|
1
|
Jiang X, Ren J, Yu G, Wu W, Chen M, Zhao Y, He C. Targeting Bile-Acid Metabolism: Nutritional and Microbial Approaches to Alleviate Ulcerative Colitis. Nutrients 2025; 17:1174. [PMID: 40218932 PMCID: PMC11990178 DOI: 10.3390/nu17071174] [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: 02/24/2025] [Revised: 03/19/2025] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Canxia He
- School of Public Health, Health Science Center, Ningbo University, Ningbo 315211, China
| |
Collapse
|
|
2
|
Barbara G, Bellini M, Portincasa P, Stanghellini V, Annibale B, Benedetti A, Cammarota G, Fries W, Usai Satta P, Corazziari ES. Bile acid diarrhea in patients with chronic diarrhea. Current appraisal and recommendations for clinical practice. Dig Liver Dis 2025; 57:680-687. [PMID: 39827025 DOI: 10.1016/j.dld.2024.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/14/2024] [Accepted: 12/23/2024] [Indexed: 01/22/2025]
Abstract
Bile Acid Diarrhea (BAD) is a common cause of chronic diarrhea, often accompanied by urgency, occasional fecal incontinence, abdominal pain, and fatigue. A nationwide survey has shown limited awareness of BAD within the Italian medical community, prompting a panel of experts to develop a Position Paper that outlines the most practical and cost-saving diagnostic investigations and treatments for this frequently overlooked condition. The document provides an overview of the epidemiology, pathophysiology, clinical manifestations, and classification of the different types of Bile Acid Diarrhea (BAD). A key focus is the diagnostic approach to identifying and managing the many undiagnosed BAD patients in both primary care and specialized medical settings. Finally, the paper addresses the optimal therapeutic strategies for BAD, including traditional bile acid sequestrants and newer, promising treatments.
Collapse
Affiliation(s)
- Giovanni Barbara
- IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Massimo Bellini
- Gastrointestinal Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J)University of Bari Aldo Moro, Bari, Italy
| | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Bruno Annibale
- Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Roma, Italy
| | - Antonio Benedetti
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ospedali Riuniti-University Hospital, Ancona, Italy
| | - Giovanni Cammarota
- Gastroenterology Unit, Fondazione Policlinico A Gemelli IRCCS, Catholic University of Medicine, Roma, Italy
| | - Walter Fries
- Clinical Unit of Gastroenterology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | | | | |
Collapse
|
|
3
|
Gawey BJ, Mars RA, Kashyap PC. The role of the gut microbiome in disorders of gut-brain interaction. FEBS J 2025; 292:1357-1377. [PMID: 38922780 PMCID: PMC11664017 DOI: 10.1111/febs.17200] [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: 01/14/2024] [Revised: 04/03/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024]
Abstract
Disorders of Gut-Brain Interaction (DGBI) are widely prevalent and commonly encountered in gastroenterology practice. While several peripheral and central mechanisms have been implicated in the pathogenesis of DGBI, a recent body of work suggests an important role for the gut microbiome. In this review, we highlight how gut microbiota and their metabolites affect physiologic changes underlying symptoms in DGBI, with a particular focus on their mechanistic influence on GI transit, visceral sensitivity, intestinal barrier function and secretion, and CNS processing. This review emphasizes the complexity of local and distant effects of microbial metabolites on physiological function, influenced by factors such as metabolite concentration, duration of metabolite exposure, receptor location, host genetics, and underlying disease state. Large-scale in vitro work has elucidated interactions between host receptors and the microbial metabolome but there is a need for future research to integrate such preclinical findings with clinical studies. The development of novel, targeted therapeutic strategies for DGBI hinges on a deeper understanding of these metabolite-host interactions, offering exciting possibilities for the future of treatment of DGBI.
Collapse
Affiliation(s)
- Brent J Gawey
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Ruben A Mars
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Purna C Kashyap
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
4
|
Ellegaard AM, Kårhus ML, Winther-Jensen M, Lund AB, Knop FK. Treatment of Bile Acid Diarrhea With Glucagon-Like Peptide 1 Receptor Agonists: A Promising Yet Understudied Approach. Clin Transl Gastroenterol 2025; 16:e00815. [PMID: 39807780 PMCID: PMC11932613 DOI: 10.14309/ctg.0000000000000815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025] Open
Abstract
Bile acid diarrhea (BAD) is a chronic and socially debilitating disease characterized by abdominal pain, diarrhea, urgency, and fecal incontinence. Recently, in a 6-week randomized controlled trial, we showed that the glucagon-like peptide 1 receptor agonist (GLP-1RA) liraglutide is superior to bile acid sequestration (considered standard-of-care) using colesevelam in reducing BAD symptoms. The emergence of new, more potent, and longer-acting GLP-1RAs has spurred an interest in these treatments in BAD management. Here, we review the literature on different GLP-1RAs in BAD treatment and outline their potential mode of actions, highlight knowledge gaps, and outline the need for further clinical evidence generation.
Collapse
Affiliation(s)
- Anne-Marie Ellegaard
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
| | - Martin L. Kårhus
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
| | - Matilde Winther-Jensen
- Center for Clinical Research and Prevention, Copenhagen University Hospital – Bispebjerg and Frederiksberg, Frederiksberg, Denmark
| | - Asger B. Lund
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K. Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital – Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
5
|
Di Ciaula A, Khalil M, Baffy G, Portincasa P. Advances in the pathophysiology, diagnosis and management of chronic diarrhoea from bile acid malabsorption: a systematic review. Eur J Intern Med 2024; 128:10-19. [PMID: 39069430 DOI: 10.1016/j.ejim.2024.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/30/2024]
Abstract
Bile acid malabsorption (BAM) is an important disorder of digestive pathophysiology as it generates chronic diarrhoea. This condition originates from intricate pathways involving bile acid synthesis and metabolism in the liver and gut, the composition of gut microbiota, enterohepatic circulation and key receptors as farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and the G-protein bile acid receptor-1 (GPBAR-1). Although symptoms can resemble those related to disorders of gut brain interaction, accurate diagnosis of BAM may greatly benefit the patient. The empiric diagnosis of BAM is primarily based on the clinical response to bile acid sequestrants. Specific tests including the 48-hour fecal bile acid test, serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19), and the 75Selenium HomotauroCholic Acid Test (SeHCAT) are not widely available. Nevertheless, lack of diagnostic standardization of BAM may account for poor recognition and delayed management. Beyond bile acid sequestrants, therapeutic approaches include the use of FXR agonists, FGF19 analogues, glucagon-like peptide-1 (GLP-1) receptor agonists, and microbiota modulation. These novel agents can best make their foray into the therapeutic armamentarium if BAM does not remain a diagnosis of exclusion. Ignoring BAM as a specific condition may continue to contribute to increased healthcare costs and reduced quality of life. Here, we aim to provide a comprehensive review of the pathophysiology, diagnosis, and management of BAM.
Collapse
Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Medical School, Bari, Italy.
| | - Mohamad Khalil
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Medical School, Bari, Italy.
| | - Gyorgy Baffy
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston, MA, USA.
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", Medical School, Bari, Italy.
| |
Collapse
|
|
6
|
Walters JRF, Sikafi R. Managing bile acid diarrhea: aspects of contention. Expert Rev Gastroenterol Hepatol 2024; 18:521-528. [PMID: 39264409 DOI: 10.1080/17474124.2024.2402353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/23/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024]
Abstract
INTRODUCTION Bile acid diarrhea is a common cause of bowel symptoms and often goes unrecognized or misdiagnosed. Many aspects of management remain contentious. AREAS COVERED The primary, idiopathic condition should be suspected in people with functional diarrhea or diarrhea-predominant irritable bowel syndrome. Secondary causes include ileal resection, inflammation, and post-cholecystectomy. Diagnostic tests vary globally, being unavailable in many countries, and further refinement of testing strategy is needed. Management is usually long-term symptom control, rather than reversal of the causative factors, which are still being defined. Bile acid sequestrants remain the main drugs used. They are relatively inexpensive, and better-quality data is now available for colesevelam. However, optimal use, including timing and formulation, needs clarification. The GLP-1 receptor agonist, liraglutide, is also effective, although mechanisms of action and whether this effect is common to other class members is unclear. They are more expensive, and availability varies. FXR agonists can also be effective but require further validation. The role of dietary factors in symptom development is a major patient concern, needing more formal studies. EXPERT OPINION To build on recent findings, bile acid diarrhea needs further investment into causes, diagnosis and therapy to guide present and future patient care.
Collapse
Affiliation(s)
- Julian R F Walters
- Department of Gastroenterology, Imperial College Healthcare NHS Trust
- Division of Digestive Diseases, Imperial College London, Hammersmith Hospital, London, UK
| | - Rafid Sikafi
- Department of Gastroenterology, Imperial College Healthcare NHS Trust
- Division of Digestive Diseases, Imperial College London, Hammersmith Hospital, London, UK
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Yang Z, Zarbl H, Guo GL. Circadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism. Mol Pharmacol 2024; 105:179-193. [PMID: 38238100 PMCID: PMC10877735 DOI: 10.1124/molpharm.123.000831] [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: 10/21/2023] [Accepted: 01/05/2024] [Indexed: 02/17/2024] Open
Abstract
The circadian clock is an endogenous biochemical timing system that coordinates the physiology and behavior of organisms to earth's ∼24-hour circadian day/night cycle. The central circadian clock synchronized by environmental cues hierarchically entrains peripheral clocks throughout the body. The circadian system modulates a wide variety of metabolic signaling pathways to maintain whole-body metabolic homeostasis in mammals under changing environmental conditions. Endocrine fibroblast growth factors (FGFs), namely FGF15/19, FGF21, and FGF23, play an important role in regulating systemic metabolism of bile acids, lipids, glucose, proteins, and minerals. Recent evidence indicates that endocrine FGFs function as nutrient sensors that mediate multifactorial interactions between peripheral clocks and energy homeostasis by regulating the expression of metabolic enzymes and hormones. Circadian disruption induced by environmental stressors or genetic ablation is associated with metabolic dysfunction and diurnal disturbances in FGF signaling pathways that contribute to the pathogenesis of metabolic diseases. Time-restricted feeding strengthens the circadian pattern of metabolic signals to improve metabolic health and prevent against metabolic diseases. Chronotherapy, the strategic timing of medication administration to maximize beneficial effects and minimize toxic effects, can provide novel insights into linking biologic rhythms to drug metabolism and toxicity within the therapeutical regimens of diseases. Here we review the circadian regulation of endocrine FGF signaling in whole-body metabolism and the potential effect of circadian dysfunction on the pathogenesis and development of metabolic diseases. We also discuss the potential of chrononutrition and chronotherapy for informing the development of timing interventions with endocrine FGFs to optimize whole-body metabolism in humans. SIGNIFICANCE STATEMENT: The circadian timing system governs physiological, metabolic, and behavioral functions in living organisms. The endocrine fibroblast growth factor (FGF) family (FGF15/19, FGF21, and FGF23) plays an important role in regulating energy and mineral metabolism. Endocrine FGFs function as nutrient sensors that mediate multifactorial interactions between circadian clocks and metabolic homeostasis. Chronic disruption of circadian rhythms increases the risk of metabolic diseases. Chronological interventions such as chrononutrition and chronotherapy provide insights into linking biological rhythms to disease prevention and treatment.
