (RYGB) in an obese (ob/ob) mouse model. METHODS 10-week-old male ob/ob mice underwent either SADI-S, RYGB, or laparotomy surgery (Sham group). General and metabolic parameters were assessed during a 5-week period thereafter. RESULTS SADI-S induced a deeper weight loss ([mean ± SEM] -41.2% ± 3.3%) than RYGB (-5.6% ± 3.5%, p < 0.001) compared with the Sham group (+6.3% ± 1.0%, p < 0.05). A significant food restriction was observed after SADI-S only (-31%, 117.4 ± 10.3 g vs. 170.2 ± 5.2 g of food at day 35 in Sham group mice, p < 0.001). Random-fed glycemia and glucose tolerance were more improved after SADI-S than RYGB. SADI-S decreased plasma cholesterol concentration by 60% (0.49 ± 0.04 g/L vs. 1.40 ± 0.10 g/L in the Sham group at day 35, p < 0.01), significantly more than RYGB (1.04 ± 0.14 g/L, p = 0.018). Plasma sitosterol/cholesterol and campesterol/cholesterol ratios were decreased after SADI-S, suggesting a reduced intestinal cholesterol absorption. SADI-S increased exogenous plasma cholesterol-D7 clearance and fecal elimination, also indicating an increased plasma cholesterol excretion. Studying a pair-fed group demonstrated that calorie restriction alone did not explain the beneficial impact of SADI-S. CONCLUSIONS SADI-S is associated with a greater improvement in lipid and glucose homeostasis than RYGB in ob/ob mice.
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Affiliation(s)
- Samuel Frey
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
- Nantes Université, CHU Nantes, Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Audrey Ayer
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
| | - Thibaud Sotin
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
| | - Victoria Lorant
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
| | - Clément Louis-Gaubert
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
- Nantes Université, CHU Nantes, Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Lucie Arnaud
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
| | - Stéphanie Billon-Crossouard
- Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France
- CRNH-Ouest Mass Spectrometry Core Facility, Nantes, France
| | - Mikael Croyal
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
- Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France
- CRNH-Ouest Mass Spectrometry Core Facility, Nantes, France
| | - Xavier Prieur
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
| | - Samy Hadjadj
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
| | - Claire Blanchard
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
- Nantes Université, CHU Nantes, Chirurgie Cancérologique, Digestive et Endocrinienne, Institut des Maladies de l'Appareil Digestif, Nantes, France
| | - Cédric Le May
- Nantes Université, CHU Nantes, CNRS, INSERM, L'institut du thorax, Nantes, France
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10
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Cottam A, Cottam D, Roslin M, Surve A. Exploring Bariatric Surgery's Impact on Weight Loss and Diabetes: Sodium and Glucose Receptor Modulation. JSLS 2024; 28:e2023.00051. [PMID: 38562948 PMCID: PMC10984375 DOI: 10.4293/jsls.2023.00051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024] Open
Abstract
Sodium-glucose cotransporters (SGLT) and glucose transporters (GLUT) have been shown to influence diabetes management by modulating glucose uptake by the intestine. Therefore, alterations in gastrointestinal anatomy during bariatric surgery can change SGLT and GLUT receptor activity. These changes offer an additional mechanism for weight loss and may explain the differential impact of the various bariatric surgical procedures. This review examines the current literature on SGLT and GLUT receptors and their effects on weight loss through genetic studies, pharmacologic inhibition, and how SGLT/GLUT receptors impact surgical physiologic modulation. A better understanding of Type I sodium-glucose cotransport receptors (SGLT-1), GLUT-2, and GLUT-5 could provide insight for improved procedures and allow us to determine the best method to tailor operations to a patient's individual needs.
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Affiliation(s)
- Austin Cottam
- Bariatric Medicine Institute, Salt Lake City, Utah, USA. (Drs A. Cottam, D. Cottam, and Surve)
- Northwell Health-Lenox Hill Hospital, New York City, New York, USA. (Dr Roslin)
| | - Daniel Cottam
- Bariatric Medicine Institute, Salt Lake City, Utah, USA. (Drs A. Cottam, D. Cottam, and Surve)
- Northwell Health-Lenox Hill Hospital, New York City, New York, USA. (Dr Roslin)
| | - Mitchell Roslin
- Bariatric Medicine Institute, Salt Lake City, Utah, USA. (Drs A. Cottam, D. Cottam, and Surve)
- Northwell Health-Lenox Hill Hospital, New York City, New York, USA. (Dr Roslin)
| | - Amit Surve
- Bariatric Medicine Institute, Salt Lake City, Utah, USA. (Drs A. Cottam, D. Cottam, and Surve)
- Northwell Health-Lenox Hill Hospital, New York City, New York, USA. (Dr Roslin)
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11
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Alabduljabbar K, Bonanos E, Miras AD, le Roux CW. Mechanisms of Action of Bariatric Surgery on Body Weight Regulation. Gastroenterol Clin North Am 2023; 52:691-705. [PMID: 37919021 DOI: 10.1016/j.gtc.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2023]
Abstract
Bariatric surgery is an effective treatment modality for obesity and obesity-associated complications. Weight loss after bariatric surgery was initially attributed to anatomic restriction or reduced energy absorption, but now it is understood that surgery treats obesity by influencing the subcortical areas of the brain to lower adipose tissue mass. There are three major phases of this process: initially the weight loss phase, followed by a phase where weight loss is maintained, and in a subset of patients a phase where weight is regained. These phases are characterized by altered appetitive behavior together with changes in energy expenditure. The mechanisms associated with the rearrangement of the gastrointestinal tract include central appetite control, release of gut peptides, change in microbiota and bile acids. However, the exact combination and timing of signals remain largely unknown.
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Affiliation(s)
- Khaled Alabduljabbar
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland; Department of Family Medicine and Polyclinics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
| | | | | | - Carel W le Roux
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Dublin, Ireland.
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12
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Revelo X, Fredrickson G, Florczak K, Barrow F, Dietsche K, Wang H, Parthiban P, Almutlaq R, Adeyi O, Herman A, Bartolomucci A, Staley C, Jahansouz C, Williams J, Mashek D, Ikramuddin S. Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH. RESEARCH SQUARE 2023:rs.3.rs-3446960. [PMID: 37961666 PMCID: PMC10635378 DOI: 10.21203/rs.3.rs-3446960/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. Here we report that VSG ameliorates MASH progression in a weight loss-independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) increase their lysosomal activity and repress inflammation in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytotic function. Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by hepatic LAMs, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.
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13
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Ross RC, Heintz EC, Zunica ERM, Townsend RL, Spence AE, Schauer PR, Kirwan JP, Axelrod CL, Albaugh VL. Bariatric surgery alters mitochondrial function in gut mucosa. Surg Endosc 2023; 37:8810-8817. [PMID: 37620650 PMCID: PMC10865135 DOI: 10.1007/s00464-023-10351-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/30/2023] [Indexed: 08/26/2023]
Abstract
BACKGROUND The obesity pandemic has worsened global disease burden, including type 2 diabetes, cardiovascular disease, and cancer. Metabolic/bariatric surgery (MBS) is the most effective and durable obesity treatment, but the mechanisms underlying its long-term weight loss efficacy remain unclear. MBS drives substrate oxidation that has been linked to improvements in metabolic function and improved glycemic control that are potentially mediated by mitochondria-a primary site of energy production. As such, augmentation of intestinal mitochondrial function may drive processes underlying the systemic metabolic benefits of MBS. Herein, we applied a highly sensitive technique to evaluate intestinal mitochondrial function ex vivo in a mouse model of MBS. METHODS Mice were randomized to surgery, sham, or non-operative control. A simplified model of MBS, ileal interposition, was performed by interposition of a 2-cm segment of terminal ileum into the proximal bowel 5 mm from the ligament of Treitz. After a four-week recovery period, intestinal mucosa of duodenum, jejunum, ileum, and interposed ileum were assayed for determination of mitochondrial respiratory function. Citrate synthase activity was measured as a marker of mitochondrial content. RESULTS Ileal interposition was well tolerated and associated with modest body weight loss and transient hypophagia relative to controls. Mitochondrial capacity declined in the native duodenum and jejunum of animals following ileal interposition relative to controls, although respiration remained unchanged in these segments. Similarly, ileal interposition lowered citrate synthase activity in the duodenum and jejunum following relative to controls but ileal function remained constant across all groups. CONCLUSION Ileal interposition decreases mitochondrial volume in the proximal intestinal mucosa of mice. This change in concentration with preserved respiration suggests a global mucosal response to segment specific nutrition signals in the distal bowel. Future studies are required to understand the causes underlying these mitochondrial changes.
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Affiliation(s)
- Robert C Ross
- Translational & Integrative Gastrointestinal & Endocrine Research (TIGER) Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, USA
| | - Elizabeth C Heintz
- Integrated Physiology & Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Elizabeth R M Zunica
- Integrated Physiology & Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - R Leigh Townsend
- Translational & Integrative Gastrointestinal & Endocrine Research (TIGER) Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, USA
| | - Amanda E Spence
- Translational & Integrative Gastrointestinal & Endocrine Research (TIGER) Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, USA
| | - Philip R Schauer
- Pennington Biomedical Research Center, Metamor Institute, Louisiana State University, Baton Rouge, LA, USA
- Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - John P Kirwan
- Integrated Physiology & Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Christopher L Axelrod
- Integrated Physiology & Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Vance L Albaugh
- Translational & Integrative Gastrointestinal & Endocrine Research (TIGER) Laboratory, Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, USA.
- Pennington Biomedical Research Center, Metamor Institute, Louisiana State University, Baton Rouge, LA, USA.
- Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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14
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Igwe JK, Surapaneni PK, Cruz E, Cole C, Njoku K, Kim J, Alaribe U, Weze K, Mohammed B. Bariatric Surgery and Inflammatory Bowel Disease: National Trends and Outcomes Associated with Procedural Sleeve Gastrectomy vs Historical Bariatric Surgery Among US Hospitalized Patients 2009-2020. Obes Surg 2023; 33:3472-3486. [PMID: 37804470 PMCID: PMC10603008 DOI: 10.1007/s11695-023-06833-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 09/04/2023] [Accepted: 09/15/2023] [Indexed: 10/09/2023]
Abstract
PURPOSE The association between bariatric surgery and IBD-related inpatient outcomes is not well characterized. We report, analyze, and compare inpatient trends and outcomes among encounters with a history of bariatric surgery (Hx-MBS) compared to those receiving bariatric surgery during index admission (PR-MBS) admitted from 2009 to 2020. METHODS Retrospective cohort design: the 2009-2020 National Inpatient Sample (NIS) databases were used to identify hospital encounters with patients aged ≥ 18 years with a history of MBS (Hx-MBS) or with procedure coding indicating MBS procedure (PR-MBS) according to International Classification of Diseases, Ninth (ICD-9-CM/ ICD-9-PCS) or Tenth Revision (ICD-10-CM/ICD-10-PCS) Clinical Modification/Procedure Coding System during index admission (ICD-9-CM: V4586; ICD-10-CM: Z9884; ICD-9-PR: 4382, 4389; ICD-10-PR: 0DB64Z3, 0DB63ZZ). Pearson χ2 analysis, analysis of variance, multivariable regression analyses, and propensity matching on independent variables were conducted to analyze significant associations between variables and for primary outcome inflammatory bowel disease-related admission, and secondary outcomes: diagnosis of nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, or chronic mesenteric ischemia during admission. RESULTS We identified 3,365,784 (76.20%) Hx-MBS hospitalizations and 1,050,900 hospitalizations with PR-MBS (23.80%). Propensity score matching analysis demonstrated significantly higher odds of inflammatory bowel disease, and chronic mesenteric ischemia for Hx-MBS compared to PR-MBS, and significantly lower odds of nonalcoholic steatohepatitis and nonalcoholic fatty liver disease for Hx-MBS compared to PR-MBS. CONCLUSION In our study, Hx-MBS was associated with significantly increased odds of inflammatory bowel disease and other GI pathologies compared to matched controls. The mechanism by which this occurs is unclear. Additional studies are needed to examine these findings.
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Affiliation(s)
- Joseph-Kevin Igwe
- School of Medicine, Department of Medicine, Stanford University, 291 Campus Drive, Stanford, CA, 94305, USA.
- Department of Medicine, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA, 30313, USA.
- American Heart Association Strategically Focused Research Network on the Science of Diversity in Clinical Trials Research Fellowship, 5001 S Miami Blvd #300, Durham, NC, 27703, USA.
| | | | - Erin Cruz
- School of Medicine, Department of Medicine, Stanford University, 291 Campus Drive, Stanford, CA, 94305, USA
| | - Cedric Cole
- Department of Medicine, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA, 30313, USA
| | - Kingsley Njoku
- Department of Medicine, Emory University School of Medicine, Atlanta, USA
| | - Jisoo Kim
- Department of Surgery, Texas Tech University Health Sciences Center at El Paso, El Paso, USA
| | - Ugo Alaribe
- School of Medicine, Caribbean Medical University, Willemstad, USA
| | - Kelechi Weze
- Department of Medicine, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA, 30313, USA
| | - Bilal Mohammed
- Department of Medicine, Ascension Saint Vincent, Indianapolis, USA
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15
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Abstract
Importance Roux-en-Y gastric bypass (RYGB) remains one of the most commonly performed operations for morbid obesity and is associated with significant long-term weight loss and comorbidity remission. However, health care utilization rates following RYGB are high and abdominal pain is reported as the most common presenting symptom for those seeking care. Observations Given the limitations of physical examination in patients with obesity, correct diagnosis of abdominal pain following RYGB depends on a careful history and appropriate use of radiologic, laboratory and endoscopic studies, as well as a clear understanding of post-RYGB anatomy. The most common etiologies of abdominal pain after RYGB are internal hernia, marginal ulcer, biliary disease (eg, cholelithiasis and choledocholithiasis), and jejunojejunal anastomotic issues. Early identification of the etiology of the pain is essential, as some causes, such as internal hernia or perforated gastrojejunal ulcer, may require urgent or emergent intervention to avoid significant morbidity. While laboratory findings and imaging may prove useful, they remain imperfect, and clinical judgment should always be used to determine if surgical exploration is warranted. Conclusions and Relevance The etiologies of abdominal pain after RYGB range from the relatively benign to potentially life-threatening. This Review highlights the importance of understanding key anatomical and technical aspects of RYGB to guide appropriate workup, diagnosis, and treatment.
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Affiliation(s)
- Brian T Fry
- Department of Surgery, University of Michigan, Ann Arbor
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16
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Gao J, Yang T, Song B, Ma X, Ma Y, Lin X, Wang H. Abnormal tryptophan catabolism in diabetes mellitus and its complications: Opportunities and challenges. Biomed Pharmacother 2023; 166:115395. [PMID: 37657259 DOI: 10.1016/j.biopha.2023.115395] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/20/2023] [Accepted: 08/26/2023] [Indexed: 09/03/2023] Open
Abstract
In recent years, the incidence rate of diabetes mellitus (DM), including type 1 diabetes mellitus(T1DM), type 2 diabetes mellitus(T2DM), and gestational diabetes mellitus (GDM), has increased year by year and has become a major global health problem. DM can lead to serious complications of macrovascular and microvascular. Tryptophan (Trp) is an essential amino acid for the human body. Trp is metabolized in the body through the indole pathway, kynurenine (Kyn) pathway and serotonin (5-HT) pathway, and is regulated by intestinal microorganisms to varying degrees. These three metabolic pathways have extensive regulatory effects on the immune, endocrine, neural, and energy metabolism systems of the body, and are related to the physiological and pathological processes of various diseases. The key enzymes and metabolites in the Trp metabolic pathway are also deeply involved in the pathogenesis of DM, playing an important role in pancreatic function, insulin resistance (IR), intestinal barrier, and angiogenesis. In DM and its complications, there is a disruption of Trp metabolic balance. Several therapy approaches for DM and complications have been proven to modify tryptophan metabolism. The metabolism of Trp is becoming a new area of focus for DM prevention and care. This paper reviews the impact of the three metabolic pathways of Trp on the pathogenesis of DM and the alterations in Trp metabolism in these diseases, expecting to provide entry points for the treatment of DM and its complications.
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Affiliation(s)
- Jialiang Gao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ting Yang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Bohan Song
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiaojie Ma
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yichen Ma
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiaowei Lin
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Hongwu Wang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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17
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Alsayed Hasan M, Schwartz S, McKenna V, Ing R. An Imbalance of Pathophysiologic Factors in Late Postprandial Hypoglycemia Post Bariatric Surgery: A Narrative Review. Obes Surg 2023; 33:2927-2937. [PMID: 37530920 DOI: 10.1007/s11695-023-06758-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 08/03/2023]
Abstract
With a rise in obesity and more patients opting for bariatric surgery, it becomes crucial to understand associated complications like postprandial hypoglycemia (PPH). After bariatric surgery, significant changes are seen in insulin sensitivity, beta cell function, glucagon-like peptide 1 (GLP-1) levels, the gut microbiome, and bile acid metabolism. And in a small subset of patients, exaggerated imbalances in these functional and metabolic processes lead to insulin-glucose mismatch and hypoglycemia. The main treatment for PPH involves dietary modifications. For those that do not respond, medications or surgical interventions are considered to reverse some of the imbalances. We present a few case reports of patients that safely tolerated GLP-1 agonists. However, larger randomized control trials are needed to further characterize PPH and understand its treatment.
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Affiliation(s)
- Marah Alsayed Hasan
- Department of Internal Medicine, Main Line Health System/Lankenau Medical Center, 100 E Lancaster Ave, Wynnewood, PA, 19096, USA.
| | - Stanley Schwartz
- Affiliate, Main Line Health System, Emeritus, University of Pennsylvania, 100 E Lancaster Ave, Wynnewood, PA, 19096, USA
| | - Victoria McKenna
- Main Line Health Bariatric Surgery - Bryn Mawr, 830 Old Lancaster Road Suite 300, Bryn Mawr, PA, 19010, USA
| | - Richard Ing
- Bariatric Center of Bryn Mawr Hospital, Main Line Health System, Bryn Mawr Medical Building North, 830 Old Lancaster Road, Bryn Mawr, PA, 19010, USA
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18
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Dan W, Wang X, Wu J, Gu Y, Liu S, Zhang H, Chang X, Shi C, Yan H, Xia M, Wang L, Jiao H, Wu H, Lou W, Gao X, Bian H, Wang J, Huang LH. The early effects of sleeve gastrectomy on postprandial chylomicron triglycerides during the progression of type 2 diabetes. Clin Chim Acta 2023; 549:117558. [PMID: 37709114 DOI: 10.1016/j.cca.2023.117558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/21/2023] [Accepted: 09/11/2023] [Indexed: 09/16/2023]
Abstract
BACKGROUND It remains unclear whether early sleeve gastrectomy (SG) improves postprandial very-low-density lipoprotein (VLDL) as well as chylomicron triglycerides (TGs) in a weight-independent manner in patients with or without type 2 diabetes (DM). Herein we investigated the early effects of SG on postprandial VLDL and chylomicron kinetics. METHODS A liquid meal test was performed before and after 1 week of SG. The plasma was collected for postprandial triglyceride-rich lipoprotein kinetics analyses, including VLDLs and chylomicrons, isolated by high-speed ultracentrifugation. Lipidomics and metabolomics were used to profile lipid and metabolite compositions of plasma and postprandial chylomicrons. De novo fatty acid synthesis in intestinal epithelial cells treated with chylomicron metabolites was examined using RT-PCR, immunoblotting, and free fatty acid measurement. RESULTS We found that patients with DM had markedly higher VLDL TGs than patients without DM, and such an increase was still retained after SG. In contrast, SG significantly decreased postprandial chylomicron TGs, but surprisingly, the degree of the reduction in patients with DM was less prominent than in patients without DM, confirmed by untargeted lipidomics analysis. Moreover, 5 unique metabolites potentially linked to de novo fatty acid synthesis from the pathway analysis were discovered by further metabolomic analysis of postprandial chylomicrons from patients with DM who underwent SG and verified by In vitro intestinal epithelial cell culture experiments. CONCLUSIONS SG in 1 week did not impact postprandial VLDL but decreased chylomicron TGs. Patients with DM keep higher postprandial chylomicron TG concentrations than patients without it after SG, potentially through some unique metabolites that increase intestinal fatty acid synthesis. These results implicate the timing for SG to reach lower intestinal fatty acid synthesis and postprandial chylomicron TG production is prior to the diagnosis of DM to potentially reduce cardiovascular risks.
