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Mendoza-Domínguez G, Garrido-Santos ZM, Lau C, Balbuena R, Santana-Vargas AD, Schmulson-Wasserman M. Real-world experience with the diagnosis of bile acid malabsorption (BAM) using serum 7-alpha-C4 and 48-hour stool bile acids. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2025:S2255-534X(25)00039-8. [PMID: 40383704 DOI: 10.1016/j.rgmxen.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 08/10/2024] [Accepted: 08/12/2024] [Indexed: 05/20/2025]
Abstract
INTRODUCTION AND AIMS Bile acid malabsorption (BAM) is responsible for 30% of cases of diarrhea-predominant irritable bowel syndrome (IBS-D) or functional diarrhea and 63.5% of cases of diarrhea following cholecystectomy. 75SeHCAT is the gold standard diagnostic method but is unavailable in Mexico. Alternatively, primary bile acid (PBA) and total bile acid (TBA) determination in 48 h stools and 7αC4 measurement have been proposed as screening tests. OBJECTIVE Our aim was to evaluate the experience with PBAs and/or TBAs and to determine whether 7αC4 is a good screening biomarker for BAM in clinical practice. MATERIAL AND METHODS An ambispective study of patients with chronic diarrhea was conducted. BAM was considered present with 7αC4 > 55 ng/mL (cost $420.00 USD), PBAs ≥ 9.8%, TBAs > 2,337 μmol/48 h, or TBAs > 1,000 μmol/48 h + PBAs > 4% (TBAs + PBAs) ($405.00 USD). However, those tests must be shipped to the US for their analysis (total cost $825.00 USD). Data were compared using the chi-square test and Student's t test, and Spearman's Rho correlations were calculated. RESULTS We analyzed 48 patients with 7αC4 (age: 58.4 ± 16.9, women: 54.2%). BAM was confirmed by 7αC4 in 12.5%, by PBAs in 38.9%; by TBAs in 5.5%, and by TBAs + PBAs in 16.7%. We found elevated 7αC4 in patients with high or normal PBA/TBA levels (correlation with TBAs: 0.542, p = 0.020; PBAs: -0.127, p = 0.605; TBAs + PBAs: -0.200, p = 0.426). Lastly, BAM identified by 7αC4 was more frequent in patients with previous cholecystectomy (22.7%) vs. those without (3.8%). CONCLUSIONS Our study confirms that 7αC4 correlates well with TBAs and is a good biomarker for BAM screening because it can be elevated, despite normal PBA/TBA levels. Additionally, it represents a 49% cost savings in BAM investigation.
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Affiliation(s)
- G Mendoza-Domínguez
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental (UME) Dr. Ruy Pérez Tamayo, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico; Programa de Estudios Combinados en Medicina (PECEM), Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Z M Garrido-Santos
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental (UME) Dr. Ruy Pérez Tamayo, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico; Programa de Estudios Combinados en Medicina (PECEM), Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - C Lau
- Laboratorios Biomédica de Referencia, Mexico City, Mexico
| | - R Balbuena
- Laboratorios Biomédica de Referencia, Mexico City, Mexico
| | - A D Santana-Vargas
- Departamento de Investigación, Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - M Schmulson-Wasserman
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental (UME) Dr. Ruy Pérez Tamayo, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico; Gastroenterología y Motilidad Gastrointestinal, Clínica Lomas Altas, Mexico City, Mexico.
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Chen H, Mo P, Xu G. Potential function of hepatic Niemann-Pick C1-like 1: cholesterol homeostasis regulation of the canalicular lipid bilayer membrane. Gastroenterol Rep (Oxf) 2025; 13:goaf010. [PMID: 40060220 PMCID: PMC11889457 DOI: 10.1093/gastro/goaf010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 07/02/2024] [Accepted: 09/20/2024] [Indexed: 04/11/2025] Open
Abstract
Niemann-Pick C1-like 1 (NPC1L1) is distributed in the human liver and intestine but only slightly expressed in the mouse liver. While it is well established that intestinal NPC1L1 is crucial for the absorption of exogenous cholesterol, the physiological and pathological roles of canalicular membrane-localized NPC1L1 in human hepatic cholesterol transport remain unclear. In this review, we discussed the potential function of human hepatic NPC1L1 and proposed that the disparity in NPC1L1 abundance between humans and mice in the liver may be attributable to their distinct bile hydrophobicity. Human hepatic NPC1L1 might interact with other proteins in the canalicular membrane, regulate membrane cholesterol homeostasis, and contribute to the stability of the canalicular lipid bilayer membrane in response to the greater detergent properties of human bile salts. We hoped to provide novel perspectives on hepatic NPC1L1 for future investigations.
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Affiliation(s)
- Hongtan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Pingfan Mo
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Guoqiang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, P. R. China
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Damianos J, Abdelnaem N, Camilleri M. Gut Goo: Physiology, Diet, and Therapy of Intestinal Mucus and Biofilms in Gastrointestinal Health and Disease. Clin Gastroenterol Hepatol 2025; 23:205-215. [PMID: 39426645 PMCID: PMC11761393 DOI: 10.1016/j.cgh.2024.09.007] [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: 07/24/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 10/21/2024]
Abstract
The gastrointestinal tract has remarkable capacity to withstand considerable insults from exposure to abrasive food particles, chemicals, allergens, and pathogenic microbes. Maintaining a robust epithelial barrier sequesters these potentially harmful substances in the lumen, preventing absorption into the systemic circulation. Normal functioning of this barrier is central in diverse physiological processes including digestion, immunity, inflammation, and gut-brain signaling. One crucial component of the barrier is the mucus layer covering the epithelium. There is increased appreciation of the importance of mucus in maintenance of the gut barrier, and how dysregulation of the mucus layer contributes to several common gastrointestinal pathologies. This manuscript reviews the physical and chemical properties of mucus, its maintenance and turnover, and its role in maintaining gut barrier integrity. The dynamic interactions of the mucus layer within the gut ecosystem are illustrated by highlighting how a weakened mucus layer or defective mucus production facilitate pathogenic microbial colonization and mucosal biofilm formation. These may potentially contribute to the pathogenesis of gastrointestinal diseases such as inflammatory bowel diseases or result in secretion and mucosal damage and inflammation in bile acid diarrhea. A final goal is to review how certain dietary factors, especially low-fiber diets and emulsifiers common in Western diets, can harm the mucus layer. This report summarizes evidence from preclinical and human studies that document damage to the mucus layer, and reviews approaches, including diets and probiotics, that promote a healthy mucus layer and break down pathogenic biofilms, thereby potentially preventing and/or treating gastrointestinal diseases that impact mucosal integrity.
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Affiliation(s)
- John Damianos
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Nada Abdelnaem
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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4
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Kim HJ, Kim HJ. [Bile Acid Diarrhea]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 83:133-142. [PMID: 38659249 DOI: 10.4166/kjg.2023.119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 04/26/2024]
Abstract
Diarrhea is a very common gastrointestinal symptom, and the presence of higher concentrations of bile acid in the colon leads to bile acid diarrhea (BAD). In BAD patients, a portion of bile from the small intestine that is normally controlled by enterohepatic circulation is present at a high concentration in the lumen of the large intestine, resulting in increased motility and secretion of the large intestine. The prevalence of BAD is estimated to be 1-2% of the general population, and it comprises one-third of the instances of diarrhea-predominant irritable bowel syndrome. The clinical symptoms of BAD include chronic diarrhea, increased frequency of defecation, urgency to defecate, fecal incontinence, and cramping abdominal pain. The pathophysiology of BAD has not yet been fully elucidated. However, recent studies have reported increased intestinal permeability, shortened intestinal transit time, and changes in the intestinal microbial community to be the possible causes of BAD. Although fecal and serum bile acid tests are widely used for diagnosis, new test methods that are non-invasive, inexpensive, and have high sensitivity and specificity are needed at various institutions to facilitate the diagnosis. The selenium homo-tauro-cholic acid (SeHCAT) test is the gold standard for BAD diagnosis and severity assessment. The validation of several other serum markers, such as 7-hydroxy-4-cholesten-3-one (serum 7αC4) and the fibroblast growth factor 19 (FGF19) for use in clinical practice is ongoing. Although bile acid sequestrants are the mainstay of treatment, the development of drugs that are more effective and have better compliance is required. Farnesoid X receptor (FXR) agonists are showing promising results.
