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Liu Y, Mao X, Li Q, Liu Y, Wu X, Chu M, Niu H, Sun L, He Y, Chang X, Guo D, Shi M, Zhang Y, Zhao J, Zhu Z. Increased serum total bile acid level is associated with improved prognosis of ischemic stroke. J Affect Disord 2025; 380:340-346. [PMID: 40147609 DOI: 10.1016/j.jad.2025.03.132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/20/2025] [Accepted: 03/22/2025] [Indexed: 03/29/2025]
Abstract
PURPOSE Bile acids are implicated in the cholesterol synthesis and lipid metabolism. We aimed to prospectively investigate the relationships between serum TBA and adverse clinical outcomes after ischemic stroke. METHODS Serum TBA levels at baseline were measured for 6609 ischemic stroke patients admitted at Minhang Hospital from January 2018 to December 2022. The primary outcome was a composite outcome of death and major disability (modified Rankin Scale [mRS] score, 3-6) at 3 months after stroke onset, and secondary outcomes included major disability (mRS score, 3-5), death (mRS score, 6), and ordered 7-level categorical score of the mRS. RESULTS During the 3-month follow-up period, a total of 2118 (34.5 %) patients experienced primary outcome. After multivariate adjustment, the odds ratios of primary outcome for the highest versus the lowest quartile of TBA were 0.71 (95 % CI, 0.58-0.88; Ptrend = 0.001). Each SD increase of log-transformed TBA was associated with a 12 % (95 % CI, 5 %-18 %) decreased risk of the primary outcome. Multiple-adjusted spline regression model showed a linear association of serum TBA levels with the primary outcome (P for linearity = 0.005). Subgroup analyses further confirmed the inverse associations between serum TBA levels and the prognosis of ischemic stroke. CONCLUSIONS Elevated serum TBA levels were independently associated with a decreased risk of adverse outcomes at 3 months after ischemic stroke, indicating that TBA might be implicated in the development of ischemic stroke and might be a prognostic biomarker for ischemic stroke.
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Affiliation(s)
- Yi Liu
- Department of Psychiatry, Affiliated Guangji Hospital of Soochow University, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Xueyu Mao
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China
| | - Qian Li
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China
| | - Yang Liu
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China; Institute of Science and Technology for Brain inspired Intelligence, Fudan University, Shanghai, China
| | - Xuechun Wu
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China
| | - Min Chu
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China
| | - Huicong Niu
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China
| | - Lulu Sun
- Department of Psychiatry, Affiliated Guangji Hospital of Soochow University, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yu He
- Department of Psychiatry, Affiliated Guangji Hospital of Soochow University, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Xinyue Chang
- Department of Psychiatry, Affiliated Guangji Hospital of Soochow University, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Daoxia Guo
- School of Nursing, Suzhou Medical College of Soochow University, Suzhou, China
| | - Mengyao Shi
- Department of Psychiatry, Affiliated Guangji Hospital of Soochow University, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Yonghong Zhang
- Department of Psychiatry, Affiliated Guangji Hospital of Soochow University, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jing Zhao
- Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China; Institute of Healthy Yangtze River Delta, Shanghai Jiao Tong University, Shanghai, China.
| | - Zhengbao Zhu
- Department of Psychiatry, Affiliated Guangji Hospital of Soochow University, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, China.
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2
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Aydin Ö, Wahlström A, de Jonge PA, Meijnikman AS, Sjöland W, Olsson L, Henricsson M, de Goffau MC, Oonk S, Bruin SC, Acherman YIZ, Marschall HU, Gerdes VEA, Nieuwdorp M, Bäckhed F, Groen AK. An integrated analysis of bile acid metabolism in humans with severe obesity. Hepatology 2025; 81:19-31. [PMID: 39010331 DOI: 10.1097/hep.0000000000000938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 03/26/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND AND AIMS Bile acids (BA) are vital regulators of metabolism. BAs are AQ6 secreted in the small intestine, reabsorbed, and transported back to the liver, where they can modulate metabolic functions. There is a paucity of data regarding the portal BA composition in humans. This study aimed to address this knowledge gap by investigating portal BA composition and the relation with peripheral and fecal BA dynamics in conjunction with the gut microbiome. APPROACH AND RESULTS Thirty-three individuals from the BARIA cohort were included. Portal plasma, peripheral plasma, and feces were collected. BA and C4 levels were measured employing mass spectrometry. FGF19 was measured using ELISA. Gut microbiota composition was determined through metagenomics analysis on stool samples. Considerable diversity in the portal BA composition was observed. The majority (n = 26) of individuals had a 9-fold higher portal than peripheral BA concentration. In contrast, 8 individuals showed lower portal BA concentration compared with peripheral and had higher levels of unconjugated and secondary BA in this compartment, suggesting more distal origin. The altered portal BA profile was associated with altered gut microbiota composition. In particular, taxa within Bacteroides were reduced in abundance in the feces of these individuals. CONCLUSIONS Characterization of the portal BA composition in relation to peripheral and fecal BA increased insight into the dynamics of BA metabolism in individuals with obesity. Peripheral BA composition was much more diverse due to microbial metabolism. About 24% of the portal samples was surprisingly low in total BA; the underlying mechanism requires further exploration.
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Affiliation(s)
- Ömrüm Aydin
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Annika Wahlström
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Patrick A de Jonge
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Abraham S Meijnikman
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Wilhelm Sjöland
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lisa Olsson
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Marcus Henricsson
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Marcus C de Goffau
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Stijn Oonk
- Department of Scientific Research, Data Science, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Sjoerd C Bruin
- Department of Bariatric Surgery, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Yair I Z Acherman
- Department of Bariatric Surgery, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Hanns-Ulrich Marschall
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Victor E A Gerdes
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Bariatric Surgery, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
- Department of Internal Medicine, Spaarne Gasthuis Hospital, Hoofddorp, the Netherlands
| | - Max Nieuwdorp
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Fredrik Bäckhed
- Wallenberg Laboratory and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Albert K Groen
- Department of Internal and (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Department of Vascular Medicine, ACS Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
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3
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Wu M, Cheng Y, Zhang R, Han W, Jiang H, Bi C, Zhang Z, Ye M, Lin X, Liu Z. Molecular mechanism and therapeutic strategy of bile acids in Alzheimer's disease from the emerging perspective of the microbiota-gut-brain axis. Biomed Pharmacother 2024; 178:117228. [PMID: 39088965 DOI: 10.1016/j.biopha.2024.117228] [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: 04/21/2024] [Revised: 07/19/2024] [Accepted: 07/28/2024] [Indexed: 08/03/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β outside neurons and Tau protein inside neurons. Various pathological mechanisms are implicated in AD, including brain insulin resistance, neuroinflammation, and endocrinal dysregulation of adrenal corticosteroids. These factors collectively contribute to neuronal damage and destruction. Recently, bile acids (BAs), which are metabolites of cholesterol, have shown neuroprotective potential against AD by targeting the above pathological changes. BAs can enter the systematic circulation and cross the blood-brain barrier, subsequently exerting neuroprotective effects by targeting several endogenous receptors. Additionally, BAs interact with the microbiota-gut-brain (MGB) axis to improve immune and neuroendocrine function during AD episodes. Gut microbes impact BA signaling in the brain through their involvement in BA biotransformation. In this review, we summarize the role and molecular mechanisms of BAs in AD while considering the MGB axis and propose novel strategies for preventing the onset and progression of AD.
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Affiliation(s)
- Menglu Wu
- Clinical Laboratory, Shaoxing Seventh People's Hospital (Affiliated Mental Health Center, Medical College of Shaoxing University), Shaoxing, Zhejiang, China; Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Yongyi Cheng
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Ruolin Zhang
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Wenwen Han
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Hanqi Jiang
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Chenchen Bi
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Ziyi Zhang
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Mengfei Ye
- Department of Psychiatry, Shaoxing Seventh People's Hospital (Affiliated Mental Health Center, Medical College of Shaoxing University), Shaoxing, Zhejiang, China
| | - Xiuqin Lin
- Clinical Laboratory, Shaoxing Seventh People's Hospital (Affiliated Mental Health Center, Medical College of Shaoxing University), Shaoxing, Zhejiang, China.
| | - Zheng Liu
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China; Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, China.
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4
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Jia W, Li Y, Cheung KCP, Zheng X. Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis. SCIENCE CHINA. LIFE SCIENCES 2024; 67:865-878. [PMID: 37515688 DOI: 10.1007/s11427-023-2353-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 04/23/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BAs) play a crucial role in nutrient absorption and act as key regulators of lipid and glucose metabolism and immune homeostasis. Through the enterohepatic circulation, BAs are synthesized, metabolized, and reabsorbed, with a portion entering the vascular circulation and distributing systemically. This allows BAs to interact with receptors in all major organs, leading to organ-organ interactions that regulate both local and global metabolic processes, as well as the immune system. This review focuses on the whole-body effects of BA-mediated metabolic and immunological regulation, including in the brain, heart, liver, intestine, eyes, skin, adipose tissue, and muscle. Targeting BA synthesis and receptor signaling is a promising strategy for the development of novel therapies for various diseases throughout the body.
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Affiliation(s)
- Wei Jia
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Yitao Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Kenneth C P Cheung
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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5
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Chen S, Shao Q, Chen J, Lv X, Ji J, Liu Y, Song Y. Bile acid signalling and its role in anxiety disorders. Front Endocrinol (Lausanne) 2023; 14:1268865. [PMID: 38075046 PMCID: PMC10710157 DOI: 10.3389/fendo.2023.1268865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Anxiety disorder is a prevalent neuropsychiatric disorder that afflicts 7.3%~28.0% of the world's population. Bile acids are synthesized by hepatocytes and modulate metabolism via farnesoid X receptor (FXR), G protein-coupled receptor (TGR5), etc. These effects are not limited to the gastrointestinal tract but also extend to tissues and organs such as the brain, where they regulate emotional centers and nerves. A rise in serum bile acid levels can promote the interaction between central FXR and TGR5 across the blood-brain barrier or activate intestinal FXR and TGR5 to release fibroblast growth factor 19 (FGF19) and glucagon-like peptide-1 (GLP-1), respectively, which in turn, transmit signals to the brain via these indirect pathways. This review aimed to summarize advancements in the metabolism of bile acids and the physiological functions of their receptors in various tissues, with a specific focus on their regulatory roles in brain function. The contribution of bile acids to anxiety via sending signals to the brain via direct or indirect pathways was also discussed. Different bile acid ligands trigger distinct bile acid signaling cascades, producing diverse downstream effects, and these pathways may be involved in anxiety regulation. Future investigations from the perspective of bile acids are anticipated to lead to novel mechanistic insights and potential therapeutic targets for anxiety disorders.
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Affiliation(s)
| | | | | | | | | | - Yan Liu
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuehan Song
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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6
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Williamson C, Nana M, Poon L, Kupcinskas L, Painter R, Taliani G, Heneghan M, Marschall HU, Beuers U. EASL Clinical Practice Guidelines on the management of liver diseases in pregnancy. J Hepatol 2023; 79:768-828. [PMID: 37394016 DOI: 10.1016/j.jhep.2023.03.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 07/04/2023]
Abstract
Liver diseases in pregnancy comprise both gestational liver disorders and acute and chronic hepatic disorders occurring coincidentally in pregnancy. Whether related to pregnancy or pre-existing, liver diseases in pregnancy are associated with a significant risk of maternal and fetal morbidity and mortality. Thus, the European Association for the Study of Liver Disease invited a panel of experts to develop clinical practice guidelines aimed at providing recommendations, based on the best available evidence, for the management of liver disease in pregnancy for hepatologists, gastroenterologists, obstetric physicians, general physicians, obstetricians, specialists in training and other healthcare professionals who provide care for this patient population.