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Affiliation(s)
- Wei Dan
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China
| | - Xinmei Wang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China
| | - Jiaqi Wu
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China
| | - Yu Gu
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China
| | - Shuangshuang Liu
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China
| | - Hongye Zhang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China
| | - Xinxia Chang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chenye Shi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hongmei Yan
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liu Wang
- Second Affiliated Hospital of Army Military Medical University, Chongqing 400037, China
| | - Heng Jiao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Haifu Wu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Wenhui Lou
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Jiaxi Wang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China.
| | - Li-Hao Huang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200433, China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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19
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Seifert G, Fagnocchi L, Edozie M, Herrmann S, Baumann H, Panzeri I, Mewes S, Aicher D, Runkel M, Lässle C, Fink J, Marjanovic G, Fichtner-Feigl S, Pospisilik JA. The DECON pilot project investigates predictive markers for successful bariatric surgery. Sci Rep 2023; 13:13401. [PMID: 37591977 PMCID: PMC10435485 DOI: 10.1038/s41598-023-40452-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 08/10/2023] [Indexed: 08/19/2023] Open
Abstract
Obesity is a chronic, multifactorial disease which is linked to a number of adverse endocrinological and metabolic conditions. Currently, bariatric surgery is one of the most effective treatments for individuals diagnosed with severe obesity. However, the current indications for bariatric surgery are based on inadequate metrics (i.e., BMI) which do not account for the complexity of the disease, nor the heterogeneity among the patient population. Moreover, there is a lack of understanding with respect to the biological underpinnings that influence successful and sustained weight loss post-bariatric surgery. Studies have implicated age and pre-surgery body weight as two factors that are associated with favorable patient outcomes. Still, there is an urgent medical need to identify other potential factors that could improve the specificity of candidate selection and better inform the treatment plan of patients with obesity. In this report, we present and describe the cohort of the DECON pilot project, a multicenter study which aims to identify predictive biomarkers of successful weight loss after bariatric surgery.
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Affiliation(s)
- Gabriel Seifert
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany.
| | | | | | - Stephan Herrmann
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - Hannah Baumann
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - Ilaria Panzeri
- Van Andel Institute, Grand Rapids, MI, 49503, USA
- Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
| | - Stephanie Mewes
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - David Aicher
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - Mira Runkel
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - Claudia Lässle
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - Jodok Fink
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - Goran Marjanovic
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - Stephan Fichtner-Feigl
- Department of General and Visceral Surgery, University Medical Center Freiburg, University of Freiburg, Freiburg,, Germany
| | - J Andrew Pospisilik
- Van Andel Institute, Grand Rapids, MI, 49503, USA.
- Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany.
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20
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Alhuzaim WM, Alajlan RM, Alshehri RA, Alanazi RM, Alsarhan LK, Alamri HK. Post-gastric Sleeve Surgery Chronic Symptoms From a Sample of Patients in Saudi Community. Cureus 2023; 15:e42000. [PMID: 37593300 PMCID: PMC10428182 DOI: 10.7759/cureus.42000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND A common bariatric procedure known as gastric sleeve surgery can cause significant weight loss and co-morbid condition alleviation. However, patients could experience persistent problems such as gastrointestinal, musculoskeletal/neural, and psychiatric disorders after surgery. This study aims to identify the most prevalent chronic symptoms following sleeve gastrectomy among a sample of Saudi patients and the impact these symptoms have on patients' lives. METHODOLOGY Patients who underwent gastric sleeve surgery at the Ensan Clinic, a facility specializing in gastroenterology, were the subjects of this retrospective cohort analysis. The study population consisted of patients who underwent gastric sleeve surgery, showed up for follow-up after the procedure, and met the inclusion and exclusion criteria. The data collection sheet is divided into seven sections. Sociodemographic information was required in the first section, gastric sleeve surgery information in the second, vital signs in the third, lab results in the fourth, past medical history in the fifth, current treatments in the sixth, and postoperative complications and chronic symptoms in the seventh and final sections. RESULTS In 117 patients, the study evaluated the effects of gastric sleeve surgery. Participants had an average age of 40.21 years, and 61.5% were female. Regarding persistent symptoms after surgery, a sizable percentage of patients mentioned digestive issues such as GERD (44.4%), dyspepsia (60.7%), vomiting (23.1%), nausea (39.3%), and abdominal distention (45.3%). A total of 34.2% of patients reported experiencing anxiety, compared to 11.1% who said they had depression or 2.6% who said they had social issues. A few patients reported experiencing neurological or musculoskeletal issues, including exhaustion (7.7%), faintness (5.1%), back or joint discomfort (7.7%), and shortness of breath (8.5%). CONCLUSION After undergoing gastric sleeve surgery, a sizable proportion of patients complained of various chronic symptoms and nutritional inadequacies, primarily gastrointestinal problems and musculoskeletal/neurological issues. The study's findings show a connection between these symptoms and surgery.
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Affiliation(s)
- Waleed M Alhuzaim
- Gastroenterology, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Raghad M Alajlan
- Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Rahaf A Alshehri
- Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Razan M Alanazi
- Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Leen K Alsarhan
- Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
| | - Hala K Alamri
- Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
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21
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Pannu PR, Chukwudi C, Wang J, Yang P, Esfahani FN, Saeidi N. Physical properties of food or bile redirection do not contribute to the intestinal adaptations after Roux-en-Y Gastric Bypass in rats. Obes Sci Pract 2023; 9:274-284. [PMID: 37287514 PMCID: PMC10242252 DOI: 10.1002/osp4.647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/28/2022] [Accepted: 10/10/2022] [Indexed: 06/09/2023] Open
Abstract
Objective Metabolic and morphological adaptations of the intestine have been suggested to play a role in the various therapeutic benefits of Roux-en-Y Gastric Bypass (RYGB) surgery. However, the precise underlying mechanisms remain unclear. In this study, the effects of physical properties of ingested food and redirection of biliopancreatic secretions on intestinal remodeling were investigated in RYGB operated rats. Methods RYGB employing two different Roux Limb (RL) lengths was performed on high fat diet induced obese rats. Post-operatively, rats were fed either Solid or isocaloric Liquid diets. Metabolic and morphological remodeling of intestine was compared across both diet forms (Solid and Liquid diets) and surgical models (Short RL and Long RL). Results RYGB surgery in rats induced weight loss and improved glucose tolerance which was independent of physical properties of ingested food and biliopancreatic secretions. Intestinal glucose utilization after RYGB was not determined by either food form or biliopancreatic secretions. The GLUT-1 expression in RL was not influenced by physical properties of food. Furthermore, both physical properties of food and biliopancreatic secretions showed no effects on intestinal morphological adaptations after RYGB. Conclusion Results of this study demonstrate that physical properties of food and bile redirection are not major determinants of intestinal remodeling after RYGB in rats.
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Affiliation(s)
- Prabh R. Pannu
- Division of General and Gastrointestinal SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Center for Engineering in Medicine and SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Shriners Children's Hospital BostonBostonMassachusettsUSA
| | - Chijioke Chukwudi
- Division of General and Gastrointestinal SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Center for Engineering in Medicine and SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Shriners Children's Hospital BostonBostonMassachusettsUSA
| | - Jianxun Wang
- Division of General and Gastrointestinal SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Center for Engineering in Medicine and SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Shriners Children's Hospital BostonBostonMassachusettsUSA
| | - Po‐Jen Yang
- Division of General and Gastrointestinal SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Center for Engineering in Medicine and SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Shriners Children's Hospital BostonBostonMassachusettsUSA
- Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan
| | - Farid Nasr Esfahani
- Division of General and Gastrointestinal SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Center for Engineering in Medicine and SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Shriners Children's Hospital BostonBostonMassachusettsUSA
| | - Nima Saeidi
- Division of General and Gastrointestinal SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Center for Engineering in Medicine and SurgeryDepartment of SurgeryMassachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
- Shriners Children's Hospital BostonBostonMassachusettsUSA
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22
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Anhê FF, Zlitni S, Zhang SY, Choi BSY, Chen CY, Foley KP, Barra NG, Surette MG, Biertho L, Richard D, Tchernof A, Lam TKT, Marette A, Schertzer J. Human gut microbiota after bariatric surgery alters intestinal morphology and glucose absorption in mice independently of obesity. Gut 2023; 72:460-471. [PMID: 36008102 PMCID: PMC9933168 DOI: 10.1136/gutjnl-2022-328185] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/05/2022] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Bariatric surgery is an effective treatment for type 2 diabetes (T2D) that changes gut microbial composition. We determined whether the gut microbiota in humans after restrictive or malabsorptive bariatric surgery was sufficient to lower blood glucose. DESIGN Women with obesity and T2D had biliopancreatic diversion with duodenal switch (BPD-DS) or laparoscopic sleeve gastrectomy (LSG). Faecal samples from the same patient before and after each surgery were used to colonise rodents, and determinants of blood glucose control were assessed. RESULTS Glucose tolerance was improved in germ-free mice orally colonised for 7 weeks with human microbiota after either BPD-DS or LSG, whereas food intake, fat mass, insulin resistance, secretion and clearance were unchanged. Mice colonised with microbiota post-BPD-DS had lower villus height/width and crypt depth in the distal jejunum and lower intestinal glucose absorption. Inhibition of sodium-glucose cotransporter (Sglt)1 abrogated microbiota-transmissible improvements in blood glucose control in mice. In specific pathogen-free (SPF) rats, intrajejunal colonisation for 4 weeks with microbiota post-BPD-DS was sufficient to improve blood glucose control, which was negated after intrajejunal Sglt-1 inhibition. Higher Parabacteroides and lower Blautia coincided with improvements in blood glucose control after colonisation with human bacteria post-BPD-DS and LSG. CONCLUSION Exposure of rodents to human gut microbiota after restrictive or malabsorptive bariatric surgery improves glycaemic control. The gut microbiota after bariatric surgery is a standalone factor that alters upper gut intestinal morphology and lowers Sglt1-mediated intestinal glucose absorption, which improves blood glucose control independently from changes in obesity, insulin or insulin resistance.
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Affiliation(s)
- Fernando F Anhê
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Soumaya Zlitni
- Department of Genetics and Medicine, Stanford University, Stanford, California, USA
| | - Song-Yang Zhang
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Béatrice So-Yun Choi
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - Cassandra Y Chen
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Kevin P Foley
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Nicole G Barra
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Michael G Surette
- Department of Medicine, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Laurent Biertho
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - Denis Richard
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - André Tchernof
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada.,School of Nutrition, Laval University, Quebec, Quebec, Canada
| | - Tony K T Lam
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Andre Marette
- Quebec Heart and Lung Institute Research Centre, Laval University, Quebec, Quebec, Canada
| | - Jonathan Schertzer
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
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23
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Sandoval DA, Patti ME. Glucose metabolism after bariatric surgery: implications for T2DM remission and hypoglycaemia. Nat Rev Endocrinol 2023; 19:164-176. [PMID: 36289368 PMCID: PMC10805109 DOI: 10.1038/s41574-022-00757-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/28/2022] [Indexed: 11/09/2022]
Abstract
Although promising therapeutics are in the pipeline, bariatric surgery (also known as metabolic surgery) remains our most effective strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Of the many available options, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are currently the most widely used procedures. RYGB and VSG have very different anatomical restructuring but both surgeries are effective, to varying degrees, at inducing weight loss and T2DM remission. Both weight loss-dependent and weight loss-independent alterations in multiple tissues (such as the intestine, liver, pancreas, adipose tissue and skeletal muscle) yield net improvements in insulin resistance, insulin secretion and insulin-independent glucose metabolism. In a subset of patients, post-bariatric hypoglycaemia can develop months to years after surgery, potentially reflecting the extreme effects of potent glucose reduction after surgery. This Review addresses the effects of bariatric surgery on glucose regulation and the potential mechanisms responsible for both the resolution of T2DM and the induction of hypoglycaemia.
