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Taylor R, Basaly V, Kong B, Yang I, Brinker AM, Capece G, Bhattacharya A, Henry ZR, Otersen K, Yang Z, Meadows V, Mera S, Joseph LB, Zhou P, Aleksunes LM, Roepke T, Buckley B, Guo GL. Effects of therapeutically approved individual bile acids on the development of metabolic dysfunction-associated steatohepatitis a low bile acid mouse model. Toxicol Sci 2024; 202:179-195. [PMID: 39302723 DOI: 10.1093/toxsci/kfae110] [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] [Indexed: 09/22/2024] Open
Abstract
Bile acid (BA) signaling dysregulation is an important etiology for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). As diverse signaling molecules synthesized in the liver by pathways initiated with CYP7A1 and CYP27A1, BAs are endogenous modulators of farnesoid x receptor (FXR). FXR activation is crucial in maintaining BA homeostasis, regulating lipid metabolism, and suppressing inflammation. Additionally, BAs interact with membrane receptors and gut microbiota to regulate energy expenditure and intestinal health. Complex modulation of BAs in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs, especially during MASLD development. Previously, we determined that acute feeding of individual BAs differentially affects lipid, inflammation, and oxidative stress pathways in a low-BA mouse model, Cyp7a1/Cyp27a1 double knockout (DKO) mice. Currently, we investigated to what degree cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological concentrations impact MASLD development in DKO mice. The results showed that these 3 BAs varied in the ability to activate hepatic and intestinal FXR, disrupt lipid homeostasis, and modulate inflammation and fibrosis. Additionally, UDCA activated intestinal FXR in these low-BA mice. Significant alterations in lipid uptake and metabolism in DKO mice following CA and DCA feeding indicate differences in cholesterol and lipid handling across genotypes. Overall, the DKO were less susceptible to weight gain, but more susceptible to MASH diet induced inflammation and fibrosis on CA and DCA supplements, whereas WT mice were more vulnerable to CA-induced fibrosis on the control diet.
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Affiliation(s)
- Rulaiha Taylor
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
| | - Veronia Basaly
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Bo Kong
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Ill Yang
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Anita M Brinker
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Gina Capece
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Anisha Bhattacharya
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Zakiyah R Henry
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
| | - Katherine Otersen
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Zhenning Yang
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
| | - Vik Meadows
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
| | - Stephanie Mera
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
| | - Laurie B Joseph
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Peihong Zhou
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Troy Roepke
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
| | - Brian Buckley
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, United States
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, NJ 08854, United States
- VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, NJ 07017, United States
- Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, United States
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Li L, Cai F, Guo C, Liu Z, Qin J, Huang J. Gut microbiome and NAFLD: impact and therapeutic potential. Front Microbiol 2024; 15:1500453. [PMID: 39664063 PMCID: PMC11632136 DOI: 10.3389/fmicb.2024.1500453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/13/2024] [Indexed: 12/13/2024] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) affects approximately 32.4% of the global population and poses a significant health concern. Emerging evidence underscores the pivotal role of the gut microbiota-including bacteria, viruses, fungi, and parasites-in the development and progression of NAFLD. Dysbiosis among gut bacteria alters key biological pathways that contribute to liver fat accumulation and inflammation. The gut virome, comprising bacteriophages and eukaryotic viruses, significantly shapes microbial community dynamics and impacts host metabolism through complex interactions. Similarly, gut fungi maintain a symbiotic relationship with bacteria; the relationship between gut fungi and bacteria is crucial for overall host health, with certain fungal species such as Candida in NAFLD patients showing detrimental associations with metabolic markers and liver function. Additionally, the "hygiene hypothesis" suggests that reduced exposure to gut parasites may affect immune regulation and metabolic processes, potentially influencing conditions like obesity and insulin resistance. This review synthesizes current knowledge on the intricate interactions within the gut microbiota and their associations with NAFLD. We highlight the therapeutic potential of targeting these microbial communities through interventions such as probiotics, prebiotics, and fecal microbiota transplantation. Addressing the complexities of NAFLD requires comprehensive strategies that consider the multifaceted roles of gut microorganisms in disease pathology.
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Affiliation(s)
| | | | | | | | | | - Jiean Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
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Zhuang T, Wang X, Wang Z, Gu L, Yue D, Wang Z, Li X, Yang L, Huang W, Ding L. Biological functions and pharmacological behaviors of bile acids in metabolic diseases. J Adv Res 2024:S2090-1232(24)00495-8. [PMID: 39522690 DOI: 10.1016/j.jare.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 11/02/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Bile acids, synthesized endogenously from cholesterol, play a central role in metabolic regulation within the enterohepatic circulatory system. Traditionally known as emulsifying agents that facilitate the intestinal absorption of vitamins and lipids, recent research reveals their function as multifaceted signal modulators involved in various physiological processes. These molecules are now recognized as key regulators of chronic metabolic diseases and immune dysfunction. Despite progress in understanding their roles, their structural diversity and the specific functions of individual bile acids remain underexplored. AIM OF REVIEW This study categorizes the bile acids based on their chemical structures and their roles as signaling molecules in physiological processes. It consolidates current knowledge and provides a comprehensive overview of the current research. The review also includes natural and semisynthetic variants that have demonstrated potential in regulating metabolic processes in animal models or clinical contexts. KEY SCIENTIFIC CONCEPTS OF REVIEW Bile acids circulate primarily within the enterohepatic circulation, where they help maintain a healthy digestive system. Disruptions in their balance are linked to metabolic disorders, hepatobiliary diseases and intestinal inflammation. Through receptor-mediated pathways, bile acids influence the progression of metabolic diseases by regulating glucose and lipid metabolism, immune function, and energy expenditure. This review aims to provide a comprehensive, systematic foundation to for understanding their physiological roles and supporting future therapeutic developments for metabolic and inflammatory diseases.
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Affiliation(s)
- Tongxi Zhuang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China; Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Zixuan Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Lihua Gu
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Dawei Yue
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Xiaohua Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200163, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
| | - Wendong Huang
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
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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.
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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.
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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.