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Affiliation(s)
- Hee Jin Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Korea
| | - Hyun Jin Kim
- Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Korea
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5
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Griffiths JA, Yoo BB, Thuy-Boun P, Cantu VJ, Weldon KC, Challis C, Sweredoski MJ, Chan KY, Thron TM, Sharon G, Moradian A, Humphrey G, Zhu Q, Shaffer JP, Wolan DW, Dorrestein PC, Knight R, Gradinaru V, Mazmanian SK. Peripheral neuronal activation shapes the microbiome and alters gut physiology. Cell Rep 2024; 43:113953. [PMID: 38517896 PMCID: PMC11132177 DOI: 10.1016/j.celrep.2024.113953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/07/2023] [Accepted: 02/27/2024] [Indexed: 03/24/2024] Open
Abstract
The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain.
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Affiliation(s)
- Jessica A Griffiths
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Bryan B Yoo
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Peter Thuy-Boun
- Departments of Molecular Medicine and Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Victor J Cantu
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
| | - Kelly C Weldon
- Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, USA; UCSD Center for Microbiome Innovation, University of California, San Diego, San Diego, CA, USA
| | - Collin Challis
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Michael J Sweredoski
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Ken Y Chan
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Taren M Thron
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Gil Sharon
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Annie Moradian
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Gregory Humphrey
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
| | - Qiyun Zhu
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
| | - Justin P Shaffer
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
| | - Dennis W Wolan
- Departments of Molecular Medicine and Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Pieter C Dorrestein
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA; Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA, USA; UCSD Center for Microbiome Innovation, University of California, San Diego, San Diego, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA; UCSD Center for Microbiome Innovation, University of California, San Diego, San Diego, CA, USA; Department of Computer Science and Engineering, University of California, San Diego, San Diego, CA, USA; Shu Chien-Gene Lay Department of Engineering, University of California, San Diego, San Diego, CA, USA; Halıcıoğlu Data Science Institute, University of California, San Diego, San Diego, CA, USA
| | - Viviana Gradinaru
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Sarkis K Mazmanian
- Division of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
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Desmet L, Thijs T, Segers A, Depoortere I. Chronic jetlag reprograms gene expression in the colonic smooth muscle layer inducing diurnal rhythmicity in the effect of bile acids on colonic contractility. Neurogastroenterol Motil 2023; 35:e14487. [PMID: 36264144 DOI: 10.1111/nmo.14487] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 09/14/2022] [Accepted: 09/27/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND Secondary bile acids entrain peripheral circadian clocks and inhibit colonic motility via the bile acid receptor GPBAR1. We aimed to investigate whether chronodisruption affected the rhythm in serum bile acid levels and whether this was associated with alterations in clock gene and Gpbar1 mRNA expression in the colonic smooth muscle layer. We hypothesized that this in turn may affect the rhythm in the inhibitory effect of secondary bile acids on colonic contractility. METHODS Mice were exposed to 4 weeks of chronic jetlag induction. The expression of Gpbar1 and clock genes was measured in colonic smooth muscle tissue using RT-qPCR over 24 h (4 h time interval). The effect of secondary bile acids on electrical field-induced neural contractions was measured isometrically in colonic smooth muscle strips. KEY RESULTS Chronic jetlag abolished the rhythmicity in serum bile acid levels. This was associated with a phase-shift in diurnal clock gene mRNA fluctuations in smooth muscle tissue. Chronic jetlag induced a rhythm in Gpbar1 expression in the colonic smooth muscle layer. In parallel, a rhythm was induced in the inhibitory effect of taurodeoxycholic acid (TDCA), but not deoxycholic acid, on neural colonic contractions that peaked together with Gpbar1 expression. CONCLUSIONS & INFERENCES Chronodisruption abolished the rhythm in bile acid levels which might contribute to a shift in smooth muscle clock gene expression. Our findings suggest that chronodisruption caused a transcriptional reprogramming in the colonic smooth layer thereby inducing a rhythm in the expression of Gpbar1 and in the inhibitory effect of TDCA on colonic contractility.
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Affiliation(s)
- Louis Desmet
- Translational Research Center for Gastrointestinal Disorders, Gut Peptide Research Lab, University of Leuven, Leuven, Belgium
| | - Theo Thijs
- Translational Research Center for Gastrointestinal Disorders, Gut Peptide Research Lab, University of Leuven, Leuven, Belgium
| | - Anneleen Segers
- Translational Research Center for Gastrointestinal Disorders, Gut Peptide Research Lab, University of Leuven, Leuven, Belgium
| | - Inge Depoortere
- Translational Research Center for Gastrointestinal Disorders, Gut Peptide Research Lab, University of Leuven, Leuven, Belgium
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Current and Future Therapeutic Options for Irritable Bowel Syndrome with Diarrhea and Functional Diarrhea. Dig Dis Sci 2022; 68:1677-1690. [PMID: 36376576 DOI: 10.1007/s10620-022-07700-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/12/2022] [Indexed: 11/15/2022]
Abstract
Irritable bowel syndrome with diarrhea and functional diarrhea are disorders of gut-brain interaction presenting with chronic diarrhea; they have significant impact on quality of life. The two conditions may exist as a continuum and their treatment may overlap. Response to first-line therapy with antispasmodics and anti-diarrheal agents is variable, leaving several patients with suboptimal symptom control and need for alternative therapeutic options. Our aim was to discuss current pharmacologic options and explore alternative therapeutic approaches and future perspectives for symptom management in irritable bowel syndrome with diarrhea and functional diarrhea. We conducted a search of PubMed, Cochrane, clinicaltrial.gov, major meeting abstracts for publications on current, alternative, and emerging drugs for irritable bowel syndrome with diarrhea and functional diarrhea. Currently approved therapeutic options for patients with first-line refractory irritable bowel syndrome with diarrhea and functional diarrhea include serotonin-3 receptor antagonists, eluxadoline and rifaximin. Despite their proven efficacy, cost and availability worldwide impact their utilization. One-third of patients with disorders of gut-brain interaction with diarrhea have bile acid diarrhea and may benefit from drugs targeting bile acid synthesis and excretion. Further understanding of underlying pathophysiology of irritable bowel syndrome with diarrhea and functional diarrhea related to bile acid metabolism, gastrointestinal transit, and microbiome has led to evaluation of novel therapeutic approaches, including fecal microbiota transplantation and enterobacterial "crapsules". These opportunities to treat disorders of gut-brain interaction with diarrhea should be followed with formal studies utilizing large samples of well-characterized patients at baseline and validated response outcomes as endpoints for regulatory approval.
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8
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Min YW, Rezaie A, Pimentel M. Bile Acid and Gut Microbiota in Irritable Bowel Syndrome. J Neurogastroenterol Motil 2022; 28:549-561. [PMID: 36250362 PMCID: PMC9577585 DOI: 10.5056/jnm22129] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/31/2022] [Indexed: 01/18/2023] Open
Abstract
Gut microbiota and their metabolites like bile acid (BA) have been investigated as causes of irritable bowel syndrome (IBS) symptoms. Primary BAs are synthesized and conjugated in the liver and released into the duodenum. BA biotransformation by gut microbiota begins in the intestine and results in production of a broad range of secondary BAs. Deconjugation is considered the gateway reaction for further modification and is mediated by bile salt hydrolase, which is widely expressed by the gut microbiota. However, gut bacteria that convert primary BAs to secondary BAs belong to a limited number of species, mainly Clostridiales. Like gut microbiota modify BA profile, BAs can shape gut microbiota via direct and indirect actions. BAs have prosecretory effects and regulates gut motility. BAs can also affect gut sensitivity. Because of the vital role of the gut microbiota and BAs in gut function, their bidirectional relationship may contribute to the pathophysiology of IBS. Individuals with IBS have been reported to have altered microbial profiles and modified BA profiles. A significant increase in fecal primary BA and a corresponding decrease in secondary BA have been observed in IBS with predominant diarrhea. In addition, primary BA was positively correlated with IBS symptoms. In IBS with predominant diarrhea, bacteria with reduced abundance mainly belonged to the genera in Ruminococcaceae and exhibited a negative correlation with primary BAs. Integrating the analysis of the gut microbiota and BAs could better understanding of IBS pathophysiology. The gap in this field needs to be further filled in the future.