Collapse
Affiliation(s)
- Zhenning Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (Z.Y., G.L.G.), Environmental and Occupational Health Sciences Institute (Z.Y., H.Z., G.L.G.), Department of Environmental and Occupational Health Justice, School of Public Health (H.Z.), Rutgers Center for Lipid Research (G.L.G.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
| | - Helmut Zarbl
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (Z.Y., G.L.G.), Environmental and Occupational Health Sciences Institute (Z.Y., H.Z., G.L.G.), Department of Environmental and Occupational Health Justice, School of Public Health (H.Z.), Rutgers Center for Lipid Research (G.L.G.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (Z.Y., G.L.G.), Environmental and Occupational Health Sciences Institute (Z.Y., H.Z., G.L.G.), Department of Environmental and Occupational Health Justice, School of Public Health (H.Z.), Rutgers Center for Lipid Research (G.L.G.), Rutgers, The State University of New Jersey, New Brunswick, New Jersey; and VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey (G.L.G.)
| |
Collapse
|
|
9
|
Yang D, Lyu C, He K, Pang K, Guo Z, Wu D. Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis and Treatment in the Era of Precision Medicine. Int J Mol Sci 2024; 25:1544. [PMID: 38338820 PMCID: PMC10855108 DOI: 10.3390/ijms25031544] [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: 12/19/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Bile acid diarrhea (BAD) is a multifaceted intestinal disorder involving intricate molecular mechanisms, including farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and Takeda G protein-coupled receptor 5 (TGR5). Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and 75Selenium HomotauroCholic acid test (75SeHCAT). Treatment primarily involves BAS and FXR agonists. However, due to the limited sensitivity and specificity of current diagnostic methods, as well as suboptimal treatment efficacy and the presence of side effects, there is an urgent need to establish new diagnostic and treatment methods. While prior literature has summarized various diagnostic and treatment methods and the pathogenesis of BAD, no previous work has linked the two. This review offers a molecular perspective on the clinical diagnosis and treatment of BAD, with a focus on FXR, FGFR4, and TGR5, emphasizing the potential for identifying additional molecular mechanisms as treatment targets and bridging the gap between diagnostic and treatment methods and molecular mechanisms for a novel approach to the clinical management of BAD.
Collapse
Affiliation(s)
- Daiyu Yang
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (D.Y.); (K.P.); (Z.G.)
| | - Chengzhen Lyu
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (C.L.); (K.H.)
| | - Kun He
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (C.L.); (K.H.)
| | - Ke Pang
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (D.Y.); (K.P.); (Z.G.)
| | - Ziqi Guo
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (D.Y.); (K.P.); (Z.G.)
| | - Dong Wu
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (C.L.); (K.H.)
| |
Collapse
|
|
10
|
Borup C, Vinter-Jensen L, Jørgensen SPG, Wildt S, Graff J, Gregersen T, Zaremba A, Andersen TB, Nøjgaard C, Timm HB, Lamazière A, Rainteau D, Hansen SH, Rumessen JJ, Munck LK. Prospective comparison of diagnostic tests for bile acid diarrhoea. Aliment Pharmacol Ther 2024; 59:39-50. [PMID: 37794830 DOI: 10.1111/apt.17739] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 05/23/2023] [Accepted: 09/21/2023] [Indexed: 10/06/2023]
Abstract
BACKGROUND Bile acid diarrhoea is often missed because gold standard nuclear medicine tauroselcholic [75-Se] acid (SeHCAT) testing has limited availability. Empirical treatment effect has unknown diagnostic performance, whereas plasma 7α-hydroxy-4-cholesten-3-one (C4) is inexpensive but lacks sensitivity. AIMS To determine diagnostic characteristics of empirical treatment and explore improvements in diagnostics with potential better availability than SeHCAT. METHODS This diagnostic accuracy study was part of a randomised, placebo-controlled trial of colesevelam. Consecutive patients with chronic diarrhoea attending SeHCAT had blood and stool sampled. Key thresholds were C4 > 46 ng/mL and SeHCAT retention ≤10%. A questionnaire recorded patient-reported empirical treatment effect. We analysed receiver operating characteristics and explored machine learning applied logistic regression and decision tree modelling with internal validation. RESULTS Ninety-six (38%) of 251 patients had SeHCAT retention ≤10%. The effect of empirical treatment assessed with test results for bile acid studies blinded had 63% (95% confidence interval 44%-79%) sensitivity and 65% (47%-80%) specificity; C4 > 46 ng/mL had 47% (37%-57%) and 92% (87%-96%), respectively. A decision tree combining C4 ≥ 31 ng/mL with ≥1.1 daily watery stools (Bristol type 6 and 7) had 70% (51%-85%) sensitivity and 95% (83%-99%) specificity. The logistic regression model, including C4, the sum of measured stool bile acids and daily watery stools, had 77% (58%-90%) sensitivity and 93% (80%-98%) specificity. CONCLUSIONS Diagnosis of bile acid diarrhoea using empirical treatment was inadequate. Exploration suggested considerable improvements in the sensitivity of C4-based testing, offering potential widely available diagnostics. Further validation is warranted. CLINICALTRIALS gov: NCT03876717.
Collapse
Affiliation(s)
- Christian Borup
- Department of Internal Medicine, Zealand University Hospital, Køge, Køge, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Lars Vinter-Jensen
- Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | | | - Signe Wildt
- Unit of Medical and Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Jesper Graff
- Department of Clinical Physiology and Nuclear Medicine, Hvidovre University Hospital, Hvidovre, Denmark
| | - Tine Gregersen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
| | - Anna Zaremba
- Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | | | - Camilla Nøjgaard
- Unit of Medical and Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Hans Bording Timm
- Unit of Medical and Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Antonin Lamazière
- Département de Métabolomique Clinique METOMICS, Hôpital Saint Antoine, Sorbonne University, Paris, France
| | - Dominique Rainteau
- Département de Métabolomique Clinique METOMICS, Hôpital Saint Antoine, Sorbonne University, Paris, France
| | - Svend Høime Hansen
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | | | - Lars Kristian Munck
- Department of Internal Medicine, Zealand University Hospital, Køge, Køge, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
11
|
Lupianez-Merly C, Dilmaghani S, Camilleri M. Recent developments in diagnosing bile acid diarrhea. Expert Rev Gastroenterol Hepatol 2023; 17:1185-1195. [PMID: 38086533 DOI: 10.1080/17474124.2023.2293814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 12/08/2023] [Indexed: 01/19/2024]
Abstract
INTRODUCTION Bile acid diarrhea (BAD) commonly causes chronic diarrhea. Symptoms may be mistaken for disorders of gut brain interaction. Due to the lack of widely available diagnostic tests and poor recognition of BAD, there is a delay in diagnosis leading to increased healthcare system burden and decreased patient quality of life. AREAS COVERED A thorough review of the literature was conducted using PubMed for articles on the biological functions of bile acids, pathophysiology and management of BAD, but focusing on diagnostic testing including 75SeHCAT retention, 7αC4, FGF-19, fecal bile acids, and single stool tests. This narrative review discusses available modalities focusing on noninvasive stool and serum testing that are more widely available and show good sensitivity and specificity for diagnosis of BAD. 75SeHCAT retention is not available in many countries. Alternative diagnostic tests include total and primary fecal bile acid (BA) excretion in 48-hour collection or a single stool sample, serum7αC4 >46 or 52.5 ng/mL, and combination of single stool and serum 7αC4 ±watery stools (Bristol Stool Form Scale 6-7). EXPERT OPINION Given the ease of serum and single stool sample acquisition and diagnostic advances, clinical practice should embrace positive diagnosis, rather than BAS therapeutic trial. BAD needs to be considered in diverse gastrointestinal diseases.
Collapse
Affiliation(s)
- Camille Lupianez-Merly
- Division of Gastroenterology and Hepatology, Mayo Clinic, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Rochester, MN, USA
| | - Saam Dilmaghani
- Division of Gastroenterology and Hepatology, Mayo Clinic, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Rochester, MN, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Rochester, MN, USA
| |
Collapse
|
|
12
|
Huang RL, Huang WK, Xiao XY, Ma LF, Gu HZR, Yang GP. Diagnosis and treatment of post-cholecystectomy diarrhoea. World J Gastrointest Surg 2023; 15:2398-2405. [PMID: 38111762 PMCID: PMC10725554 DOI: 10.4240/wjgs.v15.i11.2398] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/22/2023] [Accepted: 09/22/2023] [Indexed: 11/26/2023] Open
Abstract
The incidence of cholecystitis is relatively high in developed countries and may usually be attributed to gallstones, the treatment for which involves complete surgical removal of the gallbladder (cholecystectomy). Bile acids produced following cholecystectomy continue to flow into the duodenum but are poorly absorbed by the colon. Excessive bile acids in the colon stimulate mucosal secretion of water and electrolytes leading, in severe cases, to diarrhoea. Bile acid diarrhoea (BAD) is difficult to diagnose, requiring a comprehensive medical history and physical examination in combination with laboratory evaluation. The current work reviews the diagnosis and treatment of BAD following cholecystectomy.