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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
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Nyboe Andersen N, Wildt S, Iversen AT, Poulsen G, Jess T, Munck LK, Borup C. Risk of cancer in patients with bile acid diarrhoea: a Danish nationwide matched cohort study. BMJ Open Gastroenterol 2024; 11:e001340. [PMID: 38688717 PMCID: PMC11085898 DOI: 10.1136/bmjgast-2023-001340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 04/13/2024] [Indexed: 05/02/2024] Open
Abstract
OBJECTIVE Bile acid diarrhoea is a common cause of chronic diarrhoea. Increased levels of potentially carcinogenic bile acids in faeces, theoretically, may increase the risk of colorectal cancer in particular, but the long-term disease course is unknown. We aimed to investigate the overall and site-specific cancer risk in bile acid diarrhoea. DESIGN Adult patients with bile acid diarrhoea were identified using nationwide Danish registries from 2003 to 2020 by a diagnostic gold-standard 75-selenium tauroselcholic acid procedure followed within 6 months by sequestrant prescription. The risk of overall and site-specific cancers in cases with bile acid diarrhoea was compared with sex, age and comorbidity-adjusted matched controls. A competing risk model estimated cumulative incidence functions and cause-specific HRs. RESULTS We identified 2260 patients with bile acid diarrhoea with a mean follow-up of 5.5 years (SD 4.2). The overall cancer risk was increased by an HR of 1.32 (95% CI 1.12 to 1.54). The risk of site-specific cancer was increased in 3 of 10 cancer groups: haematological, HR 2.41 (1.36 to 4.02); skin, HR 1.33 (1.01 to 1.71); and male genital cancers, HR 1.85 (1.11 to 2.92). No increased risk of colorectal cancer was detected in patients with bile acid diarrhoea, HR 0.73 (0.34 to 1.63). CONCLUSIONS Bile acid diarrhoea was associated with an increased overall risk of cancer, especially haematological cancers, but the risk of colorectal cancer was not increased. The lack of a diagnostic code for bile acid diarrhoea and potential residual confounding are limitations, and the findings should be replicated in other cohorts.
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Affiliation(s)
| | - Signe Wildt
- Department of Gastroenterology and Hepatology, Hvidovre Hospital, Hvidovre, Denmark
| | - Aske Thorn Iversen
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Copenhagen, Denmark
| | - Gry Poulsen
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Copenhagen, Denmark
| | - Tine Jess
- Center for Molecular Prediction of Inflammatory Bowel Disease, Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, Copenhagen, Denmark
| | - Lars Kristian Munck
- Department of Gastroenterology, Zealand University Hospital Koge, Koge, Denmark
| | - Christian Borup
- Department of Gastroenterology, Zealand University Hospital Koge, Koge, Denmark
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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.
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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
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Gravina AG, Pellegrino R, Romeo M, Ventriglia L, Scognamiglio F, Tuccillo C, Loguercio C, Federico A. The use of bicarbonate-sulphate-calcium-magnesium and sodium-low drinkable water improves functional gastrointestinal symptoms in patients with non-alcoholic fatty liver disease: A prospective study. Clin Nutr ESPEN 2023; 57:281-287. [PMID: 37739669 DOI: 10.1016/j.clnesp.2023.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 06/02/2023] [Accepted: 07/06/2023] [Indexed: 09/24/2023]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease is increasingly gaining epidemiological ground in liver diseases. Among the proposed non-pharmacologic interventions, dietary interventions have been widely used. Several patients suffering from it complain of gastrointestinal symptoms unrelated to organic gastrointestinal tract disease. However, the role of drinking water quality modifications in this regard has not been investigated in depth. METHODS Patients with upper or lower functional gastrointestinal symptoms were enrolled and divided into groups based on bright liver ultrasound relief's presence (SP) or absence (NSP). These patients were asked to drink bicarbonate-sulphate-calcium-magnesium and sodium-low drinkable water (Fonte Essenziale ®) for six months. Participants were assessed at baseline (T0), at the end of six months of drinking water intake (T6), and after an additional six months of washout (T12) by questionnaires designed to evaluate lower and upper gastrointestinal symptoms (Leeds dyspepsia score, short form) severity and frequency. RESULTS A total of 61 patients were enrolled. In the SP population, the severity of lower gastrointestinal symptoms improved between T0-T6 (Z: -2.437; ES: 0.312) and worsened after the water washout (Z: -2.492; ES: 0.319). The same was for the Leeds score severity sub score in T0-T6 (Z: -2.850; ES: 0.364) and T6-T12 (Z: -2.921; ES: 0.374). These improvements seem unrelated to the severity of liver steatosis at baseline. Furthermore, no safety issues were recorded while taking the water nor during the six-month follow-up afterwards. CONCLUSION Regular six-month intake of 400 mL of Fonte Essenziale® water was associated, in the absence of dietary regimen modifications, with an improvement in some qualitative and quantitative features of upper and lower functional gastrointestinal symptoms in both an SP and NSP sample.
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Affiliation(s)
- Antonietta Gerarda Gravina
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy.
| | - Raffaele Pellegrino
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy
| | - Mario Romeo
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy
| | - Lorenzo Ventriglia
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy
| | - Flavia Scognamiglio
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy
| | - Concetta Tuccillo
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy
| | - Carmelina Loguercio
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy
| | - Alessandro Federico
- Department of Precision Medicine, Hepatogastroenterology Unit, University of Campania Luigi Vanvitelli, Via L. de Crecchio 7, 80138, Napoli, Italy
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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.
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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
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10
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Purssell H, Bennett L, Street O, Hanley KP, Hanley N, Vasant DH, Athwal VS. The prevalence and burden of Rome IV bowel disorders of gut brain interaction in patients with non-alcoholic fatty liver disease: a cross-sectional study. Sci Rep 2023; 13:8769. [PMID: 37253969 DOI: 10.1038/s41598-023-35774-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/23/2023] [Indexed: 06/01/2023] Open
Abstract
Rome IV bowel disorders of gut brain interaction (DGBI) and non-alcoholic fatty liver disease (NAFLD) are highly prevalent entities with overlapping pathophysiology and risk factors. We aimed to evaluate the prevalence and burden of Rome IV irritable bowel syndrome (IBS) in patients with NAFLD. Patients diagnosed with NAFLD were recruited from a specialist liver clinic. All participants completed assessments to determine liver fibrosis severity, including liver stiffness measurement (LSM), completed the Rome IV diagnostic questionnaire for bowel disorders of gut brain interaction, the IBS symptom severity score (IBS-SSS), and the EQ-5D-5L to measure of quality-of-life (QoL). 142 patients with NAFLD (71 (50%) female, mean age 53.5 (SD ± 14.9), BMI 35.2 (SD ± 8.1) kg/M2) were recruited. 79 (55.6%) patients met criteria for a Rome IV bowel DGBI, including 50 patients (35.2%) who met the criteria for IBS (mean IBS-SSS 277.2 (SD ± 131.5)). There was no difference in liver fibrosis scores between those with and without Rome IV IBS (FIB-4 scores p = 0.14, LSM p = 0.68). Patients with NAFLD and Rome IV IBS had significantly worse QoL scores (EQ-VAS p = 0.005 and EQ-5D-5L index p = 0.0007), impairment of usual activities of daily living (p = 0.012) and were more likely to report anxiety or depression (p = 0.038). Rome IV bowel DGBI such as IBS are highly prevalent in patients with NAFLD attending liver clinics and are associated with impaired QoL and psychosocial distress.