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Affiliation(s)
- Yang Won Min
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA.,Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ali Rezaie
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA.,Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA
| | - Mark Pimentel
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA.,Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA
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Moreno AA, Parker VJ, Winston JA, Rudinsky AJ. Dietary fiber aids in the management of canine and feline gastrointestinal disease. J Am Vet Med Assoc 2022; 260:S33-S45. [DOI: 10.2460/javma.22.08.0351] [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]
Abstract
Abstract
Dietary fiber describes a diverse assortment of nondigestible carbohydrates that play a vital role in the health of animals and maintenance of gastrointestinal tract homeostasis. The main roles dietary fiber play in the gastrointestinal tract include physically altering the digesta, modulating appetite and satiety, regulating digestion, and acting as a microbial energy source through fermentation. These functions can have widespread systemic effects. Fiber is a vital component of nearly all commercial canine and feline diets. Key features of fiber types, such as fermentability, solubility, and viscosity, have been shown to have clinical implications as well as health benefits in dogs and cats. Practitioners should know how to evaluate a diet for fiber content and the current knowledge on fiber supplementation as it relates to common enteropathies including acute diarrhea, chronic diarrhea, constipation, and hairball management. Understanding the fundamentals of dietary fiber allows the practicing clinician to use fiber optimally as a management modality.
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Affiliation(s)
- Adam A. Moreno
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
- The Comparative Hepatobiliary and Intestinal Research Program, College of Veterinary Medicine, The Ohio State University, Columbus, OH
| | - Valerie J. Parker
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
- The Comparative Hepatobiliary and Intestinal Research Program, College of Veterinary Medicine, The Ohio State University, Columbus, OH
| | - Jenessa A. Winston
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
- The Comparative Hepatobiliary and Intestinal Research Program, College of Veterinary Medicine, The Ohio State University, Columbus, OH
| | - Adam J. Rudinsky
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH
- The Comparative Hepatobiliary and Intestinal Research Program, College of Veterinary Medicine, The Ohio State University, Columbus, OH
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10
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Camilleri M, Nurko S. Bile Acid Diarrhea in Adults and Adolescents. Neurogastroenterol Motil 2022; 34:e14287. [PMID: 34751982 PMCID: PMC8957499 DOI: 10.1111/nmo.14287] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/22/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bile acids are central to enterohepatic signaling pathways activated through natural receptors, farnesoid X receptor [FXR mediates synthesis of fibroblast growth factor-19 (FGF-19)], and G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Although bile acid diarrhea (BAD) is more commonly encountered in ileal resection or disease, there is evidence documenting "idiopathic" BAD in about 20% of adolescents and 30% of adults presenting with chronic, non-bloody diarrhea often attributed to irritable bowel syndrome. Mechanism(s) leading to increased hepatic synthesis and colonic bile acid levels in "idiopathic" BAD include reduced synthesis of FGF-19 by the ileal mucosa, or genetic variation in hepatocyte proteins klotho β and FGF receptor 4 (FGFR4) that mediate negative feedback of bile acid synthesis. PURPOSE The objective of this review is to summarize the diagnosis of BAD in adults and adolescents. In addition to 75 SeHCAT retention for diagnosis of BAD, studies have validated fasting serum 7αC4 and FGF-19, respectively, by-product and inhibitor of hepatic bile acid synthesis, as well as fecal bile acid measurements. These assays are widely available through reference laboratories, and they are being simplified (eg, measurement of primary fecal bile acids in a random stool sample). BAD has also been identified as a co-factor contributing to persistent diarrhea in other diseases in remission including inflammatory bowel disease, microscopic colitis, celiac disease, and neuroendocrine tumors. In summary, advances in diagnosis of BAD provide opportunities for generalists and pediatric and adult gastroenterologists to provide targeted treatment for BAD presenting as chronic non-bloody diarrhea.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) and Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN USA
| | - Samuel Nurko
- Department of Pediatric Gastroenterology Boston Children’s Hospital Boston MA USA
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11
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Keely SJ, Urso A, Ilyaskin AV, Korbmacher C, Bunnett NW, Poole DP, Carbone SE. Contributions of bile acids to gastrointestinal physiology as receptor agonists and modifiers of ion channels. Am J Physiol Gastrointest Liver Physiol 2022; 322:G201-G222. [PMID: 34755536 PMCID: PMC8782647 DOI: 10.1152/ajpgi.00125.2021] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/28/2021] [Accepted: 11/08/2021] [Indexed: 02/03/2023]
Abstract
Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.
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Affiliation(s)
- Stephen J Keely
- Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Andreacarola Urso
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
- Department of Pharmacology, Columbia University, New York, New York
| | - Alexandr V Ilyaskin
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Christoph Korbmacher
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, New York
- Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, New York
| | - Daniel P Poole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Simona E Carbone
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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12
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Hou JJ, Wang X, Wang YM, Wang BM. Interplay between gut microbiota and bile acids in diarrhoea-predominant irritable bowel syndrome: a review. Crit Rev Microbiol 2021; 48:696-713. [PMID: 34936854 DOI: 10.1080/1040841x.2021.2018401] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease that disturbs the physiology and psychology of patients and increases the burden on families, the healthcare system, society, and economic development, affecting more and more people around the world. Despite the multiple factors that account for IBS remaining incompletely studied, emerging evidence demonstrated the abnormal changes in gut microbiota and bile acids (BAs) metabolism closely associated with IBS. Moreover, microbiota drives significant modifications for BAs, consisting of deconjugation, 7α-dehydroxylation, oxidation, epimerization, desulfation, esterification, and so on, while BAs, in turn, affect the microbiota directly or indirectly. In light of the complex connection among gut microbiota, BAs, and IBS, it is urgent to review the latest research progress in this field. In this review, we described the disorders of intestinal microecology and BAs profiles in IBS-D and also highlighted the cross-talk between gut microbiota and BAs in the context of IBS-D. Integrating these, we suggest that new therapeutic strategies targeting the microbiota-BAs axis for IBS-D, even for other related diseases caused by bacteria-bile acid dysbiosis should be expected.
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Affiliation(s)
- Jun-Jie Hou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China
| | - Xin Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China
| | - Yu-Ming Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Tianjin, China
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13
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Stamatopoulos K, O'Farrell C, Simmons M, Batchelor H. In vivo models to evaluate ingestible devices: Present status and current trends. Adv Drug Deliv Rev 2021; 177:113915. [PMID: 34371085 DOI: 10.1016/j.addr.2021.113915] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/27/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022]
Abstract
Evaluation of orally ingestible devices is critical to optimize their performance early in development. Using animals as a pre-clinical tool can provide useful information on functionality, yet it is important to recognize that animal gastrointestinal physiology, pathophysiology and anatomy can differ to that in humans and that the most suitable species needs to be selected to inform the evaluation. There has been a move towards in vitro and in silico models rather than animal models in line with the 3Rs (Replacement, Reduction and Refinement) as well as the better control and reproducibility associated with these systems. However, there are still instances where animal models provide the greatest understanding. This paper provides an overview of key aspects of human gastrointestinal anatomy and physiology and compares parameters to those reported in animal species. The value of each species can be determined based upon the parameter of interest from the ingested device when considering the use of pre-clinical animal testing.
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Affiliation(s)
- Konstantinos Stamatopoulos
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Biopharmaceutics, Pharmaceutical Development, PDS, MST, RD Platform Technology & Science, GSK, David Jack Centre, Park Road, Ware, Hertfordshire SG12 0DP, UK
| | - Connor O'Farrell
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Mark Simmons
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Hannah Batchelor
- Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, Glasgow G4 0RE, UK.