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Affiliation(s)
- Darleen A Sandoval
- Department of Paediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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24
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Liu T, Zou X, Ruze R, Xu Q. Bariatric Surgery: Targeting pancreatic β cells to treat type II diabetes. Front Endocrinol (Lausanne) 2023; 14:1031610. [PMID: 36875493 PMCID: PMC9975540 DOI: 10.3389/fendo.2023.1031610] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 01/19/2023] [Indexed: 02/17/2023] Open
Abstract
Pancreatic β-cell function impairment and insulin resistance are central to the development of obesity-related type 2 diabetes mellitus (T2DM). Bariatric surgery (BS) is a practical treatment approach to treat morbid obesity and achieve lasting T2DM remission. Traditionally, sustained postoperative glycemic control was considered a direct result of decreased nutrient intake and weight loss. However, mounting evidence in recent years implicated a weight-independent mechanism that involves pancreatic islet reconstruction and improved β-cell function. In this article, we summarize the role of β-cell in the pathogenesis of T2DM, review recent research progress focusing on the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on pancreatic β-cell pathophysiology, and finally discuss therapeutics that have the potential to assist in the treatment effect of surgery and prevent T2D relapse.
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Affiliation(s)
- Tiantong Liu
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
- School of Medicine, Tsinghua University, Beijing, China
| | - Xi Zou
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
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25
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Mining the mechanistic underpinnings of bariatric surgery: A gateway to novel and non-invasive obesity therapies? Mol Metab 2023; 68:101663. [PMID: 36587843 PMCID: PMC9938305 DOI: 10.1016/j.molmet.2022.101663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/16/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
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Okikawa S, Kashihara H, Shimada M, Yoshikawa K, Tokunaga T, Nishi M, Takasu C, Wada Y, Yoshimoto T. Effect of duodenal-jejunal bypass on diabetes in the early postoperative period. Sci Rep 2023; 13:1856. [PMID: 36726038 PMCID: PMC9892584 DOI: 10.1038/s41598-023-28923-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 01/27/2023] [Indexed: 02/03/2023] Open
Abstract
Metabolic surgery is an effective treatment for patients with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the effect of duodenal-jejunal bypass (DJB) in a rat model of T2DM during the early postoperative period. A rat model of non-obese T2DM was allocated to two groups: a sham group and a DJB group. On postoperative day 1 (1POD), oral glucose tolerance testing (OGTT) was performed and the changes of glucose transporter expressions in the small intestine was evaluated. [18F]-fluorodeoxyglucose ([18]-FDG) uptake was measured in sham- and DJB-operated rats using positron emission tomography-computed tomography (PET-CT). DJB improved the glucose tolerance of the rats on 1POD. The expression of sodium-glucose cotransporter 1 (SGLT1) and glucose transporter 1 (GLUT1) was high, and that of GLUT2 was low in the alimentary limb (AL) of rats in the DJB group. PET-CT showed that [18F]-FDG uptake was high in the proximal jejunum of DJB-operated rats. These results may show that DJB improve glucose tolerance in very early postoperative period as the result of glucose accumulation in the AL because of changes in glucose transporter expression.
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Affiliation(s)
- Shohei Okikawa
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
| | - Hideya Kashihara
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan.
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
| | - Kozo Yoshikawa
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
| | - Takuya Tokunaga
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
| | - Masaaki Nishi
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
| | - Chie Takasu
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
| | - Yuma Wada
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
| | - Toshiaki Yoshimoto
- Department of Surgery, Tokushima University, 3-18-15 Kuramoto-Cho, Tokushima, Tokushima, 770-8503, Japan
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27
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Albaugh VL, He Y, Münzberg H, Morrison CD, Yu S, Berthoud HR. Regulation of body weight: Lessons learned from bariatric surgery. Mol Metab 2023; 68:101517. [PMID: 35644477 PMCID: PMC9938317 DOI: 10.1016/j.molmet.2022.101517] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/04/2022] [Accepted: 05/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bariatric or weight loss surgery is currently the most effective treatment for obesity and metabolic disease. Unlike dieting and pharmacology, its beneficial effects are sustained over decades in most patients, and mortality is among the lowest for major surgery. Because there are not nearly enough surgeons to implement bariatric surgery on a global scale, intensive research efforts have begun to identify its mechanisms of action on a molecular level in order to replace surgery with targeted behavioral or pharmacological treatments. To date, however, there is no consensus as to the critical mechanisms involved. SCOPE OF REVIEW The purpose of this non-systematic review is to evaluate the existing evidence for specific molecular and inter-organ signaling pathways that play major roles in bariatric surgery-induced weight loss and metabolic benefits, with a focus on Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), in both humans and rodents. MAJOR CONCLUSIONS Gut-brain communication and its brain targets of food intake control and energy balance regulation are complex and redundant. Although the relatively young science of bariatric surgery has generated a number of hypotheses, no clear and unique mechanism has yet emerged. It seems increasingly likely that the broad physiological and behavioral effects produced by bariatric surgery do not involve a single mechanism, but rather multiple signaling pathways. Besides a need to improve and better validate surgeries in animals, advanced techniques, including inducible, tissue-specific knockout models, and the use of humanized physiological traits will be necessary. State-of-the-art genetically-guided neural identification techniques should be used to more selectively manipulate function-specific pathways.
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Affiliation(s)
- Vance L Albaugh
- Translational and Integrative Gastrointestinal and Endocrine Research Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Yanlin He
- Brain Glycemic and Metabolism Control Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Heike Münzberg
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Christopher D Morrison
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Sangho Yu
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Hans-Rudolf Berthoud
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
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28
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Stefater-Richards MA, Panciotti C, Feldman HA, Gourash WF, Shirley E, Hutchinson JN, Golick L, Park SW, Courcoulas AP, Stylopoulos N. Gut adaptation after gastric bypass in humans reveals metabolically significant shift in fuel metabolism. Obesity (Silver Spring) 2023; 31:49-61. [PMID: 36541157 PMCID: PMC10240542 DOI: 10.1002/oby.23585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 07/23/2022] [Accepted: 08/03/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Roux-en-Y gastric bypass surgery (RYGB) is among the most effective therapies for obesity and type 2 diabetes, and intestinal adaptation is a proposed mechanism for these effects. It was hypothesized that intestinal adaptation precedes and relates to metabolic improvement in humans after RYGB. METHODS This was a prospective, longitudinal, first-in-human study of gene expression (GE) in the "Roux limb" (RL) collected surgically/endoscopically from 19 patients with and without diabetes. GE was determined by microarray across six postoperative months, including at an early postoperative (1 month ± 15 days) time point. RESULTS RL GE demonstrated tissue remodeling and metabolic reprogramming, including increased glucose and amino acid use. RL GE signatures were established early, before maximal clinical response, and persisted. Distinct GE fingerprints predicted concurrent and future improvements in HbA1c and in weight. Human RL exhibited GE changes characterized by anabolic growth and shift in metabolic substrate use. Paradoxically, anabolic growth in RL appeared to contribute to the catabolic state elicited by RYGB. CONCLUSIONS These data support a role for a direct effect of intestinal energy metabolism to contribute to the beneficial clinical effects of RYGB, suggesting that related pathways might be potential targets of therapeutic interest for patients with obesity with or without type 2 diabetes.
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Affiliation(s)
- Margaret A. Stefater-Richards
- Center for Basic and Translational Obesity Research, Division of Endocrinology, Boston Children’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Courtney Panciotti
- Center for Basic and Translational Obesity Research, Division of Endocrinology, Boston Children’s Hospital, Boston, MA
| | - Henry A. Feldman
- Harvard Medical School, Boston, MA
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA
| | - William F. Gourash
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Eleanor Shirley
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - John N. Hutchinson
- Harvard Medical School, Boston, MA
- Department of Biostatistics, Harvard School of Public Health, Boston, MA
| | - Lena Golick
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA
| | - Sang W. Park
- Harvard Medical School, Boston, MA
- Division of Endocrinology, Boston Children’s Hospital, Boston, MA
| | - Anita P. Courcoulas
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Nicholas Stylopoulos
- Center for Basic and Translational Obesity Research, Division of Endocrinology, Boston Children’s Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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29
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Kwon Y, Lee S, Kim D, ALRomi A, Park SH, Lee CM, Kim JH, Park S. Biliopancreatic Limb Length as a Potential Key Factor in Superior Glycemic Outcomes After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes: A Meta-Analysis. Diabetes Care 2022; 45:3091-3100. [PMID: 36455123 DOI: 10.2337/dc22-0835] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Optimal length of biliopancreatic (BP) and Roux limb in Roux-en-Y gastric bypass (RYGB) for improved glycemic control are not known. PURPOSE To investigate how the lengths of the BP and Roux limbs in RYGB differentially affect postoperative glycemic outcomes in patients with type 2 diabetes. DATA SOURCES We conducted a systematic literature search using the PubMed, Embase, and the Cochrane Library databases. STUDY SELECTION We included studies that reported glycemic outcomes after RYGB and lengths of the BP and Roux limbs. DATA EXTRACTION A total of 28 articles were included for data extraction. Glycemic outcomes after RYGB were assessed on the basis of two definitions: remission and improvement. DATA SYNTHESIS We categorized the included studies into four groups according to the BP and Roux limb lengths. The type 2 diabetes remission/improvement rates were as follows: long BP-long Roux group 0.80 (95% CI 0.70-0.90)/0.81 (0.73-0.89), long BP-short Roux group 0.76 (0.66-0.87)/0.82 (0.75-0.89), short BP-long Roux group 0.57 (0.36-0.78)/0.64 (0.53-0.75), and short BP-short Roux group 0.62 (0.43-0.80)/0.53 (0.45-0.61). Meta-regression analysis also showed that a longer BP limb resulted in higher postoperative type 2 diabetes remission and improvement rates, whereas a longer Roux limb did not. There was no significant difference or heterogeneity in baseline characteristics, including diabetes-related variables, among the four groups. LIMITATIONS Not all included studies were randomized controlled trials. CONCLUSIONS Longer BP limb length led to higher rates of type 2 diabetes remission and improvement by 1 year after RYGB in comparisons with the longer Roux limb length.