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Affiliation(s)
- Huw Purssell
- Department of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Lucy Bennett
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Oliver Street
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Karen Piper Hanley
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
| | - Neil Hanley
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Dipesh H Vasant
- Department of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Varinder S Athwal
- Department of Gastroenterology and Hepatology, Manchester University NHS Foundation Trust, Manchester, UK.
- Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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11
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Gut Microbiota in Non-Alcoholic Fatty Liver Disease Patients with Inflammatory Bowel Diseases: A Complex Interplay. Nutrients 2022; 14:nu14245323. [PMID: 36558483 PMCID: PMC9785319 DOI: 10.3390/nu14245323] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/10/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
The intestinal microbiota represents the microbial community that colonizes the gastrointestinal tract and constitutes the most complex ecosystem present in nature. The main intestinal microbial phyla are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucromicrobia, with a clear predominance of the two phyla Firmicutes and Bacteroidetes which account for about 90% of the intestinal phyla. Intestinal microbiota alteration, or dysbiosis, has been proven to be involved in the development of various syndromes, such as non-alcoholic fatty liver disease, Crohn's disease, and ulcerative colitis. The present review underlines the most recurrent changes in the intestinal microbiota of patients with NAFLD, Crohn's disease, and ulcerative colitis.
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12
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BouSaba J, Sannaa W, McKinzie S, Vijayvargiya P, Chedid V, Wang XJ, Atieh J, Zheng T, Brandler J, Taylor AL, Busciglio I, Harmsen WS, Camilleri M. Impact of Bile Acid Diarrhea in Patients With Diarrhea-Predominant Irritable Bowel Syndrome on Symptoms and Quality of Life. Clin Gastroenterol Hepatol 2022; 20:2083-2090.e1. [PMID: 34871814 PMCID: PMC9166633 DOI: 10.1016/j.cgh.2021.11.035] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/26/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Bile acid diarrhea (BAD) affects approximately a quarter of patients with irritable bowel syndrome with diarrhea (IBS-D). We aimed to compare the demographics, bowel and somatic symptoms, and quality of life of patients with IBS-D, with or without BAD. METHODS On one occasion, patients with IBS-D (positive for Rome III criteria) completed the following questionnaires: bowel disease questionnaire, Hospital Anxiety and Depression inventory, general quality of life (Symptom Checklist-90), and IBS-specific quality of life. A fasting serum C4 level higher than 52.5 ng/mL was used as a biomarker for BAD. Statistical analysis included a multiple variable logistic model to identify strong predictors of BAD in IBS-D. RESULTS Among 219 patients (79% female) with IBS-D, 44 had BAD; the BAD group was significantly older and had a higher body mass index than the patients without BAD. Patients with BAD had more severe bowel dysfunction and impact on IBS-specific quality of life (need of toilet proximity) compared with patients with IBS-D without BAD. Patients with BAD were more likely than other IBS-D groups to receive antidiarrheals, bile acid binders, and antacid secretory agents. The severity of diarrhea and need of toilet proximity were predictors of BAD in IBS-D (P < .01). Patients with BAD were more likely to have a depression score higher than 8 on the Hospital Anxiety and Depression inventory. CONCLUSIONS There is a greater impact on bowel and somatic symptoms and quality of life in IBS-D with BAD compared with IBS-D without BAD. Screening for BAD in IBS-D is especially relevant, with more severe and frequent diarrhea along with urgency.
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Affiliation(s)
- Joelle BouSaba
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Wassel Sannaa
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Sanna McKinzie
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Priya Vijayvargiya
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Victor Chedid
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Xiao Jing Wang
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Jessica Atieh
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Ting Zheng
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Justin Brandler
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Ann L Taylor
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - Irene Busciglio
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota
| | - W Scott Harmsen
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota.
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13
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Di Vincenzo F, Puca P, Lopetuso LR, Petito V, Masi L, Bartocci B, Murgiano M, De Felice M, Petronio L, Gasbarrini A, Scaldaferri F. Bile Acid-Related Regulation of Mucosal Inflammation and Intestinal Motility: From Pathogenesis to Therapeutic Application in IBD and Microscopic Colitis. Nutrients 2022; 14:nu14132664. [PMID: 35807844 PMCID: PMC9268369 DOI: 10.3390/nu14132664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD) and microscopic colitis are chronic immune-mediated inflammatory disorders that affect the gastroenterological tract and arise from a complex interaction between the host’s genetic risk factors, environmental factors, and gut microbiota dysbiosis. The precise mechanistic pathways interlinking the intestinal mucosa homeostasis, the immunological tolerance, and the gut microbiota are still crucial topics for research. We decided to deeply analyze the role of bile acids in these complex interactions and their metabolism in the modulation of gut microbiota, and thus intestinal mucosa inflammation. Recent metabolomics studies revealed a significant defect in bile acid metabolism in IBD patients, with an increase in primary bile acids and a reduction in secondary bile acids. In this review, we explore the evidence linking bile acid metabolites with the immunological pathways involved in IBD pathogenesis, including apoptosis and inflammasome activation. Furthermore, we summarize the principal etiopathogenetic mechanisms of different types of bile acid-induced diarrhea (BAD) and its main novel diagnostic approaches. Finally, we discuss the role of bile acid in current and possible future state-of-the-art therapeutic strategies for both IBD and BAD.
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Affiliation(s)
- Federica Di Vincenzo
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
- Correspondence:
| | - Pierluigi Puca
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Loris Riccardo Lopetuso
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
| | - Valentina Petito
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
| | - Letizia Masi
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
| | - Bianca Bartocci
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Marco Murgiano
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Margherita De Felice
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Lorenzo Petronio
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Antonio Gasbarrini
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
| | - Franco Scaldaferri
- IBD Unit—UOS Malattie Infiammatorie Croniche Intestinali, CEMAD, Digestive Diseases Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (P.P.); (L.R.L.); (V.P.); (L.M.); (A.G.); (F.S.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go F. Vito 1, 00168 Rome, Italy; (B.B.); (M.M.); (M.D.F.); (L.P.)
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14
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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.
