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Kanda T, Sasaki-Tanaka R, Kimura N, Abe H, Yoshida T, Hayashi K, Sakamaki A, Yokoo T, Kamimura H, Tsuchiya A, Kamimura K, Terai S. Pruritus in Chronic Cholestatic Liver Diseases, Especially in Primary Biliary Cholangitis: A Narrative Review. Int J Mol Sci 2025; 26:1883. [PMID: 40076514 PMCID: PMC11900276 DOI: 10.3390/ijms26051883] [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: 01/16/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Uonuma Kikan Hospital, Minamiuonuma 949-7302, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Tomoaki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
| | - Atsunori Tsuchiya
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Chuo 409-3898, Japan;
| | - Kenya Kamimura
- Department of General Medicine, Niigata University School of Medicine, Niigata 951-9510, Japan;
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-9510, Japan (K.H.); (A.S.)
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Peng C, Ghanbari M, May A, Abeel T. Effects of antibiotic growth promoter and its natural alternative on poultry cecum ecosystem: an integrated analysis of gut microbiota and host expression. Front Microbiol 2024; 15:1492270. [PMID: 39687871 PMCID: PMC11646981 DOI: 10.3389/fmicb.2024.1492270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 11/05/2024] [Indexed: 12/18/2024] Open
Abstract
Background In-feed antibiotic growth promoters (AGPs) have been a cornerstone in the livestock industry due to their role in enhancing growth and feed efficiency. However, concerns over antibiotic resistance have driven a shift away from AGPs toward natural alternatives. Despite the widespread use, the exact mechanisms of AGPs and alternatives are not fully understood. This necessitates holistic studies that investigate microbiota dynamics, host responses, and the interactions between these elements in the context of AGPs and alternative feed additives. Methods In this study, we conducted a multifaceted investigation of how Bacitracin, a common AGP, and a natural alternative impact both cecum microbiota and host expression in chickens. In addition to univariate and static differential abundance and expression analyses, we employed multivariate and time-course analyses to study this problem. To reveal host-microbe interactions, we assessed their overall correspondence and identified treatment-specific pairs of species and host expressed genes that showed significant correlations over time. Results Our analysis revealed that factors such as developmental age substantially impacted the cecum ecosystem more than feed additives. While feed additives significantly altered microbial compositions in the later stages, they did not significantly affect overall host gene expression. The differential expression indicated that with AGP administration, host transmembrane transporters and metallopeptidase activities were upregulated around day 21. Together with the modulated kininogen binding and phenylpyruvate tautomerase activity over time, this likely contributes to the growth-promoting effects of AGPs. The difference in responses between AGP and PFA supplementation suggests that these additives operate through distinct mechanisms. Conclusion We investigated the impact of a common AGP and its natural alternative on poultry cecum ecosystem through an integrated analysis of both the microbiota and host responses. We found that AGP appears to enhance host nutrient utilization and modulate immune responses. The insights we gained are critical for identifying and developing effective AGP alternatives to advance sustainable livestock farming practices.
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Affiliation(s)
- Chengyao Peng
- Delft Bioinformatics Lab, Delft University of Technology, Delft, Netherlands
| | - Mahdi Ghanbari
- dsm-firmenich, Animal Nutrition and Health R&D Center, Tulln, Austria
| | - Ali May
- dsm-firmenich, Science and Research, Delft, Netherlands
| | - Thomas Abeel
- Delft Bioinformatics Lab, Delft University of Technology, Delft, Netherlands
- Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, United States
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Shijing T, Yinping P, Qiong Y, Deshuai L, Liancai Z, Jun T, Shaoyong L, Bochu W. Synthesis of TUDCA from chicken bile: immobilized dual-enzymatic system for producing artificial bear bile substitute. Microb Cell Fact 2024; 23:326. [PMID: 39623449 PMCID: PMC11613824 DOI: 10.1186/s12934-024-02592-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/12/2024] [Indexed: 12/06/2024] Open
Abstract
Bear bile, a valuable animal-derived medicinal substance primarily composed of tauroursodeoxycholic acid (TUDCA), is widely distributed in the medicinal market across various countries due to its significant therapeutic potential. Given the extreme cruelty involved in bear bile extraction, researchers are focusing on developing synthetic bear bile powder as a more humane alternative. This review presents an industrially practical and environmentally friendly process for producing an artificial substitute for bear bile powder using inexpensive and readily available chicken bile powder through an immobilized 7α-,7β-HSDH dual-enzymatic syste. Current technology has facilitated the industrial production of TUDCA from Tauodeoxycholic acid (TCDCA) using chicken bile powder. The review begins by examining the chemical composition, structure, and properties of bear bile, followed by an outline of the pharmacological mechanisms and manufacturing methods of TUDCA, covering chemical synthesis and biotransformation methods, and a discussion on their respective advantages and disadvantages. Finally, the process of converting chicken bile powder into bear bile powder using an immobilized 7α-Hydroxysteroid Dehydrogenases(7α-HSDH) with 7β- Hydroxysteroid Dehydrogenases (7β-HSDH) dual-enzyme system is thoroughly explained. The main objective of this review is to propose a comprehensive strategy for the complete synthesis of artificial bear bile from chicken bile within a controlled laboratory setting.
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Affiliation(s)
- Tang Shijing
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Pan Yinping
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Yang Qiong
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Lou Deshuai
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Zhu Liancai
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
| | - Tan Jun
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Liu Shaoyong
- Shanghai Kaibao Pharmaceutical Co., LTD., Shanghai, 200030, People's Republic of China
| | - Wang Bochu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
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Elbahnsi A, Dudas B, Callebaut I, Hinzpeter A, Miteva MA. ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches. Pharmaceuticals (Basel) 2024; 17:1602. [PMID: 39770445 PMCID: PMC11676857 DOI: 10.3390/ph17121602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
The ATP-binding cassette (ABC) and solute carrier (SLC) transporters play pivotal roles in cellular transport mechanisms, influencing a wide range of physiological processes and impacting various medical conditions. Recent advancements in structural biology and computational modeling have provided significant insights into their function and regulation. This review provides an overview of the current knowledge of human ABC and SLC transporters, emphasizing their structural and functional relationships, transport mechanisms, and the contribution of computational approaches to their understanding. Current challenges and promising future research and methodological directions are also discussed.
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Affiliation(s)
- Ahmad Elbahnsi
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
| | - Balint Dudas
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
| | - Isabelle Callebaut
- Muséum National d’Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie—IMPMC, Sorbonne Université, 75005 Paris, France
| | - Alexandre Hinzpeter
- CNRS, INSERM, Institut Necker Enfants Malades—INEM, Université Paris Cité, 75015 Paris, France
| | - Maria A. Miteva
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
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5
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Jarasvaraparn C, Rodrigo M, Hartley C, Karnsakul W. Exploring odevixibat's efficacy in alagille syndrome: insights from recent clinical trials and IBAT inhibitor experiences. Expert Opin Pharmacother 2024; 25:1647-1655. [PMID: 39155775 DOI: 10.1080/14656566.2024.2392873] [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: 05/21/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 08/20/2024]
Abstract
INTRODUCTION Alagille syndrome (ALGS) is a rare, genetic, multisystem disorder commonly associated with cholestatic liver disease; patients with ALGS may experience elevated serum bile acids and severe pruritus with associated impaired sleep. The ileal bile acid transporter (IBAT) is located on the luminal surface of enterocytes in the terminal ileum; this transport protein mediates resorption of conjugated bile acids for recirculation back to the liver. Inhibition of IBAT disrupts the enterohepatic circulation and leads to fecal elimination of bile acids. AREAS COVERED Here, the role of odevixibat as a novel, nonsurgical approach to interrupting the enterohepatic circulation from the intestine by inhibition of IBAT is reviewed, specifically in reference to currently available data on pharmacologic IBAT inhibition. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of cholestatic liver diseases in children including ALGS. EXPERT OPINION Odevixibat or IBAT inhibitor should be considered as a first-line treatment for ALGS to improve pruritis, quality of life and liver-related outcomes including absence of liver transplant, surgical biliary diversion, hepatic decompensation, and death.
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Affiliation(s)
- Chaowapong Jarasvaraparn
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Minna Rodrigo
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
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Avitzur Y, Jimenez L, Martincevic I, Acra S, Courtney-Martin G, Gray M, Hope K, Muise A, Prieto Jimenez PM, Taylor N, Thiagarajah JR, Martín MG. Diet management in congenital diarrheas and enteropathies - general concepts and disease-specific approach, a narrative review. Am J Clin Nutr 2024; 120:17-33. [PMID: 38734141 PMCID: PMC11251218 DOI: 10.1016/j.ajcnut.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 04/27/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024] Open
Abstract
Congenital diarrheas and enteropathies (CODE) are a group of rare, heterogenous, monogenic disorders that lead to chronic diarrhea in infancy. Definitive treatment is rarely available, and supportive treatment is the mainstay. Nutritional management in the form of either specialized formulas, restrictive diet, or parenteral nutrition support in CODE with poor enteral tolerance is the cornerstone of CODE treatment and long-term growth. The evidence to support the use of specific diet regimens and nutritional approaches in most CODE disorders is limited due to the rarity of these diseases and the scant published clinical experience. The goal of this review was to create a comprehensive guide for nutritional management in CODE, based on the currently available literature, disease mechanism, and the PediCODE group experience. Enteral diet management in CODE can be divided into 3 distinct conceptual frameworks: nutrient elimination, nutrient supplementation, and generalized nutrient restriction. Response to nutrient elimination or supplementation can lead to resolution or significant improvement in the chronic diarrhea of CODE and resumption of normal growth. This pattern can be seen in CODE due to carbohydrate malabsorption, defects in fat absorption, and occasionally in electrolyte transport defects. In contrast, general diet restriction is mainly supportive. However, occasionally it allows parenteral nutrition weaning or reduction over time, mainly in enteroendocrine defects and rarely in epithelial trafficking and polarity defects. Further research is required to better elucidate the role of diet in the treatment of CODE and the appropriate diet management for each disease.
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Affiliation(s)
- Yaron Avitzur
- Group for Improvement of Intestinal Function and Treatment (GIFT), Transplant and Regenerative Centre, SickKids Hospital, Toronto, ON, Canada; Division of Gastroenterology, Hepatology and Nutrition, SickKids Hospital, University of Toronto, Toronto, ON, Canada.
| | - Lissette Jimenez
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States; Congenital Enteropathy Program, Boston Children's Hospital, Boston, MA, United States;; Harvard Digestive Disease Center, Boston MA, United States
| | - Inez Martincevic
- Division of Gastroenterology, Hepatology and Nutrition, SickKids Hospital, University of Toronto, Toronto, ON, Canada
| | - Sari Acra
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Glenda Courtney-Martin
- Group for Improvement of Intestinal Function and Treatment (GIFT), Transplant and Regenerative Centre, SickKids Hospital, Toronto, ON, Canada; Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada
| | - Megan Gray
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Kayla Hope
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Aleixo Muise
- Division of Gastroenterology, Hepatology and Nutrition, SickKids Hospital, University of Toronto, Toronto, ON, Canada
| | - Paula M Prieto Jimenez
- Division of Gastroenterology and Nutrition, Department of Pediatrics, Mattel Children's Hospital and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
| | - Nancy Taylor
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jay R Thiagarajah
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States; Congenital Enteropathy Program, Boston Children's Hospital, Boston, MA, United States;; Harvard Digestive Disease Center, Boston MA, United States
| | - Martín G Martín
- Division of Gastroenterology and Nutrition, Department of Pediatrics, Mattel Children's Hospital and the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States.