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7
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Sisk-Hackworth L, Kelley ST, Thackray VG. Sex, puberty, and the gut microbiome. Reproduction 2023; 165:R61-R74. [PMID: 36445259 PMCID: PMC9847487 DOI: 10.1530/rep-22-0303] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/28/2022] [Indexed: 11/30/2022]
Abstract
In brief Sex differences in the gut microbiome may impact multiple aspects of human health and disease. In this study, we review the evidence for microbial sex differences in puberty and adulthood and discuss potential mechanisms driving differentiation of the sex-specific gut microbiome. Abstract In humans, the gut microbiome is strongly implicated in numerous sex-specific physiological processes and diseases. Given this, it is important to understand how sex differentiation of the gut microbiome occurs and how these differences contribute to host health and disease. While it is commonly believed that the gut microbiome stabilizes after 3 years of age, our review of the literature found considerable evidence that the gut microbiome continues to mature during and after puberty in a sex-dependent manner. We also review the intriguing, though sparse, literature on potential mechanisms by which host sex may influence the gut microbiome, and vice versa, via sex steroids, bile acids, and the immune system. We conclude that the evidence for the existence of a sex-specific gut microbiome is strong but that there is a dearth of research on how host-microbe interactions lead to this differentiation. Finally, we discuss the types of future studies needed to understand the processes driving the maturation of sex-specific microbial communities and the interplay between gut microbiota, host sex, and human health.
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Affiliation(s)
| | - Scott T. Kelley
- Department of Biology, San Diego State University, San Diego, California 92182
| | - Varykina G. Thackray
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Diego, La Jolla, California 92093
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8
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Bebelman MP, Bovyn MJ, Mayer CM, Delpierre J, Naumann R, Martins NP, Honigmann A, Kalaidzidis Y, Haas PA, Zerial M. Hepatocyte apical bulkheads provide a mechanical means to oppose bile pressure. J Cell Biol 2023; 222:213840. [PMID: 36716168 PMCID: PMC9930133 DOI: 10.1083/jcb.202208002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/15/2022] [Accepted: 01/13/2023] [Indexed: 01/31/2023] Open
Abstract
Hepatocytes grow their apical surfaces anisotropically to generate a 3D network of bile canaliculi (BC). BC elongation is ensured by apical bulkheads, membrane extensions that traverse the lumen and connect juxtaposed hepatocytes. We hypothesize that apical bulkheads are mechanical elements that shape the BC lumen in liver development but also counteract elevated biliary pressure. Here, by resolving their structure using STED microscopy, we found that they are sealed by tight junction loops, connected by adherens junctions, and contain contractile actomyosin, characteristics of mechanical function. Apical bulkheads persist at high pressure upon microinjection of fluid into the BC lumen, and laser ablation demonstrated that they are under tension. A mechanical model based on ablation results revealed that apical bulkheads double the pressure BC can hold. Apical bulkhead frequency anticorrelates with BC connectivity during mouse liver development, consistent with predicted changes in biliary pressure. Our findings demonstrate that apical bulkheads are load-bearing mechanical elements that could protect the BC network against elevated pressure.
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Affiliation(s)
- Maarten P. Bebelman
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Matthew J. Bovyn
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany,Center for Systems Biology Dresden, Dresden, Germany,Max Planck Institute for the Physics of Complex Systems, Dresden, Germany
| | - Carlotta M. Mayer
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Julien Delpierre
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Ronald Naumann
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Nuno P. Martins
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Alf Honigmann
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Yannis Kalaidzidis
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Pierre A. Haas
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany,Center for Systems Biology Dresden, Dresden, Germany,Max Planck Institute for the Physics of Complex Systems, Dresden, Germany,Pierre A. Haas:
| | - Marino Zerial
- https://ror.org/05b8d3w18Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany,Center for Systems Biology Dresden, Dresden, Germany,Cluster of Excellence Physics of Life, Technische Universität Dresden, Dresden, Germany,Correspondence to Marino Zerial:
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9
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Carson MD, Warner AJ, Hathaway-Schrader JD, Geiser VL, Kim J, Gerasco JE, Hill WD, Lemasters JJ, Alekseyenko AV, Wu Y, Yao H, Aguirre JI, Westwater C, Novince CM. Minocycline-induced disruption of the intestinal FXR/FGF15 axis impairs osteogenesis in mice. JCI Insight 2023; 8:160578. [PMID: 36413391 PMCID: PMC9870091 DOI: 10.1172/jci.insight.160578] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 11/16/2022] [Indexed: 11/24/2022] Open
Abstract
Antibiotic-induced shifts in the indigenous gut microbiota influence normal skeletal maturation. Current theory implies that gut microbiota actions on bone occur through a direct gut/bone signaling axis. However, our prior work supports that a gut/liver signaling axis contributes to gut microbiota effects on bone. Our purpose was to investigate the effects of minocycline, a systemic antibiotic treatment for adolescent acne, on pubertal/postpubertal skeletal maturation. Sex-matched specific pathogen-free (SPF) and germ-free (GF) C57BL/6T mice were administered a clinically relevant minocycline dose from age 6-12 weeks. Minocycline caused dysbiotic shifts in the gut bacteriome and impaired skeletal maturation in SPF mice but did not alter the skeletal phenotype in GF mice. Minocycline administration in SPF mice disrupted the intestinal farnesoid X receptor/fibroblast growth factor 15 axis, a gut/liver endocrine axis supporting systemic bile acid homeostasis. Minocycline-treated SPF mice had increased serum conjugated bile acids that were farnesoid X receptor (FXR) antagonists, suppressed osteoblast function, decreased bone mass, and impaired bone microarchitecture and fracture resistance. Stimulating osteoblasts with the serum bile acid profile from minocycline-treated SPF mice recapitulated the suppressed osteogenic phenotype found in vivo, which was mediated through attenuated FXR signaling. This work introduces bile acids as a potentially novel mediator of gut/liver signaling actions contributing to gut microbiota effects on bone.
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Affiliation(s)
- Matthew D Carson
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Amy J Warner
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Jessica D Hathaway-Schrader
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Vincenza L Geiser
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Joseph Kim
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
| | - Joy E Gerasco
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Drug Discovery & Biomedical Sciences, College of Pharmacy
| | - William D Hill
- Department of Pathology and Laboratory Medicine, College of Medicine
| | - John J Lemasters
- Department of Drug Discovery & Biomedical Sciences, College of Pharmacy.,Department of Biochemistry & Molecular Biology, College of Medicine
| | - Alexander V Alekseyenko
- Department of Oral Health Sciences, College of Dental Medicine.,Biomedical Informatics Center, Program for Human Microbiome Research, Department of Public Health Sciences, College of Medicine.,Department of Healthcare Leadership and Management, College of Health Professions; and
| | - Yongren Wu
- Department of Orthopedics & Physical Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.,Department of Bioengineering, College of Engineering, Clemson University, Clemson, South Carolina, USA
| | - Hai Yao
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Bioengineering, College of Engineering, Clemson University, Clemson, South Carolina, USA
| | - J Ignacio Aguirre
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA
| | - Caroline Westwater
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Chad M Novince
- Department of Oral Health Sciences, College of Dental Medicine.,Department of Pediatrics, Division of Endocrinology, College of Medicine.,Department of Stomatology, Division of Periodontics, College of Dental Medicine
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10
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Cheng ZQ, Liu TM, Ren PF, Chen C, Wang YL, Dai Y, Zhang X. Duodenal-jejunal bypass reduces serum ceramides via inhibiting intestinal bile acid-farnesoid X receptor pathway. World J Gastroenterol 2022; 28:4328-4337. [PMID: 36159007 PMCID: PMC9453759 DOI: 10.3748/wjg.v28.i31.4328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass (DJB). Serum bile acids are elevated postoperatively. However, the clinical relevance is not known. Bile acids in the peripheral circulation reflect the amount of bile acids in the gut. Therefore, a further investigation of luminal bile acids following DJB is of great significance.
AIM To investigate changes of luminal bile acids following DJB.
METHODS Salicylhydroxamic acid (SHAM), DJB, and DJB with oral chenodeoxycholic acid (CDCA) supplementation were performed in a high-fat-diet/streptozotocin-induced diabetic rat model. Body weight, energy intake, oral glucose tolerance test, luminal bile acids, serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.
RESULTS Compared to SHAM, DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor (FXR) - inhibitory bile acids within the common limb. Intestinal ceramide synthesis was repressed with decreased serum ceramides, and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.
CONCLUSION DJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels. There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.
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Affiliation(s)
- Zhi-Qiang Cheng
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Tong-Ming Liu
- Department of Colorectal and Anal Surgery, Feicheng Hospital Affiliated to Shandong First Medical University, Feicheng 271600, Shandong Province, China
| | - Peng-Fei Ren
- Department of General Surgery, Lincheng People’s Hospital, Dezhou 253500, Shandong Province, China
| | - Chang Chen
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Yan-Lei Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Yong Dai
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Xiang Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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11
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Fiamoncini J, Rist MJ, Frommherz L, Giesbertz P, Pfrang B, Kremer W, Huber F, Kastenmüller G, Skurk T, Hauner H, Suhre K, Daniel H, Kulling SE. Dynamics and determinants of human plasma bile acid profiles during dietary challenges. Front Nutr 2022; 9:932937. [PMID: 35967802 PMCID: PMC9366195 DOI: 10.3389/fnut.2022.932937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/01/2022] [Indexed: 11/30/2022] Open
Abstract
In recent years, bile acids (BA) have received great interest due to their pleiotropic biological activity and the presence of plasma membrane-bound and nuclear receptors. Moreover, BA in blood have been identified by metabolite screening approaches as biomarkers that are associated with various diseases and even with a human longevity phenotype. With the growing interest in the microbiota contribution to the health-disease trajectory, BA that undergo deconjugation and other modifications by bacteria in the large intestine have become a prime target as a microbiome diversity modifier. We here profiled BA by a quantitative and a semiquantitative approach in 15 healthy and phenotypically very similar young individuals for over a 36-h fasting period, an oral glucose tolerance test (OGTT), and an oral lipid tolerance test (OLTT). We demonstrate a remarkable heterogeneity of the responses and describe the different dynamics of the plasma changes that likely originate from different routes by which BA enters the peripheral blood, and that may represent a direct secretion from the liver into the blood and a route that reaches the blood as a spill-over after passing from the gallbladder through the intestine and the portal system. We discuss the finding that an individual transport process involved in the passage of BA could be a critical determinant in the kinetics of plasma appearance and the overall phenotypic variability found.