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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
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15
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Physiological and pathophysiological role of endocrine fibroblast growth factors. POSTEP HIG MED DOSW 2022. [DOI: 10.2478/ahem-2022-0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
The endocrine subfamily of fibroblast growth factors (FGF) includes three factors: FGF19, FGF21, FGF23. They act on distal tissues through FGF receptors (FGFRs). The FGFR activation requires two cofactors: α- and β-Klotho, which are structurally related single-pass transmembrane proteins. The endocrine FGFs regulate various metabolic processes involved in the regulation of glucose and lipid metabolism as well as bile acid circulation, vitamin D modulation, and phosphate homeostasis. The FGF-FGFR dysregulation is widely implicated in the pathogenesis of various disorders. Significant alterations in plasma FGF concentration are associated with the most prevalent chronic diseases, including dyslipidemia, type 2 diabetes, cardiovascular diseases, obesity, non-alcoholic fatty liver disease, diseases of the biliary tract, chronic kidney disease, inflammatory bowel disease, osteomalacia, various malignancies, and depression. Therefore, the endocrine FGFs may serve as disease predictors or biomarkers, as well as potential therapeutic targets. Currently, numerous analogues and inhibitors of endocrine FGFs are under development for treatment of various disorders, and recently, a human monoclonal antibody against FGF23 has been approved for treatment of X-linked hypophosphatemia. The aim of this review is to summarize the current data on physiological and pathophysiological actions of the endocrine FGF subfamily and recent research concerning the therapeutic potential of the endocrine FGF pathways.
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16
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Clinical Interest of Serum Alpha-2 Macroglobulin, Apolipoprotein A1, and Haptoglobin in Patients with Non-Alcoholic Fatty Liver Disease, with and without Type 2 Diabetes, before or during COVID-19. Biomedicines 2022; 10:biomedicines10030699. [PMID: 35327501 PMCID: PMC8945355 DOI: 10.3390/biomedicines10030699] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/06/2022] [Accepted: 03/14/2022] [Indexed: 02/04/2023] Open
Abstract
In patients with non-alcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM), alpha-2 macroglobulin (A2M), apolipoprotein A1 (ApoA1), and haptoglobin are associated with the risk of liver fibrosis, inflammation (NASH), and COVID-19. We assessed if these associations were worsened by T2DM after adjustment by age, sex, obesity, and COVID-19. Three datasets were used: the “Control Population”, which enabled standardization of protein serum levels according to age and sex (N = 27,382); the “NAFLD-Biopsy” cohort for associations with liver features (N = 926); and the USA “NAFLD-Serum” cohort for protein kinetics before and during COVID-19 (N = 421,021). The impact of T2DM was assessed by comparing regression curves adjusted by age, sex, and obesity for the liver features in “NAFLD-Biopsy”, and before and during COVID-19 pandemic peaks in “NAFLD-Serum”. Patients with NAFLD without T2DM, compared with the values of controls, had increased A2M, decreased ApoA1, and increased haptoglobin serum levels. In patients with both NAFLD and T2DM, these significant mean differences were magnified, and even more during the COVID-19 pandemic in comparison with the year 2019 (all p < 0.001), with a maximum ApoA1 decrease of 0.21 g/L in women, and a maximum haptoglobin increase of 0.17 g/L in men. In conclusion, T2DM is associated with abnormal levels of A2M, ApoA1, and haptoglobin independently of NAFLD, age, sex, obesity, and COVID-19.
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17
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Bhat N, Esteghamat F, Chaube BK, Gunawardhana K, Mani M, Thames C, Jain D, Ginsberg HN, Fernandes-Hernando C, Mani A. TCF7L2 transcriptionally regulates Fgf15 to maintain bile acid and lipid homeostasis through gut-liver crosstalk. FASEB J 2022; 36:e22185. [PMID: 35133032 PMCID: PMC9624374 DOI: 10.1096/fj.202101607r] [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: 10/15/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/13/2022]
Abstract
FGF19/FGF15 is an endocrine regulator of hepatic bile salt and lipid metabolism, which has shown promising effects in the treatment of NASH in clinical trials. FGF19/15 is transcribed and released from enterocytes of the small intestine into enterohepatic circulation in response to bile-induced FXR activation. Previously, the TSS of FGF19 was identified to bind Wnt-regulated TCF7L2/encoded transcription factor TCF4 in colorectal cancer cells. Impaired Wnt signaling and specifical loss of function of its coreceptor LRP6 have been associated with NASH. We, therefore, examined if TCF7L2/TCF4 upregulates Fgf19 in the small intestine and restrains NASH through gut-liver crosstalk. We examined the mice globally overexpressing, haploinsufficient, and conditional knockout models of TCF7L2 in the intestinal epithelium. The TCF7L2+/- mice exhibited increased plasma bile salts and lipids and developed diet-induced fatty liver disease while mice globally overexpressing TCF7L2 were protected against these traits. Comprehensive in vivo analysis revealed that TCF7L2 transcriptionally upregulates FGF15 in the gut, leading to reduced bile synthesis and diminished intestinal lipid uptake. Accordingly, VilinCreert2 ; Tcf7L2fl/fl mice showed reduced Fgf19 in the ileum, and increased plasma bile. The global overexpression of TCF7L2 in mice with metabolic syndrome-linked LRP6R611C substitution rescued the fatty liver and fibrosis in the latter. Strikingly, the hepatic levels of TCF4 were reduced and CYP7a1 was increased in human NASH, indicating the relevance of TCF4-dependent regulation of bile synthesis to human disease. These studies identify the critical role of TCF4 as an upstream regulator of the FGF15-mediated gut-liver crosstalk that maintains bile and liver triglyceride homeostasis.
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Affiliation(s)
- Neha Bhat
- Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Fatemehsadat Esteghamat
- Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Bal Krishna Chaube
- Department of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Kushan Gunawardhana
- Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Mitra Mani
- New York Medical College, Valhalla, New York, USA,Department of Internal Medicine, Columbia University College of Physicians and Surgeon, New York, New York, USA
| | - Clay Thames
- Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Henry N. Ginsberg
- Department of Internal Medicine, Columbia University College of Physicians and Surgeon, New York, New York, USA
| | | | - Arya Mani
- Department of Internal Medicine, Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut, USA,Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA
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Understanding the Role of the Gut Microbiome and Microbial Metabolites in Non-Alcoholic Fatty Liver Disease: Current Evidence and Perspectives. Biomolecules 2021; 12:biom12010056. [PMID: 35053205 PMCID: PMC8774162 DOI: 10.3390/biom12010056] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/24/2021] [Accepted: 12/30/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD begins as a relatively benign hepatic steatosis which can evolve to non-alcoholic steatohepatitis (NASH); the risk of cirrhosis and hepatocellular carcinoma (HCC) increases when fibrosis is present. NAFLD represents a complex process implicating numerous factors—genetic, metabolic, and dietary—intertwined in a multi-hit etiopathogenetic model. Recent data have highlighted the role of gut dysbiosis, which may render the bowel more permeable, leading to increased free fatty acid absorption, bacterial migration, and a parallel release of toxic bacterial products, lipopolysaccharide (LPS), and proinflammatory cytokines that initiate and sustain inflammation. Although gut dysbiosis is present in each disease stage, there is currently no single microbial signature to distinguish or predict which patients will evolve from NAFLD to NASH and HCC. Using 16S rRNA sequencing, the majority of patients with NAFLD/NASH exhibit increased numbers of Bacteroidetes and differences in the presence of Firmicutes, resulting in a decreased F/B ratio in most studies. They also present an increased proportion of species belonging to Clostridium, Anaerobacter, Streptococcus, Escherichia, and Lactobacillus, whereas Oscillibacter, Flavonifaractor, Odoribacter, and Alistipes spp. are less prominent. In comparison to healthy controls, patients with NASH show a higher abundance of Proteobacteria, Enterobacteriaceae, and Escherichia spp., while Faecalibacterium prausnitzii and Akkermansia muciniphila are diminished. Children with NAFLD/NASH have a decreased proportion of Oscillospira spp. accompanied by an elevated proportion of Dorea, Blautia, Prevotella copri, and Ruminococcus spp. Gut microbiota composition may vary between population groups and different stages of NAFLD, making any conclusive or causative claims about gut microbiota profiles in NAFLD patients challenging. Moreover, various metabolites may be involved in the pathogenesis of NAFLD, such as short-chain fatty acids, lipopolysaccharide, bile acids, choline and trimethylamine-N-oxide, and ammonia. In this review, we summarize the role of the gut microbiome and metabolites in NAFLD pathogenesis, and we discuss potential preventive and therapeutic interventions related to the gut microbiome, such as the administration of probiotics, prebiotics, synbiotics, antibiotics, and bacteriophages, as well as the contribution of bariatric surgery and fecal microbiota transplantation in the therapeutic armamentarium against NAFLD. Larger and longer-term prospective studies, including well-defined cohorts as well as a multi-omics approach, are required to better identify the associations between the gut microbiome, microbial metabolites, and NAFLD occurrence and progression.