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8
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Cheng Z, Chen Y, Schnabl B, Chu H, Yang L. Bile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets. J Adv Res 2024; 59:173-187. [PMID: 37356804 PMCID: PMC11081971 DOI: 10.1016/j.jare.2023.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/06/2023] [Accepted: 06/20/2023] [Indexed: 06/27/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) has been the second most common cause of liver transplantation in the United States. To date, NASH pathogenesis has not been fully elucidated but is multifactorial, involving insulin resistance, obesity, metabolic disorders, diet, dysbiosis, and gene polymorphism. An effective and approved therapy for NASH has also not been established. Bile acid is long known to have physiological detergent function in emulsifying and absorbing lipids and lipid-soluble molecules within the intestinal lumen. With more and more in-depth understandings of bile acid, it has been deemed to be a pivotal signaling molecule, which is capable of regulating lipid and glucose metabolism, liver inflammation, and fibrosis. In recent years, a plethora of studies have delineated that disrupted bile acid homeostasis is intimately correlated with NASH disease severity. AIMS The review aims to clarify the role of bile acid in hepatic lipid and glucose metabolism, liver inflammation, as well as liver fibrosis, and discusses the safety and efficacy of some pharmacological agents targeting bile acid and its associated pathways for NASH. KEY SCIENTIFIC CONCEPTS OF REVIEW Bile acid has a salutary effect on hepatic metabolic disorders, which can ameliorate liver fat accumulation and insulin resistance mainly through activating Takeda G-protein coupled receptor 5 and farnesoid X receptor. Moreover, bile acid also exerts anti-inflammation and anti-fibrosis properties. Furthermore, bile acid has great potential in nonalcoholic liver disease stratification and treatment of NASH.
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Affiliation(s)
- Zilu Cheng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China
| | - Yixiong Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
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Kim HJ, Kim HJ. [Bile Acid Diarrhea]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 83:133-142. [PMID: 38659249 DOI: 10.4166/kjg.2023.119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 04/26/2024]
Abstract
Diarrhea is a very common gastrointestinal symptom, and the presence of higher concentrations of bile acid in the colon leads to bile acid diarrhea (BAD). In BAD patients, a portion of bile from the small intestine that is normally controlled by enterohepatic circulation is present at a high concentration in the lumen of the large intestine, resulting in increased motility and secretion of the large intestine. The prevalence of BAD is estimated to be 1-2% of the general population, and it comprises one-third of the instances of diarrhea-predominant irritable bowel syndrome. The clinical symptoms of BAD include chronic diarrhea, increased frequency of defecation, urgency to defecate, fecal incontinence, and cramping abdominal pain. The pathophysiology of BAD has not yet been fully elucidated. However, recent studies have reported increased intestinal permeability, shortened intestinal transit time, and changes in the intestinal microbial community to be the possible causes of BAD. Although fecal and serum bile acid tests are widely used for diagnosis, new test methods that are non-invasive, inexpensive, and have high sensitivity and specificity are needed at various institutions to facilitate the diagnosis. The selenium homo-tauro-cholic acid (SeHCAT) test is the gold standard for BAD diagnosis and severity assessment. The validation of several other serum markers, such as 7-hydroxy-4-cholesten-3-one (serum 7αC4) and the fibroblast growth factor 19 (FGF19) for use in clinical practice is ongoing. Although bile acid sequestrants are the mainstay of treatment, the development of drugs that are more effective and have better compliance is required. Farnesoid X receptor (FXR) agonists are showing promising results.
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Affiliation(s)
- Hee Jin Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Korea
| | - Hyun Jin Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Korea
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Engevik MA, Thapa S, Lillie IM, Yacyshyn MB, Yacyshyn B, Percy AJ, Chace D, Horvath TD. Repurposing dried blood spot device technology to examine bile acid profiles in human dried fecal spot samples. Am J Physiol Gastrointest Liver Physiol 2024; 326:G95-G106. [PMID: 38014449 PMCID: PMC11208030 DOI: 10.1152/ajpgi.00188.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/20/2023] [Accepted: 11/25/2023] [Indexed: 11/29/2023]
Abstract
Dried blood spot (DBS) analysis has existed for >50 years, but application of this technique to fecal analysis remains limited. To address whether dried fecal spots (DFS) could be used to measure fecal bile acids, we collected feces from five subjects for each of the following cohorts: 1) healthy individuals, 2) individuals with diarrhea, and 3) Clostridioides difficile-infected patients. Homogenized fecal extracts were loaded onto quantitative DBS (qDBS) devices, dried overnight, and shipped to the bioanalytical lab at ambient temperature. For comparison, source fecal extracts were shipped on dry ice and stored frozen. After 4 mo, frozen fecal extracts and ambient DFS samples were processed and subjected to targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics with stable isotope-labeled standards. We observed no differences in the bile acid levels measured between the traditional extraction and the qDBS-based DFS methods. This pilot data demonstrates that DFS-based analysis is feasible and warrants further development for fecal compounds and microbiome applications.NEW & NOTEWORTHY Stool analysis in remote settings can be challenging, as the samples must be stored at -80°C and transported on dry ice for downstream processing. Our work indicates that dried fecal spots (DFS) on Capitainer quantitative DBS (qDBS) devices can be stored and shipped at ambient temperature and yields the same bile acid profiles as traditional samples. This approach has broad applications for patient home testing and sample collection in rural communities or resource-limited countries.
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Affiliation(s)
- Melinda A Engevik
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Santosh Thapa
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States
- Department of Pathology, Texas Children's Microbiome Center, Texas Children's Hospital, Houston, Texas, United States
| | - Ian M Lillie
- Department of Materials Science & Engineering, Cornell University, Ithaca, New York, United States
| | - Mary Beth Yacyshyn
- Division of Digestive Diseases, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Bruce Yacyshyn
- Division of Digestive Diseases, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Andrew J Percy
- Department of Applications Development, Cambridge Isotope Laboratories, Inc., Tewksbury, Massachusetts, United States
| | | | - Thomas D Horvath
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States
- Department of Pathology, Texas Children's Microbiome Center, Texas Children's Hospital, Houston, Texas, United States
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11
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He Y, Zheng J, Ye B, Dai Y, Nie K. Chemotherapy-induced gastrointestinal toxicity: Pathogenesis and current management. Biochem Pharmacol 2023; 216:115787. [PMID: 37666434 DOI: 10.1016/j.bcp.2023.115787] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/31/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
Chemotherapy is the most common treatment for malignant tumors. However, chemotherapy-induced gastrointestinal toxicity (CIGT) has been a major concern for cancer patients, which reduces their quality of life and leads to treatment intolerance and even cessation. Nevertheless, prevention and treatment for CIGT are challenging, due to the prevalence and complexity of the condition. Chemotherapeutic drugs directly damage gastrointestinal mucosa to induce CIGT, including nausea, vomiting, anorexia, gastrointestinal mucositis, and diarrhea, etc. The pathogenesis of CIGT involves multiple factors, such as gut microbiota disorders, inflammatory responses and abnormal neurotransmitter levels, that synergistically contribute to its occurrence and development. In particular, the dysbiosis of gut microbiota is usually linked to abnormal immune responses that increases inflammatory cytokines' expression, which is a common characteristic of many types of CIGT. Chemotherapy-induced intestinal neurotoxicity is also a vital concern in CIGT. Currently, modern medicine is the dominant treatment of CIGT, however, traditional Chinese medicine (TCM) has attracted interest as a complementary and alternative therapy that can greatly alleviate CIGT. Accordingly, this review aimed to comprehensively summarize the pathogenesis and current management of CIGT using PubMed and Google Scholar databases, and proposed that future research for CIGT should focus on the gut microbiota, intestinal neurotoxicity, and promising TCM therapies, which may help to develop more effective interventions and optimize managements of CIGT.
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Affiliation(s)
- Yunjing He
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jingrui Zheng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Binbin Ye
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yongzhao Dai
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ke Nie
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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12
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Villanueva CE, Hagenbuch B. Palmitoylation of solute carriers. Biochem Pharmacol 2023; 215:115695. [PMID: 37481134 PMCID: PMC10530500 DOI: 10.1016/j.bcp.2023.115695] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/05/2023] [Accepted: 07/12/2023] [Indexed: 07/24/2023]
Abstract
Post-translational modifications are an important mechanism in the regulation of protein expression, function, and degradation. Well-known post-translational modifications are phosphorylation, glycosylation, and ubiquitination. However, lipid modifications, including myristoylation, prenylation, and palmitoylation, are poorly studied. Since the early 2000s, researchers have become more interested in lipid modifications, especially palmitoylation. The number of articles in PubMed increased from about 350 between 2000 and 2005 to more than 600 annually during the past ten years. S-palmitoylation, where the 16-carbon saturated (C16:0) palmitic acid is added to free cysteine residues of proteins, is a reversible protein modification that can affect the expression, membrane localization, and function of the modified proteins. Various diseases like Huntington's and Alzheimer's disease have been linked to changes in protein palmitoylation. In humans, the addition of palmitic acid is mediated by 23 palmitoyl acyltransferases, also called DHHC proteins. The modification can be reversed by a few thioesterases or hydrolases. Numerous soluble and membrane-attached proteins are known to be palmitoylated, but among the approximately 400 solute carriers that are classified in 66 families, only 15 found in 8 families have so far been documented to be palmitoylated. Among the best-characterized transporters are the glucose transporters GLUT1 (SLC2A1) and GLUT4 (SLC2A4), the three monoamine transporters norepinephrine transporter (NET; SLC6A2), dopamine transporter (DAT; SLC6A3), and serotonin transporter (SERT; SLC6A4), and the sodium-calcium exchanger NCX1 (SLC8A1). While there is evidence from recent proteomics experiments that numerous solute carriers are palmitoylated, no details beyond the 15 transporters covered in this review are available.
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Affiliation(s)
- Cecilia E Villanueva
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Bruno Hagenbuch
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, United States.