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Affiliation(s)
- Jarlei Fiamoncini
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, Food Research Center - FoRC, University of São Paulo, São Paulo, Brazil
| | - Manuela J Rist
- Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Karlsruhe, Germany
| | - Lara Frommherz
- Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Karlsruhe, Germany
| | - Pieter Giesbertz
- Department of Nutritional Physiology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Birgit Pfrang
- Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Karlsruhe, Germany
| | - Werner Kremer
- Biophysics I, Regensburg Center for Biochemistry, Universität Regensburg, Regensburg, Germany
| | - Fritz Huber
- Department of Nutritional Physiology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Gabi Kastenmüller
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Thomas Skurk
- Chair of Nutritional Medicine, Else Kroener-Fresenius-Centre for Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Hans Hauner
- Chair of Nutritional Medicine, Else Kroener-Fresenius-Centre for Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany
| | - Karsten Suhre
- Bioinformatics Core, Research Department, Weill Cornell Medicine in Qatar, Doha, Qatar
| | - Hannelore Daniel
- Department of Nutritional Physiology, Technische Universität München, Freising-Weihenstephan, Germany
| | - Sabine E Kulling
- Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Karlsruhe, Germany
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12
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Ahmed M. Functional, Diagnostic and Therapeutic Aspects of Bile. Clin Exp Gastroenterol 2022; 15:105-120. [PMID: 35898963 PMCID: PMC9309561 DOI: 10.2147/ceg.s360563] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 07/03/2022] [Indexed: 11/23/2022] Open
Abstract
Bile is a unique body fluid synthesized in our liver. Enterohepatic circulation preserves bile in our body through its efficient synthesis, transport, absorption, and reuptake. Bile is the main excretory route for bile salts, bilirubin, and potentially harmful exogenous lipophilic substances. The primary way of eliminating cholesterol is bile. Although bile has many organic and inorganic contents, bile acid is the most physiologically active component. Bile acids have a multitude of critical physiologic functions in our body. These include emulsification of dietary fat, absorption of fat and fat-soluble vitamins, maintaining glucose, lipid, and energy homeostasis, sustenance of intestinal epithelial integrity and epithelial cell proliferation, reducing inflammation in the intestine, and prevention of enteric infection due to its antimicrobial properties. But bile acids can be harmful in certain altered conditions like cholecystectomy, terminal ileal disease or resection, cholestasis, duodenogastric bile reflux, duodenogastroesophageal bile reflux, and bile acid diarrhea. Bile acids can have malignant potentials as well. There are also important diagnostic and therapeutic roles of bile acid and bile acid modulation.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
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13
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Liu H, Kohmoto O, Sakaguchi A, Hori S, Tochigi M, Tada K, Lee Y, Kikuchi K, Ishizuka S. Taurocholic acid, a primary 12α-hydroxylated bile acid, induces leakiness in the distal small intestine in rats. Food Chem Toxicol 2022; 165:113136. [PMID: 35584729 DOI: 10.1016/j.fct.2022.113136] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/18/2022] [Accepted: 05/12/2022] [Indexed: 11/15/2022]
Abstract
A high-fat diet increases 12α-hydroxylated (12αOH) bile acid (BA) secretion in rats, and secondary BAs are responsible for the leaky gut. This study aimed to examine the role of primary 12αOH BAs in gut barrier impairment in rats using dietary cholic acid (CA) supplementation (0.5 g/kg diet). The CA diet increased the 12αOH BAs concentrations in the small and large intestine, accompanied by gut barrier impairment. Based on the luminal 12αOH BAs concentrations, ex vivo gut leakiness was determined. Deoxycholic acid increased permeability in the large intestine, whereas taurocholic acid (TCA) increased the ileal permeability, but not jejunal permeability. A Rho kinase inhibitor attenuated TCA-induced ileal permeability. Administration of vancomycin, which abolishes secondary BAs, did not influence the gut leakiness induced by the CA diet. Changes in the gut permeation marker in the tail vein blood suggested the possibility that the CA-induced leakiness occurred in the small intestine. The CA diet enhanced the phosphorylation of myosin light chain 2 and reduced claudins expressions in rat ileal epithelia. Reductions in barrier function-related genes were observed in the ileum, but not in the colon of the CA-fed rats. Overall, the present study demonstrated the significance of TCA in proximal gut leakiness.
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Affiliation(s)
- Hongxia Liu
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Ohji Kohmoto
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Ayana Sakaguchi
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Shota Hori
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Misuzu Tochigi
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Koji Tada
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Yeonmi Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155, Gaetbeol-ro, Yeonsu-gu, Incheon, 21999, Republic of Korea
| | - Keidai Kikuchi
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan
| | - Satoshi Ishizuka
- Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo, 060-8589, Japan.
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14
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Gee C, Fleuret C, Wilson A, Levine D, Elhusseiny R, Muls A, Cunningham D, Kohoutova D. Bile Acid Malabsorption as a Consequence of Cancer Treatment: Prevalence and Management in the National Leading Centre. Cancers (Basel) 2021; 13:6213. [PMID: 34944833 PMCID: PMC8699462 DOI: 10.3390/cancers13246213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 12/08/2021] [Indexed: 01/14/2023] Open
Abstract
The aim was to establish prevalence of bile acid malabsorption (BAM) and management in patients who underwent treatment for malignancy. Retrospective evaluation of data in patients seen within six months (August 2019-January 2020) was carried out. Demographic, nuclear medicine (Selenium Homocholic Acid Taurine (SeHCAT) scan result), clinical (previous malignancy, type of intervention (medication, diet), response to intervention) and laboratory (vitamin D, vitamin B12 serum levels) data were searched. In total, 265 consecutive patients were reviewed. Out of those, 87/265 (33%) patients (57 females, 66%) were diagnosed with BAM. Mean age was 59 +/- 12 years. The largest group were females with gynaecological cancer (35), followed by haematology group (15), colorectal/anal (13), prostate (9), upper gastrointestinal cancer (6), another previous malignancy (9). Severe BAM was most common in haematology (10/15; 67%) and gynaecological group (21/35; 60%). Medication and low-fat diet were commenced in 65/87 (75%), medication in 10/87 (11%), diet in 6/87 (7%). Colesevelam was used in 71/75 (95%). Symptoms improved in 74/87 (85%) patients. Vitamin D insufficiency/deficiency was diagnosed in 62/87 (71%), vitamin B12 deficiency in 39/87 (45%). BAM is a common condition in this cohort however treatments are highly effective.
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Affiliation(s)
- Caroline Gee
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
| | - Catherine Fleuret
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
| | - Ana Wilson
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
- St Marks Hospital, Watford Road, Harrow, Middlesex, London HA1 3UJ, UK
| | - Daniel Levine
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
| | - Ramy Elhusseiny
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
| | - Ann Muls
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
| | - David Cunningham
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
| | - Darina Kohoutova
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK; (C.G.); (C.F.); (A.W.); (D.L.); (R.E.); (A.M.); (D.C.)
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15
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Qi L, Tian Y, Chen Y. Circulating Bile Acid Profiles: A Need for Further Examination. J Clin Endocrinol Metab 2021; 106:3093-3112. [PMID: 34279029 DOI: 10.1210/clinem/dgab531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Indexed: 12/15/2022]
Abstract
CONTEXT Bile acids (BAs) are increasingly recognized as metabolic and chronobiologic integrators that synchronize the systemic metabolic response to nutrient availability. Alterations in the concentration and/or composition of circulating BAs are associated with a number of metabolic disorders, such as obesity, type 2 diabetes mellitus (T2DM), insulin resistance (IR), and metabolic associated fatty liver disease (MAFLD). This review summarizes recent evidence that links abnormal circulating BA profiles to multiple metabolic disorders, and discusses the possible mechanisms underlying the connections to determine the role of BA profiling as a novel biomarker for these abnormalities. EVIDENCE ACQUISITION The review is based on a collection of primary and review literature gathered from a PubMed search of BAs, T2DM, IR, and MAFLD, among other keywords. EVIDENCE SYNTHESIS Obese and IR subjects appear to have elevated fasting circulating BAs but lower postprandial increase when compared with controls. The possible underlying mechanisms are disruption in the synchronization between the feeding/fasting cycle and the properties of BA-regulated metabolic pathways. Whether BA alterations are associated per se with MAFLD remains inconclusive. However, increased fasting circulating BAs level was associated with higher risk of advanced fibrosis stage. Thus, for patients with MAFLD, dynamically monitoring the circulating BA profiles may be a promising tool for the stratification of MAFLD. CONCLUSIONS Alterations in the concentration, composition, and rhythm of circulating BAs are associated with adverse events in systemic metabolism. Subsequent investigations regarding these aspects of circulating BA kinetics may help predict future metabolic disorders and guide therapeutic interventions.
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Affiliation(s)
- Li Qi
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, 110022, Liaoning Province, China
| | - Yu Tian
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, China
| | - Yongsheng Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, China
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16
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LaBarre JL, Hirschfeld E, Soni T, Kachman M, Wigginton J, Duren W, Fleischman JY, Karnovsky A, Burant CF, Lee JM. Comparing the Fasting and Random-Fed Metabolome Response to an Oral Glucose Tolerance Test in Children and Adolescents: Implications of Sex, Obesity, and Insulin Resistance. Nutrients 2021; 13:nu13103365. [PMID: 34684365 PMCID: PMC8538092 DOI: 10.3390/nu13103365] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/12/2021] [Accepted: 09/23/2021] [Indexed: 11/25/2022] Open
Abstract
As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state. Participants were recruited as lean (n = 55, aged 8–17 years, BMI percentile 5–85%) and overweight and obese (OVOB, n = 228, aged 8–17 years, BMI percentile ≥ 85%). Untargeted metabolomics profiled 246 annotated metabolites in plasma at t0 and t60 min during the OGTT. Our results suggest that obesity and IR influence the switch from fatty acid (FA) to glucose oxidation in response to the OGTT. Obesity was associated with a blunted decline of acylcarnitines and fatty acid oxidation intermediates. In females, metabolites from the Fasted and Random-Fed OGTT were associated with HOMA-IR, including diacylglycerols, leucine/isoleucine, acylcarnitines, and phosphocholines. Our results indicate that at an early age, obesity and IR may influence the metabolome dynamics in response to a glucose challenge.
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Affiliation(s)
- Jennifer L. LaBarre
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Weight and Wellness Center, Lebanon, NH 03766, USA
- Correspondence: (J.L.L.); (J.M.L.)
| | - Emily Hirschfeld
- Susan B Meister Child Health Evaluation and Research Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Tanu Soni
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48109, USA; (T.S.); (M.K.); (J.W.); (W.D.)
| | - Maureen Kachman
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48109, USA; (T.S.); (M.K.); (J.W.); (W.D.)
| | - Janis Wigginton
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48109, USA; (T.S.); (M.K.); (J.W.); (W.D.)
| | - William Duren
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI 48109, USA; (T.S.); (M.K.); (J.W.); (W.D.)
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
| | - Johanna Y. Fleischman
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Alla Karnovsky
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
| | - Charles F. Burant
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA;
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Joyce M. Lee
- Susan B Meister Child Health Evaluation and Research Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA;
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
- Correspondence: (J.L.L.); (J.M.L.)
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17
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Reiter S, Dunkel A, Dawid C, Hofmann T. Targeted LC-MS/MS Profiling of Bile Acids in Various Animal Tissues. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:10572-10580. [PMID: 34490775 DOI: 10.1021/acs.jafc.1c03433] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Bile acids are being increasingly investigated in humans and laboratory animals as markers for various diseases in addition to their important functions, such as promoting the emulsification in fat digestion and preventing gallstone formation. In humans and animals, primary bile acids are formed from cholesterol in the liver, converted in the intestine into various secondary bile acids by the intestinal microbiota and reabsorbed in the terminal ileum, and partially returned to the liver. A universal high-throughput workflow, including a simple workup, was applied as a tool for bile acid analysis in animal studies. The complex bile acid profiles in various tissues, organs, and body fluids from different animals were mapped using a newly developed comprehensive liquid chromatography-tandem mass spectrometry method. The method can also be used in screening food to obtain information about the nutritional content of bile acids. This could be relevant to investigations on various animal diseases and on the bioavailability of bile acids that pass through the gastric tract.