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Affiliation(s)
- Yeongkeun Kwon
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, South Korea
- Center for Obesity and Metabolic Diseases, Korea University Anam Hospital, Seoul, South Korea
- Gut & Metabolism Laboratory, Korea University College of Medicine, Seoul, South Korea
| | - Sungho Lee
- Department of Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Dohyang Kim
- Department of Statistics, Daegu University, Gyeongbuk, South Korea
| | - Ahmad ALRomi
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, South Korea
| | - Shin-Hoo Park
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, South Korea
- Center for Obesity and Metabolic Diseases, Korea University Anam Hospital, Seoul, South Korea
- Gut & Metabolism Laboratory, Korea University College of Medicine, Seoul, South Korea
| | - Chang Min Lee
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, South Korea
- Gut & Metabolism Laboratory, Korea University College of Medicine, Seoul, South Korea
| | - Jong-Han Kim
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, South Korea
- Gut & Metabolism Laboratory, Korea University College of Medicine, Seoul, South Korea
| | - Sungsoo Park
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, South Korea
- Center for Obesity and Metabolic Diseases, Korea University Anam Hospital, Seoul, South Korea
- Gut & Metabolism Laboratory, Korea University College of Medicine, Seoul, South Korea
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30
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Stojanović O, Miguel-Aliaga I, Trajkovski M. Intestinal plasticity and metabolism as regulators of organismal energy homeostasis. Nat Metab 2022; 4:1444-1458. [PMID: 36396854 DOI: 10.1038/s42255-022-00679-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 10/06/2022] [Indexed: 11/18/2022]
Abstract
The small intestine displays marked anatomical and functional plasticity that includes adaptive alterations in adult gut morphology, enteroendocrine cell profile and their hormone secretion, as well as nutrient utilization and storage. In this Perspective, we examine how shifts in dietary and environmental conditions bring about changes in gut size, and describe how the intestine adapts to changes in internal state, bowel resection and gastric bypass surgery. We highlight the critical importance of these intestinal remodelling processes in maintaining energy balance of the organism, and in protecting the metabolism of other organs. The intestinal resizing is supported by changes in the microbiota composition, and by activation of carbohydrate and fatty acid metabolism, which govern the intestinal stem cell proliferation, intestinal cell fate, as well as survivability of differentiated epithelial cells. The discovery that intestinal remodelling is part of the normal physiological adaptation to various triggers, and the potential for harnessing the reversible gut plasticity, in our view, holds extraordinary promise for developing therapeutic approaches against metabolic and inflammatory diseases.
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Affiliation(s)
- Ozren Stojanović
- Department of Cell Physiology and Metabolism, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Irene Miguel-Aliaga
- MRC London Institute of Medical Sciences, London, UK.
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
| | - Mirko Trajkovski
- Department of Cell Physiology and Metabolism, Centre Medical Universitaire (CMU), Faculty of Medicine, University of Geneva, Geneva, Switzerland.
- Diabetes Centre, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
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31
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Sridhar A, Khan D, Abdelaal M, Elliott JA, Naughton V, Flatt PR, Le Roux CW, Docherty NG, Moffett CR. Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats. PLoS One 2022; 17:e0274788. [PMID: 36137097 PMCID: PMC9499270 DOI: 10.1371/journal.pone.0274788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/05/2022] [Indexed: 11/19/2022] Open
Abstract
Modification of gut-islet secretions after Roux-En-Y gastric bypass (RYBG) surgery contributes to its metabolic and anti-diabetic benefits. However, there is limited knowledge on tissue-specific hormone distribution post-RYGB surgery and how this compares with best medical treatment (BMT). In the present study, pancreatic and ileal tissues were excised from male Zucker-Diabetic Sprague Dawley (ZDSD) rats 8-weeks after RYGB, BMT (daily oral dosing with metformin 300mg/kg, fenofibrate 100mg/kg, ramipril 1mg/kg, rosuvastatin 10mg/kg and subcutaneous liraglutide 0.2mg/kg) or sham operation (laparotomy). Insulin, glucagon, somatostatin, PYY, GLP-1 and GIP expression patterns were assessed using immunocytochemistry and analyzed using ImageJ. After RYGB and BMT, body weight and plasma glucose were decreased. Intestinal morphometry was unaltered by RYGB, but crypt depth was decreased by BMT. Intestinal PYY cells were increased by both interventions. GLP-1- and GIP-cell counts were unchanged by RYGB but BMT increased ileal GLP-1-cells and decreased those expressing GIP. The intestinal contents of PYY and GLP-1 were significantly enhanced by RYGB, whereas BMT decreased ileal GLP-1. No changes of islet and beta-cell area or proliferation were observed, but the extent of beta-cell apoptosis and islet integrity calculated using circularity index were improved by both treatments. Significantly decreased islet alpha-cell areas were observed in both groups, while beta- and PYY-cell areas were unchanged. RYGB also induced a decrease in islet delta-cell area. PYY and GLP-1 colocalization with glucagon in islets was significantly decreased in both groups, while co-staining of PYY with glucagon was decreased and that with somatostatin increased. These data characterize significant cellular islet and intestinal adaptations following RYGB and BMT associated with amelioration of obesity-diabetes in ZDSD rats. The differential responses observed and particularly those within islets, may provide important clues to the unique ability of RYGB to cause diabetes remission.
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Affiliation(s)
- Ananyaa Sridhar
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Dawood Khan
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
- * E-mail:
| | - Mahmoud Abdelaal
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Jessie A. Elliott
- Department of Surgery, Trinity Centre for Health Sciences and St. James’s Hospital, Dublin, Ireland
| | - Violetta Naughton
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Peter R. Flatt
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
| | - Carel W. Le Roux
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Neil G. Docherty
- Diabetes Complications Research Centre, School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Charlotte R. Moffett
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, United Kingdom
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32
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Bohm MS, Sipe LM, Pye ME, Davis MJ, Pierre JF, Makowski L. The role of obesity and bariatric surgery-induced weight loss in breast cancer. Cancer Metastasis Rev 2022; 41:673-695. [PMID: 35870055 PMCID: PMC9470652 DOI: 10.1007/s10555-022-10050-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/06/2022] [Indexed: 02/07/2023]
Abstract
Obesity is a complex metabolic condition considered a worldwide public health crisis, and a deeper mechanistic understanding of obesity-associated diseases is urgently needed. Obesity comorbidities include many associated cancers and are estimated to account for 20% of female cancer deaths in the USA. Breast cancer, in particular, is associated with obesity and is the focus of this review. The exact causal links between obesity and breast cancer remain unclear. Still, interactions have emerged between body mass index, tumor molecular subtype, genetic background, and environmental factors that strongly suggest obesity influences the risk and progression of certain breast cancers. Supportive preclinical research uses various diet-induced obesity models to demonstrate that weight loss, via dietary interventions or changes in energy expenditure, reduces the onset or progression of breast cancers. Ongoing and future studies are now aimed at elucidating the underpinning mechanisms behind weight-loss-driven observations to improve therapy and outcomes in patients with breast cancer and reduce risk. This review aims to summarize the rapidly emerging literature on obesity and weight loss strategies with a focused discussion of bariatric surgery in both clinical and preclinical studies detailing the complex interactions between metabolism, immune response, and immunotherapy in the setting of obesity and breast cancer.
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Affiliation(s)
- Margaret S Bohm
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Laura M Sipe
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Madeline E Pye
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Matthew J Davis
- Division of Bariatric Surgery, Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Joseph F Pierre
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA
- Department of Nutritional Sciences, College of Agriculture and Life Science, The University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Liza Makowski
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- College of Medicine, UTHSC Center for Cancer Research, The University of Tennessee Health Science Center, Cancer Research Building Room 322, 19 S Manassas Street, Memphis, TN, 38163, USA.
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Samuel I, Ben-Haroush Schyr R, Arad Y, Attali T, Azulai S, Bergel M, Halfon A, Hefetz L, Hirsch T, Israeli H, Lax N, Nitzan K, Sender D, Sweetat S, Okun E, Rosenmann H, Ben-Zvi D. Sleeve Gastrectomy Reduces Glycemia but Does Not Affect Cognitive Impairment in Lean 5xFAD Mice. Front Neurosci 2022; 16:937663. [PMID: 36033613 PMCID: PMC9403181 DOI: 10.3389/fnins.2022.937663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Abstract
Obesity and hyperglycemia are risk factors for cognitive decline and for the development of Alzheimer’s Disease (AD). Bariatric surgery is an effective treatment for obesity that was shown to improve cognitive decline in obese patients. Bariatric surgery was shown to exert weight loss independent effects on metabolic diseases such as type 2 diabetes. We tested whether sleeve gastrectomy (SG), a common bariatric surgery, can affect the cognitive impairment in lean, normoglycemic female 5xFAD mice, a genetic model for AD. 5xFAD mice and wild-type (WT) littermates underwent SG or sham surgery at the age of 5 months and were tested for metabolic, behavioral, and molecular phenotypes 90 days later. SG led to a reduction in blood glucose levels and total plasma cholesterol levels in 5xFAD mice without inducing weight loss. However, the surgery did not affect the outcomes of long-term spatial memory tests in these mice. Analysis of β-Amyloid plaques corroborated the behavioral studies in showing no effect of surgery on the molecular phenotype of 5xFAD mice. In conclusion, SG leads to an improved metabolic profile in lean female 5xFAD mice without inducing weight loss but does not affect the brain pathology or behavioral phenotype. Our results suggest that the positive effects of bariatric surgery on cognitive decline in obese patients are likely attributed to weight loss and improvement in obesity sequelae, and not to weight loss independent effects of surgery.