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Camilleri M, BouSaba J. New Developments in Bile Acid Diarrhea. Gastroenterol Hepatol (N Y) 2023; 19:520-537. [PMID: 37771793 PMCID: PMC10524409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
Bile acid diarrhea (BAD) is characterized by increased frequency of bowel movements, looser stool consistency, urgency, and need for proximity to toilet facilities owing to the severity of the diarrhea, when compared with or relative to irritable bowel syndrome with diarrhea. Consequently, BAD leads to decreased quality of life. The condition is often misdiagnosed as irritable bowel syndrome with diarrhea or functional diarrhea. Patients with BAD have accelerated colonic transit, increased intestinal or colonic mucosal permeability, and altered stool microbiome composition associated with reduced dehydroxylation of primary to secondary bile acids. The established diagnostic test, selenium-75 homocholic acid taurine retention, is not available in the United States. Therefore, 48-hour fecal bile acid excretion has been the gold standard for diagnosis. With recent validation of combined measurement of primary bile acids in a single, random stool in addition to fasting serum 7α-hydroxy-4-cholesten-3-one, a practical point-of-care diagnostic test will soon be available. Randomized controlled trials have documented superiority of colesevelam to placebo and, in a separate study, superiority of the glucagon-like peptide 1 agonist liraglutide compared with colesevelam. Novel experimental approaches for BAD include farnesoid X receptor agonists and fibroblast growth factor 19 analogs. This article updates information on the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Joelle BouSaba
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Abstract
PURPOSE OF REVIEW Bile acid diarrhea (BAD) is a common but under-recognized gastrointestinal condition that manifests with increased stool frequency and urgency, and a looser stool consistency. The aim of this review is to present recent advances in the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD. RECENT FINDINGS Patients with BAD have evidence of accelerated colonic transit, increased gut mucosal permeability, altered stool microbiome composition, and decreased quality of life. Single, random stool measurements of bile acids, alone or in combination with fasting serum 7-alpha-hydroxy-4-cholesten-3-one, have shown good sensitivity and specificity for the diagnosis of BAD. Novel therapeutic approaches include farnesoid X receptor agonists and glucagon-like peptide 1 agonists. SUMMARY Recent research has led to a better understanding of the pathophysiology and mechanisms of BAD, which might pave the way towards more targeted treatment strategies for BAD. Newer, more affordable, and easier diagnostic methods facilitate the diagnosis of BAD.
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Affiliation(s)
- Joelle BouSaba
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Xie X, Liang X, Wang H, Zhu Q, Wang J, Chang Y, Leclercq E, Xue M, Wang J. Effects of paraprobiotics on bile acid metabolism and liver health in largemouth bass (Micropterus salmoides) fed a cottonseed protein concentrate-based diet. ANIMAL NUTRITION 2023; 13:302-312. [PMID: 37168448 PMCID: PMC10165182 DOI: 10.1016/j.aninu.2023.02.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 02/04/2023] [Accepted: 02/13/2023] [Indexed: 03/09/2023]
Abstract
Cottonseed protein concentrate is a sustainable fishmeal alternative in aquafeed. A 10-week experiment was conducted to investigate the effects of a cottonseed protein concentrate-based diet with and without multi-strain yeast fractions (MsYF) on growth, bile acid metabolism, and health in largemouth bass. Four hundred fish (54.0 ± 0.0 g) were casually distributed into 16 tanks (4 replicates/diet). Fish were fed with 4 iso-nitrogen and iso-energetic diets 3 times daily, including a fishmeal diet (FM), a soy protein concentrate-based diet (SPC; replacing 81% fishmeal protein), a cottonseed protein concentrate-based diet (CPC; replacing 81% fishmeal protein), and a CPC diet supplemented with 800 mg/kg MsYF (CPCY). Results showed that the survival of SPC was the lowest, i.e., 48%, with no apparent diet effect among other treatments; we omitted the SPC in additional analyses. Fish fed cottonseed protein concentrate-based diets showed lower growth than FM (P < 0.05). Fish fed CPC showed the highest nuclear dense hepatic phenotypes ratio (50%), followed by CPCY (33%) and FM (17%). Further, dietary CPC increased hepatic total cholesterol and triglyceride levels with concurrently increased cholesterol synthesis but decreased triglyceride synthesis-associated transcription levels (P < 0.05). Furthermore, dietary CPC increased bile acid synthesis but decreased bile acid transport-associated transcription levels (P < 0.05), and then induced an increment of plasma cholic acid and hepatic chenodeoxycholic acid content and the decrement of genus Romboustia (P < 0.05). Regarding the effect of MsYF, fish fed CPCY reduced hepatic lipid accumulation and total plasma bile acid content (P < 0.05) compared to CPC, suggesting an improvement in liver health. Also, dietary MsYF could reverse the microbiota community structure showing a similar gut microbial composition to FM. In conclusion, 81% of fishmeal protein replaced by cottonseed protein concentrate suppressed growth and liver health, while dietary MsYF might mitigate the negative impact of a high cottonseed protein concentrate level diet on liver functions via gut microbiota regulation.
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Bile acids and their receptors in regulation of gut health and diseases. Prog Lipid Res 2023; 89:101210. [PMID: 36577494 DOI: 10.1016/j.plipres.2022.101210] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/26/2022]
Abstract
It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.
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Juthi RT, Sazed SA, Sarmin M, Haque R, Alam MS. COVID-19 and diarrhea: putative mechanisms and management. Int J Infect Dis 2023; 126:125-131. [PMID: 36403817 PMCID: PMC9672967 DOI: 10.1016/j.ijid.2022.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/08/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19), has recently posed a threat to global health by spreading at a high rate and taking millions of lives worldwide. Along with the respiratory symptoms, there are gastrointestinal manifestations and one of the most common gastrointestinal symptoms is diarrhea which is seen in a significant percentage of COVID-19 patients. LITERATURE REVIEW Several studies have shown the plausible correlation between overexpressed angiotensin converting enzyme 2 (ACE2) in enterocytes and SARS-CoV-2, as ACE2 is the only known receptor for the virus entry. Along with the dysregulated ACE2, there are other contributing factors such as gut microbiome dysbiosis, adverse effects of antiviral and antibiotics for treating infections and inflammatory response to SARS-CoV-2 which bring about increased permeability of gut cells and subsequent occurrence of diarrhea. Few studies found that the SARS-CoV-2 is capable of damaging liver cells too. No single effective treatment option is available. LIMITATIONS Confirmed pathophysiology is still unavailable. Studies regarding global population are also insufficient. CONCLUSION In this review, based on the previous works and literature, we summarized the putative molecular pathophysiology of COVID-19 associated diarrhea, concomitant complications and the standard practices of management of diarrhea and hepatic manifestations in international setups.
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Affiliation(s)
- Rifat Tasnim Juthi
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Saiful Arefeen Sazed
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Monira Sarmin
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Rashidul Haque
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Mohammad Shafiul Alam
- Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh,Corresponding author. Mohammad Shafiul Alam, Scientist, Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), 68 Shaheed Tajuddin Ahmed Sarani, Mohakhali, Dhaka-1212, Bangladesh. Tel: +8801711-469232
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Fat Malabsorption and Ursodeoxycholic Acid Treatment in Children With Reduced Organic Solute Transporter-α (SLC51A) Expression. JPGN REPORTS 2022; 3. [PMID: 36148443 PMCID: PMC9491403 DOI: 10.1097/pg9.0000000000000229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Di Vincenzo F, Puca P, Lopetuso LR, Petito V, Masi L, Bartocci B, Murgiano M, De Felice M, Petronio L, Gasbarrini A, Scaldaferri F. Bile Acid-Related Regulation of Mucosal Inflammation and Intestinal Motility: From Pathogenesis to Therapeutic Application in IBD and Microscopic Colitis. Nutrients 2022; 14:nu14132664. [PMID: 35807844 PMCID: PMC9268369 DOI: 10.3390/nu14132664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) and microscopic colitis are chronic immune-mediated inflammatory disorders that affect the gastroenterological tract and arise from a complex interaction between the host’s genetic risk factors, environmental factors, and gut microbiota dysbiosis. The precise mechanistic pathways interlinking the intestinal mucosa homeostasis, the immunological tolerance, and the gut microbiota are still crucial topics for research. We decided to deeply analyze the role of bile acids in these complex interactions and their metabolism in the modulation of gut microbiota, and thus intestinal mucosa inflammation. Recent metabolomics studies revealed a significant defect in bile acid metabolism in IBD patients, with an increase in primary bile acids and a reduction in secondary bile acids. In this review, we explore the evidence linking bile acid metabolites with the immunological pathways involved in IBD pathogenesis, including apoptosis and inflammasome activation. Furthermore, we summarize the principal etiopathogenetic mechanisms of different types of bile acid-induced diarrhea (BAD) and its main novel diagnostic approaches. Finally, we discuss the role of bile acid in current and possible future state-of-the-art therapeutic strategies for both IBD and BAD.
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Affiliation(s)
- Federica Di Vincenzo
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
- Correspondence:
| | - Pierluigi Puca
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Loris Riccardo Lopetuso
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
| | - Valentina Petito
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
| | - Letizia Masi
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
| | - Bianca Bartocci
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Marco Murgiano
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Margherita De Felice
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Lorenzo Petronio
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Antonio Gasbarrini
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Franco Scaldaferri
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
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20
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Li C, Yu S, Li X, Cao Y, Li M, Ji G, Zhang L. Medicinal Formula Huazhi-Rougan Attenuates Non-Alcoholic Steatohepatitis Through Enhancing Fecal Bile Acid Excretion in Mice. Front Pharmacol 2022; 13:833414. [PMID: 35721143 PMCID: PMC9198489 DOI: 10.3389/fphar.2022.833414] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Huazhi-Rougan (HZRG) formula is a Traditional Chinese medicine prescription, and has been widely used to treat non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and the underlying mechanisms of HZRG have not yet been characterized. Here we showed that 4-week HZRG treatment alleviated methionine-choline-deficiency (MCD) diet-induced NASH in C57BL/6J mice, as evidenced by the improvement of hepatic steatosis and inflammation, as well as the decrease of serum levels of alanine and aspartate transaminases. Fecal 16S rDNA sequencing indicated that HZRG reduced the enrichment of pathogenic bacteria and increased the abundance of bacteria gena that are involved in bile acid (BA) conversation. The alteration of fecal and serum BA profile suggested that HZRG enhanced fecal BA excretion, and reduced the reabsorption of toxic secondary BA species (LCA, DCA, HCA). We further analyzed the BA receptors and transporters, and found that HZRG inhibited the expression of ileal bile acid transporter, and organic solute transporter subunit β, and increased the expression of intestinal tight junction proteins (ZO-1, Occludin, Claudin-2). The modulation of gut dysbiosis and BA profile, as well as the improvement of the intestinal environment, may contribute to the decrease of the p-65 subunit of NF-κB phosphorylation, liver F4/80 positive macrophages, inflammatory cytokine IL-1β and TNF-α expression. In conclusion, HZRG treatment enhances fecal BA excretion via inhibiting BA transporters, modulates BA profiles, gut dysbiosis as well as the intestinal environment, thus contributing to the beneficial effect of HZRG on NASH mice.