Collapse
Affiliation(s)
- Rang-Lang Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of The Central South University, Changsha 410013, Hunan Province, China
| | - Wen-Kai Huang
- Department of General Medicine, The Third Xiangya Hospital of The Central South University, Changsha 410013, Hunan Province, China
| | - Xiang-Yi Xiao
- The Xiangya School of Medicine, The Central South University, Changsha 410013, Hunan Province, China
| | - Lin-Feng Ma
- The Xiangya School of Medicine, The Central South University, Changsha 410013, Hunan Province, China
| | - He-Zi-Rui Gu
- The Xiangya School of Medicine, The Central South University, Changsha 410013, Hunan Province, China
| | - Guo-Ping Yang
- Department of Clinical Pharmacy, The Third Hospital of The Central South University, Changsha 410013, Hunan Province, China
| |
Collapse
|
|
13
|
Ng JJJ, Loo WM, Siah KTH. Associations between irritable bowel syndrome and non-alcoholic fatty liver disease: A systematic review. World J Hepatol 2023; 15:925-938. [PMID: 37547029 PMCID: PMC10401413 DOI: 10.4254/wjh.v15.i7.925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/12/2023] [Accepted: 07/03/2023] [Indexed: 07/21/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is associated with obesity and metabolic syndrome. IBS and non-alcoholic fatty liver disease (NAFLD) are highly prevalent entities worldwide and may share similar mechanisms including gut dysbiosis, impaired intestinal mucosal barrier and immune system activation.
AIM To systematically review their association according to the Preferred Reporting Items for Systemic Review and Meta-analyses guidelines.
METHODS PubMed, EMBASE and Cochrane Database of Systematic Reviews were searched for relevant papers. Manual searches were also performed.
RESULTS Six studies were included. Both IBS and NAFLD subjects had significantly more metabolic risk factors like hypertension, obesity, dyslipidaemia and diabetes. Our review showed that 23.2% to 29.4% of NAFLD patients had IBS. IBS was significantly higher in NAFLD patients compared with patients without NAFLD (23.2% vs 12.5%, P < 0.01). A higher proportion of IBS patients had NAFLD (65.8% to 74.0%). IBS patients were three times more likely to have NAFLD compared with non-IBS patients (P < 0.001). Two studies showed a significant correlation between the severity of IBS and NAFLD. The proportion of NAFLD subjects with IBS increased with NAFLD severity.
CONCLUSION Further prospective studies are warranted to evaluate the relationship and shared pathways between IBS and NAFLD, potentially leading to the development of future therapeutics.
Collapse
Affiliation(s)
- Jareth Jun Jie Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Wai Mun Loo
- AliveoMedical, Mount Alvernia and Mount Elizabeth Hospitals, Singapore 574623, Singapore
| | - Kewin Tien Ho Siah
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore 119228, Singapore
- Department of Medicine, National University Hospital, Singapore 119228, Singapore
| |
Collapse
|
|
14
|
Borup C, Vinter-Jensen L, Jørgensen SPG, Wildt S, Graff J, Gregersen T, Zaremba A, Borup Andersen T, Nøjgaard C, Timm HB, Rainteau D, Hansen SH, Rumessen JJ, Munck LK. Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial. Lancet Gastroenterol Hepatol 2023; 8:321-331. [PMID: 36758570 DOI: 10.1016/s2468-1253(22)00401-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 02/11/2023]
Abstract
BACKGROUND Bile acid diarrhoea is a common but overlooked cause of chronic watery diarrhoea. Plasma 7α-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic [75Se] acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including colesevelam. We aimed to determine the efficacy and safety of colesevelam in bile acid diarrhoea. METHODS In this randomised, double-blind, placebo-controlled, investigator-initiated phase 4 trial of the sequestrant colesevelam in bile acid diarrhoea (SINBAD), we enrolled consecutive patients aged 18-79 years without inflammatory bowel disease attending SeHCAT testing for suspected bile acid diarrhoea at four Danish secondary care centres. Participants were randomly allocated 1:1 to receive 12 days of treatment with colesevelam (overencapsulated tablets of 625 mg) or placebo, with the starting dose of two capsules twice daily and titrated to effect during the first 5 days of treatment. A pharmacist independent of the clinical investigators generated a randomisation list on the web page randomization.com using block randomisation (randomisation was not stratified). C4 and SeHCAT diagnostic results were blinded during treatment. We treated all patients with diarrhoea, with a daily mean of 3·0 or more bowel movements or 1·0 or more watery bowel movements (Bristol stool scale type 6 and 7). Remission was defined as the absence of both these criteria during treatment days 6-12. The primary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by C4 concentration greater than 46 ng/mL. A secondary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by SeHCAT retention of 10% or less. This trial is registered with ClinicalTrials.gov, NCT03876717. FINDINGS Between Oct 25, 2018, and July 1, 2021, 168 patients were randomly assigned to receive colesevelam (n=84) or placebo (n=84). 41 patients had C4 concentration greater than 46 ng/mL (22 assigned to the colesevelam group and 19 to the placebo group). For the C4-defined primary outcome, 14 (64%) of 22 participants receiving colesevelam versus three (16%) of 19 participants receiving placebo achieved remission (adjusted odds ratio 9·1, 95% CI 1·9-62·8; p=0·011). For the SeHCAT-defined secondary outcome, 75 of the 168 participants had retention of less than 10% (37 assigned to the colesevelam group and 38 assigned to the placebo group); 22 (59%) of 37 participants receiving colesevelam achieved remission versus five (13%) of 38 participants receiving placebo (adjusted odds ratio 11·1, 95% CI 3·4-45·6; p=0·00020). There were no serious adverse events. Common adverse events were transient. For patients receiving colesevelam within the primary outcome population, five had abdominal pain, nine had bloating, and four had nausea. For patients receiving placebo, four had abdominal pain, four had bloating, and one had nausea. No participants with bile acid diarrhoea withdrew due to adverse events. INTERPRETATION Colesevelam was superior to placebo at inducing remission of bile acid diarrhoea diagnosed with C4 concentration greater than 46 ng/mL. Secondary outcome data suggest similar efficacy treating SeHCAT-defined bile acid diarrhoea. Colesevelam was safe during the treatment. FUNDING Fabrikant Vilhelm Pedersen og hustrus mindelegat; recommended by the Novo Nordisk Foundation.
Collapse
Affiliation(s)
- Christian Borup
- Zealand University Hospital, Department of Internal Medicine, Køge, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Lars Vinter-Jensen
- Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | | | - Signe Wildt
- Unit of Medical and Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Jesper Graff
- Department of Clinical Physiology and Nuclear Medicine, Hvidovre University Hospital, Hvidovre, Denmark
| | - Tine Gregersen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
| | - Anna Zaremba
- Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | | | - Camilla Nøjgaard
- Unit of Medical and Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Hans Bording Timm
- Unit of Medical and Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Dominique Rainteau
- Hôpital Saint Antoine, Sorbonne University, Département de Métabolomique Clinique METOMICS, Paris, France
| | - Svend Høime Hansen
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | | | - Lars Kristian Munck
- Zealand University Hospital, Department of Internal Medicine, Køge, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
15
|
Niang LY, Heckroth M, Mathur P, Abell TL. Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities. Expert Opin Investig Drugs 2023; 32:245-262. [PMID: 36872904 DOI: 10.1080/13543784.2023.2186222] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
INTRODUCTION Gastroparesis (Gp) and related disorders such as chronic unexplained nausea and vomiting and functional dyspepsia, known as gastropareis syndromes (GpS), have large unmet needs. Mainstays of GpS treatments are diet and drugs. AREAS COVERED The purpose of this review is to explore potential new medications and other therapies for gastroparesis. Before discussing possible new drugs, the currently used drugs are discussed. These include dopamine receptor antagonists, 5-hydroxytryptamine receptor agonists and antagonists, neurokinin-1 receptor antagonists and other anti-emetics. The article also considers future drugs that may be used for Gp, based on currently known pathophysiology. EXPERT OPINION Gaps in knowledge about the pathophysiology of gastroparesis and related syndromes are critical to developing therapeutic agents that will be successful. Recent major developments in the gastroparesis arena are related to microscopic anatomy, cellular function, and pathophysiology. The major challenges moving forward will be to develop the genetic and biochemical correlates of these major developments in gastroparesis research.
Collapse
Affiliation(s)
- Le Yu Niang
- Department of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA
| | - Matthew Heckroth
- Department of Medicine, University of Louisville, Louisville, Kentucky, USA
| | - Prateek Mathur
- Department of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA
| | - Thomas L Abell
- Department of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA
| |
Collapse
|
|
16
|
Gillard J, Leclercq IA. Biological tuners to reshape the bile acid pool for therapeutic purposes in non-alcoholic fatty liver disease. Clin Sci (Lond) 2023; 137:65-85. [PMID: 36601783 PMCID: PMC9816373 DOI: 10.1042/cs20220697] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/08/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023]
Abstract
Bile acids synthesized within the hepatocytes are transformed by gut microorganisms and reabsorbed into the portal circulation. During their enterohepatic cycling, bile acids act as signaling molecules by interacting with receptors to regulate pathways involved in many physiological processes. The bile acid pool, composed of a variety of bile acid species, has been shown to be altered in diseases, hence contributing to disease pathogenesis. Thus, understanding the changes in bile acid pool size and composition in pathological processes will help to elaborate effective pharmacological treatments. Five crucial steps along the enterohepatic cycle shape the bile acid pool size and composition, offering five possible targets for therapeutic intervention. In this review, we provide an insight on the strategies to modulate the bile acid pool, and then we discuss the potential benefits in non-alcoholic fatty liver disease.
Collapse
Affiliation(s)
- Justine Gillard
- Laboratory of Hepato‐Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| | - Isabelle A. Leclercq
- Laboratory of Hepato‐Gastroenterology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
| |
Collapse
|
|
17
|
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: 47] [Impact Index Per Article: 23.5] [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.
Collapse
|
|
18
|
Storr M, Gross M, Madisch A, von Arnim U, Mönnikes H, Walters J, Krammer H, Keller J. Chologene Diarrhö, Stiefkind der chronischen Diarrhö
– Prävalenz, Diagnostik und Therapie. AKTUELLE ERNÄHRUNGSMEDIZIN 2022. [DOI: 10.1055/a-1923-0760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Die chologene Diarrhö ist eine der häufigsten nicht
diagnostizierten Ursachen der chronischen Diarrhö, der zahlreiche
verschiedene Pathophysiologien zugrunde liegen können. Auch nach
Ausschlussdiagnostik der häufigeren Ursachen verbleiben bis zu
5% der Bevölkerung von einer ungeklärten chronischen
Diarrhö betroffen. In diesem Kollektiv findet sich in bis zu 50%
als Ursache eine chologene Diarrhö.