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Purssell H, Whorwell PJ, Athwal VS, Vasant DH. Non-alcoholic fatty liver disease in irritable bowel syndrome: More than a coincidence? World J Hepatol 2021; 13:1816-1827. [PMID: 35069992 PMCID: PMC8727221 DOI: 10.4254/wjh.v13.i12.1816] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 08/01/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) and non-alcoholic fatty liver disease (NAFLD) are amongst the most common gastrointestinal and liver conditions encountered in primary and secondary care. Recently, there has been interest in the apparent co-incidence of NAFLD in patients with IBS mainly driven by improved understanding of their shared risk factors and pathophysiology. In this paper we summarize the shared risk factors which include; overlapping nutritional and dietary factors as well as shared putative mechanisms of pathophysiology. These include changes in the gut microbiome, gut permeability, immunity, small bowel bacterial overgrowth and bile acid metabolism. This paper describes how these shared risk factors and etiological factors may have practical clinical implications for these highly prevalent conditions. It also highlights some of the limitations of current epidemiological data relating to estimates of the overlapping prevalence of the two conditions which have resulted in inconsistent results and, therefore the need for further research. Early recognition and management of the overlap could potentially have impacts on treatment outcomes, compliance and morbidity of both conditions. Patients with known IBS who have abnormal liver function tests or significant risk factors for NAFLD should be investigated appropriately for this possibility. Similarly, IBS should be considered in patients with NAFLD and symptoms of abdominal pain associated with defecation, an altered bowel habit and bloating.
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Affiliation(s)
- Huw Purssell
- Hepatology, Manchester University NHS Foundation Trust, Manchester M23 9LT, United Kingdom
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester M23 9LT, United Kingdom
| | - Peter J Whorwell
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester M23 9LT, United Kingdom
- Neurogastroenterology Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, United Kingdom
| | - Varinder S Athwal
- Hepatology, Manchester University NHS Foundation Trust, Manchester M23 9LT, United Kingdom
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester M23 9LT, United Kingdom
| | - Dipesh H Vasant
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester M23 9LT, United Kingdom
- Neurogastroenterology Unit, Department of Gastroenterology, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester M23 9LT, United Kingdom.
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Radun R, Trauner M. Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities. Semin Liver Dis 2021; 41:461-475. [PMID: 34289507 PMCID: PMC8492195 DOI: 10.1055/s-0041-1731707] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.
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Affiliation(s)
- Richard Radun
- Department of Internal Medicine III, Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria
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21
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Goon DE, Ab-Rahim S, Mohd Sakri AH, Mazlan M, Tan JK, Abdul Aziz M, Mohd Noor N, Ibrahim E, Sheikh Abdul Kadir SH. Untargeted serum metabolites profiling in high-fat diet mice supplemented with enhanced palm tocotrienol-rich fraction using UHPLC-MS. Sci Rep 2021; 11:21001. [PMID: 34697380 PMCID: PMC8546078 DOI: 10.1038/s41598-021-00454-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/01/2021] [Indexed: 01/14/2023] Open
Abstract
Excessive high fat dietary intake promotes risk of developing non-alcoholic fatty liver disease (NAFLD) and predisposed with oxidative stress. Palm based tocotrienol-rich fraction (TRF) has been reported able to ameliorate oxidative stress but exhibited poor bioavailability. Thus, we investigated whether an enhanced formulation of TRF in combination with palm kernel oil (medium-chain triglycerides) (ETRF) could ameliorate the effect of high-fat diet (HFD) on leptin-deficient male mice. All the animals were divided into HFD only (HFD group), HFD supplemented with ETRF (ETRF group) and HFD supplemented with TRF (TRF group) and HFD supplemented with PKO (PKO group). After 6 weeks, sera were collected for untargeted metabolite profiling using UHPLC-Orbitrap MS. Univariate analysis unveiled alternation in metabolites for bile acids, amino acids, fatty acids, sphingolipids, and alkaloids. Bile acids, lysine, arachidonic acid, and sphingolipids were downregulated while xanthine and hypoxanthine were upregulated in TRF and ETRF group. The regulation of these metabolites suggests that ETRF may promote better fatty acid oxidation, reduce oxidative stress and pro-inflammatory metabolites and acts as anti-inflammatory in fatty liver compared to TRF. Metabolites regulated by ETRF also provide insight of its role in fatty liver. However, further investigation is warranted to identify the mechanisms involved.