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Affiliation(s)
- Chunlin Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Siyu Yu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoxiao Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Cao
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Meng Li
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. Int J Mol Sci 2022; 23:ijms23116046. [PMID: 35682726 PMCID: PMC9181207 DOI: 10.3390/ijms23116046] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 02/04/2023] Open
Abstract
Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.
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22
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Choudhuri S, Klaassen CD. Molecular Regulation of Bile Acid Homeostasis. Drug Metab Dispos 2022; 50:425-455. [PMID: 34686523 DOI: 10.1124/dmd.121.000643] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/20/2021] [Indexed: 11/22/2022] Open
Abstract
Bile acids have been known for decades to aid in the digestion and absorption of dietary fats and fat-soluble vitamins in the intestine. The development of gene knockout mice models and transgenic humanized mouse models have helped us understand other functions of bile acids, such as their role in modulating fat, glucose, and energy metabolism, and in the molecular regulation of the synthesis, transport, and homeostasis of bile acids. The G-protein coupled receptor TGR5 regulates the bile acid induced alterations of intermediary metabolism, whereas the nuclear receptor FXR regulates bile acid synthesis and homeostasis. However, this review indicates that unidentified factors in addition to FXR must exist to aid in the regulation of bile acid synthesis and homeostasis. SIGNIFICANCE STATEMENT: This review captures the present understanding of bile acid synthesis, the role of bile acid transporters in the enterohepatic circulation of bile acids, the role of the nuclear receptor FXR on the regulation of bile acid synthesis and bile acid transporters, and the importance of bile acids in activating GPCR signaling via TGR5 to modify intermediary metabolism. This information is useful for developing drugs for the treatment of various hepatic and intestinal diseases, as well as the metabolic syndrome.
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Affiliation(s)
- Supratim Choudhuri
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland (S.C.) and Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas (C.D.K.)
| | - Curtis D Klaassen
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland (S.C.) and Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas (C.D.K.)
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Shulpekova Y, Shirokova E, Zharkova M, Tkachenko P, Tikhonov I, Stepanov A, Sinitsyna A, Izotov A, Butkova T, Shulpekova N, Nechaev V, Damulin I, Okhlobystin A, Ivashkin V. A Recent Ten-Year Perspective: Bile Acid Metabolism and Signaling. Molecules 2022; 27:molecules27061983. [PMID: 35335345 PMCID: PMC8953976 DOI: 10.3390/molecules27061983] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 11/22/2022] Open
Abstract
Bile acids are important physiological agents required for the absorption, distribution, metabolism, and excretion of nutrients. In addition, bile acids act as sensors of intestinal contents, which are determined by the change in the spectrum of bile acids during microbial transformation, as well as by gradual intestinal absorption. Entering the liver through the portal vein, bile acids regulate the activity of nuclear receptors, modify metabolic processes and the rate of formation of new bile acids from cholesterol, and also, in all likelihood, can significantly affect the detoxification of xenobiotics. Bile acids not absorbed by the liver can interact with a variety of cellular recipes in extrahepatic tissues. This provides review information on the synthesis of bile acids in various parts of the digestive tract, its regulation, and the physiological role of bile acids. Moreover, the present study describes the involvement of bile acids in micelle formation, the mechanism of intestinal absorption, and the influence of the intestinal microbiota on this process.
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Affiliation(s)
- Yulia Shulpekova
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Elena Shirokova
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Maria Zharkova
- Department of Hepatology University Clinical Hospital No.2, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia;
| | - Pyotr Tkachenko
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Igor Tikhonov
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Alexander Stepanov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
| | - Alexandra Sinitsyna
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
- Correspondence: ; Tel.: +7-499-764-98-78
| | - Alexander Izotov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
| | - Tatyana Butkova
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; (A.S.); (A.S.); (A.I.); (T.B.)
| | | | - Vladimir Nechaev
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Igor Damulin
- Branch of the V. Serbsky National Medical Research Centre for Psychiatry and Narcology, 127994 Moscow, Russia;
| | - Alexey Okhlobystin
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
| | - Vladimir Ivashkin
- Chair of Internal Diseases Propedeutics, Gastroenterology and Hepatology, Sechenov First Moscow State Medical University (Sechenov University), 119048 Moscow, Russia; (Y.S.); (E.S.); (P.T.); (I.T.); (V.N.); (A.O.); (V.I.)
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van de Wiel SM, Porteiro B, Belt SC, Vogels EW, Bolt I, Vermeulen JL, de Waart DR, Verheij J, Muncan V, Oude Elferink RP, van de Graaf SF. Differential and organ-specific functions of organic solute transporter alpha and beta in experimental cholestasis. JHEP Rep 2022; 4:100463. [PMID: 35462858 PMCID: PMC9019253 DOI: 10.1016/j.jhepr.2022.100463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023] Open
Abstract
Background & Aims Organic solute transporter (OST) subunits OSTα and OSTβ facilitate bile acid efflux from the enterocyte into the portal circulation. Patients with deficiency of OSTα or OSTβ display considerable variation in the level of bile acid malabsorption, chronic diarrhea, and signs of cholestasis. Herein, we generated and characterized a mouse model of OSTβ deficiency. Methods Ostβ-/- mice were generated using CRISR/Cas9 and compared to wild-type and Ostα-/- mice. OSTβ was re-expressed in livers of Ostβ-/- mice using adeno-associated virus serotype 8 vectors. Cholestasis was induced in both models by bile duct ligation (BDL) or 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) feeding. Results Similar to Ostα-/- mice, Ostβ-/- mice exhibited elongated small intestines with blunted villi and increased crypt depth. Increased expression levels of ileal Fgf15, and decreased Asbt expression in Ostβ-/- mice indicate the accumulation of bile acids in the enterocyte. In contrast to Ostα-/- mice, induction of cholestasis in Ostβ-/- mice by BDL or DDC diet led to lower survival rates and severe body weight loss, but an improved liver phenotype. Restoration of hepatic Ostβ expression via adeno-associated virus-mediated overexpression did not rescue the phenotype of Ostβ-/- mice. Conclusions OSTβ is pivotal for bile acid transport in the ileum and its deficiency leads to an intestinal phenotype similar to Ostα-/- mice, but it exerts distinct effects on survival and the liver phenotype, independent of its expression in the liver. Our findings provide insights into the variable clinical presentation of patients with OSTα and OSTβ deficiencies. Lay summary Organic solute transporter (OST) subunits OSTα and OSTβ together facilitate the efflux of conjugated bile acids into the portal circulation. Ostα knockout mice have longer and thicker small intestines and are largely protected against experimental cholestatic liver injury. Herein, we generated and characterized Ostβ knockout mice for the first time. Ostα and Ostβ knockout mice shared a similar phenotype under normal conditions. However, in cholestasis, Ostβ knockout mice had a worsened overall phenotype which indicates a separate and specific role of OSTβ, possibly as an interacting partner of other intestinal proteins.
This manuscript describes the first mouse model of OSTβ deficiency. Ostβ-/- mice are viable and fertile, but show increased length and weight of the small intestine, blunted villi and deeper crypts. Ostβ deficiency leads to an altered microbiome compared to both wild-type and Ostα-/- mice. Cholestasis led to lower survival and worse body weight loss, but an improved liver phenotype, in Ostβ-/- mice compared to Ostα-/- mice.
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Affiliation(s)
- Sandra M.W. van de Wiel
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Begoña Porteiro
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Saskia C. Belt
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Esther W.M. Vogels
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Isabelle Bolt
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Jacqueline L.M. Vermeulen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - D. Rudi de Waart
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Joanne Verheij
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Pathology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Vanesa Muncan
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Ronald P.J. Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
- Corresponding author. Address: Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands; Tel.: 020-5668832, fax: 020-5669190
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Wang J, Bakker W, Zheng W, de Haan L, Rietjens IMCM, Bouwmeester H. Exposure to the mycotoxin deoxynivalenol reduces the transport of conjugated bile acids by intestinal Caco-2 cells. Arch Toxicol 2022; 96:1473-1482. [PMID: 35224661 PMCID: PMC9013688 DOI: 10.1007/s00204-022-03256-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/17/2022] [Indexed: 11/25/2022]
Abstract
Conjugated bile acids are synthesized in liver and subsequently secreted into the intestinal lumen from which they are actively reabsorbed and transported back to liver. The efficient enterohepatic circulation of conjugated bile acids is important to maintain homeostasis. The mycotoxin deoxynivalenol (DON) is a fungal secondary metabolite that contaminates cereal food. Upon human exposure, it can cause intestinal dysfunction. We explored the effects of DON exposure on the intestinal absorption of conjugated bile acids and the expression of bile acid transporters using an in vitro model based on Caco-2 cell layers grown in transwells. Our study shows that the transport rate of taurocholic acid (TCA) is decreased after 48-h pre-exposure of the Caco-2 cells to 2 µM DON, which is a realistic intestinal DON concentration. Exposure to DON downregulates expression of the genes coding for the apical sodium-dependent bile acid transporter (ASBT), the ileal bile acid-binding protein (IBABP) and the organic solute transporter α (OSTα), and it counteracts the agonist activity of Farnesoid X receptor (FXR) agonist GW4064 on these genes. In addition, the transport of ten taurine or glycine-conjugated bile acids in a physiological relevant mixture by the intestinal Caco-2 cell layers was decreased after pre-exposure of the cells to DON, pointing at a potential for DON-mediated accumulation of the conjugated bile acids at the intestinal luminal side. Together the results reveal that DON inhibits intestinal bile acid reabsorption by reducing the expression of bile acid transporters thereby affecting bile acid intestinal kinetics, leading to bile acid malabsorption in the intestine. Our study provides new insights into the hazards of DON exposure.
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Affiliation(s)
- Jingxuan Wang
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - Wouter Bakker
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Weijia Zheng
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Laura de Haan
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Hans Bouwmeester
- Division of Toxicology, Wageningen University and Research, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
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26
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Shirohata A, Ariyoshi R, Fujigaki S, Tanaka K, Morikawa T, Sanuki T, Kinoshita Y. A case of COVID-19 diarrhea relieved by bile acid sequestrant administration. Clin J Gastroenterol 2022; 15:393-400. [PMID: 35122223 PMCID: PMC8815721 DOI: 10.1007/s12328-022-01598-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/22/2022] [Indexed: 11/30/2022]
Abstract
Patients with coronavirus disease 2019 exhibit various gastrointestinal symptoms. Although diarrhea is reported in many cases, the pathophysiology of diarrhea has not been fully clarified. Herein, we report a case of coronavirus disease 2019 with diarrhea that was successfully relieved by the administration of a bile acid sequestrant. The patient was a 59-year-old man whose pneumonia was treated by the administration of glucocorticoids and mechanical ventilation. However, beginning on the 30th hospital day, he developed severe watery diarrhea (up to 10 times a day). Colonoscopy detected ulcers in the terminal ileum and ascending colon. The oral administration of a bile acid sequestrant, colestimide, improved his diarrhea quickly. Ileal inflammation is reported to suppress expression of the gut epithelial apical sodium-dependent bile acid transporter. It decreases bile acid absorption at the distal ileum and increases colonic delivery of bile acids, resulting in bile acid diarrhea. In summary, the clinical course of the case presented in this report suggests that bile acid diarrhea is a possible mechanism of watery diarrhea observed in patients with coronavirus disease 2019.