Collapse
|
|
19
|
Current and Future Therapeutic Options for Irritable Bowel Syndrome with Diarrhea and Functional Diarrhea. Dig Dis Sci 2022; 68:1677-1690. [PMID: 36376576 DOI: 10.1007/s10620-022-07700-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/12/2022] [Indexed: 11/15/2022]
Abstract
Irritable bowel syndrome with diarrhea and functional diarrhea are disorders of gut-brain interaction presenting with chronic diarrhea; they have significant impact on quality of life. The two conditions may exist as a continuum and their treatment may overlap. Response to first-line therapy with antispasmodics and anti-diarrheal agents is variable, leaving several patients with suboptimal symptom control and need for alternative therapeutic options. Our aim was to discuss current pharmacologic options and explore alternative therapeutic approaches and future perspectives for symptom management in irritable bowel syndrome with diarrhea and functional diarrhea. We conducted a search of PubMed, Cochrane, clinicaltrial.gov, major meeting abstracts for publications on current, alternative, and emerging drugs for irritable bowel syndrome with diarrhea and functional diarrhea. Currently approved therapeutic options for patients with first-line refractory irritable bowel syndrome with diarrhea and functional diarrhea include serotonin-3 receptor antagonists, eluxadoline and rifaximin. Despite their proven efficacy, cost and availability worldwide impact their utilization. One-third of patients with disorders of gut-brain interaction with diarrhea have bile acid diarrhea and may benefit from drugs targeting bile acid synthesis and excretion. Further understanding of underlying pathophysiology of irritable bowel syndrome with diarrhea and functional diarrhea related to bile acid metabolism, gastrointestinal transit, and microbiome has led to evaluation of novel therapeutic approaches, including fecal microbiota transplantation and enterobacterial "crapsules". These opportunities to treat disorders of gut-brain interaction with diarrhea should be followed with formal studies utilizing large samples of well-characterized patients at baseline and validated response outcomes as endpoints for regulatory approval.
Collapse
|
|
20
|
Chen J, Stringer R, Shah B, Gu J, Zhang Y, Hackling M, Prince W, Woessner R. Drug-Drug Interaction Studies to Evaluate the Effect of Inhibition of UGT1A1 and CYP3A4 and Induction of CYP3A4 on the Pharmacokinetics of Tropifexor in Healthy Subjects. Clin Pharmacol Drug Dev 2022; 11:1253-1263. [PMID: 35962468 DOI: 10.1002/cpdd.1140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 06/06/2022] [Indexed: 01/27/2023]
Abstract
Tropifexor, a farnesoid X receptor agonist, is currently under clinical development for the treatment of nonalcoholic steatohepatitis. Tropifexor undergoes glucuronidation by uridine 5'-diphosphoglucuronosyltransferase (UGT) 1A1 and oxidation by cytochrome P450 (CYP) 3A4, as reported in in vitro studies. Here, we report the results from 2 drug-drug interaction studies. Study 1 enrolled 20 healthy subjects to investigate the effect of the UGT1A1 inhibitor atazanavir (ATZ) on tropifexor pharmacokinetics (PK). Study 2 had 2 cohorts with 16 healthy subjects each to investigate the effect of the strong CYP3A4 inhibitor itraconazole and strong CYP3A4 inducer rifampin on the PK of tropifexor. Coadministration of ATZ reduced the maximum plasma concentration (Cmax ) of tropifexor by 40%; however, it did not lead to increased exposure of tropifexor (both area under the plasma concentration-time curve [AUC] from time 0 to the last quantifiable concentration [AUClast ] and AUC from time 0 to infinity [AUCinf ] reduced by only 10%), suggesting minor relevance of the UGT1A1 pathway for clearance of tropifexor and no expected drug-drug interactions based on UGT1A1 inhibition. Inhibition of CYP3A4 by itraconazole increased the Cmax of tropifexor by only 9% and exposure (both AUClast and AUCinf ) by 47%, suggesting a weak effect of strong CYP3A4 inhibitors on tropifexor PK. Inducing CYP3A4 with rifampin decreased Cmax (55%) and AUC (AUClast by 79% and AUCinf by 77%). Coadministration of tropifexor with either ATZ, itraconazole, or rifampin was well tolerated.
Collapse
Affiliation(s)
- Jin Chen
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Rowan Stringer
- Novartis Institutes for BioMedical Research, PK Sciences, Basel, Switzerland
| | - Bharti Shah
- Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA
| | - Jessie Gu
- Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA
| | - Yiming Zhang
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | - Melissa Hackling
- Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA
| | - William Prince
- Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA
| | - Ralph Woessner
- Novartis Institutes for BioMedical Research, PK Sciences, Basel, Switzerland
| |
Collapse
|
|
21
|
Fallon CM, Smyth JS, Quach A, Lajczak-McGinley N, O’Toole A, Barrett KE, Sheridan H, Keely SJ. Pentacyclic triterpenes modulate farnesoid X receptor expression in colonic epithelial cells: implications for colonic secretory function. J Biol Chem 2022; 298:102569. [PMID: 36209824 PMCID: PMC9663526 DOI: 10.1016/j.jbc.2022.102569] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 10/01/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important regulator of intestinal and metabolic function. Previous studies suggest that pentacyclic triterpenes (PCTs), a class of plant-derived bioactive phytochemical, can modulate FXR activity and may therefore offer therapeutic benefits. Here, we investigated the effects of a prototypical PCT, hederagenin (HG), on FXR expression, activity, and antisecretory actions in colonic epithelial cells. T84 cells and murine enteroid-derived monolayers were employed to assess HG effects on FXR expression and activity in colonic epithelia. We measured mRNA levels by qRT-PCR and protein by ELISA and immunoblotting. Transepithelial Cl− secretion was assessed as changes in short circuit current in Ussing chambers. We determined HG treatment (5–10 μM) alone did not induce FXR activation but significantly increased expression of the receptor, both in T84 cells and murine enteroid-derived monolayers. This effect was accompanied by enhanced FXR activity, as assessed by FGF-15/19 induction in response to the synthetic, GW4064, or natural FXR agonist, chenodeoxycholic acid. Effects of HG on FXR expression and activity were mimicked by another PCT, oleanolic acid. Furthermore, we found FXR-induced downregulation of cystic fibrosis transmembrane conductance regulator Cl− channels and inhibition of transepithelial Cl− secretion were enhanced in HG-treated cells. These data demonstrate that dietary PCTs have the capacity to modulate FXR expression, activity, and antisecretory actions in colonic epithelial cells. Based on these data, we propose that plants rich in PCTs, or extracts thereof, have excellent potential for development as a new class of “FXR-targeted nutraceuticals”.
Collapse
|
|
22
|
Panzitt K, Zollner G, Marschall HU, Wagner M. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol 2022; 552:111678. [PMID: 35605722 DOI: 10.1016/j.mce.2022.111678] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/25/2022]
Abstract
The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
Collapse
Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
| |
Collapse
|
|
23
|
Mori H, Svegliati Baroni G, Marzioni M, Di Nicola F, Santori P, Maroni L, Abenavoli L, Scarpellini E. Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota. Metabolites 2022; 12:647. [PMID: 35888771 PMCID: PMC9320384 DOI: 10.3390/metabo12070647] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/01/2022] [Accepted: 07/01/2022] [Indexed: 02/04/2023] Open
Abstract
Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are characterized by the concepts of lipo- and glucotoxicity. NAFLD is characterized by the accumulation of different lipidic species within the hepatocytes. Bile acids (BA), derived from cholesterol, and conjugated and stored in the gallbladder, help the absorption/processing of lipids, and modulate host inflammatory responses and gut microbiota (GM) composition. The latter is the new "actor" that links the GI tract and liver in NAFLD pathogenesis. In fact, the discovery and mechanistic characterization of hepatic and intestinal farnesoid X receptor (FXR) shed new light on the gut-liver axis. We conducted a search on the main medical databases for original articles, reviews, meta-analyses of randomized clinical trials, and case series using the following keywords, their acronyms, and their associations: farnesoid X receptor, bile acids metabolism, gut microbiota, dysbiosis, and liver steatosis. Findings on the synthesis, metabolism, and conjugation processes of BAs, and their action on FXR, change the understanding of NAFLD physiopathology. In detail, BAs act as ligands to several FXRs with GM modulation. On the other hand, the BAs pool is modulated by GM, thus, regulating FXRs functioning in the frame of liver fat deposition and fibrosis development. In conclusion, BAs passed from their role of simple lipid absorption and metabolism agents to messengers between the gut and liver, modulated by GM.