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Affiliation(s)
- Sinah Reiter
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
- ZIEL-Institute for Food and Health, Technical University of Munich, Weihenstephaner Berg 1, 85354 Freising, Germany
| | - Andreas Dunkel
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Lise-Meitner-Straße 34, 85354 Freising, Germany
| | - Corinna Dawid
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
| | - Thomas Hofmann
- Chair of Food Chemistry and Molecular Sensory Science, Technical University of Munich, Lise-Meitner-Straße 34, D-85354 Freising, Germany
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18
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Sauerbruch T, Hennenberg M, Trebicka J, Beuers U. Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction. Front Physiol 2021; 12:718783. [PMID: 34393832 PMCID: PMC8358446 DOI: 10.3389/fphys.2021.718783] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.
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Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology I, University Hospital, LMU Munich, Munich, Germany
| | - Jonel Trebicka
- Translational Hepatology, Medical Department, University of Frankfurt, Frankfurt, Germany
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
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19
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Perino A, Velázquez-Villegas LA, Bresciani N, Sun Y, Huang Q, Fénelon VS, Castellanos-Jankiewicz A, Zizzari P, Bruschetta G, Jin S, Baleisyte A, Gioiello A, Pellicciari R, Ivanisevic J, Schneider BL, Diano S, Cota D, Schoonjans K. Central anorexigenic actions of bile acids are mediated by TGR5. Nat Metab 2021; 3:595-603. [PMID: 34031591 PMCID: PMC7610881 DOI: 10.1038/s42255-021-00398-4] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 04/26/2021] [Indexed: 12/21/2022]
Abstract
Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain1, yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs2 and an established regulator of peripheral metabolism3-8. Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system.
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Laura A Velázquez-Villegas
- Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F., Mexico
| | - Nadia Bresciani
- Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Yu Sun
- Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Qingyao Huang
- Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Valérie S Fénelon
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300, Bordeaux, France
| | | | - Philippe Zizzari
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300, Bordeaux, France
| | - Giuseppe Bruschetta
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | - Sungho Jin
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA
| | - Aiste Baleisyte
- Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Antimo Gioiello
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | | | - Julijana Ivanisevic
- Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Bernard L Schneider
- Bertarelli Platform for Gene Therapy, Ecole Polytechnique Fédérale de Lausanne, Geneva, Switzerland
| | - Sabrina Diano
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY, USA
| | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, F-3300, Bordeaux, France
| | - Kristina Schoonjans
- Institute of Bioengineering, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
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20
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Mitchell AL, Ovadia C, Syngelaki A, Souretis K, Martineau M, Girling J, Vasavan T, Fan HM, Seed PT, Chambers J, Walters J, Nicolaides K, Williamson C. Re-evaluating diagnostic thresholds for intrahepatic cholestasis of pregnancy: case-control and cohort study. BJOG 2021; 128:1635-1644. [PMID: 33586324 DOI: 10.1111/1471-0528.16669] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2021] [Indexed: 12/27/2022]
Abstract
OBJECTIVE To determine the optimal total serum bile acid (TSBA) threshold and sampling time for accurate intrahepatic cholestasis of pregnancy (ICP) diagnosis. DESIGN Case-control, retrospective cohort studies. SETTING Antenatal clinics, clinical research facilities. POPULATION Women with ICP or uncomplicated pregnancies. METHODS Serial TSBA measurements were performed pre-/postprandially in 42 women with ICP or uncomplicated pregnancy. Third-trimester non-fasting TSBA reference ranges were calculated from 561 women of black, south Asian and white ethnicity. Rates of adverse perinatal outcomes for women with ICP but peak non-fasting TSBA below the upper reference range limit were compared with those in healthy populations. MAIN OUTCOME MEASURES Sensitivity and specificity of common TSBA thresholds for ICP diagnosis, using fasting and postprandial TSBA. Calculation of normal reference ranges of non-fasting TSBA. RESULTS Concentrations of TSBA increased markedly postprandially in all groups, with overlap between healthy pregnancy and mild ICP (TSBA <40 μmol/l). The specificity of ICP diagnosis was higher when fasting, but corresponded to <30% sensitivity for diagnosis of mild disease. Using TSBA ≥40 μmol/l to define severe ICP, fasting measurements identified 9% (1/11), whereas non-fasting measurements detected over 91% with severe ICP. The highest upper limit of the non-fasting TSBA reference range was 18.3 µmol/l (95% confidence interval: 15.0-35.6 μmol/l). A re-evaluation of published ICP meta-analysis data demonstrated no increase in spontaneous preterm birth or stillbirth in women with TSBA <19 µmol/l. CONCLUSIONS Postprandial TSBA levels are required to identify high-risk ICP pregnancies (TSBA ≥40 μmol/l). The postprandial rise in TSBA in normal pregnancy indicates that a non-fasting threshold of ≥19 µmol/l would improve diagnostic accuracy. TWEETABLE ABSTRACT Non-fasting bile acids improve the diagnostic accuracy of intrahepatic cholestasis of pregnancy diagnosis.
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Affiliation(s)
- A L Mitchell
- Department of Women and Children's Health, King's College London, Guy's Campus, London, UK
| | - C Ovadia
- Department of Women and Children's Health, King's College London, Guy's Campus, London, UK
| | - A Syngelaki
- Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital, London, UK
| | - K Souretis
- Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital, London, UK
| | - M Martineau
- Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Campus, London, UK
| | - J Girling
- Obstetrics and Gynaecology Department, West Middlesex University Hospital, Middlesex, UK
| | - T Vasavan
- Department of Women and Children's Health, King's College London, Guy's Campus, London, UK
| | - H M Fan
- Department of Women and Children's Health, King's College London, Guy's Campus, London, UK
| | - P T Seed
- Department of Women and Children's Health, King's College London, St Thomas' Campus, London, UK
| | - J Chambers
- Women's Health Research Centre, Imperial College London, London, UK
| | - Jrf Walters
- Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Campus, London, UK
| | - K Nicolaides
- Harris Birthright Research Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital, London, UK
| | - C Williamson
- Department of Women and Children's Health, King's College London, Guy's Campus, London, UK
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21
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Bhargava P, Smith MD, Mische L, Harrington E, Fitzgerald KC, Martin K, Kim S, Reyes AA, Gonzalez-Cardona J, Volsko C, Tripathi A, Singh S, Varanasi K, Lord HN, Meyers K, Taylor M, Gharagozloo M, Sotirchos ES, Nourbakhsh B, Dutta R, Mowry EM, Waubant E, Calabresi PA. Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation. J Clin Invest 2021; 130:3467-3482. [PMID: 32182223 DOI: 10.1172/jci129401] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
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Affiliation(s)
- Pavan Bhargava
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Matthew D Smith
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Leah Mische
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Emily Harrington
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Kyle Martin
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Sol Kim
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | | | - Christina Volsko
- Department of Neuroscience, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Ajai Tripathi
- Department of Neuroscience, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Sonal Singh
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Kesava Varanasi
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Hannah-Noelle Lord
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Keya Meyers
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Michelle Taylor
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Marjan Gharagozloo
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Elias S Sotirchos
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Bardia Nourbakhsh
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Ranjan Dutta
- Department of Neuroscience, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Ellen M Mowry
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
| | | | - Peter A Calabresi
- Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA
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22
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Trunz LM, Guglielmo FF, Selvarajan SK, Naringrekar HV, Alturki A, Dave JK, Mitchell DG. Biliary excretion of gadobenate dimeglumine causing degradation of magnetic resonance cholangiopancreatography (MRCP). Abdom Radiol (NY) 2021; 46:562-569. [PMID: 32743690 DOI: 10.1007/s00261-020-02686-1] [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: 06/07/2020] [Revised: 07/21/2020] [Accepted: 07/25/2020] [Indexed: 11/24/2022]
Abstract
PURPOSE To assess the effect of gadobenate dimeglumine on magnetic resonance cholangiopancreatography (MRCP) and determine an appropriate time frame for performing MRCP sequences. MATERIALS AND METHODS 2D MRCP sequences obtained after intravenous administration of gadobenate dimeglumine or gadobutrol over 14 months were reviewed retrospectively in randomized order by five abdominal radiologists, using a 3-point scale to rate biliary and pancreatic duct clarity (1 = no-, 2 = limited-, 3 = good visualization). Intraclass correlation coefficients were computed and mean scores were compared for both agents. For gadobenate dimeglumine exams, time delays between arterial phase and MRCP acquisition times were analyzed concerning duct clarity. For gadobutrol, only exams with delays ≥ 15 min were included. RESULTS 134 exams (107 gadobenate dimeglumine, 27 gadobutrol) were included. Moderate reliability for pancreatic duct visualization and excellent reliability for visualization of intrahepatic bile ducts and upper and lower extrahepatic bile ducts were noted. No difference in mean scores was noted for pancreatic duct visualization (p = 0.66). Bile duct segment scores were lower with gadobenate dimeglumine (mean: 2.1-2.6) compared with gadobutrol (mean: 2.8-2.9) (p ≤ 0.006). For gadobenate dimeglumine, visualization scores varied depending on the delay between the arterial phase and MRCP acquisition (p ≤ 0.047). Good visualization for all bile duct segments was noted with delays of 7.2-9.4 min (95% confidence interval; mean 8.3 min). CONCLUSION Bile duct clarity degraded on MRCP images with an increasing delay following gadobenate dimeglumine injection. 2D MRCP, thus, should be performed within 7.2 min after obtaining the arterial phase sequence to ensure good visualization of the entire biliary system.
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Affiliation(s)
- Lukas M Trunz
- Department of Radiology, Thomas Jefferson University Hospital, 111 S 11th Street, Philadelphia, PA, 19107, USA.
| | - Flavius F Guglielmo
- Department of Radiology, Thomas Jefferson University Hospital, 111 S 11th Street, Philadelphia, PA, 19107, USA
| | - Santosh K Selvarajan
- Department of Radiology, Thomas Jefferson University Hospital, 111 S 11th Street, Philadelphia, PA, 19107, USA
| | - Haresh V Naringrekar
- Department of Radiology, Thomas Jefferson University Hospital, 111 S 11th Street, Philadelphia, PA, 19107, USA
| | - Abdullah Alturki
- Department of Radiology, Thomas Jefferson University Hospital, 111 S 11th Street, Philadelphia, PA, 19107, USA
| | - Jaydev K Dave
- Department of Radiology, Thomas Jefferson University Hospital, 111 S 11th Street, Philadelphia, PA, 19107, USA
| | - Donald G Mitchell
- Department of Radiology, Thomas Jefferson University Hospital, 111 S 11th Street, Philadelphia, PA, 19107, USA
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23
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Howlett-Prieto Q, Langer C, Rezania K, Soliven B. Modulation of immune responses by bile acid receptor agonists in myasthenia gravis. J Neuroimmunol 2020; 349:577397. [PMID: 32979707 DOI: 10.1016/j.jneuroim.2020.577397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/13/2020] [Accepted: 09/14/2020] [Indexed: 01/13/2023]
Abstract
Bile acids bind to multiple receptors, including Takeda G protein-coupled receptor 5 (TGR5) and farnesoid-X-receptors alpha (FXRα). We compared the response of PBMCs to the activation of these receptors in healthy controls and myasthenic patients. We found that TGR5 is a more potent negative regulator of T cell cytokine response than FXRα in both groups. In contrast, TGR5 and FXRα agonists elicit distinct B cell responses in myasthenia compared to controls, specifically on the frequency of IL-6+ B cells and regulatory B cells, as well as IL-10 secretion from PBMCs. We propose that TGR5 is a potential therapeutic target in myasthenia.