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Affiliation(s)
- Danial Efendy Goon
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Sharaniza Ab-Rahim
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
| | - Amir Hakimi Mohd Sakri
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Musalmah Mazlan
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000, Kuala Lumpur, Malaysia
| | - Mardiana Abdul Aziz
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Norizal Mohd Noor
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Effendi Ibrahim
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
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Copper deficiency and nonalcoholic fatty liver disease: The chicken or the egg? Clin Nutr 2021; 40:4914. [PMID: 34358837 DOI: 10.1016/j.clnu.2021.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/04/2021] [Indexed: 12/21/2022]
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Seniuk I, Al-Sahlanee BJA, Bakri AAB, Kravchenko V, Shovkova O. Study of laxative and hepatoprotective activity of extracts obtained from Prunus domestica fruits. PHARMACIA 2021. [DOI: 10.3897/pharmacia.68.e64159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The experimental work focused on the study of the pharmacological properties of extracts obtained from the Prunus domestica fruits to create a prospective laxative drug with moderate hepatoprotective properties. Prunus domestica fruit extracts have been shown to have a pronounced laxative and moderate hepatoprotective effect. Extract containing fibers at a dose of 200 mg/kg was selected as the most active extract for laxative and hepatoprotective activity among all extracts from the Prunus domestica fruits. It was conventionally named “Prunophyte”. Studies of the specific pharmacological action of “Prunophyte” extract in a model of comorbid functional constipation on the background of combined alcoholic liver disease in rats showed that “Prunophyte” at a dose of 200 mg/kg had positive dynamics in the treatment of constipation on the background of subacute liver disease. In some cases it exceeded the effects of combination therapy with drugs “Silibor” at a dose of 25 mg/kg and “Senadexin” at a dose of 14 mg/kg. “Prunophyte” extract, in contrast to “Senodexin”, did not cause signs of diarrhea in animals, which may be a beneficial feature of this drug in subsequent clinical use. This drug has shown that it can be a promising alternative to a one-time complex treatment with herbal laxatives and hepatoprotectors, which will avoid polypragmatism in the treatment of comorbid conditions in gastroenterology associated with functional constipation and liver dysfunction.
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Zhou R, Llorente C, Cao J, Zaramela LS, Zeng S, Gao B, Li SZ, Welch RD, Huang FQ, Qi LW, Pan C, Huang Y, Zhou P, Beussen I, Zhang Y, Bryam G, Fiehn O, Wang L, Liu EH, Yu RT, Downes M, Evans RM, Goglin K, Fouts DE, Brenner DA, Bode L, Fan X, Zengler K, Schnabl B. Intestinal α1-2-Fucosylation Contributes to Obesity and Steatohepatitis in Mice. Cell Mol Gastroenterol Hepatol 2021; 12:293-320. [PMID: 33631374 PMCID: PMC8166943 DOI: 10.1016/j.jcmgh.2021.02.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 02/13/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Fucosyltransferase 2 (Fut2)-mediated intestinal α1- 2-fucosylation is important for host-microbe interactions and has been associated with several diseases, but its role in obesity and hepatic steatohepatitis is not known. The aim of this study was to investigate the role of Fut2 in a Western-style diet-induced mouse model of obesity and steatohepatitis. METHODS Wild-type (WT) and Fut2-deficient littermate mice were used and features of the metabolic syndrome and steatohepatitis were assessed after 20 weeks of Western diet feeding. RESULTS Intestinal α1-2-fucosylation was suppressed in WT mice after Western diet feeding, and supplementation of α1-2-fucosylated glycans exacerbated obesity and steatohepatitis in these mice. Fut2-deficient mice were protected from Western diet-induced features of obesity and steatohepatitis despite an increased caloric intake. These mice have increased energy expenditure and thermogenesis, as evidenced by a higher core body temperature. Protection from obesity and steatohepatitis associated with Fut2 deficiency is transmissible to WT mice via microbiota exchange; phenotypic differences between Western diet-fed WT and Fut2-deficient mice were reduced with antibiotic treatment. Fut2 deficiency attenuated diet-induced bile acid accumulation by altered relative abundance of bacterial enzyme 7-α-hydroxysteroid dehydrogenases metabolizing bile acids and by increased fecal excretion of secondary bile acids. This also was associated with increased intestinal farnesoid X receptor/fibroblast growth factor 15 signaling, which inhibits hepatic synthesis of bile acids. Dietary supplementation of α1-2-fucosylated glycans abrogates the protective effects of Fut2 deficiency. CONCLUSIONS α1-2-fucosylation is an important host-derived regulator of intestinal microbiota and plays an important role for the pathogenesis of obesity and steatohepatitis in mice.
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Affiliation(s)
- Rongrong Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University and Key Laboratory of Viral Hepatitis, Hunan, Changsha, China; Department of Medicine, University of California San Diego, La Jolla, California
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Jinling Cao
- Department of Medicine, University of California San Diego, La Jolla, California; College of Food Science and Engineering, Shanxi Agricultural University, Shanxi, Taigu, China
| | - Livia S Zaramela
- Department of Pediatrics, University of California San Diego, La Jolla, California
| | - Suling Zeng
- Department of Medicine, University of California San Diego, La Jolla, California; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Bei Gao
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Shang-Zhen Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Ryan D Welch
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | - Feng-Qing Huang
- The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Lian-Wen Qi
- The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Chuyue Pan
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yan Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University and Key Laboratory of Viral Hepatitis, Hunan, Changsha, China
| | - Pengchen Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University and Key Laboratory of Viral Hepatitis, Hunan, Changsha, China
| | - Iris Beussen
- National Institutes of Health West Coast Metabolomics Center, University of California, Davis, California
| | - Ying Zhang
- National Institutes of Health West Coast Metabolomics Center, University of California, Davis, California; Department of Chemistry, University of California, Davis, California
| | - Gregory Bryam
- National Institutes of Health West Coast Metabolomics Center, University of California, Davis, California
| | - Oliver Fiehn
- National Institutes of Health West Coast Metabolomics Center, University of California, Davis, California
| | - Lirui Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - E-Hu Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Ruth T Yu
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, California
| | | | | | - David A Brenner
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Lars Bode
- Department of Pediatrics and Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence, University of California San Diego, La Jolla, California
| | - Xuegong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University and Key Laboratory of Viral Hepatitis, Hunan, Changsha, China
| | - Karsten Zengler
- Department of Pediatrics, University of California San Diego, La Jolla, California; Department of Bioengineering, University of California San Diego, La Jolla, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.
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Gao B, Sakaguchi K, Ogawa T, Kagawa Y, Kubo H, Shimizu T. Functional Analysis of Induced Human Ballooned Hepatocytes in a Cell Sheet-Based Three Dimensional Model. Tissue Eng Regen Med 2021; 18:217-224. [PMID: 33517537 DOI: 10.1007/s13770-020-00297-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/22/2020] [Accepted: 08/26/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Ballooned hepatocytes (BH) are a key histological hallmark of nonalcoholic steatohepatitis (NASH), yet their consequences for liver-specific functions are unknown. METHODS In our previous study, an experimental model of human induced-BHs (iBH) has been successfully developed based on cell sheet technology. This study aimed to determine the functions of iBHs in the primary human hepatocyte/normal human dermal fibroblast (PHH/NHDF) co-culture cell sheets. Normal hepatocytes in the PHH/3T3-J2 co-culture cell sheets were set as a control, since 3T3-J2 murine embryonic fibroblasts have exhibited previously long term maintenance of PHH functions. RESULTS It was found that, albumin secretion was not affected in iBHs, but urea synthesis as well as cytochrome P450 enzyme (CYP) activities including CYP1A2 and CYP3A4, were significantly reduced in iBHs. Besides, loss of bile canaliculi was observed in iBHs. These findings are consistent with clinical studies of human NASH. In addition, PHH/NHDF cell sheets demonstrated two fold higher TGF-β1 secretion compared with PHH/3T3-J2 cell sheets. Furthermore, treatment with a TGF-β inhibitor and a semi-synthetic bile acid analogue (obeticholic acid, phase 3 trial of NASH therapy) ameliorated the histological appearance of established iBHs. CONCLUSION In summary, this study demonstrates the priority of iBHs in recapitulating not only histology but also clinically relevant hepatic dysfunctions in human NASH and suggests TGF-β and bile acid related signal pathway may play important roles in the formation of iBHs.