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Affiliation(s)
- Itia Samuel
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Rachel Ben-Haroush Schyr
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Yhara Arad
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
- Department of Military Medicine and Tzameret, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Tamar Attali
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Shira Azulai
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Michael Bergel
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Aviv Halfon
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
- Department of Military Medicine and Tzameret, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Liron Hefetz
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
- Department of Military Medicine and Tzameret, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Tamir Hirsch
- The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel
- The Paul Feder Laboratory on Alzheimer’s Disease Research, Bar-Ilan University, Ramat Gan, Israel
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel
| | - Hadar Israeli
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Neta Lax
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Keren Nitzan
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Dana Sender
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Sahar Sweetat
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
| | - Eitan Okun
- The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel
- The Paul Feder Laboratory on Alzheimer’s Disease Research, Bar-Ilan University, Ramat Gan, Israel
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel
| | - Hanna Rosenmann
- Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
- *Correspondence: Hanna Rosenmann,
| | - Danny Ben-Zvi
- Department of Developmental Biology and Cancer Research, The Institute of Medical Research Israel-Canada, The Hebrew University of Jerusalem-Hadassah Medical School, Jerusalem, Israel
- Danny Ben-Zvi,
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Shibib L, Al-Qaisi M, Ahmed A, Miras AD, Nott D, Pelling M, Greenwald SE, Guess N. Reversal and Remission of T2DM - An Update for Practitioners. Vasc Health Risk Manag 2022; 18:417-443. [PMID: 35726218 PMCID: PMC9206440 DOI: 10.2147/vhrm.s345810] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 05/10/2022] [Indexed: 01/04/2023] Open
Abstract
Over the past 50 years, many countries around the world have faced an unchecked pandemic of obesity and type 2 diabetes (T2DM). As best practice treatment of T2DM has done very little to check its growth, the pandemic of diabesity now threatens to make health-care systems economically more difficult for governments and individuals to manage within their budgets. The conventional view has been that T2DM is irreversible and progressive. However, in 2016, the World Health Organization (WHO) global report on diabetes added for the first time a section on diabetes reversal and acknowledged that it could be achieved through a number of therapeutic approaches. Many studies indicate that diabetes reversal, and possibly even long-term remission, is achievable, belying the conventional view. However, T2DM reversal is not yet a standardized area of practice and some questions remain about long-term outcomes. Diabetes reversal through diet is not articulated or discussed as a first-line target (or even goal) of treatment by any internationally recognized guidelines, which are mostly silent on the topic beyond encouraging lifestyle interventions in general. This review paper examines all the sustainable, practical, and scalable approaches to T2DM reversal, highlighting the evidence base, and serves as an interim update for practitioners looking to fill the practical knowledge gap on this topic in conventional diabetes guidelines.
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Affiliation(s)
- Lina Shibib
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Mo Al-Qaisi
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Ahmed Ahmed
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Alexander D Miras
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - David Nott
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Marc Pelling
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Stephen E Greenwald
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK
| | - Nicola Guess
- School of Life Sciences, Westminster University, London, UK
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Sheehan A, Goldfine A, Bajwa M, Wolfs D, Kozuka C, Piper J, Fowler K, Patti ME. Pramlintide for post-bariatric hypoglycaemia. Diabetes Obes Metab 2022; 24:1021-1028. [PMID: 35137513 PMCID: PMC9035096 DOI: 10.1111/dom.14665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/27/2022] [Accepted: 02/06/2022] [Indexed: 11/27/2022]
Abstract
AIMS The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycaemic excursions and insulin secretion, and thus to determine the efficacy of pramlintide on frequency and severity of hypoglycaemia in post-bariatric hypoglycaemia (PBH). MATERIALS AND METHODS Participants with PBH following gastric bypass were recruited from outpatient clinics at the Joslin Diabetes Center, Boston, Massachusetts for an open-label study of pramlintide efficacy over 8 weeks. Twenty-three participants were assessed for eligibility, 20 participants had at least one pramlintide dose, and 14 completed the study. A mixed-meal tolerance test (MMTT) was performed at baseline and after 8 weeks of subcutaneous pramlintide with a sequential dose increase to a maximum of 120 micrograms (mean 69 ± 32 mcg) three times daily. The primary endpoint was change in glucose excursions during the MMTT. Secondary measures included MMTT insulin response, satiety and dumping score, percentage time with sensor glucose (SG) <3.9 mM, and number of days with minimum SG <3 mM, during masked continuous glucose monitoring. RESULTS There were no differences in MMTT glucose, glucagon or insulin between baseline and post treatment. We observed no significant change in satiety or dumping scores. The overall frequency of low SG values did not change, although there was substantial inter-individual variability. CONCLUSIONS In PBH, pramlintide does not modulate glycaemic or insulin responses, satiety, or dumping scores during an MMTT and does not impact glycaemic excursions or decrease low SG levels in the outpatient setting.
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Affiliation(s)
- Amanda Sheehan
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Allison Goldfine
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Muhammed Bajwa
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Danielle Wolfs
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Chisayo Kozuka
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Jacqueline Piper
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Kristen Fowler
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Mary Elizabeth Patti
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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36
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The Obesogenic and Glycemic Effect of Bariatric Surgery in a Family with a Melanocortin 4 Receptor Loss-of-Function Mutation. Metabolites 2022; 12:metabo12050430. [PMID: 35629934 PMCID: PMC9143288 DOI: 10.3390/metabo12050430] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 01/25/2023] Open
Abstract
We report the long-term response to bariatric surgery in a singular family of four adolescents with severe obesity (41–82 kg/m2), homozygous for the C271R loss-of-function mutation in the melanocortin 4 receptor (MC4R), and three adults heterozygous for the same mutation. All patients had similar sociodemographic backgrounds and were followed for an average of 7 years. Three of the four homozygous patients regained their full weight (42–77 kg/m2), while the fourth lost weight but remained obese with a body mass index of 60 kg/m2. Weight regain was associated with relapse of most comorbidities, yet hyperglycemia did not relapse or was delayed. A1c levels were reduced in homozygous and heterozygous patients. The long-term follow-up data on this very unique genetic setting show that weight loss and amelioration of obesity following bariatric surgery require active MC4R signaling, while the improvement in glycemia is in part independent of weight loss. The study validates animal models and demonstrates the importance of biological signaling in the regulation of weight, even after bariatric surgery.
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Elebring E, Wallenius V, Casselbrant A, Docherty NG, le Roux CW, Marschall HU, Fändriks L. A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers. Nutrients 2022; 14:nu14091961. [PMID: 35565929 PMCID: PMC9100393 DOI: 10.3390/nu14091961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/27/2022] [Accepted: 05/04/2022] [Indexed: 11/27/2022] Open
Abstract
Background and aims: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved. Methods: Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures. Results: HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression. Conclusion: Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853).
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Affiliation(s)
- Erik Elebring
- Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, Sweden; (E.E.); (V.W.); (A.C.)
| | - Ville Wallenius
- Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, Sweden; (E.E.); (V.W.); (A.C.)
- Department of Surgery, Sahlgrenska University Hospital, SE41345 Gothenburg, Sweden
| | - Anna Casselbrant
- Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, Sweden; (E.E.); (V.W.); (A.C.)
| | - Neil G. Docherty
- Metabolic Medicine, School of Medicine, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland; (N.G.D.); (C.W.l.R.)
| | - Carel W. le Roux
- Metabolic Medicine, School of Medicine, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland; (N.G.D.); (C.W.l.R.)
| | - Hanns-Ulrich Marschall
- Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, Sweden;
- Department of Medicine, Sahlgrenska University Hospital, SE41345 Gothenburg, Sweden
| | - Lars Fändriks
- Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, Sweden; (E.E.); (V.W.); (A.C.)
- Department of Surgery, Sahlgrenska University Hospital, SE41345 Gothenburg, Sweden
- Correspondence: ; Tel.: +46-313424123
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Abu-Gazala S, Bergel M, Arad Y, Hefetz L, Azulai S, Baker A, Haran A, Israeli H, Kleiman D, Samuel I, Tsubary U, Permyakova A, Tam J, Ben-Haroush Schyr R, Ben-Zvi D. Generation and characterization of a mouse model for one anastomosis gastric bypass surgery. Am J Physiol Endocrinol Metab 2022; 322:E414-E424. [PMID: 35285295 DOI: 10.1152/ajpendo.00416.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
One anastomosis gastric bypass (OAGB) surgery became a common bariatric procedure in recent years. In this surgery, the distal stomach, duodenum, and proximal jejunum are bypassed, leading to weight loss, improvement in metabolic parameters, and a change in hormonal secretion. We sought to generate and characterize a mouse model for OAGB. Mice fed for 26 wk on a high-fat diet were assigned to OAGB, sham surgery, or caloric restriction and were followed for 50 more days on a high-fat diet. Physiological and histological parameters of the mice were compared during and at the end of the experiment. OAGB-operated mice lost weight and displayed low levels of plasma lipids, high insulin sensitivity, and rapid glucose metabolism compared with sham-operated mice. OAGB-operated mice had higher energy expenditure, higher levels of glucagon-like peptide (GLP-1), and lower albumin than weight-matched calorie-restricted mice. There was no difference in the histology of the endocrine pancreas. The livers of OAGB mice had little hepatic steatosis yet presented with a large number of phagocytic cells. The OAGB mouse model recapitulates many of the phenotypes described in patients that underwent OAGB and enables molecular and physiological studies on the outcome of this surgery.NEW & NOTEWORTHY A mouse model for one anastomosis gastric bypass (OAGB) surgery displays similar outcomes to clinical reports and enables to study the weight loss-dependent and -independent effects of this bariatric surgery.
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Affiliation(s)
- Samir Abu-Gazala
- Department of Surgery, Hadassah Medical Center-Ein Kerem, Jerusalem, Israel
- Department of Surgery, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael Bergel
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Yhara Arad
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
- Department of Military Medicine and Tzameret, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Liron Hefetz
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
- Department of Military Medicine and Tzameret, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shira Azulai
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Aaron Baker
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Arnon Haran
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Hadar Israeli
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Doron Kleiman
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Itia Samuel
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Uria Tsubary
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
- Department of Military Medicine and Tzameret, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Anna Permyakova
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Joseph Tam
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rachel Ben-Haroush Schyr
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Danny Ben-Zvi
- Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
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39
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Camastra S, Palumbo M, Santini F. Nutrients handling after bariatric surgery, the role of gastrointestinal adaptation. Eat Weight Disord 2022; 27:449-461. [PMID: 33895917 PMCID: PMC8933374 DOI: 10.1007/s40519-021-01194-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/10/2021] [Indexed: 01/19/2023] Open
Abstract
Bariatric surgery determines a rearrangement of the gastrointestinal tract that influences nutrient handling and plays a role in the metabolic changes observed after surgery. Most of the changes depend on the accelerated gastric emptying observed in Roux-en-Y gastric bypass (RYGB) and, to a lesser extent, in sleeve gastrectomy (SG). The rapid delivery of meal into the jejunum, particularly after RYGB, contributes to the prompt appearance of glucose in peripheral circulation. Glucose increase is the principal determinant of GLP-1 increase with the consequent stimulation of insulin secretion, the latter balanced by a paradoxical glucagon increase that stimulates EGP to prevent hypoglycaemia. Protein digestion and amino acid absorption appear accelerated after RYGB but not after SG. After RYGB, the adaptation of the gut to the new condition participates to the metabolic change. The intestinal transit is delayed, the gut microbioma is changed, the epithelium becomes hypertrophic and increases the expression of glucose transporter and of the number of cell secreting hormones. These changes are not observed after SG. After RYGB-less after SG-bile acids (BA) increase, influencing glucose metabolism probably modulating FXR and TGR5 with an effect on insulin sensitivity. Muscle, hepatic and adipose tissue insulin sensitivity improve, and the gut reinforces the recovery of IS by enhancing glucose uptake and through the effect of the BA. The intestinal changes observed after RYGB result in a light malabsorption of lipid but not of carbohydrate and protein. In conclusion, functional and morphological adaptations of the gut after RYGB and SG activate inter-organs cross-talk that modulates the metabolic changes observed after surgery.Level of evidence Level V, narrative literature review.