Collapse
Affiliation(s)
- Hideki Mori
- T.A.R.G.I.D., Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Leuven, Belgium;
| | | | - Marco Marzioni
- Gastroenterology Clinic; Università Politecnica delle Marche, 60121 Ancona, Italy; (M.M.); (L.M.)
| | - Francesca Di Nicola
- Hepatology Outpatient Clinic and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy; (F.D.N.); (P.S.)
| | - Pierangelo Santori
- Hepatology Outpatient Clinic and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy; (F.D.N.); (P.S.)
| | - Luca Maroni
- Gastroenterology Clinic; Università Politecnica delle Marche, 60121 Ancona, Italy; (M.M.); (L.M.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy;
| | - Emidio Scarpellini
- T.A.R.G.I.D., Gasthuisberg University Hospital, KU Leuven, Herestraat 49, 3000 Leuven, Belgium;
- Hepatology Outpatient Clinic and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, 63074 San Benedetto del Tronto, Italy; (F.D.N.); (P.S.)
| |
Collapse
|
|
24
|
Kumar A, Galbraith N, Al-Hassi HO, Jain M, Phipps O, Butterworth J, Steed H, McLaughlin J, Brookes MJ. The impact of treatment with bile acid sequestrants on quality of life in patients with bile acid diarrhoea. BMC Gastroenterol 2022; 22:325. [PMID: 35778677 PMCID: PMC9250209 DOI: 10.1186/s12876-022-02404-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 06/09/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Bile acid diarrhoea (BAD) can be severely debilitating and negatively affect patients' quality of life (QoL). We carried out a multi-centre prospective study exploring QoL outcomes in patients with BAD after treatment with colesevelam. METHODS Patients with or without a positive 23-seleno-25-homotaurocholic acid (SeHCAT) scan were recruited and categorised into four groups: SeHCAT negative control group (CG), idiopathic BAD, post-cholecystectomy (PC) and post-terminal ileal resection for Crohn's disease (CD). Patients with a positive SeHCAT were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL was evaluated by EQ-5D-3L, SF-36, IBDQ-32 at each visit (where relevant). Patients with a negative SeHCAT (CG cohort) completed one set of questionnaires before being discharged from the study. RESULTS 47 patients (BAD = 24, PC = 12, CD = 11) completed paired QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. There was a significant improvement in IBDQ-32 mean scores before and after treatment in CD patients [134.6 (95%CI 112.5-156.6) and 158.4 (136.1-180.6), respectively (p = 0.007). Following treatment, BAD patients had significantly improved mean SF-36 scores in the "Role limitation due to physical health" dimension (p = 0.02) and in the overall mental component summary (p = 0.03). Prior to starting treatment, BAD patients had the lowest scores in the 'activity' dimension of the EQ-5D-3L (p = 0.04), which improved significantly after treatment (p = 0.002). Overall, the BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, while the PC cohort showed a general decline in mean scores after treatment. 55% of patients clinically responded to treatment of which 41.7%, 58.3% and 81.8% responded from the BAD, PC and CD groups respectively. Correlations between those deemed as responders with improvements on the SF-36 and EQ-5D dimensions were not statistically significant. CONCLUSION Our results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists. Trial registration Ethical approval REC Ref: 16/LO/1325.
Collapse
Affiliation(s)
- Aditi Kumar
- The Royal Wolverhampton NHS Trust, Wolverhampton Road, Wolverhampton, WV10 0QP, UK. .,Faculty of Science and Engineering, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK.
| | - Niall Galbraith
- Faculty of Science and Engineering, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK
| | - Hafid O Al-Hassi
- Faculty of Science and Engineering, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK
| | - Manushri Jain
- The Royal Wolverhampton NHS Trust, Wolverhampton Road, Wolverhampton, WV10 0QP, UK
| | - Oliver Phipps
- Faculty of Science and Engineering, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton, UK
| | | | - Helen Steed
- The Royal Wolverhampton NHS Trust, Wolverhampton Road, Wolverhampton, WV10 0QP, UK.,School of Medicine and Clinical Practice, Faculty of Sciences and Engineering, University of Wolverhampton, Wolverhampton, UK
| | - John McLaughlin
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,Department of Gastroenterology, Salford Royal Foundation Trust, Stott Lane, Salford, UK
| | - Matthew J Brookes
- The Royal Wolverhampton NHS Trust, Wolverhampton Road, Wolverhampton, WV10 0QP, UK.,School of Medicine and Clinical Practice, Faculty of Sciences and Engineering, University of Wolverhampton, Wolverhampton, UK
| |
Collapse
|
|
25
|
Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 2022; 19:432-450. [PMID: 35165436 DOI: 10.1038/s41575-021-00566-7] [Citation(s) in RCA: 208] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 02/06/2023]
Abstract
Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.
Collapse
|
|
26
|
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.
Collapse
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.)
| |
Collapse
|
|
27
|
Carneiro PV, Montenegro NDA, Lana A, Amato AA, Santos GM. Lipids from gut microbiota: pursuing a personalized treatment. Trends Mol Med 2022; 28:631-643. [PMID: 35739018 DOI: 10.1016/j.molmed.2022.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/16/2022] [Accepted: 06/01/2022] [Indexed: 10/18/2022]
Abstract
The discovery of microbiome metabolites has enlivened the field of fecal transplantation for therapeutic purposes. However, the transfer of pathogenic living organisms was recently observed to limit its therapeutic potential by increasing the risk of infection. Lipids produced by gut microbiota enter the circulation and control many phenotypic changes associated with microbiota composition. Fecal lipids significantly impact the regulation of several cell signaling pathways, including inflammation. Focusing on these molecules, we review how bioactive gut microbiota-associated lipids affect cellular functioning and clinical outcome. Here, we interrogate whether the gut microbiota can be considered a cutting-edge biotechnological tool for rapid metabolic engineering of meaningful lipids to offer a novel personalized therapy.
Collapse
Affiliation(s)
- Pamela V Carneiro
- Laboratório de Farmacologia Molecular, Universidade de Brasília, Brasília, Brasil
| | | | - Addison Lana
- Department of Cellular and Molecular Medicine, University of California, San Diego, CA, USA
| | - Angelica A Amato
- Laboratório de Farmacologia Molecular, Universidade de Brasília, Brasília, Brasil
| | - Guilherme M Santos
- Laboratório de Farmacologia Molecular, Universidade de Brasília, Brasília, Brasil.
| |
Collapse
|
|
28
|
Marasco G, Cremon C, Barbaro MR, Falangone F, Montanari D, Capuani F, Mastel G, Stanghellini V, Barbara G. Pathophysiology and Clinical Management of Bile Acid Diarrhea. J Clin Med 2022; 11:jcm11113102. [PMID: 35683489 PMCID: PMC9180966 DOI: 10.3390/jcm11113102] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 11/16/2022] Open
Abstract
Bile acid malabsorption (BAM) represents a common cause of chronic diarrhea whose prevalence is under-investigated. We reviewed the evidence available regarding the pathophysiology and clinical management of bile acid diarrhea (BAD). BAD results from dysregulation of the enterohepatic recirculation of bile acids. It has been estimated that 25–33% of patients with functional diarrhea and irritable bowel syndrome with diarrhea have BAM. Currently, the selenium homotaurocholic acid test is the gold standard for BAD diagnosis and severity assessment. However, it is an expensive method and not widely available. The validation of the utility in the clinical practice of several other serum markers, such as 7α-hydroxy-4-cholesten-3-one (C4) and the fibroblast growth factor 19 (FGF19) is ongoing. The first-line treatment of patients with BAD is bile acid sequestrants. Patients that are refractory to first-line therapy should undergo further diagnostics to confirm the diagnosis and to treat the underlying cause of BAD. An early and correct diagnosis of BAD would improve patient’s quality of life, avoiding additional diagnostic tests that burden health care systems. Considering the limited availability and tolerability of specific medications for BAD treatment, future research is awaited to identify other therapeutic approaches, such as gut microbiota modulating therapies.
Collapse
Affiliation(s)
- Giovanni Marasco
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Cesare Cremon
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Maria Raffaella Barbaro
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
| | - Francesca Falangone
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Sapienza, 00185 Rome, Italy;
| | - Davide Montanari
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Federica Capuani
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Giada Mastel
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Vincenzo Stanghellini
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Giovanni Barbara
- Division of Internal Medicine, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy; (G.M.); (C.C.); (M.R.B.); (D.M.); (F.C.); (G.M.); (V.S.)
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
- Correspondence: ; Tel.: +39-0512144103
| |
Collapse
|
|
29
|
Way GW, Jackson KG, Muscu SR, Zhou H. Key Signaling in Alcohol-Associated Liver Disease: The Role of Bile Acids. Cells 2022; 11:1374. [PMID: 35456053 PMCID: PMC9031669 DOI: 10.3390/cells11081374] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 02/01/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a spectrum of diseases, the onset and progression of which are due to chronic alcohol use. ALD ranges, by increasing severity, from hepatic steatosis to alcoholic hepatitis (AH) and alcohol-associated cirrhosis (AC), and in some cases, can lead to the development of hepatocellular carcinoma (HCC). ALD continues to be a significant health burden and is now the main cause of liver transplantations in the United States. ALD leads to biological, microbial, physical, metabolic, and inflammatory changes in patients that vary depending on disease severity. ALD deaths have been increasing in recent years and are projected to continue to increase. Current treatment centers focus on abstinence and symptom management, with little in the way of resolving disease progression. Due to the metabolic disruption and gut dysbiosis in ALD, bile acid (BA) signaling and metabolism are also notably affected and play a prominent role in disease progression in ALD, as well as other liver disease states, such as non-alcoholic fatty liver disease (NAFLD). In this review, we summarize the recent advances in the understanding of the mechanisms by which alcohol consumption induces hepatic injury and the role of BA-mediated signaling in the pathogenesis of ALD.
Collapse
Affiliation(s)
- Grayson W. Way
- Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Kaitlyn G. Jackson
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA; (K.G.J.); (S.R.M.)
| | - Shreya R. Muscu
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA; (K.G.J.); (S.R.M.)
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA; (K.G.J.); (S.R.M.)
- Central Virginia Veterans Healthcare System, Richmond, VA 23249, USA
| |
Collapse
|
|
30
|
Keely SJ, Barrett KE. Intestinal secretory mechanisms and diarrhea. Am J Physiol Gastrointest Liver Physiol 2022; 322:G405-G420. [PMID: 35170355 PMCID: PMC8917926 DOI: 10.1152/ajpgi.00316.2021] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/31/2023]
Abstract
One of the primary functions of the intestinal epithelium is to transport fluid and electrolytes to and from the luminal contents. Under normal circumstances, absorptive and secretory processes are tightly regulated such that absorption predominates, thereby enabling conservation of the large volumes of water that pass through the intestine each day. However, in conditions of secretory diarrhea, this balance becomes dysregulated, so that fluid secretion, driven primarily by Cl- secretion, overwhelms absorptive capacity, leading to increased loss of water in the stool. Secretory diarrheas are common and include those induced by pathogenic bacteria and viruses, allergens, and disruptions to bile acid homeostasis, or as a side effect of many drugs. Here, we review the cellular and molecular mechanisms by which Cl- and fluid secretion in the intestine are regulated, how these mechanisms become dysregulated in conditions of secretory diarrhea, currently available and emerging therapeutic approaches, and how new strategies to exploit intestinal secretory mechanisms are successfully being used in the treatment of constipation.