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Affiliation(s)
- Botao Gao
- Guangdong Key Lab of Medical Electronic Instruments and Polymer Materials Products, National Engineering Research Center for Healthcare Devices, Guangdong Institute of Medical Instruments, Guangdong Academy of Sciences, Guangzhou, 510550, China.,Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Katsuhisa Sakaguchi
- Department of Integrative Bioscience and Biomedical Engineering, Graduate School of Advanced Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo, 162-8480, Japan
| | - Tetsuya Ogawa
- Ogino Memorial Laboratory, Nihon Kohden Corporation, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Yuki Kagawa
- Ogino Memorial Laboratory, Nihon Kohden Corporation, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Hirotsugu Kubo
- Ogino Memorial Laboratory, Nihon Kohden Corporation, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
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Zhou J, Tripathi M, Sinha RA, Singh BK, Yen PM. Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease. HEPATOMA RESEARCH 2021; 7:11. [PMID: 33490737 PMCID: PMC7116620 DOI: 10.20517/2394-5079.2020.134] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder worldwide. It comprises a spectrum of conditions that range from steatosis to non-alcoholic steatohepatitis, with progression to cirrhosis and hepatocellular carcinoma. Currently, there is no FDA-approved pharmacological treatment for NAFLD. The pathogenesis of NAFLD involves genetic and environmental/host factors, including those that cause changes in intestinal microbiota and their metabolites. In this review, we discuss recent findings on the relationship(s) of microbiota signature with severity of NAFLD and the role(s) microbial metabolites in NAFLD progression. We discuss how metabolites may affect NAFLD progression and their potential to serve as biomarkers for NAFLD diagnosis or therapeutic targets for disease management.
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Affiliation(s)
- Jin Zhou
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Madhulika Tripathi
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Brijesh Kumar Singh
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Paul M. Yen
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
- Duke Molecular Physiology Institute, Durham, NC 27701, USA
- Duke University School of Medicine, Durham, NC 27710, USA
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Abstract
Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.
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Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging. Physiol Rev 2020; 101:683-731. [PMID: 32790577 DOI: 10.1152/physrev.00049.2019] [Citation(s) in RCA: 237] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Hadrien Demagny
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Laura Velazquez-Villegas
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
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29
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Abstract
Excessive fecal bile acid (BA) loss causes symptoms in a large proportion of people diagnosed with irritable bowel syndrome with diarrhea, a common functional bowel disorder. This BA diarrhea (BAD) results from increased hepatic synthesis of BAs, with impaired negative feedback regulation by the ileal hormone fibroblast growth factor 19 (FGF19). In this issue of the JCI, Zhao et al. investigated BA metabolism, including fecal BAs, serum BAs, and FGF19, in patients and controls. They identified associations between fecal bacterial BA metabolism and specific microbiota, especially Clostridium scindens. These findings have been tested in a mouse model using microbiota transplants and antibiotic treatment. This group of organisms has potential as a biomarker for BAD and to be a target for therapy.
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Affiliation(s)
- Julian Rf Walters
- Division of Digestive Diseases, Department of Metabolism, Digestion, and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom.,Gastroenterology, Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Julian R Marchesi
- Division of Digestive Diseases, Department of Metabolism, Digestion, and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom.,School of Biosciences, Cardiff University, Cardiff, United Kingdom
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30
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Fitzpatrick LR, Jenabzadeh P. IBD and Bile Acid Absorption: Focus on Pre-clinical and Clinical Observations. Front Physiol 2020; 11:564. [PMID: 32595517 PMCID: PMC7303840 DOI: 10.3389/fphys.2020.00564] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/07/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) causes chronic inflammation affecting the GI tract. It is classified as consisting of Crohn’s Disease (CD) and Ulcerative Colitis (UC). Bile Acid absorption is altered in both pre-clinical models of Inflammatory Bowel Disease (IB) and in human IBD. The bile acid transporter apical sodium dependent bile acid transporter (ASBT) showed decreased expression in rats with TNBS colitis. Decreased ASBT expression has also been described in murine, canine and rabbit models of intestinal inflammation. Human IBD studies have shown that an inflamed ileum can interrupt enterohepatic recirculation of bile acid, which could be due to inflammatory cytokine induced repression of the ASBT promoter. There are different hypotheses as to why ASBT is downregulated during CD. In addition, one study has demonstrated the beneficial effect of a glucocorticoid on ASBT expression, when treating IBD. Our aim in this paper was to systematically review various aspects of bile acid malabsorption in animal models of intestinal inflammation, as well as in IBD.
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Affiliation(s)
- Leo R Fitzpatrick
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
| | - Paniz Jenabzadeh
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, California Northstate University, Elk Grove, CA, United States
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31
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Weaver MJ, McHenry SA, Sayuk GS, Gyawali CP, Davidson NO. Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes. Hepatol Commun 2020; 4:493-503. [PMID: 32258945 PMCID: PMC7109338 DOI: 10.1002/hep4.1485] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 01/13/2020] [Indexed: 12/16/2022] Open
Abstract
Irritable bowel syndrome with diarrhea (IBS-D) and NAFLD are both common conditions that may be influenced by shared pathways of altered bile acid (BA) signaling and homeostatic regulation. Pathophysiological links between IBS-D and altered BA metabolism include altered signaling through the ileal enterokine and fibroblast growth factor 19 (FGF19) as well as increased circulating levels of 7α-hydroxy-4-cholesten-3-one, a metabolic intermediate that denotes increased hepatic BA production from cholesterol. Defective production or release of FGF19 is associated with increased BA production and BA diarrhea in some IBS-D patients. FGF19 functions as a negative regulator of hepatic cholesterol 7α-hydroxylase; therefore, reduced serum FGF19 effectively de-represses hepatic BA production in a subset of IBS-D patients, causing BA diarrhea. In addition, FGF19 modulates hepatic metabolic homeostatic response signaling by means of the fibroblast growth factor receptor 4/klotho beta receptor to activate cascades involved in hepatic lipogenesis, fatty acid oxidation, and insulin sensitivity. Emerging evidence of low circulating FGF19 levels in subsets of patients with pediatric and adult NAFLD demonstrates altered enterohepatic BA homeostasis in NAFLD. Conclusion: Here we outline how understanding of shared pathways of aberrant BA homeostatic signaling may guide targeted therapies in some patients with IBS-D and subsets of patients with NAFLD.