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Affiliation(s)
- Akira Shirohata
- Department of Gastroenterology, Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan.
| | - Ryusuke Ariyoshi
- Department of Gastroenterology, Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan
| | - Seiji Fujigaki
- Department of Gastroenterology, Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan
| | - Katsuhide Tanaka
- Department of Gastroenterology, Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan
| | - Teruhisa Morikawa
- Department of Gastroenterology, Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan
| | - Tsuyoshi Sanuki
- Department of Gastroenterology, Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan
| | - Yoshikazu Kinoshita
- Department of Gastroenterology, Steel Memorial Hirohata Hospital, 3-1 Yumesaki-cho, Hirohata-ku, Himeji, Hyogo, 671-1122, Japan
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27
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Keely SJ, Urso A, Ilyaskin AV, Korbmacher C, Bunnett NW, Poole DP, Carbone SE. Contributions of bile acids to gastrointestinal physiology as receptor agonists and modifiers of ion channels. Am J Physiol Gastrointest Liver Physiol 2022; 322:G201-G222. [PMID: 34755536 PMCID: PMC8782647 DOI: 10.1152/ajpgi.00125.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/28/2021] [Accepted: 11/08/2021] [Indexed: 02/03/2023]
Abstract
Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.
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Affiliation(s)
- Stephen J Keely
- Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Andreacarola Urso
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
- Department of Pharmacology, Columbia University, New York, New York
| | - Alexandr V Ilyaskin
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Christoph Korbmacher
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, New York
- Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, New York
| | - Daniel P Poole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Simona E Carbone
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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28
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Kiriyama Y, Nochi H. Physiological Role of Bile Acids Modified by the Gut Microbiome. Microorganisms 2021; 10:68. [PMID: 35056517 PMCID: PMC8777643 DOI: 10.3390/microorganisms10010068] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 12/13/2022] Open
Abstract
Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and then released into the intestine via the gallbladder. After the deconjugation of glycine or taurine by the gut microbiome, primary BAs are converted into secondary BAs by the gut microbiome through modifications such as dehydroxylation, oxidation, and epimerization. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine. Thus, unconjugated primary Bas, as well as conjugated and unconjugated secondary BAs, have been modified by the gut microbiome. Some of the BAs reabsorbed from the intestine spill into the systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues, whereas some of the BAs are not reabsorbed and bind to receptors in the terminal ileum. BAs play crucial roles in the physiological regulation of various tissues. Furthermore, various factors, such as diet, age, and antibiotics influence BA composition. Here, we review recent findings regarding the physiological roles of BAs modified by the gut microbiome in the metabolic, immune, and nervous systems.
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Affiliation(s)
- Yoshimitsu Kiriyama
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido 1314-1, Sanuki 769-2193, Kagawa, Japan;
- Laboratory of Neuroendocrinology, Institute of Neuroscience, Tokushima Bunri University, Shido 1314-1, Sanuki 769-2193, Kagawa, Japan
| | - Hiromi Nochi
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido 1314-1, Sanuki 769-2193, Kagawa, Japan;
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Roth K, Yang Z, Agarwal M, Liu W, Peng Z, Long Z, Birbeck J, Westrick J, Liu W, Petriello MC. Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury. ENVIRONMENT INTERNATIONAL 2021; 157:106843. [PMID: 34479135 PMCID: PMC8490327 DOI: 10.1016/j.envint.2021.106843] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/22/2021] [Accepted: 08/19/2021] [Indexed: 05/22/2023]
Abstract
BACKGROUND Epidemiological studies have shown Per- and polyfluoroalkyl substances (PFAS) to be associated with diseases of dysregulated lipid and sterol homeostasis such as steatosis and cardiometabolic disorders. However, the majority of mechanistic studies rely on single chemical exposures instead of identifying mechanisms related to the toxicity of PFAS mixtures. OBJECTIVES The goal of the current study is to investigate mechanisms linking exposure to a PFAS mixture with alterations in lipid metabolism, including increased circulating cholesterol and bile acids. METHODS Male and female wild-type C57BL/6J mice were fed an atherogenic diet used in previous studies of pollutant-accelerated atherosclerosis and exposed to water containing a mixture of 5 PFAS representing legacy, replacement, and alternative subtypes (i.e., PFOA, PFOS, PFNA, PFHxS, and GenX), each at a concentration of 2 mg/L, for 12 weeks. Changes at the transcriptome and metabolome level were determined by RNA-seq and high-resolution mass spectrometry, respectively. RESULTS We observed increased circulating cholesterol, sterol metabolites, and bile acids due to PFAS exposure, with some sexual dimorphic effects. PFAS exposure increased hepatic injury, demonstrated by increased liver weight, hepatic inflammation, and plasma alanine aminotransferase levels. Females displayed increased lobular and portal inflammation compared to the male PFAS-exposed mice. Hepatic transcriptomics analysis revealed PFAS exposure modulated multiple metabolic pathways, including those related to sterols, bile acids, and acyl carnitines, with multiple sex-specific differences observed. Finally, we show that hepatic and circulating levels of PFOA were increased in exposed females compared to males, but this sexual dimorphism was not the same for other PFAS examined. DISCUSSION Exposure of mice to a mixture of PFAS results in PFAS-mediated modulation of cholesterol levels, possibly through disruption of enterohepatic circulation.
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Affiliation(s)
- Katherine Roth
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA
| | - Zhao Yang
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA
| | - Manisha Agarwal
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA
| | - Wendy Liu
- Department of Pathology, University Hospitals, Cleveland Medical Center, Cleveland, OH 44106, USA
| | - Zheyun Peng
- Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202, USA
| | - Ze Long
- Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202, USA
| | - Johnna Birbeck
- Department of Chemistry, Lumigen Instrumentation Center, Wayne State University, Detroit, MI 48202, USA
| | - Judy Westrick
- Department of Chemistry, Lumigen Instrumentation Center, Wayne State University, Detroit, MI 48202, USA
| | - Wanqing Liu
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Wayne State University, Detroit, MI 48202, USA
| | - Michael C Petriello
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48202, USA.
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30
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Qie D, Zhang Y, Gong X, He Y, Qiao L, Lu G, Li Y. SLC10A2 deficiency-induced congenital chronic bile acid diarrhea and stunting. Mol Genet Genomic Med 2021; 9:e1740. [PMID: 34192422 PMCID: PMC8404231 DOI: 10.1002/mgg3.1740] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/17/2021] [Accepted: 06/15/2021] [Indexed: 12/18/2022] Open
Abstract
Background Diarrhea is a common occurrence in children below the age of 5 years. In chronic cases, it induces malnutrition that severely stunts growth. Bile acid diarrhea (BAD), caused by malabsorption of bile acid (BA), is a rare form of chronic diarrhea seldom observed in pediatric patients. Here, we present a clinical report on a novel case of chronic BAD, with severe stunting in an infant, induced by a homozygous mutation of SLC10A2. Methods We performed DNA extraction, whole‐exome sequencing analysis, and mutation analysis of SLC10A2 to obtain genetic data on the patient. We subsequently analyzed the patient's clinical and genetic data. Results The patient's clinical manifestations were chronic diarrhea with increased BAs in the feces and extreme stunting, which was diagnosed as BAD. A homozygous mutation of SLC10A2 at the c.313T>C (rs201206937) site was detected. Conclusion Our report reveals the youngest case illustrating the characteristics of BAD induced by genetic variant at 313T>C, and the second case entailing a clear association between a SLC10A2 genetic mutation and the onset of BAD. Our findings expand the mutant spectrum of the SLC10A2 gene and contribute to the refinement of the genotype–phenotype mapping of severe stunting induced by pediatric BAD. Moreover, they highlight the value of molecular genetic screening for diagnosing BAD in young patients.
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Affiliation(s)
- Di Qie
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Sichuan University, Chengdu, Sichuan, China
| | - Yulin Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Sichuan University, Chengdu, Sichuan, China
| | - Xue Gong
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Sichuan University, Chengdu, Sichuan, China
| | - Yunru He
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Sichuan University, Chengdu, Sichuan, China
| | - Lina Qiao
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Sichuan University, Chengdu, Sichuan, China
| | - Guoyan Lu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Sichuan University, Chengdu, Sichuan, China
| | - Yifei Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, Sichuan University, Chengdu, Sichuan, China
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Li N, Koester ST, Lachance DM, Dutta M, Cui JY, Dey N. Microbiome-encoded bile acid metabolism modulates colonic transit times. iScience 2021; 24:102508. [PMID: 34142026 PMCID: PMC8188381 DOI: 10.1016/j.isci.2021.102508] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/08/2021] [Accepted: 04/18/2021] [Indexed: 12/17/2022] Open
Abstract
Gut motility is regulated by the microbiome via mechanisms that include bile acid metabolism. To localize the effects of microbiome-generated bile acids, we colonized gnotobiotic mice with different synthetic gut bacterial communities that were metabolically phenotyped using a functional in vitro screen. Using two different marker-based assays of gut transit, we inferred that bile acids exert effects on colonic transit. We validated this using an intra-colonic bile acid infusion assay and determined that these effects were dependent upon signaling via the bile acid receptor, TGR5. The intra-colonic bile acid infusion experiments further revealed sex-biased bile acid-specific effects on colonic transit, with lithocholic acid having the largest pro-motility effect. Transcriptional responses of the enteric nervous system (ENS) were stereotypic, regional, and observed in response to different microbiota, their associated bile acid profiles, and even to a single diet ingredient, evidencing exquisite sensitivity of the ENS to environmental perturbations.