Collapse
Affiliation(s)
- Stephen J Keely
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Kim E Barrett
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California
- Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, California
| |
Collapse
|
|
31
|
Camilleri M, Nurko S. Bile Acid Diarrhea in Adults and Adolescents. Neurogastroenterol Motil 2022; 34:e14287. [PMID: 34751982 PMCID: PMC8957499 DOI: 10.1111/nmo.14287] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/22/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bile acids are central to enterohepatic signaling pathways activated through natural receptors, farnesoid X receptor [FXR mediates synthesis of fibroblast growth factor-19 (FGF-19)], and G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Although bile acid diarrhea (BAD) is more commonly encountered in ileal resection or disease, there is evidence documenting "idiopathic" BAD in about 20% of adolescents and 30% of adults presenting with chronic, non-bloody diarrhea often attributed to irritable bowel syndrome. Mechanism(s) leading to increased hepatic synthesis and colonic bile acid levels in "idiopathic" BAD include reduced synthesis of FGF-19 by the ileal mucosa, or genetic variation in hepatocyte proteins klotho β and FGF receptor 4 (FGFR4) that mediate negative feedback of bile acid synthesis. PURPOSE The objective of this review is to summarize the diagnosis of BAD in adults and adolescents. In addition to 75 SeHCAT retention for diagnosis of BAD, studies have validated fasting serum 7αC4 and FGF-19, respectively, by-product and inhibitor of hepatic bile acid synthesis, as well as fecal bile acid measurements. These assays are widely available through reference laboratories, and they are being simplified (eg, measurement of primary fecal bile acids in a random stool sample). BAD has also been identified as a co-factor contributing to persistent diarrhea in other diseases in remission including inflammatory bowel disease, microscopic colitis, celiac disease, and neuroendocrine tumors. In summary, advances in diagnosis of BAD provide opportunities for generalists and pediatric and adult gastroenterologists to provide targeted treatment for BAD presenting as chronic non-bloody diarrhea.
Collapse
Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) and Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN USA
| | - Samuel Nurko
- Department of Pediatric Gastroenterology Boston Children’s Hospital Boston MA USA
| |
Collapse
|
|
32
|
Elwing JE, Atassi H, Rogers BD, Sayuk GS. Emerging therapies in the management of Irritable Bowel Syndrome (IBS). Expert Opin Emerg Drugs 2022; 27:55-73. [PMID: 35266839 DOI: 10.1080/14728214.2022.2052043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a common, symptom-based disorder of chronic abdominal pain and altered bowel habits. The pathogenesis of IBS is multifactorial, leading to the potential for the development of multiple, diverse treatment strategies. This mechanistic heterogeneity also leads to the realization that available therapies are only effective in a subset of IBS suffers. Current US Food and Drug Administration (FDA) approved therapies for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) are reviewed. Limited symptom responses and side effect experiences lead to considerable patient dissatisfaction with currently available IBS treatments. Only a small percentage of IBS patients are on prescription therapies underscoring the potential market and need for additional therapeutic options. AREAS COVERED : Expanding on currently available therapies, the serotonergic and endogenous opioid receptor systems continue to be a focus of future IBS treatment development. Additional novel emerging therapies include the endogenous cannabinoid system, bile acid secretion and sequestration, and exploit our enhanced understanding of visceral sensory signaling and intestinal secretomotor function. EXPERT OPINION While challenges remain for the future development of IBS therapies, the diverse etiologies underlying the disorder present an opportunity for novel therapies. Hence, great potential is anticipated for future IBS treatment options.
Collapse
Affiliation(s)
- Jill E Elwing
- St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA
| | - Hadi Atassi
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
| | - Benjamin D Rogers
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gregory S Sayuk
- St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA.,Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
| |
Collapse
|
|
33
|
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.
Collapse
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
| |
Collapse
|
|
34
|
Singh R, Zogg H, Ghoshal UC, Ro S. Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders. Front Pharmacol 2022; 13:808195. [PMID: 35145413 PMCID: PMC8822166 DOI: 10.3389/fphar.2022.808195] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) have been re-named as disorders of gut-brain interactions. These conditions are not only common in clinical practice, but also in the community. In reference to the Rome IV criteria, the most common FGIDs, include functional dyspepsia (FD) and irritable bowel syndrome (IBS). Additionally, there is substantial overlap of these disorders and other specific gastrointestinal motility disorders, such as gastroparesis. These disorders are heterogeneous and are intertwined with several proposed pathophysiological mechanisms, such as altered gut motility, intestinal barrier dysfunction, gut immune dysfunction, visceral hypersensitivity, altered GI secretion, presence and degree of bile acid malabsorption, microbial dysbiosis, and alterations to the gut-brain axis. The treatment options currently available include lifestyle modifications, dietary and gut microbiota manipulation interventions including fecal microbiota transplantation, prokinetics, antispasmodics, laxatives, and centrally and peripherally acting neuromodulators. However, treatment that targets the pathophysiological mechanisms underlying the symptoms are scanty. Pharmacological agents that are developed based on the cellular and molecular mechanisms underlying pathologies of these disorders might provide the best avenue for future pharmaceutical development. The currently available therapies lack long-term effectiveness and safety for their use to treat motility disorders and FGIDs. Furthermore, the fundamental challenges in treating these disorders should be defined; for instance, 1. Cause and effect cannot be disentangled between symptoms and pathophysiological mechanisms due to current therapies that entail the off-label use of medications to treat symptoms. 2. Despite the knowledge that the microbiota in our gut plays an essential part in maintaining gut health, their exact functions in gut homeostasis are still unclear. What constitutes a healthy microbiome and further, the precise definition of gut microbial dysbiosis is lacking. More comprehensive, large-scale, and longitudinal studies utilizing multi-omics data are needed to dissect the exact contribution of gut microbial alterations in disease pathogenesis. Accordingly, we review the current treatment options, clinical insight on pathophysiology, therapeutic modalities, current challenges, and therapeutic clues for the clinical care and management of functional dyspepsia, gastroparesis, irritable bowel syndrome, functional constipation, and functional diarrhea.
Collapse
Affiliation(s)
- Rajan Singh
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Hannah Zogg
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, United States
| |
Collapse
|
|
35
|
Wang Y, Zheng L, Zhou Z, Yao D, Huang Y, Liu B, Duan Y, Li Y. Review article: insights into the bile acid-gut microbiota axis in intestinal failure-associated liver disease-redefining the treatment approach. Aliment Pharmacol Ther 2022; 55:49-63. [PMID: 34713470 DOI: 10.1111/apt.16676] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/04/2021] [Accepted: 10/15/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Intestinal failure-associated liver disease (IFALD) increases mortality of patients with intestinal failure (IF), but lacks effective prevention or treatment approaches. Bile acids, gut microbiota and the host have close and complex interactions, which play a central role in modulating host immune and metabolic homeostasis. Increasing evidence suggests that derangement of the bile acid-gut microbiota (BA-GM) axis contributes to the development of IFALD. AIMS To review the BA-GM axis in the pathogenesis and clinical applications of IFALD, and to explore future directions for effective disease management. METHODS We conducted a literature search on bile acid and gut microbiota in IF and liver diseases. RESULTS The BA-GM axis demonstrates a unique IF signature manifesting as an increase in primary-to-secondary bile acids ratio, disturbed enterohepatic circulation, blunted bile acid signalling pathways, gut microbial dysbiosis, and altered microbial metabolic outputs. Bile acids and gut microbiota shape the compositional and functional alterations of each other in IF; collaboratively, they promote immune dysfunction and metabolic aberration in the liver. Diagnostic markers and treatments targeting the BA-GM axis showed promising potential in the management of IFALD. CONCLUSIONS Bile acids and gut microbiota play a central role in the development of IFALD and make attractive biomarkers as well as therapeutic targets. A multitarget, individualised therapy aiming at different parts of the BA-GM axis may provide optimal clinical benefits and requires future investigation.
Collapse
Affiliation(s)
- Yaoxuan Wang
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Lei Zheng
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Zhiyuan Zhou
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Danhua Yao
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Yuhua Huang
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Bin Liu
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Yantao Duan
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| | - Yousheng Li
- Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
| |
Collapse
|
|
36
|
Zhang B, Kuipers F, de Boer JF, Kuivenhoven JA. Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles. J Clin Med 2021; 11:jcm11010004. [PMID: 35011746 PMCID: PMC8745251 DOI: 10.3390/jcm11010004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.
Collapse
Affiliation(s)
- Boyan Zhang
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
| | - Folkert Kuipers
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
- Correspondence: (J.F.d.B.); (J.A.K.)
| | - Jan Albert Kuivenhoven
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Correspondence: (J.F.d.B.); (J.A.K.)
| |
Collapse
|
|
37
|
Xie AJ, Mai CT, Zhu YZ, Liu XC, Xie Y. Bile acids as regulatory molecules and potential targets in metabolic diseases. Life Sci 2021; 287:120152. [PMID: 34793769 DOI: 10.1016/j.lfs.2021.120152] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/06/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023]
Abstract
Bile acids are important hydroxylated steroids that are synthesized in the liver from cholesterol for intestinal absorption of lipids and other fatty-nutrient. They also display remarkable and immense functions such as regulating immune responses, managing the apoptosis of cells, participating in glucose metabolism, and so on. Some bile acids were used for the treatment or prevention of diseases such as gallstones, primary biliary cirrhosis, and colorectal cancer. Meanwhile, the accumulation of toxic bile acids leads to apoptosis, necrosis, and inflammation. Alteration of bile acids metabolism, as well as the gut microbiota that interacted with bile acids, contributes to the pathogenesis of metabolic diseases. Therefore, the purpose of this review is to summarize the current functions and pre-clinical or clinical applications of bile acids, and to further discuss the alteration of bile acids in metabolic disorders as well as the manipulation of bile acids metabolism as potential therapeutic targets.