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14
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Medical Therapies for Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterol Clin North Am 2021; 50:611-637. [PMID: 34304791 DOI: 10.1016/j.gtc.2021.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Diarrhea-predominant irritable bowel syndrome is a common functional gastrointestinal disorder that manifests with abdominal pain and diarrheal bowel patterns, without structural explanation. Diarrhea-predominant irritable bowel syndrome is a heterogeneous condition resulting from diverse pathophysiologic processes. Treatment strategies with varied mechanisms of action are beneficial in its management. The clinician must become familiar with a multi-dimensional approach to irritable bowel syndrome. The 3 approved medications are central to disease management. Effective treatment uses off-label medications and emerging therapies and a growing number of over-the-counter and supplemental agents to optimize symptom improvement for the patient with diarrhea-predominant irritable bowel syndrome.
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15
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Abstract
INTRODUCTION Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation. METHODS We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry). RESULTS For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo. DISCUSSION Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.
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16
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Wei W, Wang HF, Zhang Y, Zhang YL, Niu BY, Yao SK. Altered metabolism of bile acids correlates with clinical parameters and the gut microbiota in patients with diarrhea-predominant irritable bowel syndrome. World J Gastroenterol 2020; 26:7153-7172. [PMID: 33362374 PMCID: PMC7723672 DOI: 10.3748/wjg.v26.i45.7153] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/21/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bile acids (BAs) have attracted attention in the research of irritable bowel syndrome with predominant diarrhea (IBS-D) due to their ability to modulate bowel function and their tight connection with the gut microbiota. The composition of the fecal BA pool in IBS-D patients is reportedly different from that in healthy populations. We hypothesized that BAs may participate in the pathogenesis of IBS-D and the altered BA profile may be correlated with the gut microbiome. AIM To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota. METHODS Fifty-five IBS-D patients diagnosed according to the Rome IV criteria and twenty-eight age-, sex-, and body mass index-matched healthy controls (HCs) were enrolled in this study at the gastroenterology department of China-Japan Friendship Hospital. First, clinical manifestations were assessed with standardized questionnaires, and visceral sensitivity was evaluated via the rectal distension test using a high-resolution manometry system. Fecal primary BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA), secondary BAs including deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) as well as the corresponding tauro- and glyco-BAs were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry. The gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between fecal BAs with clinical features and gut microbiota were explored. RESULTS Fecal CA (IBS-D: 3037.66 [282.82, 6917.47] nmol/g, HC: 20.19 [5.03, 1304.28] nmol/g; P < 0.001) and CDCA (IBS-D: 1721.86 [352.80, 2613.83] nmol/g, HC: 57.16 [13.76, 1639.92] nmol/g; P < 0.001) were significantly increased, while LCA (IBS-D: 1621.65 [58.99, 2396.49] nmol/g, HC: 2339.24 [1737.09, 2782.40]; P = 0.002] and UDCA (IBS-D: 8.92 [2.33, 23.93] nmol/g, HC: 17.21 [8.76, 33.48] nmol/g; P = 0.025) were significantly decreased in IBS-D patients compared to HCs. Defecation frequency was positively associated with CA (r = 0.294, P = 0.030) and CDCA (r = 0.290, P = 0.032) and negatively associated with DCA (r = -0.332, P = 0.013) and LCA (r = -0.326, P = 0.015) in IBS-D patients. In total, 23 of 55 IBS-D patients and 15 of 28 HCs participated in the visceral sensitivity test. The first sensation threshold was negatively correlated with CDCA (r = -0.459, P = 0.028) in IBS-D patients. Furthermore, the relative abundance of the family Ruminococcaceae was significantly decreased in IBS-D patients (P < 0.001), and 12 genera were significantly lower in IBS-D patients than in HCs (P < 0.05), with 6 belonging to Ruminococcaceae. Eleven of these genera were negatively correlated with primary BAs and positively correlated with secondary BAs in all subjects. CONCLUSION The altered metabolism of BAs in the gut of IBS-D patients was associated with diarrhea and visceral hypersensitivity and might be ascribed to dysbiosis, especially the reduction of genera in Ruminococcaceae.
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Affiliation(s)
- Wei Wei
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hui-Fen Wang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yu Zhang
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yan-Li Zhang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bing-Yu Niu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
- Graduate School, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Shu-Kun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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17
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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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18
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Abstract
There are ten good reasons why it is important to think about abnormalities in bile acid control in inflammatory bowel disease. Before reviewing these reasons, it is relevant to review essential elements in the enterohepatic circulation, synthesis and actions of bile acids.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Corresponding author: Michael Camilleri, MD, Mayo Clinic, Charlton 8–110, 200 First St. S.W., Rochester, MN 55905, USA. Tel: 507-266-2305;
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19
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Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study. J Hepatol 2020; 73:231-240. [PMID: 32234329 DOI: 10.1016/j.jhep.2020.03.024] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/27/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. METHODS In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. RESULTS Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. CONCLUSIONS Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. LAY SUMMARY A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. CLINICAL TRIAL IDENTIFIER NCT02787304.
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20
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Balestrieri P, Ribolsi M, Guarino MPL, Emerenziani S, Altomare A, Cicala M. Nutritional Aspects in Inflammatory Bowel Diseases. Nutrients 2020; 12:372. [PMID: 32023881 PMCID: PMC7071234 DOI: 10.3390/nu12020372] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are chronic, relapsing, inflammatory disorders of the digestive tract that characteristically develop in adolescence and early adulthood. The reported prevalence of malnutrition in inflammatory bowel disease (IBD) patients ranges between 20% and 85%. Several factors, including reduced oral food intake, malabsorption, chronic blood and proteins loss, and intestinal bacterial overgrowth, contribute to malnutrition in IBD patients. Poor nutritional status, as well as selective malnutrition or sarcopenia, is associated with poor clinical outcomes, response to therapy and, therefore, quality of life. The nutritional assessment should include a dietetic evaluation with the assessment of daily caloric intake and energy expenditure, radiological assessment, and measurement of functional capacity.
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Affiliation(s)
- Paola Balestrieri
- Unit of Gastroenterology, Campus Bio-Medico University, 00128 Rome, Italy; (M.R.); (M.P.L.G.); (S.E.); (A.A.); (M.C.)
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21
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O'Donovan SM, Crowley EK, Brown JRM, O'Sullivan O, O'Leary OF, Timmons S, Nolan YM, Clarke DJ, Hyland NP, Joyce SA, Sullivan AM, O'Neill C. Nigral overexpression of α-synuclein in a rat Parkinson's disease model indicates alterations in the enteric nervous system and the gut microbiome. Neurogastroenterol Motil 2020; 32:e13726. [PMID: 31576631 DOI: 10.1111/nmo.13726] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 09/02/2019] [Accepted: 09/02/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND A hallmark feature of Parkinson's disease (PD) is the build-up of α-synuclein protein aggregates throughout the brain; however α-synuclein is also expressed in enteric neurons. Gastrointestinal (GI) symptoms and pathology are frequently reported in PD, including constipation, increased intestinal permeability, glial pathology, and alterations to gut microbiota composition. α-synuclein can propagate through neuronal systems but the site of origin of α-synuclein pathology, whether it be the gut or the brain, is still unknown. Physical exercise is associated with alleviating symptoms of PD and with altering the composition of the gut microbiota. METHODS This study investigated the effects of bilateral nigral injection of adeno-associated virus (AAV)-α-synuclein on enteric neurons, glia and neurochemistry, the gut microbiome, and bile acid metabolism in rats, some of whom were exposed to voluntary exercise. KEY RESULTS Nigral overexpression of α-synuclein resulted in significant neuronal loss in the ileal submucosal plexus with no change in enteric glia. In contrast, the myenteric plexus showed a significant increase in glial expression, while neuronal numbers were maintained. Concomitant alterations were observed in the gut microbiome and related bile acid metabolism. Voluntary running protected against neuronal loss, increased enteric glial expression, and modified gut microbiome composition in the brain-injected AAV-α-synuclein PD model. CONCLUSIONS AND INFERENCES These results show that developing nigral α-synuclein pathology in this PD model exerts significant alterations on the enteric nervous system (ENS) and gut microbiome that are receptive to modification by exercise. This highlights brain to gut communication as an important mechanism in PD pathology.