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Affiliation(s)
- Quentin Howlett-Prieto
- Department of Neurology, The University of Chicago, Chicago, IL 60637, United States of America
| | - Collin Langer
- Department of Neurology, The University of Chicago, Chicago, IL 60637, United States of America
| | - Kourosh Rezania
- Department of Neurology, The University of Chicago, Chicago, IL 60637, United States of America
| | - Betty Soliven
- Department of Neurology, The University of Chicago, Chicago, IL 60637, United States of America.
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24
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Sumi K, Osada K, Sakuda M, Ashida K, Nakazato K. Fermented milk retains beneficial effects on skeletal muscle protein anabolism after processing by centrifugation and supernatant removal. J Dairy Sci 2020; 104:1336-1350. [PMID: 33246620 DOI: 10.3168/jds.2020-18780] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/28/2020] [Indexed: 12/25/2022]
Abstract
Lactobacillus-fermented milk can stimulate anabolic effects in skeletal muscle. Fermented milk containing Lactobacillus produces aqueous molecules, such as free AA and lactate. This study aimed to investigate how processing fermented milk by centrifugation and removal of supernatant affects AA absorption and postprandial skeletal muscle protein synthesis (MPS) when mice are fed fermented milk. We gavaged male Sprague-Dawley rats with skim milk (S), fermented milk (F), or processed fermented milk (P), and examined the total AA content in portal vein blood (reflecting AA absorption) and plantaris muscle MPS at 30, 60, and 90 min following administration. Relative to fasted rats, at 30 min the total AA concentration in portal vein blood from rats in the P groups was significantly higher, followed by F and S, respectively. The MPS rates were higher for the F or P groups compared with the S group. Phosphorylation levels of p70S6 kinase in the P and F groups were significantly higher than those for the S group 30 min after administration, although the level of Akt phosphorylation was similar among the groups. These results suggested that fermentation improves AA absorption that in turn enhances postprandial MPS via Akt-independent mechanisms, and that processed fermented milk retains these favorable effects on MPS.
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Affiliation(s)
- K Sumi
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co. Ltd., 1-29-1 Nanakuni, Hachiouji, Tokyo 192-0919, Japan.
| | - K Osada
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co. Ltd., 1-29-1 Nanakuni, Hachiouji, Tokyo 192-0919, Japan
| | - M Sakuda
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co. Ltd., 1-29-1 Nanakuni, Hachiouji, Tokyo 192-0919, Japan
| | - K Ashida
- Food Microbiology and Function Research Laboratories, R&D Division, Meiji Co. Ltd., 1-29-1 Nanakuni, Hachiouji, Tokyo 192-0919, Japan
| | - K Nakazato
- Department of Exercise Physiology, Nippon Sport Science University, 7-1-1 Fukasawa, Setagaya-ku, Tokyo, Japan
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25
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Distinct Postprandial Bile Acids Responses to a High-Calorie Diet in Men Volunteers Underscore Metabolically Healthy and Unhealthy Phenotypes. Nutrients 2020; 12:nu12113545. [PMID: 33228154 PMCID: PMC7699492 DOI: 10.3390/nu12113545] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/10/2020] [Accepted: 11/18/2020] [Indexed: 12/30/2022] Open
Abstract
Bile acids (BAs) regulate dietary lipid hydrolysis and absorption in the proximal intestine. Several studies have highlighted a determinant role of circulating levels and/or metabolism of BAs in the pathogenesis of major cardiometabolic diseases. Whether changes in BA profiles are causative or are consequence of these diseases remains to be determined. Healthy male volunteers (n = 71) underwent a postprandial exploration following consumption of a hypercaloric high fat typical Western meal providing 1200 kcal. We investigated variations of circulating levels of 28 BA species, together with BA synthesis marker 7α-hydroxy-4-cholesten-3-one (C4) over an approximately diurnal 12 h period. Analysis of BA variations during the postprandial time course revealed two major phenotypes with opposite fluctuations, i.e., circulating levels of each individual species of unconjugated BAs were reduced after meal consumption whereas those of tauro- and glyco-conjugated BAs were increased. By an unbiased classification strategy based on absolute postprandial changes in BA species levels, we classified subjects into three distinct clusters; the two extreme clusters being characterized by the smallest absolute changes in either unconjugated-BAs or conjugated-BAs. Finally, we demonstrated that our clustering based on postprandial changes in BA profiles was associated with specific clinical and biochemical features, including postprandial triglyceride levels, BMI or waist circumference. Altogether, our study reveals that postprandial profiles/patterns of BAs in response to a hypercaloric high fat challenge is associated with healthy or unhealthy metabolic phenotypes that may help in the early identification of subjects at risk of developing metabolic disorders.
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26
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Bile Acids: A Communication Channel in the Gut-Brain Axis. Neuromolecular Med 2020; 23:99-117. [PMID: 33085065 DOI: 10.1007/s12017-020-08625-z] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/08/2020] [Indexed: 02/08/2023]
Abstract
Bile acids are signalling hormones involved in the regulation of several metabolic pathways. The ability of bile acids to bind and signal through their receptors is modulated by the gut microbiome, since the microbiome contributes to the regulation and synthesis of bile acids as well to their physiochemical properties. From the gut, bacteria have been shown to send signals to the central nervous system via their metabolites, thus affecting the behaviour and brain function of the host organism. In the last years it has become increasingly evident that bile acids affect brain function, during normal physiological and pathological conditions. Although bile acids may be synthesized locally in the brain, the majority of brain bile acids are taken up from the systemic circulation. Since the composition of the brain bile acid pool may be regulated by the action of intestinal bacteria, it is possible that bile acids function as a communication bridge between the gut microbiome and the brain. However, little is known about the molecular mechanisms and the physiological roles of bile acids in the central nervous system. The possibility that bile acids may be a direct link between the intestinal microbiome and the brain is also an understudied subject. Here we review the influence of gut bacteria on the bile acid pool composition and properties, as well as striking evidence showing the role of bile acids as neuroactive molecules.
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27
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Hepatic Bile Acid Reuptake in the Rat Depends on Bile Acid Conjugation but Not on Agonistic Properties towards FXR and TGR5. Molecules 2020; 25:molecules25102371. [PMID: 32443832 PMCID: PMC7288213 DOI: 10.3390/molecules25102371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/25/2020] [Accepted: 05/13/2020] [Indexed: 11/24/2022] Open
Abstract
Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are the two known bile acid (BA) sensitive receptors and are expressed in the intestine and liver as well as in extra-enterohepatic tissues. The physiological effects of extra-enterohepatic FXR/TRG5 remain unclear. Further, the extent BAs escape liver reabsorption and how they interact with extra-enterohepatic FXR/TGR5 is understudied. We investigated if hepatic BA reuptake differed between BAs agonistic for FXR and TGR5 compared to non-agonists in the rat. Blood was collected from the portal vein and inferior caval vein from anesthetized rats before and 5, 20, 30, and 40 min post stimulation with sulfated cholecystokinin-8. Plasma concentrations of 20 different BAs were assessed by liquid chromatography coupled to mass spectrometry. Total portal vein BA AUC was 3–4 times greater than in the vena cava inferior (2.7 ± 0.6 vs. 0.7 ± 0.2 mM x min, p < 0.01, n = 8) with total unconjugated BAs being 2–3-fold higher than total conjugated BAs (AUC 8–10 higher p < 0.05 for both). However, in both cases, absolute ratios varied greatly among different BAs. The average hepatic reuptake of BAs agonistic for FXR/TGR5 was similar to non-agonists. However, as the sum of non-agonist BAs in vena portae was 2–3-fold higher than the sum agonist (p < 0.05), the peripheral BA pool was composed mostly of non-agonist BAs. We conclude that hepatic BA reuptake varies substantially by type and does not favor FXR/TGR5 BAs agonists.
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28
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Johansson H, Svensson JF, Almström M, Van Hul N, Rudling M, Angelin B, Nowak G, Fischler B, Ellis E. Regulation of bile acid metabolism in biliary atresia: reduction of FGF19 by Kasai portoenterostomy and possible relation to early outcome. J Intern Med 2020; 287:534-545. [PMID: 31976601 DOI: 10.1111/joim.13028] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Fibroblast growth factor 19 (FGF19) is produced in the small intestine and is involved in suppression of hepatic bile acid (BA) synthesis. FGF19 is also expressed in the liver and serum levels are elevated in adults with cholestatic liver disease. This may reflect a rescue mechanism to dampen liver injury caused by increased intrahepatic BAs. OBJECTIVES To examine circulating FGF19 at early stages of biliary atresia and at short-term follow-up post-Kasai portoenterostomy (KPE) in relation to noncholestatic infants. The relationship between FGF19, BAs and markers for BA synthesis and hepatic gene expression of factors involved in BA metabolism were also evaluated. METHODS Liver tissue, portal and peripheral blood samples were obtained from fifteen patients at KPE; additional blood was collected 4-6 months after surgery. Two control groups were included; to examine possible changes related to surgery and to compare FGF19 in biliary atresia to noncholestatic infants. RESULTS Circulating FGF19 levels correlated to its hepatic gene expression at time of KPE in biliary atresia and levels were elevated compared to noncholestatic infants. At follow-up, FGF19 levels were markedly reduced, and the decline coincided with reductions in bilirubin and conjugated chenodeoxycholic acid and with increased levels of the BA synthesis marker C4. CONCLUSION Elevated circulating FGF19 in biliary atresia is of hepatic origin and reduced following KPE. Changes in serum FGF19 may reflect the level of restoration of the enterohepatic circulation, and this warrants further long-term studies on the role of FGF19 in the cholestatic liver.