Collapse
Affiliation(s)
- Ai-Jin Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Chu-Tian Mai
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Yi-Zhun Zhu
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau
| | - Xian-Cheng Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China.
| | - Ying Xie
- School of Pharmacy, Macau University of Science and Technology, Taipa, Macau.
| |
Collapse
|
|
38
|
Koelfat KV, Picot D, Chang X, Desille‐Dugast M, van Eijk HM, van Kuijk SM, Lenicek M, Layec S, Carsin M, Dussaulx L, Seynhaeve E, Trivin F, Lacaze L, Thibault R, Schaap FG, Olde Damink SW. Chyme Reinfusion Restores the Regulatory Bile Salt-FGF19 Axis in Patients With Intestinal Failure. Hepatology 2021; 74:2670-2683. [PMID: 34133768 PMCID: PMC8596508 DOI: 10.1002/hep.32017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 04/20/2021] [Accepted: 05/22/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Automated chyme reinfusion (CR) in patients with intestinal failure (IF) and a temporary double enterostomy (TDE) restores intestinal function and protects against liver injury, but the mechanisms are incompletely understood. The aim was to investigate whether the beneficial effects of CR relate to functional recovery of enterohepatic signaling through the bile salt-FGF19 axis. APPROACH AND RESULTS Blood samples were collected from 12 patients, 3 days before, at start, and 1, 3, 5, and 7 weeks after CR initiation. Plasma FGF19, total bile salts (TBS), 7-α-hydroxy-4-cholesten-3-one (C4; a marker of bile salt synthesis), citrulline (CIT), bile salt composition, liver tests, and nutritional risk indices were determined. Paired small bowel biopsies prior to CR and after 21 days were taken, and genes related to bile salt homeostasis and enterocyte function were assessed. CR induced an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis through endocrine FGF19 action. TBS remained unaltered during CR. Intestinal farnesoid X receptor was up-regulated after 21 days of CR. Secondary and deconjugated bile salt fractions were increased after CR, reflecting restored microbial metabolism of host bile salts. Furthermore, CIT and albumin levels gradually rose after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status, and amelioration of liver injury. CR increased gene transcripts related to enterocyte number, carbohydrate handling, and bile salt homeostasis. Finally, the reciprocal FGF19/C4 response after 7 days predicted the plasma CIT time course. CONCLUSIONS CR in patients with IF-TDE restored bile salt-FGF19 signaling and improved gut-liver function. Beneficial effects of CR are partly mediated by recovery of the bile salt-FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.
Collapse
Affiliation(s)
- Kiran V.K. Koelfat
- Department of SurgeryMaastricht University Medical CenterMaastrichtthe Netherlands,NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtthe Netherlands
| | - Denis Picot
- Department of Nutritional and Digestive RehabilitationClinique Saint YvesRennesFrance
| | - Xinwei Chang
- Department of SurgeryMaastricht University Medical CenterMaastrichtthe Netherlands,NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtthe Netherlands
| | - Mireille Desille‐Dugast
- INSERM, INRAEUniversity of RennesNutrition Metabolisms and CancerNuMeCanNutrition UnitCRB SantéCHU RennesRennesFrance
| | - Hans M. van Eijk
- Department of SurgeryMaastricht University Medical CenterMaastrichtthe Netherlands,NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtthe Netherlands
| | - Sander M.J. van Kuijk
- Department of Clinical Epidemiology and Medical Technology AssessmentMaastricht University Medical CenterMaastrichtthe Netherlands
| | - Martin Lenicek
- Institute of Medical Biochemistry and Laboratory Diagnostics1st Faculty of MedicineCharles UniversityPragueCzech Republic
| | - Sabrina Layec
- Department of Nutritional and Digestive RehabilitationClinique Saint YvesRennesFrance
| | - Marie Carsin
- Department of Nutritional and Digestive RehabilitationClinique Saint YvesRennesFrance
| | - Laurence Dussaulx
- Department of Nutritional and Digestive RehabilitationClinique Saint YvesRennesFrance
| | - Eloi Seynhaeve
- Department of Nutritional and Digestive RehabilitationClinique Saint YvesRennesFrance
| | - Florence Trivin
- Department of Nutritional and Digestive RehabilitationClinique Saint YvesRennesFrance
| | - Laurence Lacaze
- INSERM, INRAEUniversity of RennesNutrition Metabolisms and CancerNuMeCanNutrition UnitCRB SantéCHU RennesRennesFrance
| | - Ronan Thibault
- INSERM, INRAEUniversity of RennesNutrition Metabolisms and CancerNuMeCanNutrition UnitCRB SantéCHU RennesRennesFrance
| | - Frank G. Schaap
- Department of SurgeryMaastricht University Medical CenterMaastrichtthe Netherlands,NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtthe Netherlands,Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
| | - Steven W.M. Olde Damink
- Department of SurgeryMaastricht University Medical CenterMaastrichtthe Netherlands,NUTRIM School of Nutrition and Translational Research in MetabolismMaastricht UniversityMaastrichtthe Netherlands,Department of General, Visceral and Transplantation SurgeryRWTH University Hospital AachenAachenGermany
| |
Collapse
|
|
39
|
Simbrunner B, Trauner M, Reiberger T. Review article: therapeutic aspects of bile acid signalling in the gut-liver axis. Aliment Pharmacol Ther 2021; 54:1243-1262. [PMID: 34555862 PMCID: PMC9290708 DOI: 10.1111/apt.16602] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues. AIM This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies. METHODS We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease. RESULTS Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target. CONCLUSIONS Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.
Collapse
Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| |
Collapse
|
|
40
|
Meadows V, Kennedy L, Ekser B, Kyritsi K, Kundu D, Zhou T, Chen L, Pham L, Wu N, Demieville J, Hargrove L, Glaser S, Alpini G, Francis H. Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling. Hepatology 2021; 74:2684-2698. [PMID: 34164827 PMCID: PMC9337218 DOI: 10.1002/hep.32028] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 06/08/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)/FGF15. Patients with primary sclerosing cholangitis (PSC) typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis. In bile-duct-ligated (BDL) MC-deficient mice (B6.Cg-KitW-sh /HNihrJaeBsmJ [KitW-sh ]), ductular reaction (DR) and liver fibrosis decrease compared with BDL wild type, and MC injection exacerbates liver damage in normal mice. APPROACH AND RESULTS In this study, we demonstrated that MC-FXR regulates biliary FXR/FGF15, DR, and hepatic fibrosis and alters intestinal FXR/FGF15. We found increased MC number and biliary FXR expression in patients with liver injury compared with control. Histamine and FGF19 serum levels and small heterodimer partner expression increase in patients PSC and PSC-IBD compared with healthy controls. MC injection increased liver damage, DR, inflammation, biliary senescence/senescence-associated secretory phenotype (SASP), fibrosis, and histamine in KitW-sh mice. Inhibition of MC-FXR before injection reduced these parameters. BDL and KitW-sh mice injected with MCs displayed increased TBA content, biliary FXR/FGF15, and intestinal inflammation, which decreased in BDL KitW-sh and KitW-sh mice injected with MC-FXR. MCs increased ileal FXR/FGF15 expression in KitW-sh mice that was reduced following FXR inhibition. BDL and multidrug resistance 2/ATP-binding cassette family 2 member 4 knockout (Mdr2-/- ) mice, models of PSC, displayed increased intestinal MC infiltration and FXR/FGF15 expression. These were reduced following MC stabilization with cromolyn sodium in Mdr2-/- mice. In vitro, MC-FXR inhibition decreased biliary proliferation/SASP/FGF and hepatic stellate cell activation. CONCLUSIONS Our studies demonstrate that MC-FXR plays a key role in liver damage and DR, including TBA regulation through alteration of intestinal and biliary FXR/FGF15 signaling.
Collapse
Affiliation(s)
- Vik Meadows
- Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Linh Pham
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Jennifer Demieville
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Laura Hargrove
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX
| | - Gianfranco Alpini
- Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Heather Francis
- Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN,Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| |
Collapse
|
|
41
|
Abstract
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.
Collapse
|
|
42
|
Abstract
Antifibrotic therapies for the treatment of liver fibrosis represent an unconquered area of drug development. The significant involvement of the gut microbiota as a driving force in a multitude of liver disease, be it pathogenesis or fibrotic progression, suggest that targeting the gut–liver axis, relevant signaling pathways, and/or manipulation of the gut’s commensal microbial composition and its metabolites may offer opportunities for biomarker discovery, novel therapies and personalized medicine development. Here, we review potential links between bacterial translocation and deficits of host-microbiome compartmentalization and liver fibrosis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies, translated from our current knowledge of the gut–liver axis, targeted at restoring intestinal eubiosis, ameliorating hepatic fibrosis and rising portal hypertension that characterize and define the course of decompensated cirrhosis.
Collapse
|
|
43
|
Orozco-Aguilar J, Simon F, Cabello-Verrugio C. Redox-Dependent Effects in the Physiopathological Role of Bile Acids. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4847941. [PMID: 34527174 PMCID: PMC8437588 DOI: 10.1155/2021/4847941] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/17/2021] [Indexed: 12/17/2022]
Abstract
Bile acids (BA) are recognized by their role in nutrient absorption. However, there is growing evidence that BA also have endocrine and metabolic functions. Besides, the steroidal-derived structure gives BA a toxic potential over the biological membrane. Thus, cholestatic disorders, characterized by elevated BA on the liver and serum, are a significant cause of liver transplant and extrahepatic complications, such as skeletal muscle, central nervous system (CNS), heart, and placenta. Further, the BA have an essential role in cellular damage, mediating processes such as membrane disruption, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) and oxidative stress. The purpose of this review is to describe the BA and their role on hepatic and extrahepatic complications in cholestatic diseases, focusing on the association between BA and the generation of oxidative stress that mediates tissue damage.
Collapse
Affiliation(s)
- Josué Orozco-Aguilar
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8370146, Chile
- Laboratory of Integrative Physiopathology, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
| |
Collapse
|
|
44
|
Camilleri M. New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders. Gastroenterology 2021; 161:761-764. [PMID: 33989661 PMCID: PMC8380736 DOI: 10.1053/j.gastro.2021.04.079] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/26/2021] [Accepted: 04/28/2021] [Indexed: 12/16/2022]
Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
45
|
|
|
46
|
Wang-Lakshman L, Miao Z, Wang L, Gu H, Kagan M, Gu J, McNamara E, Walles M, Woessner R, Camenisch G, Einolf HJ, Chen J. Evaluation of the Absorption, Metabolism, and Excretion of a Single Oral 1-mg Dose of Tropifexor in Healthy Male Subjects and the Concentration Dependence of Tropifexor Metabolism. Drug Metab Dispos 2021; 49:548-562. [PMID: 33952610 DOI: 10.1124/dmd.120.000349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 04/06/2021] [Indexed: 12/14/2022] Open
Abstract
Tropifexor (NVP-LJN452) is a highly potent, selective, nonsteroidal, non-bile acid farnesoid X receptor agonist for the treatment of nonalcoholic steatohepatitis. Its absorption, metabolism, and excretion were studied after a 1-mg oral dose of [14C]tropifexor was given to four healthy male subjects. Mass balance was achieved with ∼94% of the administered dose recovered in excreta through a 312-hour collection period. Fecal excretion of tropifexor-related radioactivity played a major role (∼65% of the total dose). Tropifexor reached a maximum blood concentration (Cmax) of 33.5 ng/ml with a median time to reach Cmax of 4 hours and was eliminated with a plasma elimination half-life of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (∼92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metabolism appeared to be the major clearance pathway of tropifexor. Metabolites containing multiple oxidative modifications and combined oxidation and glucuronidation were also observed in human excreta. The involvement of direct glucuronidation could not be ruled out based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Because of these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study. SIGNIFICANCE STATEMENT: Tropifexor was found to be primarily cleared from the human body via oxidative metabolism. In vitro metabolism experiments revealed that the relative contribution of oxidation and glucuronidation was concentration-dependent, with glucuronidation as the predominant pathway at higher concentrations and the oxidative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development.