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Affiliation(s)
- Sarah M O'Donovan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.,Cork Neuroscience Centre, University College Cork, Cork, Ireland
| | - Erin K Crowley
- Cork Neuroscience Centre, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | | | - Orla O'Sullivan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Teagasc Food Research Centre Moorepark, Cork, Ireland
| | - Olivia F O'Leary
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Cork Neuroscience Centre, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Suzanne Timmons
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Cork Neuroscience Centre, University College Cork, Cork, Ireland.,Centre of Gerontology and Rehabilitation, University College Cork, Cork, Ireland
| | - Yvonne M Nolan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Cork Neuroscience Centre, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - David J Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,School of Microbiology, University College Cork, Cork, Ireland
| | - Niall P Hyland
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Physiology, University College Cork, Cork, Ireland
| | - Susan A Joyce
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Aideen M Sullivan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Cork Neuroscience Centre, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Cora O'Neill
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.,Cork Neuroscience Centre, University College Cork, Cork, Ireland
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22
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Busnelli M, Manzini S, Chiesa G. The Gut Microbiota Affects Host Pathophysiology as an Endocrine Organ: A Focus on Cardiovascular Disease. Nutrients 2019; 12:E79. [PMID: 31892152 PMCID: PMC7019666 DOI: 10.3390/nu12010079] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/18/2019] [Accepted: 12/24/2019] [Indexed: 12/12/2022] Open
Abstract
It is widely recognized that the microorganisms inhabiting our gastrointestinal tract-the gut microbiota-deeply affect the pathophysiology of the host. Gut microbiota composition is mostly modulated by diet, and gut microorganisms communicate with the different organs and tissues of the human host by synthesizing hormones and regulating their release. Herein, we will provide an updated review on the most important classes of gut microbiota-derived hormones and their sensing by host receptors, critically discussing their impact on host physiology. Additionally, the debated interplay between microbial hormones and the development of cardiovascular disease will be thoroughly analysed and discussed.
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Affiliation(s)
| | | | - Giulia Chiesa
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy;
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23
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Roda G, Porru E, Katsanos K, Skamnelos A, Kyriakidi K, Fiorino G, Christodoulou D, Danese S, Roda A. Serum Bile Acids Profiling in Inflammatory Bowel Disease Patients Treated with Anti-TNFs. Cells 2019; 8:cells8080817. [PMID: 31382518 PMCID: PMC6721523 DOI: 10.3390/cells8080817] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/24/2019] [Accepted: 08/01/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD), represent systematic chronic conditions with a deficient intestinal absorption. We first attempt to investigate the serum bile acids (sBAs) profile in a large cohort of IBD patients to evaluate changes under anti-TNF alpha treatment. Methods: Forty CD and 40 UC patients were enrolled and BAs were quantified by high-pressure liquid chromatography-electrospray-tandem mass spectrometry (HPLC-ES-MS/MS). Up to 15 different sBAs concentrations and clinical biomarkers where added to a Principal Component Analysis (PCA) to discriminate IBD from healthy conditions and treatment. Results: PCA allowed a separation into two clusters within CD (biologic-free patients and patients treated with anti-TNF alpha drugs and healthy subjects) but not UC. The first included CD. CD patients receiving anti-TNF alpha have an increase in total sBAs (4.11 ± 1.23 μM) compared to patients not exposed. Secondary BAs significantly increase after anti-TNF alpha treatment (1.54 ± 0.83 μM). Furthermore, multivariate analysis based on sBA concentration highlighted a different qualitative sBAs profile for UC and CD patients treated with conventional therapy. Conclusion: According to our results, anti-TNF alpha in CD restores the sBA profile by re-establishing the physiological levels. These findings indicate that, secondary BAs might serve as an indirect biomarker of the healing process.
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Affiliation(s)
- Giulia Roda
- IBD Unit, Humanitas Research Hospital, 20089 Milan, Italy
| | - Emanuele Porru
- Department of Chemistry G. Ciamician, Alma Mater Studiorum University of Bologna, 40100 Bologna, Italy
| | - Konstantinos Katsanos
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Ioannina School of Health Sciences 45110 Ioannina, Greece
| | - Alexandros Skamnelos
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Ioannina School of Health Sciences 45110 Ioannina, Greece
| | - Kallirroi Kyriakidi
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Ioannina School of Health Sciences 45110 Ioannina, Greece
| | - Gionata Fiorino
- IBD Unit, Humanitas Research Hospital, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20089 Milan, Italy
| | - Dimitrios Christodoulou
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Ioannina School of Health Sciences 45110 Ioannina, Greece
| | - Silvio Danese
- IBD Unit, Humanitas Research Hospital, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20089 Milan, Italy
| | - Aldo Roda
- Department of Chemistry G. Ciamician, Alma Mater Studiorum University of Bologna, 40100 Bologna, Italy
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24
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Microbiome: In Search of Mechanistic Information and Relevance. Am J Gastroenterol 2019; 114:1014-1016. [PMID: 31211707 DOI: 10.14309/ajg.0000000000000306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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25
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Abstract
INTRODUCTION Chronic idiopathic constipation (CC) is highly prevalent worldwide. A subset of patients with CC have reduced fecal (and by inference, intra-colonic) bile acids (BA). Elobixibat, a locally-acting ileal bile acid transporter (IBAT) inhibitor, leads to increased BA delivery to the colon and represents a new class of treatment for CC. BAs accelerate colonic transit and increase colonic secretion. Therefore, IBAT inhibitors have potential to treat patients with CC. Areas covered: Rationale for IBAT inhibitor in therapeutics, and preclinical and clinical pharmacology of elobixibat: In vitro, elobixibat is a highly potent, selective IBAT inhibitor. In humans, elobixibat accelerated colonic transit. In phase 2A, 2B and 3 studies in CC, elobixibat was efficacious, well tolerated and safe. An open-label, phase 3 trial (52 weeks) confirmed the safety of elobixibat. Elobixibat reduces LDL cholesterol, increases serum GLP-1, and has potential in metabolic syndrome. Expert commentary: Uniquely among current treatments of CC, elobixibat stimulates both motor and secretory functions in the colon. These dual effects suggest that, when approved, elobixibat may be a first-line choice for constipation associated with colonic BA deficiency and a second-line treatment for all patients with CC and constipation-predominant irritable bowel syndrome. Further studies are required to confirm efficacy for relief of CC. Once approved, elobixibat will likely become a second-line choice for treatment of CC.
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Affiliation(s)
- Victor Chedid
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Priya Vijayvargiya
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Michael Camilleri
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
- b Pharmacology, and Physiology , Mayo Clinic College of Medicine and Science, ConsultantDivision of Gastroenterology and Hepatology, Mayo Clinic , Rochester , MN , USA
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Siebers N, Palmer M, Silberg DG, Jennings L, Bliss C, Martin PT. Absorption, Distribution, Metabolism, and Excretion of [ 14C]-Volixibat in Healthy Men: Phase 1 Open-Label Study. Eur J Drug Metab Pharmacokinet 2018; 43:91-101. [PMID: 28702877 PMCID: PMC5794849 DOI: 10.1007/s13318-017-0429-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background and Objectives Volixibat is a potent inhibitor of the apical sodium-dependent bile acid transporter in development for the treatment of nonalcoholic steatohepatitis. This phase 1, open-label study investigated the absorption, distribution, metabolism, and excretion of [14C]-volixibat in heathy men. Methods Eligible men (n = 8) aged 18–50 years (body mass index 18.0–30.0 kg/m2; weight >50 kg) received a single oral dose of [14C]-volixibat 50 mg containing ~5.95 µCi radioactivity. The primary objectives were to assess the pharmacokinetics of [14C]-volixibat and to determine the total radioactivity in whole blood, plasma, urine, and feces at pre-selected time points over 6 days. The secondary objectives were to characterize metabolites and to assess the safety and tolerability. Results Low concentrations of volixibat (range 0–0.179 ng/mL) were detected in plasma up to 8 h following administration; the pharmacokinetic parameters could not be calculated. No radioactivity was observed in plasma or whole blood. The percentage (mean ± standard deviation) of total radioactivity in urine was 0.01 ± 0.007%. The vast majority (92.3 ± 5.25%) of volixibat was recovered in feces (69.2 ± 33.1% within 24 h). Unchanged volixibat was the only radioactive component detected in feces. Adverse events were mild in severity and mostly gastrointestinal. Changes in laboratory values were not clinically meaningful. Conclusions Following oral administration, [14C]-volixibat was excreted unchanged from the parent compound almost exclusively via fecal excretion, indicating that the drug is minimally absorbed. Consistent with other studies, adverse events were primarily gastrointestinal in nature. ClinicalTrials.gov identifier NCT02571192. Electronic supplementary material The online version of this article (doi:10.1007/s13318-017-0429-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nicholas Siebers
- Covance Clinical Research Unit, 3402 Kinsman Boulevard, Madison, WI, 53704, USA.