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Affiliation(s)
- H Johansson
- From the, Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.,Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - J F Svensson
- Division of Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - M Almström
- Division of Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - N Van Hul
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - M Rudling
- Unit for Metabolism, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - B Angelin
- Unit for Metabolism, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - G Nowak
- From the, Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.,Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - B Fischler
- Division of Paediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.,Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden
| | - E Ellis
- From the, Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.,Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden
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29
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Eiken A, Fuglsang S, Eiken M, Svane MS, Kuhre RE, Wewer Albrechtsen NJ, Hansen SH, Trammell SAJ, Svenningsen JS, Rehfeld JF, Bojsen-Møller KN, Jørgensen NB, Holst JJ, Madsbad S, Madsen JL, Dirksen C. Bilio-enteric flow and plasma concentrations of bile acids after gastric bypass and sleeve gastrectomy. Int J Obes (Lond) 2020; 44:1872-1883. [PMID: 32317753 DOI: 10.1038/s41366-020-0578-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 03/04/2020] [Accepted: 03/27/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND/OBJECTIVES Bile acids in plasma are elevated after bariatric surgery and may contribute to metabolic improvements, but underlying changes in bile flow are poorly understood. We assessed bilio-enteric flow of bile and plasma bile concentrations in individuals with Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with matched non-surgical controls (CON). SUBJECTS/METHODS Fifteen RYGB, 10 SG and 15 CON underwent 99Tc-mebrofenin cholescintigraphy combined with intake of a high-fat 111In-DTPA-labelled meal and frequent blood sampling. A 75Se-HCAT test was used to assess bile acid retention. RESULTS After RYGB, gallbladder filling was decreased (p = 0.045 versus CON), basal flow of bile into the small intestine increased (p = 0.005), bile acid retention augmented (p = 0.021) and basal bile acid plasma concentrations elevated (p = 0.009). During the meal, foods passed unimpeded through the gastric pouch resulting in almost instant postprandial mixing of bile and foods, but the postprandial rise in plasma bile acids was brief and associated with decreased overall release of fibroblast growth factor-19 (FGF-19) compared with CON (p = 0.033). After SG, bile flow and retention were largely unaltered (p > 0.05 versus CON), but gastric emptying was accelerated (p < 0.001) causing earlier mixture of bile and foods also in this group. Neither basal nor postprandial bile acid concentrations differed between SG and CON. CONCLUSIONS Bilio-enteric bile flow is markedly altered after RYGB resulting in changes in plasma concentrations of bile acids and FGF-19, whereas bile flow and plasma concentrations are largely unaltered after SG.
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Affiliation(s)
- Aleksander Eiken
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| | - Stefan Fuglsang
- Department of Clinical Physiology and Nuclear Medicine, Centre for Functional Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark
| | - Markus Eiken
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| | - Maria S Svane
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| | - Rune E Kuhre
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai J Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department. of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Svend H Hansen
- Department. of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Samuel A J Trammell
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens S Svenningsen
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department. of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | | | - Nils B Jørgensen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| | - Jens J Holst
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark
| | - Jan L Madsen
- Department of Clinical Physiology and Nuclear Medicine, Centre for Functional Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark
| | - Carsten Dirksen
- Department of Endocrinology, Hvidovre Hospital, Hvidovre, Denmark.
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30
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Villette R, Kc P, Beliard S, Salas Tapia MF, Rainteau D, Guerin M, Lesnik P. Unraveling Host-Gut Microbiota Dialogue and Its Impact on Cholesterol Levels. Front Pharmacol 2020; 11:278. [PMID: 32308619 PMCID: PMC7145900 DOI: 10.3389/fphar.2020.00278] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 02/26/2020] [Indexed: 12/12/2022] Open
Abstract
Disruption in cholesterol metabolism, particularly hypercholesterolemia, is a significant cause of atherosclerotic cardiovascular disease. Large interindividual variations in plasma cholesterol levels are traditionally related to genetic factors, and the remaining portion of their variance is accredited to environmental factors. In recent years, the essential role played by intestinal microbiota in human health and diseases has emerged. The gut microbiota is currently viewed as a fundamental regulator of host metabolism and of innate and adaptive immunity. Its bacterial composition but also the synthesis of multiple molecules resulting from bacterial metabolism vary according to diet, antibiotics, drugs used, and exposure to pollutants and infectious agents. Microbiota modifications induced by recent changes in the human environment thus seem to be a major factor in the current epidemic of metabolic/inflammatory diseases (diabetes mellitus, liver diseases, inflammatory bowel disease, obesity, and dyslipidemia). Epidemiological and preclinical studies report associations between bacterial communities and cholesterolemia. However, such an association remains poorly investigated and characterized. The objectives of this review are to present the current knowledge on and potential mechanisms underlying the host-microbiota dialogue for a better understanding of the contribution of microbial communities to the regulation of cholesterol homeostasis.
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Affiliation(s)
- Remy Villette
- INSERM, UMRS U1166, "Integrative Biology of Atherosclerosis" and Sorbonne Université, Paris, France
| | - Pukar Kc
- INSERM, UMRS U1166, "Integrative Biology of Atherosclerosis" and Sorbonne Université, Paris, France
| | - Sophie Beliard
- Aix-Marseille Université, INSERM U1263, INRA, C2VN, Marseille, France.,APHM, La Conception Hospital, Marseille, France
| | | | - Dominique Rainteau
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint Antoine, Département de Métabolomique Clinique, Paris, France
| | - Maryse Guerin
- INSERM, UMRS U1166, "Integrative Biology of Atherosclerosis" and Sorbonne Université, Paris, France
| | - Philippe Lesnik
- INSERM, UMRS U1166, "Integrative Biology of Atherosclerosis" and Sorbonne Université, Paris, France
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31
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Voronova V, Sokolov V, Al-Khaifi A, Straniero S, Kumar C, Peskov K, Helmlinger G, Rudling M, Angelin B. A Physiology-Based Model of Bile Acid Distribution and Metabolism Under Healthy and Pathologic Conditions in Human Beings. Cell Mol Gastroenterol Hepatol 2020; 10:149-170. [PMID: 32112828 PMCID: PMC7240226 DOI: 10.1016/j.jcmgh.2020.02.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 02/19/2020] [Accepted: 02/19/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Disturbances of the enterohepatic circulation of bile acids (BAs) are seen in a number of clinically important conditions, including metabolic disorders, hepatic impairment, diarrhea, and gallstone disease. To facilitate the exploration of underlying pathogenic mechanisms, we developed a mathematical model built on quantitative physiological observations across different organs. METHODS The model consists of a set of kinetic equations describing the syntheses of cholic, chenodeoxycholic, and deoxycholic acids, as well as time-related changes of their respective free and conjugated forms in the systemic circulation, the hepatoportal region, and the gastrointestinal tract. The core structure of the model was adapted from previous modeling research and updated based on recent mechanistic insights, including farnesoid X receptor-mediated autoregulation of BA synthesis and selective transport mechanisms. The model was calibrated against existing data on BA distribution and feedback regulation. RESULTS According to model-based predictions, changes in intestinal motility, BA absorption, and biotransformation rates affected BA composition and distribution differently, as follows: (1) inhibition of transintestinal BA flux (eg, in patients with BA malabsorption) or acceleration of intestinal motility, followed by farnesoid X receptor down-regulation, was associated with colonic BA accumulation; (2) in contrast, modulation of the colonic absorption process was predicted to not affect the BA pool significantly; and (3) activation of ileal deconjugation (eg, in patents with small intestinal bacterial overgrowth) was associated with an increase in the BA pool, owing to higher ileal permeability of unconjugated BA species. CONCLUSIONS This model will be useful in further studying how BA enterohepatic circulation modulation may be exploited for therapeutic benefits.
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Affiliation(s)
- Veronika Voronova
- Department of Pharmacological Modeling, M&S Decisions, Moscow, Russia,Correspondence Address correspondence to: Veronika Voronova, M&S Decisions 125167, Naryshkinskaya Alley, 5, Building 1, Moscow, Russian Federation. fax: +7(495)7975535.
| | - Victor Sokolov
- Department of Pharmacological Modeling, M&S Decisions, Moscow, Russia
| | - Amani Al-Khaifi
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden,Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden,Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Sara Straniero
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden,Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Chanchal Kumar
- Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden,Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden
| | - Kirill Peskov
- Department of Pharmacological Modeling, M&S Decisions, Moscow, Russia,Computational Oncology Group, Sechenov First Moscow State Medical University of the Russian Ministry of Health, Moscow, Russia
| | - Gabriel Helmlinger
- Clinical Pharmacology and Safety Sciences, BioPharmaceuticals Research and Development, AstraZeneca, Boston, Massachusetts
| | - Mats Rudling
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden,Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Bo Angelin
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden,Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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Johansson H, Søndergaard JN, Jorns C, Kutter C, Ellis ECS. Chenodeoxycholic Acid Modulates Bile Acid Synthesis Independent of Fibroblast Growth Factor 19 in Primary Human Hepatocytes. Front Endocrinol (Lausanne) 2020; 11:554922. [PMID: 33692750 PMCID: PMC7937932 DOI: 10.3389/fendo.2020.554922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 12/14/2020] [Indexed: 12/27/2022] Open
Abstract
Bile acids (BAs) are detergents essential for intestinal absorption of lipids. Disruption of BA homeostasis can lead to severe liver damage. BA metabolism is therefore under strict regulation by sophisticated feedback mechanisms. The hormone-like protein Fibroblast growth factor 19 (FGF19) is essential for maintaining BA homeostasis by down regulating BA synthesis. Here, the impact of both FGF19 and chenodeoxycholic acid (CDCA) on primary human hepatocytes was investigated and a possible autocrine/paracrine function of FGF19 in regulation of BA synthesis evaluated. Primary human hepatocytes were treated with CDCA, recombinant FGF19 or conditioned medium containing endogenously produced FGF19. RNA sequencing revealed that treatment with CDCA causes deregulation of transcripts involved in BA metabolism, whereas treatment with FGF19 had minor effects. CDCA increased FGF19 mRNA expression within 1 h. We detected secretion of the resulting FGF19 protein into medium, mimicking in vivo observations. Furthermore, medium enriched with endogenously produced FGF19 reduced BA synthesis by down regulating CYP7A1 gene expression. However, following knockdown of FGF19, CDCA still independently decreased BA synthesis, presumably through the regulatory protein small heterodimer partner (SHP). In summary, we show that in primary human hepatocytes CDCA regulates BA synthesis in an FGF19-independent manner.
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Affiliation(s)
- Helene Johansson
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Nørskov Søndergaard
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Carl Jorns
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Claudia Kutter
- Science for Life Laboratory, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Ewa C. S. Ellis
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden
- *Correspondence: Ewa C. S. Ellis,
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Ahmad TR, Haeusler RA. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nat Rev Endocrinol 2019; 15:701-712. [PMID: 31616073 PMCID: PMC6918475 DOI: 10.1038/s41574-019-0266-7] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/11/2019] [Indexed: 12/12/2022]
Abstract
Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research.
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Affiliation(s)
- Tiara R Ahmad
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
| | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY, USA.
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
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Li W, Shu S, Cheng L, Hao X, Wang L, Wu Y, Yuan Z, Zhou J. Fasting serum total bile acid level is associated with coronary artery disease, myocardial infarction and severity of coronary lesions. Atherosclerosis 2019; 292:193-200. [PMID: 31811964 DOI: 10.1016/j.atherosclerosis.2019.11.026] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 11/17/2019] [Accepted: 11/27/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Bile acids play important roles in lipid metabolism. Several studies have found that patients with coronary artery disease (CAD) have lower bile acid fecal excretion compared to individuals without CAD. However, few studies have focused on the roles of more accessible serum total bile acids (TBA) in the progression of CAD. The aim of this study was to explore the potential relationship between fasting serum TBA and the presence of CAD, myocardial infarction (MI) and severity of coronary lesions. METHODS A total of 7438 consecutive patients with suspected CAD, who had undergone coronary angiography, were enrolled. The severity of coronary lesions was evaluated using the Gensini score (GS). The relationships between fasting serum TBA and the presence and severity of CAD were evaluated. RESULTS CAD patients had lower serum TBA than individuals without CAD, and patients with MI had lower TBA than those without CAD. Spline analyses showed an L-shaped relationship of the fasting serum TBA with the presence and severity of CAD, and the breakpoint approximated the normal upper limit (10 μmol/L). A lower TBA concentration (less than the median 3.6 μmol/L) was independently and significantly associated with the presence and severity of CAD, especially for the presence of MI (odds ratios 2.04, 95% confidence interval (1.71-2.44), C-index 0.9269). CONCLUSIONS Fasting serum TBA level is highly associated with the presence and severity of CAD in patients undergoing coronary angiography for suspected CAD.