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Affiliation(s)
- Naisi Li
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Sean T. Koester
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Daniel M. Lachance
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA, USA
| | - Moumita Dutta
- Department of Environmental and Occupational Health Services, University of Washington, Seattle, WA, USA
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Services, University of Washington, Seattle, WA, USA
| | - Neelendu Dey
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Microbiome Research Initiative, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, WA, USA
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32
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Koda R, Miyazaki S, Iino N, Sato Y, Hirano K, Sunami E, Kosugi S, Kanefuji T, Ogose A, Narita I. Vitamin D Deficiency-induced Osteomalacia in a Patient with Anorexia Nervosa. Intern Med 2021; 60:1731-1736. [PMID: 33390486 PMCID: PMC8222131 DOI: 10.2169/internalmedicine.5911-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
A 48-year-old woman with a 9-year-history of anorexia nervosa (AN) was admitted complaining of generalized bone pain. Blood tests showed hypocalcemia and hyperphosphatasemia, and a radiological survey revealed multiple rib fractures, suggesting complication with osteomalacia. Two years earlier, she had undergone subtotal colectomy for colon cancer. Her serum 25-hydroxy vitamin D concentration was below the detectable level. In addition to a poor nutritional intake and insufficient sun exposure, malabsorption of fat-soluble substances in the intestine and phosphate loss from the kidneys might have contributed to the development of her osteomalacia.
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Affiliation(s)
- Ryo Koda
- Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Satoru Miyazaki
- Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Noriaki Iino
- Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Yo Sato
- Department of Digestive and General Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Kenichiro Hirano
- Department of Digestive and General Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Eiji Sunami
- Department of Digestive and General Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Shinichi Kosugi
- Department of Digestive and General Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Tsutomu Kanefuji
- Department of Gastroenterology and Hepatology, Tsubame Rosai Hospital, Japan
| | - Akira Ogose
- Department of Orthopedic Surgery, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Science, Japan
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Kunst RF, Verkade HJ, Oude Elferink RP, van de Graaf SF. Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology. Hepatology 2021; 73:2577-2585. [PMID: 33222321 PMCID: PMC8252069 DOI: 10.1002/hep.31651] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/29/2020] [Accepted: 11/12/2020] [Indexed: 12/14/2022]
Abstract
Bile salts play a pivotal role in lipid homeostasis, are sensed by specialized receptors, and have been implicated in various disorders affecting the gut or liver. They may play a role either as culprit or as potential panacea. Four very efficient transporters mediate most of the hepatic and intestinal bile salt uptake and efflux, and are each essential for the efficient enterohepatic circulation of bile salts. Starting from the intestinal lumen, conjugated bile salts cross the otherwise impermeable lipid bilayer of (primarily terminal ileal) enterocytes through the apical sodium-dependent bile acid transporter (gene SLC10A2) and leave the enterocyte through the basolateral heteromeric organic solute transporter, which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B). The Na+ -taurocholate cotransporting polypeptide (gene SLC10A1) efficiently clears the portal circulation of bile salts, and the apical bile salt export pump (gene ABCB11) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional Na+ -taurocholate cotransporting polypeptide or organic solute transporter have been described, completing the quartet of bile acid transport deficiencies, as apical sodium-dependent bile acid transporter and bile salt export pump deficiencies were already known for years. Novel pathophysiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. Conclusion: We provide a concise overview of the four main bile salt transport pathways and of their status as possible targets of interventions in cholestatic or metabolic disorders.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- Animals
- Bile Acids and Salts/metabolism
- Biological Transport, Active/drug effects
- Biological Transport, Active/physiology
- Drug Development
- Enterohepatic Circulation/drug effects
- Enterohepatic Circulation/physiology
- Humans
- Membrane Transport Proteins/genetics
- Membrane Transport Proteins/metabolism
- Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors
- Organic Anion Transporters, Sodium-Dependent/genetics
- Organic Anion Transporters, Sodium-Dependent/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Symporters/antagonists & inhibitors
- Symporters/genetics
- Symporters/metabolism
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Affiliation(s)
- Roni F. Kunst
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
- Amsterdam Gastroenterology Endocrinology MetabolismAmsterdamthe Netherlands
| | - Henkjan J. Verkade
- Pediatric Gastroenterology/HepatologyDepartment of PediatricsUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Ronald P.J. Oude Elferink
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
- Amsterdam Gastroenterology Endocrinology MetabolismAmsterdamthe Netherlands
- Department of Gastroenterology and HepatologyAmsterdam UMCUniversity of AmsterdamAmsterdamthe Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
- Amsterdam Gastroenterology Endocrinology MetabolismAmsterdamthe Netherlands
- Department of Gastroenterology and HepatologyAmsterdam UMCUniversity of AmsterdamAmsterdamthe Netherlands
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Cheng Y, Schlosser P, Hertel J, Sekula P, Oefner PJ, Spiekerkoetter U, Mielke J, Freitag DF, Schmidts M, Kronenberg F, Eckardt KU, Thiele I, Li Y, Köttgen A. Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism. Nat Commun 2021; 12:964. [PMID: 33574263 PMCID: PMC7878905 DOI: 10.1038/s41467-020-20877-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023] Open
Abstract
Metabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e-7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.
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Affiliation(s)
- Yurong Cheng
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Pascal Schlosser
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Johannes Hertel
- School of Medicine, National University of Ireland, Galway, University Road, Galway, Ireland
- University of Greifswald, University Medicine Greifswald, Department of Psychiatry and Psychotherapy, Greifswald, Germany
| | - Peggy Sekula
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Peter J Oefner
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Ute Spiekerkoetter
- Department of General Pediatrics and Adolescent Medicine, Medical Center and Faculty of Medicine - University of Freiburg, Freiburg, Germany
| | - Johanna Mielke
- Bayer AG, Division Pharmaceuticals, Open Innovation & Digital Technologies, Wuppertal, Germany
| | - Daniel F Freitag
- Bayer AG, Division Pharmaceuticals, Open Innovation & Digital Technologies, Wuppertal, Germany
| | - Miriam Schmidts
- Department of General Pediatrics and Adolescent Medicine, Medical Center and Faculty of Medicine - University of Freiburg, Freiburg, Germany
| | - Florian Kronenberg
- Institute of Genetic Epidemiology, Department of Genetics and Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ines Thiele
- School of Medicine, National University of Ireland, Galway, University Road, Galway, Ireland
- Division of Microbiology, National University of Ireland, Galway, University Road, Galway, Ireland
- APC Microbiome Ireland, Galway, Ireland
| | - Yong Li
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
- CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
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35
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Habib SM, Zwicker BL, Wykes L, Agellon LB. Sexually dimorphic response of mice to the Western-style diet caused by deficiency of fatty acid binding protein 6 (Fabp6). Physiol Rep 2021; 9:e14733. [PMID: 33527741 PMCID: PMC7851434 DOI: 10.14814/phy2.14733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 11/24/2022] Open
Abstract
Bile acids are natural detergents that aid in the absorption of dietary lipids. Fatty acid binding protein 6 (Fabp6) is a component of the bile acid recovery system that operates in the small intestine. The aim of this study was to determine if Fabp6 deficiency causes dietary fat malabsorption. Wild-type and Fabp6-deficient mice were fed a Western-style diet (WSD) or a reference low-fat diet (LFD) for 10 weeks. The body weight gain, bile acid excretion, fat excretion, energy metabolism, and major gut microbial phyla of the mice were assessed at the end of the controlled diet period. Fabp6-/- mice exhibited enhanced excretion of both bile acids and fat on the WSD but not on the LFD diet. Paradoxically, male Fabp6-/- mice, but not female Fabp6-/- mice, had greater adiposity despite increased fat excretion. Analysis of energy intake and of expenditure by indirect calorimetry revealed sex differences in physical activity level and respiratory quotient, but these did not account for the enhanced adiposity displayed by male Fabp6-/- mice. Analysis of stool DNA showed sex-specific changes in the abundance of major phyla of bacteria in response to Fabp6 deficiency and WSD feeding. The results obtained indicate that the malabsorption of bile acids that occurs in Fabp6-/- mice is associated with dietary fat malabsorption on the high-fat diet but not on the low-fat diet. The WSD induced a sexually dimorphic increase in adiposity displayed by Fabp6-/- mice and sexually distinct pattern of change in gut microbiota composition.
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Affiliation(s)
- Salam M. Habib
- School of Human NutritionMcGill UniversityMontrealQCCanada
| | - Brittnee L. Zwicker
- School of Human NutritionMcGill UniversityMontrealQCCanada
- Present address:
McGill University Health CentreMontrealQCH4A 3J1Canada
| | - Linda Wykes
- School of Human NutritionMcGill UniversityMontrealQCCanada
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36
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van de Peppel IP, Verkade HJ, Jonker JW. Metabolic consequences of ileal interruption of the enterohepatic circulation of bile acids. Am J Physiol Gastrointest Liver Physiol 2020; 319:G619-G625. [PMID: 32938201 DOI: 10.1152/ajpgi.00308.2020] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The enterohepatic circulation of bile acids comprises a tightly regulated process of hepatic bile acid secretion, intestinal reabsorption and transport back to the liver. Disruption of this process has significant consequences for gastrointestinal, liver and whole body homeostasis and therefore offers opportunities for therapeutic intervention. In this review we discuss the effects of (pharmacological) interruption of the enterohepatic circulation at different levels. Recently, several studies have been published on ileal interruption of the enterohepatic circulation of bile acids, targeting the apical-sodium dependent bile acid transporter (ASBT, SLC10A2), as therapy for various diseases. However, ambiguous results have been reported and in-depth mechanistic insights are lacking. Here we discuss these novel studies and review the current knowledge on the consequences of ASBT inhibition and its potential effects on physiology and metabolism.
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Affiliation(s)
- Ivo P van de Peppel
- Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Henkjan J Verkade
- Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Johan W Jonker
- Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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37
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Hughes LE, Ford C, Brookes MJ, Gama R. Bile acid diarrhoea: Current and potential methods of diagnosis. Ann Clin Biochem 2020; 58:22-28. [PMID: 32998535 DOI: 10.1177/0004563220966139] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chronic diarrhoea is common and mostly due to diarrhoea predominant irritable bowel syndrome. Diarrhoea predominant irritable bowel syndrome affects about 11% of the population; however, up to a third of these patients actually have bile acid diarrhoea. There are, therefore, more than one million sufferers of bile acid diarrhoea in the UK. Bile acid diarrhoea is caused by small bowel malabsorption of bile acids and the increased bile acids in the large intestine cause diarrhoea. Once diagnosed, the treatment of bile acid diarrhoea is simple and effective. Bile acid diarrhoea , however, is often not diagnosed because of a lack of easily available and reliable diagnostic methods. In the United Kingdom, the radiolabelled 23-seleno-25-homotaurocholic acid test is the gold-standard method of diagnosis. 23-seleno-25-homotaurocholic acid test, however, is expensive, inconvenient to the patient, involves radiation exposure and has limited availability. As such, a laboratory biomarker is desirable. This review briefly discusses the pathophysiology and management of bile acid diarrhoea and critically evaluates methods for its diagnosis, including serum 7α-hydroxy-4-cholesten-3-one, faecal bile acid measurement, serum fibroblast growth factor 19, urine-2-propanol, and the 14C-glycocholate breath and stool test.