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Yde J, Larsen HM, Laurberg S, Krogh K, Moeller HB. Chronic diarrhoea following surgery for colon cancer-frequency, causes and treatment options. Int J Colorectal Dis 2018; 33:683-694. [PMID: 29589108 DOI: 10.1007/s00384-018-2993-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2018] [Indexed: 02/04/2023]
Abstract
PURPOSE The growing population of survivors after colon cancer warrants increased attention to the long-term outcome of surgical treatment. The change in bowel anatomy after resection disrupts normal gastrointestinal function and may cause symptoms. Thus, many patients surviving colon cancer have to cope with bowel dysfunction for the rest of their lives. We here aim to provide an overview of the literature on this topic. METHODS We review long-term functional outcomes of surgical treatment for colon cancer, the underlying pathology, and treatment options. RESULTS Common symptoms include constipation, urge for defecation and diarrhoea. Causes of diarrhoea after colon cancer surgery are sparsely studied, but they probably include bile acid malabsorption, small intestinal bacterial overgrowth and disruption of the ileal brake. Specific diagnosis should be made to allow individual treatment based on the underlying pathology. Studies on treatment of functional problems after surgery for colon cancer are extremely few, but some lessons can be drawn from the treatment of other patient groups having undergone colon surgery. CONCLUSION Diarrhoea is likely a common long-term complication after colon cancer surgery. Attention to this complication and a specific diagnosis will aid the targeted treatment of patients suffering from this complication.
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Affiliation(s)
- Jonathan Yde
- Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 3, Building 1233, 8000, Aarhus, Denmark
| | - Helene M Larsen
- Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.,Danish Cancer Society Centre for Research and Late Adverse Effects After Cancer in the Pelvic Organs, Aarhus University Hospital, Aarhus, Denmark
| | - Søren Laurberg
- Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.,Danish Cancer Society Centre for Research and Late Adverse Effects After Cancer in the Pelvic Organs, Aarhus University Hospital, Aarhus, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.,Danish Cancer Society Centre for Research and Late Adverse Effects After Cancer in the Pelvic Organs, Aarhus University Hospital, Aarhus, Denmark
| | - Hanne B Moeller
- Department of Biomedicine, Aarhus University, Wilhelm Meyers Alle 3, Building 1233, 8000, Aarhus, Denmark.
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Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial. Lancet Gastroenterol Hepatol 2018; 3:537-547. [PMID: 29805116 DOI: 10.1016/s2468-1253(18)30123-7] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 03/30/2018] [Accepted: 04/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND A subset of patients with constipation has reduced colonic bile acid concentrations, which are associated with slow colonic transit. In a previous study, elobixibat, a locally acting ileal bile acid transporter inhibitor, accelerated colonic transit in Japanese patients with functional constipation. In this study, we aimed to determine the efficacy of elobixibat for short-term treatment of chronic constipation, and safety, patient satisfaction, and quality of life with long-term treatment. METHODS We did two phase 3 studies of patients aged 20-80 years in Japan with at least 6 months of chronic constipation, who satisfied Rome III criteria for functional constipation, including fewer than three spontaneous bowel movements per week. The first trial, including patients enrolled at 16 clinics, was a 2-week, randomised, double-blind, placebo-controlled study in which (after a 2-week run-in period) patients were randomly assigned (1:1) to either elobixibat 10 mg/day for 2 weeks or placebo. Randomisation was done with permuted block method (block size six) without stratification. Masking to treatment allocation was achieved with identical appearances of elobixibat and placebo, which were supplied in sealed, opaque containers. Group assignment was concealed from patients, investigators, and analysts. The second trial, including patients enrolled at 34 clinics or hospitals, was an open-label, 1-year study in which all patients received elobixibat; participants could titrate the dose to 5 mg/day or 15 mg/day, or maintain the 10 mg/day dose. In both studies, participants took the study drug as an oral tablet once per day before breakfast. The primary outcome of the 2-week randomised trial was the change from baseline (ie, last week of the 2-week run-in) in the frequency of spontaneous bowel movements during week 1 of treatment. The primary outcome of the 52-week open-label trial was safety (type, severity, and incidence of adverse drug reactions) at all times from treatment initiation. All efficacy analyses were based on the modified intention-to-treat (ITT) population without imputation for any missing data. Safety analyses included all patients who received at least one dose of study drug. These trials are registered with the Japan Pharmaceutical Information Center (numbers JapicCTI-153061 and JapicCTI-153062) and have been completed. FINDINGS Between Nov 4, 2015, and June 11, 2016, we assigned 133 patients to treatment in the 2-week randomised trial: 70 to elobixibat (69 included in the modified ITT and safety populations) and 63 to placebo. The frequency of spontaneous bowel movements per week during week 1 of treatment was greater with elobixibat (least-squares mean 6·4, 95% CI 5·3-7·6) than with placebo (1·7, 1·2-2·2), p<0·0001). Between Oct 31, 2015, and March 15, 2017, we allocated 341 patients to 52 weeks of elobixibat (340 included in the modified ITT and safety populations). 163 (48%) patients in the 52-week trial had an adverse drug reaction, the most common of which were mild gastrointestinal disorders (in 135 [40%] patients). Inguinal hernia was reported in one patient with elobixibat in the 52-week study as a moderate adverse drug reaction. The most common adverse drug reactions in both trials were mild abdominal pain (13 [19%] patients with elobixibat and one [2%] with placebo in the 2-week randomised trial, and 82 [24%] patients in the 52-week trial) and diarrhoea (nine [13%] patients with elobixibat and none with placebo in the 2-week randomised trial and 50 [15%] in the 52-week trial). INTERPRETATION Elobixibat resolved constipation in the short-term, and was well tolerated with both short-term and long-term treatment. The evidence supports the use of this novel approach to increase intracolonic concentrations of endogenous bile acid for the treatment of chronic constipation. FUNDING EA Pharma and Mochida Pharmaceutical.
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Home-Based Transcutaneous Neuromodulation Improved Constipation via Modulating Gastrointestinal Hormones and Bile Acids. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:2086163. [PMID: 29853946 PMCID: PMC5949156 DOI: 10.1155/2018/2086163] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 03/20/2018] [Indexed: 02/08/2023]
Abstract
This study aims to investigate the role of transcutaneous neuromodulation (TN) on the regulation of gastrointestinal hormones and bile acids in patients with functional constipation (FC). Twenty FC patients were treated with TN for four weeks. The effects of TN on symptoms were evaluated by questionnaires. Plasma levels of serotonin (5-HT), motilin, somatostatin, and vasoactive intestinal peptide (VIP) were measured by ELISA and 12 individual bile acids assayed by liquid chromatography tandem mass spectrometry. Results were as follows. (1) TN treatment increased the frequency of spontaneous bowel movement, improved the Bristol Stool Score, and reduced Patient Assessment of Constipation Symptom score and Patient Assessment of Constipation Quality of Life score. (2) FC patients showed decreased plasma levels of 5-HT, motilin, and VIP and an increased plasma level of somatostatin (P < 0.05). Four-week TN treatment increased plasma levels of 5-HT and motilin and decreased the plasma level of somatostatin in the FC patients (P < 0.05). (3) Taurocholic deoxycholate, taurocholic acid, and taurocholic lithocholic acid were increased in the FC patients (P < 0.005) but reduced by TN treatment (P < 0.05). This study has suggested that the therapy may improve the symptoms of FC by alleviating the disorders of gastrointestinal hormones and bile acids.