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Affiliation(s)
- Wenyuan Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shan Shu
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lele Cheng
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiang Hao
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Lijun Wang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yue Wu
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zuyi Yuan
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.
| | - Juan Zhou
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an, Shaanxi, China.
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35
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Kaddurah-Daouk R, Hankemeier T, Scholl EH, Baillie R, Harms A, Stage C, Dalhoff KP, Jűrgens G, Taboureau O, Nzabonimpa GS, Motsinger-Reif AA, Thomsen R, Linnet K, Rasmussen HB. Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2019; 7:525-533. [PMID: 30169917 PMCID: PMC6118295 DOI: 10.1002/psp4.12309] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 04/17/2018] [Indexed: 12/29/2022]
Abstract
Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value = 0.001) and a phosphatidylcholine (q value = 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value = 0.040) and several high polyunsaturated fatty acid lipids (PUFAs). The half‐maximal inhibitory concentration (IC50) values of chenodeoxycholate and taurocholate were 13.55 and 19.51 μM, respectively, consistent with a physiological significance. In silico analysis suggested that bile acid inhibition of CES1 involved both binding to the active and superficial sites of the enzyme. We initiated identification of metabolites predicting PKs of drugs metabolized by CES1 and suggest lipids to regulate or be regulated by this enzyme.
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Affiliation(s)
- Rima Kaddurah-Daouk
- Duke Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA.,Duke Institute for Brain Sciences, Duke University, Durham, North Carolina, USA
| | - Thomas Hankemeier
- Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.,Netherlands Metabolomics Centre, Leiden, The Netherlands
| | - Elizabeth H Scholl
- Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA
| | | | - Amy Harms
- Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands.,Netherlands Metabolomics Centre, Leiden, The Netherlands
| | - Claus Stage
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Frederiksberg, Denmark
| | - Kim P Dalhoff
- Department of Clinical Pharmacology, Bispebjerg and Frederiksberg University Hospital, Frederiksberg, Denmark
| | - Gesche Jűrgens
- Clinical Pharmacological Unit, Zealand University Hospital, Roskilde, Denmark
| | - Olivier Taboureau
- INSERM, UMRS 973, MTi, Université Paris Diderot, Paris Cedex, France
| | - Grace S Nzabonimpa
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark
| | - Alison A Motsinger-Reif
- Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.,Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA
| | - Ragnar Thomsen
- Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Kristian Linnet
- Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Henrik B Rasmussen
- Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark.,Department of Science and Environment, Roskilde University, Roskilde, Denmark
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Baier V, Cordes H, Thiel C, Castell JV, Neumann UP, Blank LM, Kuepfer L. A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients. Front Physiol 2019; 10:1192. [PMID: 31611804 PMCID: PMC6777137 DOI: 10.3389/fphys.2019.01192] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 09/03/2019] [Indexed: 12/23/2022] Open
Abstract
Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.
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Affiliation(s)
- Vanessa Baier
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany.,Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Henrik Cordes
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - Christoph Thiel
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - José V Castell
- Unit of Experimental Hepatology, IIS Hospital La Fe, Faculty of Medicine, University of Valencia and CIBEREHD, Valencia, Spain
| | - Ulf P Neumann
- Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Lars M Blank
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - Lars Kuepfer
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
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Chen Y, Lu J, Nemati R, Plank LD, Murphy R. Acute Changes of Bile Acids and FGF19 After Sleeve Gastrectomy and Roux-en-Y Gastric Bypass. Obes Surg 2019; 29:3605-3621. [PMID: 31273649 DOI: 10.1007/s11695-019-04040-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CONTEXT Gastric bypass (GBP) and sleeve gastrectomy (SG) are both effective bariatric treatments that cause sustained weight loss as well as improvement of type 2 diabetes mellitus (T2DM). The underlying mechanisms are under investigation, including the contribution of alterations in bile acids (BAs) in achieving or maintaining the beneficial metabolic effects after bariatric surgery. AIMS The aim of this study is to investigate the acute and short-term effects of GBP and SG on BA compositions and fibroblast growth factor 19 (FGF19) in obese individuals with T2DM and to evaluate any correlations between changes in these measures with glucose metabolic improvements. METHODS The levels of both fasting and postprandial plasma BA compositions after oral glucose tolerance test (OGTT), fasting FGF19 and various metabolic indices were measured 1 day before and at 3 days and 3 months after GBP and SG in 19 obese patients (GBP = 8, SG = 11) with T2DM. RESULTS Body weight loss was observed after both GBP and SG 3 months post-operatively, with no significant difference between the two intervention groups (15.0 ± 3.1% vs. 13.9 ± 5.2%, P = 0.761). At 3 days post-operation, FGF19 levels increased significantly in both surgery groups (GBP, 118.3 ± 57.3 vs. 363.6 ± 131.0 pg mL-1, post-operation P = 0.008; SG, 173.2 ± 127.8 vs. 422.0 ± 243.6 pg mL-1, post-operation P = 0.001). Fasting and postprandial increases from pre-operative values in secondary (r = 0.57, P = 0.02; r = 0.58, P = 0.01), conjugated (r = 0.50, P = 0.01; r = 0.48, P = 0.04), glycine-conjugated (r = 0.52, P = 0.05; r = 0.46, P = 0.05) and secondary-conjugated (r = 0.53, P = 0.02; r = 0.60, P = 0.01) BAs correlated with decreases in the postprandial states of glucose (defined by area under the curve (AUC) over 120 min (AUC0-120min)). Increases in postprandial primary-conjugated BAs were found to be associated with decreases in HOMA-IR (r = 0.45, P = 0.05). However, increases in fasting and postprandial taurine-conjugated BA correlated with decreases in both basal insulin secretion rate (r = 0.47, P = 0.04; r = 0.48, P = 0.04) and C-peptide level (r = 0.45, P = 0.05; r = 0.47, P = 0.04). After 3 months, fasting and postprandial increases in secondary (r = 0.51, P = 0.03; r = 0.48, P = 0.04), secondary-conjugated (r = 0.52, P = 0.02; r = 0.51, P = 0.03) and non-12α-OH (r = 0.51, P = 0.02; r = 0.58, P = 0.01) BAs were found to correlate with increases in Stumvoll Insulin Sensitivity Index. Increases in both fasting and postprandial 12α-OH BAs were correlated with the decreases in glucose AUC (r = 0.46, P = 0.05; r = 0.41, P = 0.04). CONCLUSIONS Both GBP and SG achieve increases in many BA species as early as 3 days post-operation, which are sustained at 3 months post-operation. Rises in secondary BA and conjugated forms are correlated with early improvements in glucose metabolism at 3 days post-operation. These along with 12α-OH BA correlated with improved glucose metabolism at 3 months post-operation, suggesting they may contribute to the observed T2DM remission after bariatric surgery.
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Affiliation(s)
- Yutao Chen
- College of Life and Marine Sciences, Shenzhen University, Shenzhen, Guangdong Province, China.,School of Science and School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Private Bag 92006, Auckland, 1142, New Zealand
| | - Jun Lu
- College of Life and Marine Sciences, Shenzhen University, Shenzhen, Guangdong Province, China. .,School of Science and School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Private Bag 92006, Auckland, 1142, New Zealand. .,Institute of Biomedical Technology, Auckland University of Technology, Private Bag 92006, Auckland, 1142, New Zealand. .,College of Food Engineering and Nutrition Sciences, Shaanxi Normal University, Xi'an, 710119, China.
| | - Reza Nemati
- School of Science and School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Private Bag 92006, Auckland, 1142, New Zealand
| | - Lindsay D Plank
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Rinki Murphy
- Auckland Diabetes Centre, Auckland District Health Board, Auckland, New Zealand. .,Whitiora Diabetes Department, Counties Manukau District Health Board, Auckland, New Zealand. .,Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. .,Maurice Wilkins Centre for Biodiscovery, Auckland, New Zealand.
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Christiansen CB, Trammell SAJ, Wewer Albrechtsen NJ, Schoonjans K, Albrechtsen R, Gillum MP, Kuhre RE, Holst JJ. Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents. Am J Physiol Gastrointest Liver Physiol 2019; 316:G574-G584. [PMID: 30767682 DOI: 10.1152/ajpgi.00010.2019] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrate that BAs represent a major physiological stimulus for colonic L-cell secretion. NEW & NOTEWORTHY By the use of isolated perfused rodent colon preparations we show that bile acids are potent and direct promoters of colonic glucagon-like-peptide 1 and peptide-YY secretion. The study provides convincing evidence that basolateral Takeda-G protein-coupled-receptor 5 activation is mediating the effects of bile acids in the colon and thus add to the existing literature described for L cells in the ileum.
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Affiliation(s)
- Charlotte Bayer Christiansen
- Novo Nordic Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Samuel Addison Jack Trammell
- Novo Nordic Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Nicolai Jacob Wewer Albrechtsen
- Novo Nordic Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Department of Clinical Biochemistry, Rigshospitalet, Copenhagen , Denmark.,Clinical Proteomics, Novo Nordic Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne , Switzerland
| | - Reidar Albrechtsen
- Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Matthew Paul Gillum
- Novo Nordic Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Rune Ehrenreich Kuhre
- Novo Nordic Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
| | - Jens Juul Holst
- Novo Nordic Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark
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39
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Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP. Systemic bile acids induce insulin resistance in a TGR5-independent manner. Am J Physiol Endocrinol Metab 2019; 316:E782-E793. [PMID: 30779633 PMCID: PMC6732652 DOI: 10.1152/ajpendo.00362.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 02/04/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023]
Abstract
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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Affiliation(s)
- Kristen E Syring
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
| | - Travis J Cyphert
- Department of Biological Sciences, Marshall University College of Science, Huntington, West Virginia
| | - Thomas C Beck
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center , Nashville, Tennessee
| | - Nicholas A Mignemi
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
| | - Owen P McGuinness
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine , Nashville, Tennessee
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40
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Abstract
Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here, the basic chemistry and regulation of bile acids as well as their metabolic effects will be reviewed. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined.
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Affiliation(s)
- Emma Rose McGlone
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - Stephen R Bloom
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
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41
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Donkers JM, Roscam Abbing RLP, van de Graaf SFJ. Developments in bile salt based therapies: A critical overview. Biochem Pharmacol 2018; 161:1-13. [PMID: 30582898 DOI: 10.1016/j.bcp.2018.12.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 12/20/2018] [Indexed: 01/06/2023]
Abstract
Bile acids, amphipathic molecules known for their facilitating role in fat absorption, are also recognized as signalling molecules acting via nuclear and membrane receptors. Of the bile acid-activated receptors, the Farnesoid X Receptor (FXR) and the G protein-coupled bile acid receptor-1 (Gpbar1 or TGR5) have been studied most extensively. Bile acid signaling is critical in the regulation of bile acid metabolism itself, but it also plays a significant role in glucose, lipid and energy metabolism. Activation of FXR and TGR5 leads to reduced hepatic bile salt load, improved insulin sensitivity and glucose regulation, increased energy expenditure, and anti-inflammatory effects. These beneficial effects render bile acid signaling an interesting therapeutic target for the treatment of diseases such as cholestasis, non-alcoholic fatty liver disease, and diabetes. Here, we summarize recent findings on bile acid signaling and discuss potential and current limitations of bile acid receptor agonist and modulators of bile acid transport as future therapeutics for a wide-spectrum of diseases.