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Affiliation(s)
- Lauren E Hughes
- Clinical Chemistry, Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Clare Ford
- Clinical Chemistry, Royal Wolverhampton NHS Trust, Wolverhampton, UK
| | - Matthew J Brookes
- Department of Gastroenterology, Royal Wolverhampton NHS Trust, Wolverhampton, UK.,Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, UK
| | - Rousseau Gama
- Clinical Chemistry, Royal Wolverhampton NHS Trust, Wolverhampton, UK.,School of Medicine and Clinical Practice, Wolverhampton University, Wolverhampton, UK
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38
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Fitzpatrick LR, Jenabzadeh P. IBD and Bile Acid Absorption: Focus on Pre-clinical and Clinical Observations. Front Physiol 2020; 11:564. [PMID: 32595517 PMCID: PMC7303840 DOI: 10.3389/fphys.2020.00564] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/07/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) causes chronic inflammation affecting the GI tract. It is classified as consisting of Crohn’s Disease (CD) and Ulcerative Colitis (UC). Bile Acid absorption is altered in both pre-clinical models of Inflammatory Bowel Disease (IB) and in human IBD. The bile acid transporter apical sodium dependent bile acid transporter (ASBT) showed decreased expression in rats with TNBS colitis. Decreased ASBT expression has also been described in murine, canine and rabbit models of intestinal inflammation. Human IBD studies have shown that an inflamed ileum can interrupt enterohepatic recirculation of bile acid, which could be due to inflammatory cytokine induced repression of the ASBT promoter. There are different hypotheses as to why ASBT is downregulated during CD. In addition, one study has demonstrated the beneficial effect of a glucocorticoid on ASBT expression, when treating IBD. Our aim in this paper was to systematically review various aspects of bile acid malabsorption in animal models of intestinal inflammation, as well as in IBD.
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Affiliation(s)
- Leo R Fitzpatrick
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
| | - Paniz Jenabzadeh
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
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Abstract
Early diagnosis of diarrhea is critical to prevent disease progression. Diarrhea in newborns can be congenital or acquired; acquired diarrheas are the major cause in infants. Congenital diarrheal diseases are rare and include defects in digestion, absorption, and transport of nutrients, and electrolytes; disorders of enterocyte differentiation and polarization; defects of enteroendocrine cell differentiation; dysregulation of the intestinal immune response; and dysfunction of the immune system. This review discusses the clinical approach that may help in early identification and management of different congenital diarrheal diseases.
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Affiliation(s)
- Mira Younis
- Department of Neonatology, Cleveland Clinic Children's, 9500 Euclid Avenue, M31-37, Cleveland, OH 44195, USA; Cleveland Clinic Lerner's College of Medicine, EC-10 Cleveland Clinic, 9501 Euclid Ave, Cleveland, OH 44195, USA
| | - Radhika Rastogi
- Cleveland Clinic Lerner's College of Medicine, EC-10 Cleveland Clinic, 9501 Euclid Ave, Cleveland, OH 44195, USA
| | - Ankur Chugh
- Pediatric Gastroenterology, Medical College of Wisconsin, 9000 W. Wisconsin Av, 6(th) Floor Clinics, Suite 610, Milwaukee, WI 53226, USA
| | - Shantanu Rastogi
- Newborn Services, George Washington University Hospital, Children's National Medical Center, 900 23rd Street, NW G2092, Washington, DC 20037, USA
| | - Hany Aly
- Department of Neonatology, Cleveland Clinic Children's, 9500 Euclid Avenue, M31-37, Cleveland, OH 44195, USA; Cleveland Clinic Lerner's College of Medicine, EC-10 Cleveland Clinic, 9501 Euclid Ave, Cleveland, OH 44195, USA.
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40
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Li T, Chiang JYL. Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease. Hepatobiliary Surg Nutr 2020; 9:152-169. [PMID: 32355674 PMCID: PMC7188552 DOI: 10.21037/hbsn.2019.09.03] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/26/2019] [Indexed: 12/12/2022]
Abstract
Bile acids are synthesized from cholesterol only in hepatocytes. Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine. Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor TGR5. FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis. In addition, bile acid-activated cellular signaling pathways regulate metabolic homeostasis, immunity, and cell proliferation in various metabolically active organs. In the small and large intestine, gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects. In turn, bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity. Currently, bile acid-based therapies including systemic and intestine-restricted FXR agonists, TGR5 agonists, fibroblast growth factor 19 analogue, intestine FXR antagonists, and intestine apical sodium-bile acid transporter (ASBT) inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis (NASH). These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest. More recently, human and experimental alcoholic liver disease (ALD) has been associated with disrupted bile acid homeostasis. In additional, new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.
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Affiliation(s)
- Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - John Y. L. Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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Abstract
Congenital diarrheal disorders are heterogeneous conditions characterized by diarrhea with onset in the first years of life. They range from simple temporary conditions, such as cow's milk protein intolerance to irreversible complications, such as microvillous inclusion disease with significant morbidity and mortality. Advances in genomic medicine have improved our understanding of these disorders, leading to an ever-increasing list of identified causative genes. The diagnostic approach to these conditions consists of establishing the presence of diarrhea by detailed review of the history, followed by characterizing the composition of the diarrhea, the response to fasting, and with further specialized testing.
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Affiliation(s)
- Abdul Aziz Elkadri
- Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, USA.
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42
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Ticho AL, Malhotra P, Manzella CR, Dudeja PK, Saksena S, Gill RK, Alrefai WA. S-acylation modulates the function of the apical sodium-dependent bile acid transporter in human cells. J Biol Chem 2020; 295:4488-4497. [PMID: 32071081 DOI: 10.1074/jbc.ra119.011032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 02/06/2020] [Indexed: 01/16/2023] Open
Abstract
The ileal apical sodium-dependent bile acid transporter (ASBT) is crucial for the enterohepatic circulation of bile acids. ASBT function is rapidly regulated by several posttranslational modifications. One reversible posttranslational modification is S-acylation, involving the covalent attachment of fatty acids to cysteine residues in proteins. However, whether S-acylation affects ASBT function and membrane expression has not been determined. Using the acyl resin-assisted capture method, we found that the majority of ASBT (∼80%) was S-acylated in ileal brush border membrane vesicles from human organ donors, as well as in HEK293 cells stably transfected with ASBT (2BT cells). Metabolic labeling with alkyne-palmitic acid (100 μm for 15 h) also showed that ASBT is S-acylated in 2BT cells. Incubation with the acyltransferase inhibitor 2-bromopalmitate (25 μm for 15 h) significantly reduced ASBT S-acylation, function, and levels on the plasma membrane. Treatment of 2BT cells with saturated palmitic acid (100 μm for 15 h) increased ASBT function, whereas treatment with unsaturated oleic acid significantly reduced ASBT function. Metabolic labeling with alkyne-oleic acid (100 μm for 15 h) revealed that oleic acid attaches to ASBT, suggesting that unsaturated fatty acids may decrease ASBT's function via a direct covalent interaction with ASBT. We also identified Cys-314 as a potential S-acylation site. In conclusion, these results provide evidence that S-acylation is involved in the modulation of ASBT function. These findings underscore the potential for unsaturated fatty acids to reduce ASBT function, which may be useful in disorders in which bile acid toxicity is implicated.
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Affiliation(s)
- Alexander L Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Illinois 60612-7332
| | - Pooja Malhotra
- Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Illinois 60612-7332
| | - Christopher R Manzella
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Illinois 60612-7332
| | - Pradeep K Dudeja
- Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Illinois 60612-7332.,Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
| | - Seema Saksena
- Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Illinois 60612-7332.,Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Illinois 60612-7332
| | - Waddah A Alrefai
- Division of Gastroenterology and Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Illinois 60612-7332 .,Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
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Wang L, Zhou Y, Wang X, Zhang G, Guo B, Hou X, Ran J, Zhang Q, Li C, Zhao X, Geng Y, Feng S. Mechanism of Asbt ( Slc10a2)-related bile acid malabsorption in diarrhea after pelvic radiation. Int J Radiat Biol 2020; 96:510-519. [PMID: 31900034 DOI: 10.1080/09553002.2020.1707324] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background: Radiation is a mode of treatment for many pelvic malignancies, most of which originate in the gynecologic, gastrointestinal, and genitourinary systems. However, the healthy gut is unavoidably included in the irradiation volume, resulting in undesirable results that manifest as radiation-induced diarrhea (RID), which is the most common side effect of radiation therapy and significantly affects the patients' quality of life. This study aimed to investigate the potential mechanism of diarrhea after pelvic radiotherapy in rats based on the effect of radiation on bile acid homeostasis and sodium-dependent bile acid transporter (Asbt).Methods: In this experimental study, male Sprague-Dawley rats were divided into the following groups - pelvic irradiation, cholestyramine-concurrent radiation, and control groups. The rats in the pelvic irradiation group were irradiated in the pelvic region with 2 Gy per day for five consecutive days. The total bile acid (TBA) levels in the ileum, colon, and feces were measured using automatic biochemical analyzer, and the levels of individual bile acids were evaluated by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The mRNA and protein expression of Asbt in ileum were assessed by qRT-PCR and Western blot assay. The rats in the cholestyramine-concurrent radiation group were administered with cholestyramine, a bile acid-chelating resin, and concurrent radiation for 5 days. The body weight of rats was monitored daily, and the degree of diarrhea was scored.Results: Diarrhea was observed at 2 and 3 days post-pelvic radiation. The TBA levels were significantly decreased at 4 and 5 days post-radiation in the ileum (p < .01, p < .01) and increased at 4 and 5 days post-radiation in the colon (p < .05, p < .05). The fecal excretions of TBA were significantly increased at 3, 4, and 5 days post-radiation (p < .05). The levels of individual bile acids were significantly decreased in the ileum and increased in the colon and feces, post-radiation. The mRNA and protein expression of Asbt in the ileum gradually decreased with increasing days of pelvic radiation and significantly decreased at 3 and 5 days post-radiation, respectively. Furthermore, a significant decrease in body weight was observed post-pelvic radiation, and cholestyramine administration did not reverse the weight loss. However, the incidence of RID was decreased after administration of cholestyramine.Conclusions: Bile acid malabsorption is partially responsible for RID post-pelvic radiation in rats, and the potential mechanism is related to the downregulation of the ileal Asbt.