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Eastwood MA, Eastwood J, Ford MJ. The Irritable Bowel Syndrome: A Disease or a Response? Discussion Paper. J R Soc Med 2018; 80:219-21. [PMID: 3585889 PMCID: PMC1290763 DOI: 10.1177/014107688708000410] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The irritable bowel syndrome is a problem commonly found in the population as a whole, in general practice and in general hospital and specialist gastroenterological clinical practice. A population survey found that 14% of those interviewed exhibited symptoms of the irritable bowel syndrome but did not present to their general practitioner. In the gastroenterology clinic it is said to represent approximately one-third to one-half of referrals1.
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Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med 2018; 215:383-396. [PMID: 29339445 PMCID: PMC5789421 DOI: 10.1084/jem.20171965] [Citation(s) in RCA: 318] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/11/2022] Open
Abstract
Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration. Alterations in BA metabolism and signaling are associated with obesity and type 2 diabetes mellitus (T2DM), whereas treatment of T2DM patients with BA sequestrants, or bariatric surgery in morbidly obese patients, results in a significant improvement in glycemic response that is associated with changes in the BA profile and signaling. Herein, we review the roles of BAs in glucose metabolism in health and disease; highlight the limitations, unknowns, and challenges in understanding the impact of BAs on the glycemic response; and discuss how this knowledge may be harnessed to develop innovative therapeutic approaches for the treatment of hyperglycemia and diabetes.
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Affiliation(s)
- Hagit Shapiro
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | | | - Daniel Halstuch
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Eran Elinav
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
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Tiessen RG, Kennedy CA, Keller BT, Levin N, Acevedo L, Gedulin B, van Vliet AA, Dorenbaum A, Palmer M. Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial. BMC Gastroenterol 2018; 18:3. [PMID: 29304731 PMCID: PMC5756385 DOI: 10.1186/s12876-017-0736-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 12/22/2017] [Indexed: 12/12/2022] Open
Abstract
Background Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). Methods Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). Results Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. Conclusions Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013). Electronic supplementary material The online version of this article (10.1186/s12876-017-0736-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Renger G Tiessen
- Early Development Services, Pharmaceutical Research Associates (PRA) Health Sciences, Van Swietenlaan 6, 9728 NZ Groningen, PO Box 8144, 9702, Groningen, KC, Netherlands.
| | - Ciara A Kennedy
- Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA
| | - Bradley T Keller
- Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA
| | - Nancy Levin
- Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA
| | - Lisette Acevedo
- Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA
| | - Bronislava Gedulin
- Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA
| | - Andre A van Vliet
- Early Development Services, Pharmaceutical Research Associates (PRA) Health Sciences, Van Swietenlaan 6, 9728 NZ Groningen, PO Box 8144, 9702, Groningen, KC, Netherlands
| | - Alejandro Dorenbaum
- Lumena Pharmaceuticals Inc. (part of the Shire group of companies), 12531 High Bluff Drive, Suite 110, San Diego, CA, 92130, USA
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Determining an optimal clinical dose of elobixibat, a novel inhibitor of the ileal bile acid transporter, in Japanese patients with chronic constipation: a phase II, multicenter, double-blind, placebo-controlled randomized clinical trial. J Gastroenterol 2018; 53:525-534. [PMID: 28840422 PMCID: PMC5866829 DOI: 10.1007/s00535-017-1383-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 08/09/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Elobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose-finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat. METHODS Japanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined. RESULTS Among 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (±standard deviation) were significantly higher than baseline (5.7 ± 4.2 and 5.6 ± 3.5 times per week, respectively, compared with 2.6 ± 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once-daily oral doses up to 15 mg for 2 weeks. CONCLUSIONS Our study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation. CLINICAL TRIAL REGISTRATION NUMBER JapicCTI-142608.
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Malhi H, Camilleri M. Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases. Curr Opin Pharmacol 2017; 37:80-86. [PMID: 29102744 DOI: 10.1016/j.coph.2017.09.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 09/19/2017] [Accepted: 09/20/2017] [Indexed: 12/27/2022]
Abstract
Bile acids are central signals in enterohepatic communication and also integrate microbiota-derived signals into this signaling axis. Discovery of the tissue distribution and signaling pathways activated by the natural receptors for bile acids, farnesoid X receptor and G protein-coupled bile acid receptor 1 (GPBAR1) also known as TGR5, and bile acid transporters has led to the development of therapeutic agents that target these molecules. Obeticholic acid, a selective FXR agonist, and NGM282, a non-mitogenic FGF-19 analog, are two of the agents in this pipeline. Obeticholic acid has been approved by regulatory agencies for use in patients with primary biliary cholangitis.
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Affiliation(s)
- Harmeet Malhi
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
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Kim NH, Park JH, Park JS, Joung YH. The Effect of Deoxycholic Acid on Secretion and Motility in the Rat and Guinea Pig Large Intestine. J Neurogastroenterol Motil 2017; 23:606-615. [PMID: 28554984 PMCID: PMC5628994 DOI: 10.5056/jnm16201] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 02/18/2017] [Accepted: 03/12/2017] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Bile acid is an important luminal factor that affects gastrointestinal motility and secretion. We investigated the effect of bile acid on secretion in the proximal and distal rat colon and coordination of bowel movements in the guinea pig colon. Methods The short-circuit current from the mucosal strip of the proximal and distal rat colon was compared under control conditions after induction of secretion with deoxycholic acid (DCA) as well as after inhibition of secretion with indomethacin, 1,2-bis (o-aminophenoxy) ethane-N,N,N′,N′-tetra-acetic acid (an intracellular calcium chelator; BAPTA), and tetrodotoxin (TTX) using an Ussing chamber. Colonic pressure patterns were also evaluated in the extracted guinea pig colon during resting, DCA stimulation, and inhibition by TTX using a newly developed pressure-sensing artificial stool. Results The secretory response in the distal colon was proportionate to the concentration of DCA. Also, indomethacin, BAPTA, and TTX inhibited chloride secretion in response to DCA significantly (P < 0.05). However, these changes were not detected in the proximal colon. When we evaluated motility, we found that DCA induced an increase in luminal pressure at the proximal, middle, and distal sensors of an artificial stool simultaneously during the non-peristaltic period (P < 0.05). In contrast, during peristalsis, DCA induced an increase in luminal pressure at the proximal sensor and a decrease in pressure at the middle and distal sensors of the artificial stool (P < 0.05). Conclusions DCA induced a clear segmental difference in electrogenic secretion. Also, DCA induced a more powerful peristaltic contraction only during the peristaltic period.
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Affiliation(s)
- Nam Hee Kim
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Korea
| | - Jung Ho Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University College of Medicine, Seoul, Korea
| | - Jae-Soon Park
- Department of Electronics and Control Engineering, Hanbat National University, Daejeon, Korea
| | - Yeun-Ho Joung
- Department of Electronics and Control Engineering, Hanbat National University, Daejeon, Korea
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Abstract
PURPOSE OF REVIEW Our objective was to review advances in bile acids in health and disease published in the last 2 years. Bile acid diarrhea (BAD) is recognized as a common cause of chronic diarrhea, and its recognition has been facilitated by development of new screening tests. RECENT FINDINGS Primary BAD can account for 30% of cases of chronic diarrhea. The mechanisms leading to BAD include inadequate feedback regulation by fibroblast growth factor 19 (FGF-19) from ileal enterocytes, abnormalities in synthesis or degradation of proteins involved in FGF-19 regulation in hepatocytes and variations as a function of the bile acid receptor, TGR5 (GPBAR1). SeHCAT is the most widely used test for diagnosis of BAD. There has been significant validation of fasting serum FGF-19 and 7 α-hydroxy-cholesten-3-one (C4), a surrogate measure of bile acid synthesis. Bile acid sequestrants are the primary treatments for BAD; the farnesoid X-receptor-FGF-19 pathway provides alternative therapeutic targets for BAD. Bile acid-stimulated intestinal mechanisms contribute to the beneficial effects of bariatric surgery on obesity, glycemic control and the treatment of recurrent Clostridium difficile infection. SUMMARY Renewed interest in the role of bile acids is leading to novel management of diverse diseases besides BAD.