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Affiliation(s)
- Joanne M Donkers
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands
| | - Reinout L P Roscam Abbing
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands
| | - Stan F J van de Graaf
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands.
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42
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Al-Khaifi A, Straniero S, Voronova V, Chernikova D, Sokolov V, Kumar C, Angelin B, Rudling M. Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism. J Intern Med 2018; 284:546-559. [PMID: 29964306 DOI: 10.1111/joim.12811] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans. METHODS Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied. RESULTS Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine. CONCLUSIONS Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.
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Affiliation(s)
- A Al-Khaifi
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.,Department of Medicine, Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Novum, Stockholm, Sweden.,Department of Biochemistry, College of Medicine, Sultan Qaboos University, Muscat 123, Oman
| | - S Straniero
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.,Department of Medicine, Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Novum, Stockholm, Sweden
| | | | | | | | - C Kumar
- Department of Medicine, Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Novum, Stockholm, Sweden.,Translational Sciences, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - B Angelin
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.,Department of Medicine, Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Novum, Stockholm, Sweden
| | - M Rudling
- Metabolism Unit, Endocrinology, Metabolism and Diabetes, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.,Department of Medicine, Karolinska Institutet/AstraZeneca Integrated CardioMetabolic Center (KI/AZ ICMC), Novum, Stockholm, Sweden
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43
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van Niekerk G, Davis T, de Villiers W, Engelbrecht AM. The role of bile acids in nutritional support. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2018; 22:231. [PMID: 30268137 PMCID: PMC6164178 DOI: 10.1186/s13054-018-2160-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 08/13/2018] [Indexed: 12/13/2022]
Abstract
Nutritional support continues to receive much attention as a possible intervention to prevent loss of lean tissue mass, promote recovery and re-establish proper immune function in critical care patients. Yet there remains much controversy regarding the clinical efficacy of such interventions. In addition to the direct effect of nutrition in terms of micro- and macronutrient content, nutritional formulations may exert an effect via the physiological response to feeding. Here, we highlight the key role of postprandial reabsorbed bile acids in attenuating both the inflammatory response and autophagy. These observations suggest that not all patients would benefit from aggressive nutritional support.
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Affiliation(s)
- Gustav van Niekerk
- Stellenbosch University, Stellenbosch Central, Stellenbosch, 7599, South Africa.
| | - Tanja Davis
- Stellenbosch University, Stellenbosch Central, Stellenbosch, 7599, South Africa
| | - Willem de Villiers
- Stellenbosch University, Stellenbosch Central, Stellenbosch, 7599, South Africa
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44
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Jackson JP, Freeman KM, St. Claire RL, Black CB, Brouwer KR. Cholestatic Drug Induced Liver Injury: A Function of Bile Salt Export Pump Inhibition and Farnesoid X Receptor Antagonism. ACTA ACUST UNITED AC 2018. [DOI: 10.1089/aivt.2018.0011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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45
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Guiastrennec B, Sonne DP, Bergstrand M, Vilsbøll T, Knop FK, Karlsson MO. Model-Based Prediction of Plasma Concentration and Enterohepatic Circulation of Total Bile Acids in Humans. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2018; 7:603-612. [PMID: 30070437 PMCID: PMC6157686 DOI: 10.1002/psp4.12325] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/12/2018] [Indexed: 12/11/2022]
Abstract
Bile acids released postprandially can modify the rate and extent of lipophilic compounds' absorption. This study aimed to predict the enterohepatic circulation (EHC) of total bile acids (TBAs) in response to caloric intake from their spillover in plasma. A model for TBA EHC was combined with a previously developed gastric emptying (GE) model. Longitudinal gallbladder volumes and TBA plasma concentration data from 30 subjects studied after ingestion of four different test drinks were supplemented with literature data. Postprandial gallbladder refilling periods were implemented to improve model predictions. The TBA hepatic extraction was reduced with the high-fat drink. Basal and nutrient-induced gallbladder emptying rates were altered by type 2 diabetes (T2D). The model was predictive of the central trend and the variability of gallbladder volume and TBA plasma concentration for all test drinks. Integration of this model within physiological pharmacokinetic modeling frameworks could improve the predictions for lipophilic compounds' absorption considerably.
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Affiliation(s)
| | - David P Sonne
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.,Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark
| | - Martin Bergstrand
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.,Pharmetheus AB, Uppsala, Sweden
| | - Tina Vilsbøll
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mats O Karlsson
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
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46
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Eggink HM, van Nierop FS, Schooneman MG, Boelen A, Kalsbeek A, Koehorst M, ten Have GA, de Brauw LM, Groen AK, Romijn JA, Deutz NE, Soeters MR. Transhepatic bile acid kinetics in pigs and humans. Clin Nutr 2018; 37:1406-1414. [DOI: 10.1016/j.clnu.2017.06.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/13/2017] [Accepted: 06/13/2017] [Indexed: 01/06/2023]
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47
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Enright EF, Griffin BT, Gahan CG, Joyce SA. Microbiome-mediated bile acid modification: Role in intestinal drug absorption and metabolism. Pharmacol Res 2018; 133:170-186. [DOI: 10.1016/j.phrs.2018.04.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 04/07/2018] [Accepted: 04/12/2018] [Indexed: 01/03/2023]
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48
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Johansson H, Mörk LM, Li M, Sandblom AL, Björkhem I, Höijer J, Ericzon BG, Jorns C, Gilg S, Sparrelid E, Isaksson B, Nowak G, Ellis E. Circulating Fibroblast Growth Factor 19 in Portal and Systemic Blood. J Clin Exp Hepatol 2018; 8:162-168. [PMID: 29892179 PMCID: PMC5992265 DOI: 10.1016/j.jceh.2017.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/22/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Bile acid homeostasis is essential and imbalance may lead to liver damage and liver failure. The bile acid induced intestinal factor fibroblast growth factor 19 (FGF19) has been identified as a key protein for mediating negative feedback inhibition of bile acid synthesis. The aim of the study was to define FGF19 and bile acid concentrations in portal and systemic blood in the fasted and postprandial state. We also addressed the question if physiological portal levels of FGF19 can be extrapolated from the concentration in systemic blood. METHODS Portal and systemic blood was collected from 75 fasted patients undergoing liver surgery and from three organ donors before and after enteral nutrition. Serum concentration of FGF19 was determined with ELISA and bile acid concentration with gas chromatography-mass spectrometry. RESULTS Concentration of bile acids was twice as high in portal compared to systemic blood in the fasted group and 3-5 times higher in the postprandial group. FGF19 increased after enteral nutrition but did not differ between portal and systemic blood, in either group. In addition, a strong, positive correlation between bile acids and FGF19 was found. CONCLUSION Our results confirm that bile acids drive the postprandial increase of circulating FGF19 but a hepatic clearance of FGF19 is unlikely. We conclude that systemic concentrations of FGF19 reflect portal concentrations of FGF19.
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Affiliation(s)
- Helene Johansson
- Division of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Lisa-Mari Mörk
- Division of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Meng Li
- Division of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Anita L. Sandblom
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Ingemar Björkhem
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Jonas Höijer
- Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Bo-Göran Ericzon
- Division of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Carl Jorns
- Division of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Stefan Gilg
- Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Ernesto Sparrelid
- Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Bengt Isaksson
- Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Greg Nowak
- Division of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Ewa Ellis
- Division of Transplantation Surgery, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden
- Address for correspondence: Ewa Ellis, Assistant Professor, Liver Cell Lab F67, Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. Tel.: +46 8 585 800 86/73 415 1880. http://www.ki.se/clintec/levercellslaboratoriet
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49
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Jadeja RN, Thounaojam MC, Bartoli M, Khurana S. Deoxycholylglycine, a conjugated secondary bile acid, reduces vascular tone by attenuating Ca 2+ sensitivity via rho kinase pathway. Toxicol Appl Pharmacol 2018; 348:14-21. [PMID: 29660437 DOI: 10.1016/j.taap.2018.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 04/02/2018] [Accepted: 04/10/2018] [Indexed: 01/25/2023]
Abstract
Patients with cirrhosis have reduced systemic vascular resistance and elevated circulating bile acids (BAs). Previously, we showed that secondary conjugated BAs impair vascular tone by reducing vascular smooth muscle cell (VSMC) Ca2+ influx. In this study, we investigated the effect of deoxycholylglycine (DCG), on Ca2+ sensitivity in reducing vascular tone. First, we evaluated the effects of DCG on U46619- and phorbol-myristate-acetate (PMA)-induced vasoconstriction. DCG reduced U46619-induced vascular tone but failed to reduce PMA-induced vasoconstriction. Then, by utilizing varied combinations of diltiazem (voltage-dependent Ca2+ channel [VDCC] inhibitor), Y27632 (RhoA kinase [ROCK] inhibitor) and chelerythrine (PKC inhibitor) for the effect of DCG on U46619-induced vasoconstriction, we ascertained that DCG inhibits VDCC and ROCK pathway with no effect on PKC. We further assessed the effect of DCG on ROCK pathway. In β-escin-permeabilized arteries, DCG reduced high-dose Ca2+- and GTPγS (a ROCK activator)-induced vasoconstriction. In rat vascular smooth muscle cells (VSMCs), DCG reduced U46619-induced phosphorylation of myosin light chain subunit (MLC20) and myosin phosphatase target subunit-1 (MYPT1). In permeabilized VSMCs, DCG reduced Ca2+- and GTPγS-mediated MLC20 and MYPT1 phosphorylation, and further, reduced GTPγS-mediated membrane translocation of RhoA. In VSMCs, long-term treatment with DCG had no effect on ROCK2 and RhoA expression. In conclusion, DCG attenuates vascular Ca2+ sensitivity and tone via inhibiting ROCK pathway. These results enhance our understanding of BAs-mediated regulation of vascular tone and provide a platform to develop new treatment strategies to reduce arterial dysfunction in cirrhosis.
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Affiliation(s)
- Ravirajsinh N Jadeja
- Digestive Health Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Menaka C Thounaojam
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Manuela Bartoli
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Sandeep Khurana
- Digestive Health Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
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50
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Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med 2018; 215:383-396. [PMID: 29339445 PMCID: PMC5789421 DOI: 10.1084/jem.20171965] [Citation(s) in RCA: 308] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/11/2022] Open
Abstract
Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration. Alterations in BA metabolism and signaling are associated with obesity and type 2 diabetes mellitus (T2DM), whereas treatment of T2DM patients with BA sequestrants, or bariatric surgery in morbidly obese patients, results in a significant improvement in glycemic response that is associated with changes in the BA profile and signaling. Herein, we review the roles of BAs in glucose metabolism in health and disease; highlight the limitations, unknowns, and challenges in understanding the impact of BAs on the glycemic response; and discuss how this knowledge may be harnessed to develop innovative therapeutic approaches for the treatment of hyperglycemia and diabetes.
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Affiliation(s)
- Hagit Shapiro
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | | | - Daniel Halstuch
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Eran Elinav
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
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