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Affiliation(s)
- Lina Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China.,Department of Radiation Therapy, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yan Zhou
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaohu Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China.,Gansu Provincial Cancer Hospital, Lanzhou, China.,Lanzhou Heavy Ion Hospital, Lanzhou, China
| | - Guangwen Zhang
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - Bin Guo
- Department of Radiation Therapy, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaoming Hou
- Department of Radiation Therapy, The First Hospital of Lanzhou University, Lanzhou, China
| | - Juntao Ran
- Department of Radiation Therapy, The First Hospital of Lanzhou University, Lanzhou, China
| | | | - Chengcheng Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xueshan Zhao
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Yichao Geng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Shuangwu Feng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
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Yoshitsugu R, Kikuchi K, Hori S, Iwaya H, Hagio M, Shimizu H, Hira T, Ishizuka S. Correlation between 12α-hydroxylated bile acids and insulin secretion during glucose tolerance tests in rats fed a high-fat and high-sucrose diet. Lipids Health Dis 2020; 19:9. [PMID: 31941510 PMCID: PMC6964016 DOI: 10.1186/s12944-020-1193-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 01/10/2020] [Indexed: 01/07/2023] Open
Abstract
Background Previously, we found a significant relationship in a rat study between energy intake and bile acid (BA) metabolism especially 12α-hydroxylated (12αOH) BAs. The present study was designed to reveal relationships among BA metabolism, glucose tolerance, and cecal organic acids in rats fed a high-fat and high-sucrose diet (HFS) by using multivariate and multiple regression analyses in two types of glucose tolerance tests (GTTs). Methods Male WKAH/HkmSlc rats were fed with a control or a HFS for 13 weeks. Oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT) were performed at week 9 and 11, respectively. BAs were analyzed by using ultra high-performance liquid chromatography-mass spectrometry. Organic acid concentrations in cecal contents were analyzed by using ultra high-performance liquid chromatography with post-column pH buffered electric conductivity method. Results A positive correlation of aortic 12αOH BA concentration was observed with energy intake and visceral adipose tissue weight. We found that an increase of 12αOH BAs in enterohepatic circulation, intestinal contents and feces in the HFS-fed rats compared to those in control rats regardless of no significant increase of total BA concentration in the feces in the test period. Fecal 12αOH BA concentration was positively correlated with maximal insulin level in OGTT and area under curve of insulin in IPGTT. There was a positive correlation between aortic 12αOH BAs concentration and changes in plasma glucose level in both OGTT and IPGTT. In contrast, a decrease in the concentration of organic acids was observed in the cecal contents of the HFS-fed rats. Multiple linear regression analysis in the IPGTT revealed that the concentrations of aortic 12αOH BA and cecal acetic acid were the predictors of insulin secretion. Moreover, there was a positive correlation between concentration of portal 12αOH BAs and change in insulin concentration of peripheral blood in the IPGTT. Conclusion The distribution analysis of BA compositions accompanied by GTTs revealed a close relationship between 12αOH BA metabolism and insulin secretion in GTTs in rats.
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Affiliation(s)
- Reika Yoshitsugu
- Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan
| | - Keidai Kikuchi
- Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan
| | - Shota Hori
- Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan
| | - Hitoshi Iwaya
- Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan
| | - Masahito Hagio
- Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan
| | - Hidehisa Shimizu
- Institute of Life and Environmental Science, Academic Assembly, Shimane University, Matsue, 690-8504, Japan
| | - Tohru Hira
- Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan
| | - Satoshi Ishizuka
- Research Faculty of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo, 060-8589, Japan.
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019; 10:21-56. [PMID: 31853951 PMCID: PMC7171925 DOI: 10.1002/cphy.c190007] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol 10:21-56, 2020.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
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Abstract
Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.
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Affiliation(s)
| | - Hartmut Jaeschke
- †Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Sundaram S, Palaniappan B, Nepal N, Chaffins S, Sundaram U, Arthur S. Mechanism of Dyslipidemia in Obesity-Unique Regulation of Ileal Villus Cell Brush Border Membrane Sodium-Bile Acid Cotransport. Cells 2019; 8:E1197. [PMID: 31623375 PMCID: PMC6830326 DOI: 10.3390/cells8101197] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/01/2019] [Accepted: 10/02/2019] [Indexed: 02/06/2023] Open
Abstract
In obesity, increased absorption of dietary fat contributes to altered lipid homeostasis. In turn, dyslipidemia of obesity leads to many of the complications of obesity. Bile acids are necessary for the absorption of dietary fat. In the mammalian intestine, apical sodium-dependent bile acid cotransporter (ASBT; SLC10A2) is exclusively responsible for the reabsorption of bile acids in the terminal ileum. In rat and mice models of obesity and importantly in obese humans, ASBT was increased in ileal villus cells. The mechanism of stimulation of ASBT was secondary to an increase in ASBT expression in villus cell brush border membrane. The stimulation of ASBT was not secondary to the altered Na-extruding capacity of villus cells during obesity. Further, increased Farnesoid X receptor (FXR) expression in villus cells during obesity likely mediated the increase in ASBT. Moreover, enhanced FXR expression increased the expression of bile-acid-associated proteins (IBABP and OSTα) that are responsible for handling bile acids absorbed via ASBT in villus cells during obesity. Thus, this study demonstrated that in an epidemic condition, obesity, the dyslipidemia that leads to many of the complications of the condition, may, at least in part, be due to deregulation of intestinal bile acid absorption.
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Affiliation(s)
- Shanmuga Sundaram
- Department of Clinical and Translational Sciences, Appalachian Center for Cellular transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA.
| | - Balasubramanian Palaniappan
- Department of Clinical and Translational Sciences, Appalachian Center for Cellular transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA.
| | - Niraj Nepal
- Department of Clinical and Translational Sciences, Appalachian Center for Cellular transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA.
| | - Shaun Chaffins
- Department of Clinical and Translational Sciences, Appalachian Center for Cellular transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA.
| | - Uma Sundaram
- Department of Clinical and Translational Sciences, Appalachian Center for Cellular transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA.
| | - Subha Arthur
- Department of Clinical and Translational Sciences, Appalachian Center for Cellular transport in Obesity Related Disorders, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA.
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Kemis JH, Linke V, Barrett KL, Boehm FJ, Traeger LL, Keller MP, Rabaglia ME, Schueler KL, Stapleton DS, Gatti DM, Churchill GA, Amador-Noguez D, Russell JD, Yandell BS, Broman KW, Coon JJ, Attie AD, Rey FE. Genetic determinants of gut microbiota composition and bile acid profiles in mice. PLoS Genet 2019; 15:e1008073. [PMID: 31465442 PMCID: PMC6715156 DOI: 10.1371/journal.pgen.1008073] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 06/14/2019] [Indexed: 02/03/2023] Open
Abstract
The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.
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Affiliation(s)
- Julia H. Kemis
- Department of Bacteriology, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Vanessa Linke
- Department of Chemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Kelsey L. Barrett
- Department of Bacteriology, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Frederick J. Boehm
- Department of Statistics, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Lindsay L. Traeger
- Department of Bacteriology, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Mark P. Keller
- Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Mary E. Rabaglia
- Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Kathryn L. Schueler
- Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Donald S. Stapleton
- Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Daniel M. Gatti
- Jackson Laboratory, Bar Harbor, Maine, United States of America
| | | | - Daniel Amador-Noguez
- Department of Bacteriology, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Jason D. Russell
- Department of Chemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Brian S. Yandell
- Department of Statistics, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Karl W. Broman
- Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Joshua J. Coon
- Department of Chemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- Morgridge Institute for Research, Madison, Wisconsin, United States of America
- Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Alan D. Attie
- Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Federico E. Rey
- Department of Bacteriology, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
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Gellert-Kristensen H, Dalila N, Fallgaard Nielsen S, Grønne Nordestgaard B, Tybjaerg-Hansen A, Stender S. Identification and Replication of Six Loci Associated With Gallstone Disease. Hepatology 2019; 70:597-609. [PMID: 30325047 DOI: 10.1002/hep.30313] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 10/06/2018] [Indexed: 12/14/2022]
Abstract
Gallstone disease is a common complex disease that confers a substantial economic burden on society. The genetic underpinnings of gallstone disease remain incompletely understood. We aimed to identify genetic associations with gallstone disease using publicly available data from the UK Biobank and two large Danish cohorts. We extracted genetic associations with gallstone disease from the Global Biobank Engine (GBE), an online browser of genome-wide associations in UK Biobank participants (14,940 cases and 322,268 controls). Significant associations (P < 5 × 10-8 ) were retested in two Copenhagen cohorts (comprising 1,522 cases and 18,266 controls). In the Copenhagen cohorts, we also tested whether a genetic risk score was associated with gallstone disease and whether individual gallstone loci were associated with plasma levels of lipids, lipoproteins, and liver enzymes. We identified 19 loci to be associated with gallstone disease in the GBE. Of these, 12 were replicated in the Copenhagen cohorts, including six previously unknown loci (in hepatocyte nuclear factor 4 alpha [HNF4A], fucosyltransferase 2, serpin family A member 1 [SERPINA1], jumonji domain containing 1C, AC074212.3, and solute carrier family 10A member 2 [SLC10A2]) and six known loci (in adenosine triphosphate binding cassette subfamily G member 8 [ABCG8], sulfotransferase family 2A member 1, cytochrome P450 7A1, transmembrane 4 L six family member 4, ABCB4, and tetratricopeptide repeat domain 39B). Five of the gallstone associations are protein-altering variants, and three (HNF4A p.Thr139Ile, SERPINA1 p.Glu366Lys, and SLC10A2 p.Pro290Ser) conferred per-allele odds ratios for gallstone disease of 1.30-1.36. Individuals with a genetic risk score >2.5 (prevalence 1%) had a 5-fold increased risk of gallstones compared to those with a score <1.0 (11%). Of the 19 lithogenic loci, 11 and ten exhibited distinct patterns of association with plasma levels of lipids and liver enzymes, respectively. Conclusion: We identified six susceptibility loci for gallstone disease.
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Affiliation(s)
| | - Nawar Dalila
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Sune Fallgaard Nielsen
- Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.,The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark
| | - Børge Grønne Nordestgaard
- Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.,The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.,The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anne Tybjaerg-Hansen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.,The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.,The Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefan Stender
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
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The Biosynthesis, Signaling, and Neurological Functions of Bile Acids. Biomolecules 2019; 9:biom9060232. [PMID: 31208099 PMCID: PMC6628048 DOI: 10.3390/biom9060232] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 12/13/2022] Open
Abstract
Bile acids (BA) are amphipathic steroid acids synthesized from cholesterol in the liver. They act as detergents to expedite the digestion and absorption of dietary lipids and lipophilic vitamins. BA are also considered to be signaling molecules, being ligands of nuclear and cell-surface receptors, including farnesoid X receptor and Takeda G-protein receptor 5. Moreover, BA also activate ion channels, including the bile acid-sensitive ion channel and epithelial Na+ channel. BA regulate glucose and lipid metabolism by activating these receptors in peripheral tissues, such as the liver and brown and white adipose tissue. Recently, 20 different BA have been identified in the central nervous system. Furthermore, BA affect the function of neurotransmitter receptors, such as the muscarinic acetylcholine receptor and γ-aminobutyric acid receptor. BA are also known to be protective against neurodegeneration. Here, we review recent findings regarding the biosynthesis, signaling, and neurological functions of BA.
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