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Affiliation(s)
- Stefania Camastra
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy. .,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy.
| | - Maria Palumbo
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy
| | - Ferruccio Santini
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy.,Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
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40
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Blonde GD, Mathes CM, Inui T, Hamel EA, Price RK, Livingstone MBE, Le Roux CW, Spector AC. Oromotor and somatic taste reactivity during sucrose meals reveals internal state and stimulus palatability after gastric bypass in rats. Am J Physiol Regul Integr Comp Physiol 2022; 322:R204-R218. [PMID: 35043683 PMCID: PMC8858674 DOI: 10.1152/ajpregu.00285.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 11/22/2022]
Abstract
After Roux-en-Y gastric bypass (RYGB), rats consume less high-energy foods and fluids, though whether this reflects a concomitant change in palatability remains unclear. By measuring behavior during intraorally delivered liquid meals across days (1 water, 8 sucrose sessions), we showed that RYGB rats (RYGB, n = 8/sex) consumed less 1.0 M sucrose than their sham surgery counterparts (SHAM, n = 8 males, n = 11 females) but displayed similarly high levels of ingestive taste reactivity responses at the start of infusions. Relative to water, both groups increased intake of sucrose, and ingestive responses were dominated by tongue protrusions rather than mouth movements. Thus, RYGB animals still found sucrose palatable despite consuming less than the SHAM group. As the intraoral infusion progressed but before meal termination, aversive behavior remained low and both RYGB and SHAM animals showed fewer ingestive responses, predominantly mouth movements as opposed to tongue protrusions. This shift in responsiveness unrelated to surgical manipulation suggests negative alliesthesia, or a decreased palatability, as rats approach satiation. Notably, only in RYGB rats, across sessions, there was a striking emergence of aversive behavior immediately after the sucrose meal. Thus, although lower intake in RYGB rats seems independent of the hedonic taste properties of sucrose, taste reactivity behavior in these animals immediately after termination of a liquid meal appears to be influenced by postoral events and reflects a state of nimiety or excessive consumption. Measurement of taste reactivity behaviors during an intraorally delivered meal represents a promising way to make inferences about internal state in nonverbal preclinical models.
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Affiliation(s)
- Ginger D Blonde
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida
| | - Clare M Mathes
- Department of Neuroscience, Baldwin Wallace University, Berea, Ohio
| | - Tadashi Inui
- Department of Oral Physiology, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Elizabeth A Hamel
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida
| | - Ruth K Price
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - M Barbara E Livingstone
- Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
| | - Carel W Le Roux
- Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland
| | - Alan C Spector
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida
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41
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Prasad M, Mark V, Ligon C, Dutia R, Nair N, Shah A, Laferrère B. Role of the Gut in the Temporal Changes of β-Cell Function After Gastric Bypass in Individuals With and Without Diabetes Remission. Diabetes Care 2022; 45:469-476. [PMID: 34857533 PMCID: PMC8914419 DOI: 10.2337/dc21-1270] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 11/10/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The role of the gut in diabetes remission after Roux-en-Y gastric bypass (RYGB) is incompletely understood. We assessed the temporal change in insulin secretory capacity after RYGB, using oral and intravenous (IV) glucose, in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS Longitudinal, prospective measures of β-cell function were assessed after oral glucose intake and graded glucose infusion in individuals with severe obesity and diabetes studied at 0, 3 (n = 29), 12 (n = 24), and 24 (n = 20) months after RYGB. Data were collected between 2015 and 2019 in an academic clinical research center. RESULTS The decreases in body weight, fat mass, waist circumference, and insulin resistance after surgery (all P < 0.001 at 12 and 24 months) did not differ according to diabetes remission status. In contrast, both the magnitude and temporal changes in β-cell glucose sensitivity after oral glucose intake differed by remission status (P = 0.04): greater (6.5-fold; P < 0.01) and sustained in those in full remission, moderate and not sustained past 12 months in those with partial remission (3.3-fold; P < 0.001), and minimal in those not experiencing remission (2.7-fold; P = not significant). The improvement in β-cell function after IV glucose administration was not apparent until 12 months, significant only in those in full remission, and only ∼33% of that observed after oral glucose intake. Preintervention β-cell function and its change after surgery predicted remission; weight loss and insulin sensitivity did not. CONCLUSIONS Our data show the time course of changes in β-cell function after RYGB. The improvement in β-cell function after RYGB, but not changes in weight loss or insulin sensitivity, drives diabetes remission.
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Affiliation(s)
- Malini Prasad
- New York Nutrition Obesity Research Center, Columbia University Irving Medical Center, New York, NY
| | - Victoria Mark
- New York Nutrition Obesity Research Center, Columbia University Irving Medical Center, New York, NY
| | - Chanel Ligon
- Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Roxanne Dutia
- New York Nutrition Obesity Research Center, Columbia University Irving Medical Center, New York, NY
| | - Nandini Nair
- Division of Endocrinology, Columbia University Irving Medical Center, New York, NY
| | - Ankit Shah
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ
| | - Blandine Laferrère
- New York Nutrition Obesity Research Center, Columbia University Irving Medical Center, New York, NY.,Department of Medicine, Columbia University Irving Medical Center, New York, NY.,Division of Endocrinology, Columbia University Irving Medical Center, New York, NY
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42
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Bypassing Different Parts of the Small Intestine Determines Different Metabolic Effects in Streptozotocin-Induced Diabetic Rats. Obes Surg 2022; 32:671-681. [DOI: 10.1007/s11695-021-05785-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 11/04/2021] [Accepted: 11/08/2021] [Indexed: 11/09/2022]
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43
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Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations. Int J Mol Sci 2022; 23:ijms23031126. [PMID: 35163046 PMCID: PMC8835548 DOI: 10.3390/ijms23031126] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/17/2022] Open
Abstract
Roux-en-Y gastric bypass (RYGB) surgery has been proven successful in weight loss and improvement of co-morbidities associated with obesity. Chronic complications such as malabsorption of micronutrients in up to 50% of patients underline the need for additional therapeutic approaches. We investigated systemic RYGB surgery effects in a liquid sucrose diet-induced rat obesity model. After consuming a diet supplemented with high liquid sucrose for eight weeks, rats underwent RYGB or control sham surgery. RYGB, sham pair-fed, and sham ad libitum-fed groups further continued on the diet after recovery. Notable alterations were revealed in microbiota composition, inflammatory markers, feces, liver, and plasma metabolites, as well as in brain neuronal activity post-surgery. Higher fecal 4-aminobutyrate (GABA) correlated with higher Bacteroidota and Enterococcus abundances in RYGB animals, pointing towards the altered enteric nervous system (ENS) and gut signaling. Favorable C-reactive protein (CRP), serine, glycine, and 3-hydroxybutyrate plasma profiles in RYGB rats were suggestive of reverted obesity risk. The impact of liquid sucrose diet and caloric restriction mainly manifested in fatty acid changes in the liver. Our multi-modal approach reveals complex systemic changes after RYGB surgery and points towards potential therapeutic targets in the gut-brain system to mimic the surgery mode of action.
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Seyfried F, Phetcharaburanin J, Glymenaki M, Nordbeck A, Hankir M, Nicholson JK, Holmes E, Marchesi JR, Li JV. Roux-en-Y gastric bypass surgery in Zucker rats induces bacterial and systemic metabolic changes independent of caloric restriction-induced weight loss. Gut Microbes 2022; 13:1-20. [PMID: 33535876 PMCID: PMC7872092 DOI: 10.1080/19490976.2021.1875108] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Mechanisms of Roux-en-Y gastric bypass (RYGB) surgery are not fully understood. This study aimed to investigate weight loss-independent bacterial and metabolic changes, as well as the absorption of bacterial metabolites and bile acids through the hepatic portal system following RYGB surgery. Three groups of obese Zucker (fa/fa) rats were included: RYGB (n = 11), sham surgery and body weight matched with RYGB (Sham-BWM, n = 5), and sham surgery fed ad libitum (Sham-obese, n = 5). Urine and feces were collected at multiple time points, with portal vein and peripheral blood obtained at the end of the study. Metabolic phenotyping approaches and 16S rRNA gene sequencing were used to determine the biochemical and bacterial composition of the samples, respectively. RYGB surgery-induced distinct metabolic and bacterial disturbances, which were independent of weight loss through caloric restriction. RYGB resulted in lower absorption of phenylalanine and choline, and higher urinary concentrations of host-bacterial co-metabolites (e.g., phenylacetylglycine, indoxyl sulfate), together with higher fecal trimethylamine, suggesting enhanced bacterial aromatic amino acid and choline metabolism. Short chain fatty acids (SCFAs) were lower in feces and portal vein blood from RYGB group compared to Sham-BWM, accompanied with lower abundances of Lactobacillaceae, and Ruminococcaceae known to contain SCFA producers, indicating reduced bacterial fiber fermentation. Fecal γ-amino butyric acid (GABA) was found in higher concentrations in RYGB than that in Sham groups and could play a role in the metabolic benefits associated with RYGB surgery. While no significant difference in urinary BA excretion, RYGB lowered both portal vein and circulating BA compared to Sham groups. These findings provide a valuable resource for how dynamic, multi-systems changes impact on overall metabolic health, and may provide potential therapeutic targets for developing downstream non-surgical treatment for metabolic disease.