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Affiliation(s)
- Michael J. Weaver
- Division of GastroenterologyWashington University School of MedicineSt. LouisMO
| | - Scott A. McHenry
- Division of GastroenterologyWashington University School of MedicineSt. LouisMO
| | - Gregory S. Sayuk
- Division of GastroenterologyWashington University School of MedicineSt. LouisMO
- U.S. Department of Veterans AffairsVA St. Louis Health Care SystemJohn Cochran DivisionSt. LouisMO
| | - C. Prakash Gyawali
- Division of GastroenterologyWashington University School of MedicineSt. LouisMO
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32
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Takemori H, Hamamoto A, Isogawa K, Ito M, Takagi M, Morino H, Miura T, Oshida K, Shibata T. Mouse model of metformin-induced diarrhea. BMJ Open Diabetes Res Care 2020; 8:8/1/e000898. [PMID: 32213489 PMCID: PMC7170402 DOI: 10.1136/bmjdrc-2019-000898] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 01/18/2020] [Accepted: 03/03/2020] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Metformin, an oral medication used for type 2 diabetes mellitus, is the most commonly prescribed drug with less economic burden of patients. Although metformin's efficacy and safety have long been recognized, approximately 5% of the patients treated with this drug develop severe diarrhea as an adverse effect and have to abandon treatment. Because there is no animal model to study metformin-induced diarrhea, it is hard to develop methods to maintain quality of life of patients prescribed with metformin. RESEARCH DESIGN AND METHODS Using mouse models, we tried to develop an evaluation system for metformin-induced diarrhea to improve diarrheal symptoms in patients with diabetes. Healthy (C57BL/6J) and diabetic obese (db/db) mice were subjected to a stepwise dose escalation of metformin (250 mg/kg/day (125 mg/kg twice daily oral dose)-1000 mg/kg/day (500 mg/kg twice daily oral dose)), and fecal moisture contents and their score were monitored. To evaluate anti-diarrheal medications, wood creosote (a traditional medicine) was tested. Several groups of enterobacteria in fresh feces were examined by using PCR. RESULTS 1000 mg/kg/day (four times maximal effective dose) of metformin significantly increased fecal moisture content. Although no symptoms of diarrhea were observed in healthy C57BL/6J mice, the same dose of metformin induced severe diarrhea in diabetic obese db/db mice. A reduction in PCR signals for the Firmicutes group was associated with metformin-induced diarrhea. Wood creosote reduced diarrhea (high water-content) without affecting metformin's efficacy or enterobacterial flora levels. CONCLUSIONS We have created the first animal model of metformin-induced diarrhea using db/db mice, which will provide better quality of life for patients suffering from diarrhea caused by metformin.
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Affiliation(s)
- Hiroshi Takemori
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Akie Hamamoto
- Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan
| | - Kenta Isogawa
- Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan
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Gottlieb A, Canbay A. Why Bile Acids Are So Important in Non-Alcoholic Fatty Liver Disease (NAFLD) Progression. Cells 2019; 8:cells8111358. [PMID: 31671697 PMCID: PMC6912605 DOI: 10.3390/cells8111358] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/27/2019] [Accepted: 10/28/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disease, affecting not just the liver, but also all other organs in the body. Despite an increasing amount of people worldwide developing NAFLD and having it progress to non-alcoholic steatohepatitis (NASH) and potentially cirrhosis, there is still no approved therapy. Therefore, huge efforts are being made to find and develop a successful treatment. One of the special interests is understanding the liver-gut axis and especially the role of bile acids in the progression of NAFLD. Farnesoid X receptor (FXR)-agonists have been approved und used in other liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and have shown signs of being able to decrease inflammation and potentially steatosis. This review will mainly focus on targets/ligands that play an important role in bile acid metabolism and give an overview of ongoing clinical as well as pre-clinical trials. With the complexity of the issue, we did not aim at giving a complete review, rather highlighting important targets and potential treatments that could be approved for NAFLD/NASH treatment within the next few years.
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Affiliation(s)
- Aline Gottlieb
- Department of Physiology, Johns Hopkins University, Baltimore, MD 21224, USA.
| | - Ali Canbay
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany.
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Shin A, Xu H, Imperiale TF. Associations of chronic diarrhoea with non-alcoholic fatty liver disease and obesity-related disorders among US adults. BMJ Open Gastroenterol 2019; 6:e000322. [PMID: 31523443 PMCID: PMC6711435 DOI: 10.1136/bmjgast-2019-000322] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 07/16/2019] [Accepted: 07/24/2019] [Indexed: 12/20/2022] Open
Abstract
Mechanisms explaining observed associations between diarrhoea and obesity or increased body mass index (BMI) are unclear.
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Affiliation(s)
- Andrea Shin
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Huiping Xu
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Thomas F Imperiale
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Center of Innovation, Health Services Research and Development, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, United States
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35
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iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation. Cells 2019; 8:cells8080879. [PMID: 31409057 PMCID: PMC6721660 DOI: 10.3390/cells8080879] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/26/2019] [Accepted: 08/08/2019] [Indexed: 12/30/2022] Open
Abstract
Background: Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β-/- mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2β is located in the endoplasmic reticulum (ER), we investigated the mechanisms for this by focusing on hepatic ER unfolded protein response (UPR), ER PL, and enterohepatic bile acids (BA). Methods: Female WT (wild-type) and iPla2β-/- mice were fed with chow or MCD for 5 weeks. PL and BA profiles were measured by liquid chromatography-mass spectrometry. Gene expression analyses were performed. Results: MCD feeding of WT mice caused a decrease of ER PL subclasses, which were further decreased by iPla2β deficiency. This deficiency alone or combined with MCD downregulated the expression of liver ER UPR proteins and farnesoid X-activated receptor. The downregulation under MCD was concomitant with an elevation of BA in the liver and peripheral blood and an increase of biliary epithelial cell proliferation measured by cytokeratin 19. Conclusion: iPla2β deficiency combined with MCD severely disturbed ER PL composition and caused inactivation of UPR, leading to downregulated Fxr, exacerbated BA, and ductular proliferation. Our study provides insights into iPla2β inactivation for injury susceptibility under normal conditions and liver fibrosis and cholangiopathies during MCD feeding.
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