Collapse
Affiliation(s)
- Lydia Wang-Lakshman
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Zhuang Miao
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Lai Wang
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Helen Gu
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Mark Kagan
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Jessie Gu
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Elizabeth McNamara
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Markus Walles
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Ralph Woessner
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Gian Camenisch
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Heidi J Einolf
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| | - Jin Chen
- Novartis Institute for BioMedical Research, East Hanover, New Jersey (L.W.-L., Z.M., L.W., H.G., M.K., H.J.E., J.C.); Novartis Institute for BioMedical Research, Cambridge, Massachusetts (J.G., E.M.); and Novartis Institute for BioMedical Research, Basel, Switzerland (M.W., R.W., G.C.)
| |
Collapse
|
|
47
|
Aksan A, Farrag K, Blumenstein I, Schröder O, Dignass AU, Stein J. Chronic intestinal failure and short bowel syndrome in Crohn's disease. World J Gastroenterol 2021; 27:3440-3465. [PMID: 34239262 PMCID: PMC8240052 DOI: 10.3748/wjg.v27.i24.3440] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/24/2021] [Accepted: 03/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic intestinal failure (CIF) is a rare but feared complication of Crohn's disease. Depending on the remaining length of the small intestine, the affected intestinal segment, and the residual bowel function, CIF can result in a wide spectrum of symptoms, from single micronutrient malabsorption to complete intestinal failure. Management of CIF has improved significantly in recent years. Advances in home-based parenteral nutrition, in particular, have translated into increased survival and improved quality of life. Nevertheless, 60% of patients are permanently reliant on parenteral nutrition. Encouraging results with new drugs such as teduglutide have added a new dimension to CIF therapy. The outcomes of patients with CIF could be greatly improved by more effective prevention, understanding, and treatment. In complex cases, the care of patients with CIF requires a multidisciplinary approach involving not only physicians but also dietitians and nurses to provide optimal intestinal rehabilitation, nutritional support, and an improved quality of life. Here, we summarize current literature on CIF and short bowel syndrome, encompassing epidemiology, pathophysiology, and advances in surgical and medical management, and elucidate advances in the understanding and therapy of CIF-related complications such as catheter-related bloodstream infections and intestinal failure-associated liver disease.
Collapse
Affiliation(s)
- Aysegül Aksan
- Institute of Nutritional Sciences, Justus-Liebig-Universität, Giessen 35392, Germany
- Department of Clinical Research, Interdisziplinäres Crohn Colitis Centrum Rhein-Main, Frankfurt am Main 60594, Germany
| | - Karima Farrag
- Department of Clinical Research, Interdisziplinäres Crohn Colitis Centrum Rhein-Main, Frankfurt am Main 60594, Germany
- Department of Gastroenterology and Clinical Nutrition, DGD Kliniken Sachsenhausen, Teaching Hospital of the JW Goethe University, Frankfurt am Main 60594, Germany
| | - Irina Blumenstein
- Department of Gastroenterology, Hepatology and Clinical Nutrition, First Medical Clinic, JW Goethe University Hospital, Frankfurt am Main 60529, Germany
| | - Oliver Schröder
- Department of Clinical Research, Interdisziplinäres Crohn Colitis Centrum Rhein-Main, Frankfurt am Main 60594, Germany
- Department of Gastroenterology and Clinical Nutrition, DGD Kliniken Sachsenhausen, Teaching Hospital of the JW Goethe University, Frankfurt am Main 60594, Germany
| | - Axel U Dignass
- Department of Medicine I, Agaplesion Markus Hospital, Goethe-University, Frankfurt am Main 60431, Germany
| | - Jürgen Stein
- Department of Clinical Research, Interdisziplinäres Crohn Colitis Centrum Rhein-Main, Frankfurt am Main 60594, Germany
- Department of Gastroenterology and Clinical Nutrition, DGD Kliniken Sachsenhausen, Teaching Hospital of the JW Goethe University, Frankfurt am Main 60594, Germany
- Institute of Pharmaceutical Chemistry, JW Goethe University, 60438 Frankfurt am Main, Germany
| |
Collapse
|
|
48
|
Markers of Bile Acid Metabolism in Pediatric Diarrhea Predominant Irritable Bowel Syndrome and Healthy Controls. J Pediatr Gastroenterol Nutr 2021; 72:859-865. [PMID: 33976086 DOI: 10.1097/mpg.0000000000003067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Excessive fecal bile acids in adults have been associated with diarrhea-predominant irritable bowel syndrome (IBS-D), but their role in pediatric IBS-D is unknown. Serum markers including 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor-19 (FGF-19) were validated in adults to detect bile acid diarrhea (BAD) compared to 48-hour fecal bile acid collection (48FBA). Our aims were to assess fasting serum C4 and FGF-19 and 48FBA in a pediatric population, to compare measurements in IBS-D patients and healthy controls (HC), and to determine the prevalence of BAD among children with IBS-D. METHODS Using a cross-sectional design, 26 patients with IBS-D and 56 HC were recruited in two pediatric tertiary care centers. Fasting serum C4 and FGF-19 and 48FBA were obtained. Participants completed a 7-day bowel diary coinciding with stool collection. Associations were analyzed using Spearman correlations. RESULTS Mean age was 14.7 ± 2.5 years (42.3% female) in IBS-D and 12.6 ± 2.4 years (39.3% female) in HC. There was a significant correlation of C4 with 48FBA (r = 0.48, P < 0.05) and an inverse association with FGF-19 (r = -0.43, P < 0.05). No significant differences were noted in C4 (P = 0.32), FGF-19 (P = 0.1), or 48FBA (P = 0.5) between IBS-D and HC groups; however, 20% of IBS-D patients had elevated C4 and 28% had low FGF-19 values.Fecal primary BA was significantly correlated with stool frequency (r = 0.45, P < 0.002). CONCLUSIONS Correlations of C4 with 48FBA and FGF-19 are confirmed in a pediatric population. Twenty percent of pediatric patients with IBS-D had abnormal fasting serum C4. This serum test could be applied to identify BAD in pediatric IBS-D.
Collapse
|
|
49
|
Zhang Z, Zhou H, Guan M, Zhou X, Liang X, Lv Y, Bai L, Zhang J, Gong P, Liu T, Yi H, Wang J, Zhang L. Lactobacillus casei YRL577 combined with plant extracts reduce markers of non-alcoholic fatty liver disease in mice. Br J Nutr 2021; 125:1081-1091. [PMID: 32718364 DOI: 10.1017/s0007114520003013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Probiotics and plant extracts are considered to prevent the development of non-alcoholic fatty liver disease (NAFLD). The present study explores the effects of using both probiotics and plant extracts on NAFLD. The present study evaluated the effects of plant extracts on lipid droplet accumulation and the growth of probiotics in vitro. A C57BL/6 mouse model was used to examine the effects of probiotics and plant extracts on NAFLD. Body weight and food intake were measured. The levels of serum lipids, oxidative stress and the liver injury index were determined using commercial kits. Haematoxylin and eosin staining, GC and real-time PCR were also used for analysis. The results revealed that administration of Lactobacillus casei YRL577 and L. paracasei X11 with resveratrol (RES) or tea polyphenols (TP) significantly reduced the levels of total cholesterol, TAG and LDL-cholesterol and increased the level of the HDL-cholesterol. The groups of L. casei YRL577 with RES and TP also regulated the liver structure, oxidative stress and injury. Furthermore, L. casei YRL577 with TP exhibited a more positive effect towards improving the NAFLD and increased the concentrations of the butyric acid than other three combined groups. L. casei YRL577 with TP up-regulated the mRNA levels of the farnesoid X receptor and fibroblast growth factor 15 and decreased the mRNA levels of the apical Na-dependent bile acid transporter. These findings showed that L. casei YRL577 + TP-modified genes in the intestinal bile acid pathway improved markers of NAFLD.
Collapse
Affiliation(s)
- Zhe Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Hui Zhou
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Meiyu Guan
- Qingdao Central Hospital, Qingdao, 266042, People's Republic of China
| | - Xiaohong Zhou
- Qingdao Central Hospital, Qingdao, 266042, People's Republic of China
| | - Xi Liang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Youyou Lv
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Lu Bai
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Junxue Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Pimin Gong
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Tongjie Liu
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Huaxi Yi
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Jingfeng Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| | - Lanwei Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, Shandong, People's Republic of China
| |
Collapse
|
|
50
|
Kulkarni AV, Tevethia HV, Arab JP, Candia R, Premkumar M, Kumar P, Sharma M, Reddy DN, Padaki NR. Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2021; 45:101675. [PMID: 33722778 DOI: 10.1016/j.clinre.2021.101675] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/17/2021] [Accepted: 03/03/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA. METHODS We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA. RESULTS Seven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55-3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6-1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12-18.81; p < 0.001), 10 mg: 5.18 (2-13.41; p = 0.001), 25 mg: 2.36 (0.94-5.93; p = 0.06), 50 mg: 4.08 (1.05-15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA. CONCLUSIONS Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.
Collapse
Affiliation(s)
- Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India.
| | | | - Juan Pablo Arab
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Roberto Candia
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | | | - Pramod Kumar
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Mithun Sharma
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - D Nageshwar Reddy
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Nagaraja Rao Padaki
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| |
Collapse
|