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Affiliation(s)
- Florian Seyfried
- Department of General, Visceral, Transplant, Vascular, and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Jutarop Phetcharaburanin
- Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College LondonLondon, UK,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Maria Glymenaki
- Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College LondonLondon, UK
| | - Arno Nordbeck
- Department of General, Visceral, Transplant, Vascular, and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Mohammed Hankir
- Department of General, Visceral, Transplant, Vascular, and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Jeremy K Nicholson
- Division of Organisms and Environment, School of Biosciences, Institute of Health Futures, Murdoch University, Perth, Western Australia, Australia
| | - Elaine Holmes
- Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College LondonLondon, UK,Division of Organisms and Environment, School of Biosciences, Institute of Health Futures, Murdoch University, Perth, Western Australia, Australia
| | - Julian R. Marchesi
- Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College LondonLondon, UK,School of Biosciences, Cardiff University, Cardiff, UK
| | - Jia V. Li
- Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College LondonLondon, UK,CONTACT Jia V. Li Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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45
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Akalestou E, Miras AD, Rutter GA, le Roux CW. Mechanisms of Weight Loss After Obesity Surgery. Endocr Rev 2022; 43:19-34. [PMID: 34363458 PMCID: PMC8755990 DOI: 10.1210/endrev/bnab022] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Indexed: 02/07/2023]
Abstract
Obesity surgery remains the most effective treatment for obesity and its complications. Weight loss was initially attributed to decreased energy absorption from the gut but has since been linked to reduced appetitive behavior and potentially increased energy expenditure. Implicated mechanisms associating rearrangement of the gastrointestinal tract with these metabolic outcomes include central appetite control, release of gut peptides, change in microbiota, and bile acids. However, the exact combination and timing of signals remain largely unknown. In this review, we survey recent research investigating these mechanisms, and seek to provide insights on unanswered questions over how weight loss is achieved following bariatric surgery which may eventually lead to safer, nonsurgical weight-loss interventions or combinations of medications with surgery.
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Affiliation(s)
- Elina Akalestou
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Alexander D Miras
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.,Lee Kong Chian Imperial Medical School, Nanyang Technological University, Singapore.,University of Montreal Hospital Research Centre, Montreal, QC, Canada
| | - Carel W le Roux
- Diabetes Complications Research Centre, University College Dublin, Ireland.,Diabetes Research Group, School of Biomedical Science, Ulster University, Belfast, UK
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46
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Oh JH, Kang CW, Wang EK, Nam JH, Lee S, Park KH, Lee EJ, Cho A, Ku CR. Altered Glucose Metabolism and Glucose Transporters in Systemic Organs After Bariatric Surgery. Front Endocrinol (Lausanne) 2022; 13:937394. [PMID: 35909546 PMCID: PMC9329688 DOI: 10.3389/fendo.2022.937394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
The Roux-en-Y gastric bypass (RYGB) is highly effective in the remission of obesity and associated diabetes. The mechanisms underlying obesity and type 2 diabetes mellitus remission after RYGB remain unclear. This study aimed to evaluate the changes in continuous dynamic FDG uptake patterns after RYGB and examine the correlation between glucose metabolism and its transporters in variable endocrine organs using 18F-fluoro-2-deoxyglucose positron emission tomography images. Increased glucose metabolism in specific organs, such as the small intestine and various fat tissues, is closely associated with improved glycemic control after RYGB. In Otsuka Long-Evans Tokushima Fatty rats fed with high-fat diets, RYGB operation increases intestine glucose transporter expression and various fat tissues' glucose transporters, which are not affected by insulin. The fasting glucose decrement was significantly associated with RYGB, sustained weight loss, post-RYGB oral glucose tolerance test (OGTT) area under the curve (AUC), glucose transporter, or glycolytic enzymes in the small bowel and various fat tissues. High intestinal glucose metabolism and white adipose tissue-dependent glucose metabolism correlated with metabolic benefit after RYGB. These findings suggest that the newly developed glucose biodistribution accompanied by increased glucose transporters is a mechanism associated with the systemic effect of RYGB.
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Affiliation(s)
- Ju Hun Oh
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, College of Medicine, Seoul, South Korea
- Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Chan Woo Kang
- Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Eun Kyung Wang
- Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Jung Ho Nam
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, College of Medicine, Seoul, South Korea
- Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Soohyun Lee
- Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Kyeong Hye Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, South Korea
| | - Eun Jig Lee
- Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea
| | - Arthur Cho
- Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Cheol Ryong Ku, ; Arthur Cho,
| | - Cheol Ryong Ku
- Department of Internal Medicine, Endocrinology, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Cheol Ryong Ku, ; Arthur Cho,
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47
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Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα. Nat Commun 2021; 12:7031. [PMID: 34857752 PMCID: PMC8639731 DOI: 10.1038/s41467-021-27133-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 11/05/2021] [Indexed: 02/08/2023] Open
Abstract
Intestinal surface changes in size and function, but what propels these alterations and what are their metabolic consequences is unknown. Here we report that the food amount is a positive determinant of the gut surface area contributing to an increased absorptive function, reversible by reducing daily food. While several upregulated intestinal energetic pathways are dispensable, the intestinal PPARα is instead necessary for the genetic and environment overeating-induced increase of the gut absorptive capacity. In presence of dietary lipids, intestinal PPARα knock-out or its pharmacological antagonism suppress intestinal crypt expansion and shorten villi in mice and in human intestinal biopsies, diminishing the postprandial triglyceride transport and nutrient uptake. Intestinal PPARα ablation limits systemic lipid absorption and restricts lipid droplet expansion and PLIN2 levels, critical for droplet formation. This improves the lipid metabolism, and reduces body adiposity and liver steatosis, suggesting an alternative target for treating obesity.
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48
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Dreyfuss JM, Yuchi Y, Dong X, Efthymiou V, Pan H, Simonson DC, Vernon A, Halperin F, Aryal P, Konkar A, Sebastian Y, Higgs BW, Grimsby J, Rondinone CM, Kasif S, Kahn BB, Foster K, Seeley R, Goldfine A, Djordjilović V, Patti ME. High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control. Nat Commun 2021; 12:6951. [PMID: 34845204 PMCID: PMC8630169 DOI: 10.1038/s41467-021-27289-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 11/11/2021] [Indexed: 12/13/2022] Open
Abstract
To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020.
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Affiliation(s)
- Jonathan M Dreyfuss
- Bioinformatics and Biostatistics Core, Research Division, Joslin Diabetes Center, Boston, MA, USA
- Biomedical Engineering, Boston University, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Yixing Yuchi
- Harvard Medical School, Boston, MA, USA
- Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA
- Vertex Pharmaceuticals, Boston, MA, USA
| | - Xuehong Dong
- Harvard Medical School, Boston, MA, USA
- Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA
- Department of Endocrinology, Diabetes & Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Vissarion Efthymiou
- Harvard Medical School, Boston, MA, USA
- Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA
| | - Hui Pan
- Bioinformatics and Biostatistics Core, Research Division, Joslin Diabetes Center, Boston, MA, USA
- Biomedical Engineering, Boston University, Boston, MA, USA
| | - Donald C Simonson
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Ashley Vernon
- Harvard Medical School, Boston, MA, USA
- Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA
| | - Florencia Halperin
- Harvard Medical School, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Form Health, Boston, MA, USA
| | - Pratik Aryal
- Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Anish Konkar
- MedImmune, Gaithersburg, MD, USA
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | - Joseph Grimsby
- MedImmune, Gaithersburg, MD, USA
- AstraZeneca, Gaithersburg, MD, USA
| | | | - Simon Kasif
- Biomedical Engineering, Boston University, Boston, MA, USA
| | - Barbara B Kahn
- Harvard Medical School, Boston, MA, USA
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Kathleen Foster
- Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA
| | - Randy Seeley
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Allison Goldfine
- Harvard Medical School, Boston, MA, USA
- Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Novartis Institute for Biomedical Research, Cambridge, MA, USA
| | - Vera Djordjilović
- Department of Economics, Ca' Foscari University of Venice, Venice, Italy
| | - Mary Elizabeth Patti
- Harvard Medical School, Boston, MA, USA.
- Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA.
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49
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Yukina MY, Chernova MO, Troshina EA, Evdoshenko VV, Platonova NM. Postprandial hypoglycemia after upper gastrointestinal tract surgery: prevalence and pathophysiology (part 1). ALMANAC OF CLINICAL MEDICINE 2021; 49:285-296. [DOI: 10.18786/2072-0505-2021-49-029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Nowadays obesity is a major health problem worldwide. Surgery is the most promising treatment for morbid obesity. There are two types of bariatric procedures, one to reduce the food intake volume and the other to limit the absorption of nutrients. Despite the indisputable advantages of bariatric surgery for weight loss, it is necessary to remember the potential risk of severe complications, such as hypoglycemic syndrome at 2 to 3 hours after ingestion of rapidly absorbable carbohydrates manifested by adrenergic and neuroglycopenic symptoms. According to the literature, the prevalence of post-bariatric postprandial hyperinsulinemic hypoglycemia (PHH) varies from 10% to 75%. PHH in post-bariatric patients should be differentiated from the syndrome of non-insulinoma pancreatogenic hypoglycemia and from insulinoma; however, these diseases are described also in patients after bariatric surgery.The mechanisms of PHH as an outcome of shunting bariatric procedures are currently not fully clear. According to the recent studies, incretin hypersecretion in response to the accelerated flow of carbohydrates into the small intestine plays a leading role in the inappropriate excess production of insulin by the pancreas. In addition, there are hypotheses on a slower normalization of insulin production during more rapid bodyweight decrease and regression of insulin resistance, the role of alpha-cell dysfunction, disturbed negative feedback between insulin and ghrelin, compensatory hyperplasia and hypertrophy of the remaining enterocytes (including L-cells), changes in gut microflora, bile acids level and composition. A number of other mechanisms have also been proposed that require further studies.
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Affiliation(s)
| | | | | | - V. V. Evdoshenko
- Institute of Plastic Surgery and Cosmetology; N.I. Pirogov Russian National Research Medical University
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Wu B, Ye Y, Xie S, Li Y, Sun X, Lv M, Yang L, Cui N, Chen Q, Jensen LD, Cui D, Huang G, Zuo J, Zhang S, Liu W, Yang Y. Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis. Cancer Res 2021; 81:5506-5522. [PMID: 34535458 DOI: 10.1158/0008-5472.can-21-1180] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/19/2021] [Accepted: 09/15/2021] [Indexed: 11/16/2022]
Abstract
High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.
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Affiliation(s)
- Biying Wu
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ying Ye
- Department of Oral Implantology, School and Hospital of Stomatology, Tongji University; Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Sisi Xie
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yintao Li
- Phase I Clinical Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China
| | - Xiaoting Sun
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengyuan Lv
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ling Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Nan Cui
- Department of Reproductive Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qiying Chen
- Department of Cardiology, Huashan Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Lasse D Jensen
- Department of Medicine, Health and Caring Science, Division of Diagnostics and Specialist Medicine, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Dongmei Cui
- Shenzhen Eye Hospital, Shenzhen Key Laboratory of Ophthalmology, Affiliated Shenzhen Eye Hospital of Jinan University, Shenzhen, China
| | - Guichun Huang
- Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Ji Zuo
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Shaochong Zhang
- Shenzhen Eye Hospital, Shenzhen Key Laboratory of Ophthalmology, Affiliated Shenzhen Eye Hospital of Jinan University, Shenzhen, China
| | - Wen Liu
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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