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Peleman C, Camilleri M, Busciglio I, Burton D, Donato L, Zinsmeister AR. Colonic Transit and Bile Acid Synthesis or Excretion in Patients With Irritable Bowel Syndrome-Diarrhea Without Bile Acid Malabsorption. Clin Gastroenterol Hepatol 2017; 15:720-727.e1. [PMID: 27856362 PMCID: PMC5401790 DOI: 10.1016/j.cgh.2016.11.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 10/19/2016] [Accepted: 11/01/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Bile acids (BAs) are passively absorbed to a different extent along the mammalian colon, so that levels are lower in the feces than in proximal colon. Our aim was to explore associations among total, primary, and secretory BA in stool and colonic transit in patients with irritable bowel syndrome-diarrhea (IBS-D) without overt BA malabsorption (BAM). METHODS In a cross-sectional observational study of 116 patients with IBS-D recruited from local communities in Minnesota, we measured total and individual main fecal BA excretion, fecal fat and fecal weight over 48 hours, fasting serum levels of C4 (surrogate for BA synthesis), and overall colonic transit by scintigraphy (geometric center at 24 hours and 48 hours). Patients without overt BAM were assigned to groups based on total fecal BA level below 2337 μmol/48 hours (n = 86) or serum levels of C4 below 47.1 ng/mL (n = 91). We used Spearman correlations to test study hypotheses with correction for 14 correlations tested (P < .0036). Data from 30 healthy volunteers were used as control subjects. RESULTS Patients with IBS-D who had increased or normal total BA excretion in stool or BA synthesis had higher stool proportions of primary BAs (especially chenodeoxycholate), compared with healthy control subjects. In patients with IBS-D without overt BAM (normal 48-hour total fecal BA or serum C4), there were significant positive correlations between total fecal BA, fecal primary and secretory BA, fecal weight, and increased geometric center at 24 and 48 hours (P < .0036). Normal and slightly increased levels of total fecal BA have greatest effects on colonic transit at 48 hours. CONCLUSIONS In the absence of overt BAM, the total, primary, and secretory BAs in stool contribute to the acceleration of colonic transit and fecal weight in the diarrhea of patients with IBS-D.
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Affiliation(s)
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
| | | | | | - Leslie Donato
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Alan R. Zinsmeister
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
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Relationship between early onset severe intrahepatic cholestasis of pregnancy and higher risk of meconium-stained fluid. PLoS One 2017; 12:e0176504. [PMID: 28437442 PMCID: PMC5402936 DOI: 10.1371/journal.pone.0176504] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 04/11/2017] [Indexed: 12/27/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease. The risk of adverse fetal outcome has been associated with the severity of maternal hypercholanemia after diagnosis. Objective To investigate whether there is a relationship between the severity and timing of onset of hypercholanemia and the risk of meconium-stained amniotic fluid (MSAF) and adverse neonatal events. Study design The study included 382 pregnancies complicated by ICP managed at a referral hospital in Buenos Aires (Argentina) between June 2009 and December 2013. The patients were classified into three groups according to the severity of hypercholanemia at diagnosis; mild (10–19.9 μmol/L), moderate (20–39.9 μmol/L) and severe (≥40 μmol/L). Their clinical characteristics and pregnancy outcomes were investigated in a prospective observational study. Results Higher risk of MSAF was observed when ICP appeared early in gestation or when hypercholanemia was more severe. Taking both parameters into account an MSAF risk factor (MRF) was defined. Based on a model of positive/negative predictive values, a cut-off point of MRF = 3 was selected, which prioritized sensitivity versus specificity. In ICP patients with MRF>3, the probability of MSAF was enhanced 4-fold. An increase in the frequency of MSAF was also associated with higher serum levels at diagnosis of alanine transaminase, alkaline phosphatase and direct bilirubin. Conclusions The risk of MSAF is associated not only with the magnitude of hypercholanemia at diagnosis but also with the early gestational onset of raised maternal serum bile acids.
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Gunaydin B, Tuna AT. Anesthetic considerations for liver diseases unique to pregnancy. World J Anesthesiol 2016; 5:54-61. [DOI: 10.5313/wja.v5.i3.54] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 07/01/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Liver diseases that are most unique to pregnancy consist of hyperemesis gravidarum, acute fatty liver of pregnancy, intrahepatic cholestasis of pregnancy, and hemolysis, elevated liver enzymes and low platelets syndrome. In this review, risk factors, etiology, symptoms, diagnosis, prognosis and treatment of each entity followed by principles of anesthetic management based on the case reports or retrospective records will be addressed.
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Abstract
Diarrhea is a feature of several chronic intestinal disorders that are associated with increased delivery of bile acids into the colon. Although the prevalence of bile acid diarrhea is high, affecting approximately 1% of the adult population, current therapies often are unsatisfactory. By virtue of its capacity to inhibit colonic epithelial fluid secretion and to down-regulate hepatic bile acid synthesis through induction of the ileal fibroblast growth factor 19 release, the nuclear bile acid receptor, farnesoid X receptor, represents a promising target for the development of new therapeutic approaches. Here, we review our current understanding of the pathophysiology of bile acid diarrhea and the current evidence supporting a role for farnesoid X receptor agonists in treatment of the disease.
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Key Words
- ASBT, apical sodium-linked bile acid transporter
- BAD, bile acid diarrhea
- Bile Acid Diarrhea
- C4, 7α-hydroxy-4-cholesten-3-one
- CA, cholic acid
- CDCA, chenodeoxycholic acid
- Chloride Secretion
- DCA, deoxycholic acid
- EHC, enterohepatic circulation
- Enterohepatic Circulation
- Epithelium
- FGF-19
- FGF19, fibroblast growth factor 19
- FXR, farnesoid X receptor
- LCA, lithocholic acid
- OCA, obeticholic acid
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Affiliation(s)
- Stephen J. Keely
- Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland,Correspondence Address correspondence to: Stephen J. Keely, MD, Molecular Medicine Laboratories, Royal College of Surgeons in Ireland, Education and Research Centre, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland. fax: +3531 809 3778.Molecular Medicine LaboratoriesRoyal College of Surgeons in IrelandEducation and Research CentreSmurfit BuildingBeaumont HospitalDublin 9Ireland
| | - Julian R.F. Walters
- Division of Digestive Diseases, Hammersmith Hospital, Imperial College London, London, United Kingdom
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Barbara G, Feinle-Bisset C, Ghoshal UC, Quigley EM, Santos J, Vanner S, Vergnolle N, Zoetendal EG. The Intestinal Microenvironment and Functional Gastrointestinal Disorders. Gastroenterology 2016; 150:S0016-5085(16)00219-5. [PMID: 27144620 DOI: 10.1053/j.gastro.2016.02.028] [Citation(s) in RCA: 216] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 02/09/2016] [Indexed: 12/02/2022]
Abstract
For decades, interactions between the enteric neuromuscular apparatus and the central nervous system have served as the primary focus of pathophysiological research in the functional gastrointestinal disorders. The accumulation of patient reports, as well as clinical observations, has belatedly led to an interest in the role of various luminal factors and their interactions with each other and the host in functional gastrointestinal disorders. Most prominent among these factors has been the role of food. As a consequence, while not always evidence-based, dietary interventions are enjoying a renaissance in irritable bowel syndrome management. Not surprisingly, given its exploration in many disease states, the gut microbiota has also been studied in functional gastrointestinal disorders; data remain inconclusive. Likewise, there is also a considerable body of experimental and some clinical data to link functional gastrointestinal disorders pathogenesis to disturbances in epithelial barrier integrity, abnormal entero-endocrine signaling and immune activation. These data provide growing evidence supporting the existence of micro-organic changes, particularly in subgroups of patients with functional dyspepsia and IBS. However, their exact role in the complex pathophysiology and symptom generation of functional gastrointestinal disorders needs to be further studied and elucidated particularly with longitudinal and interventional studies.
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Affiliation(s)
- Giovanni Barbara
- Department of Medical and Surgical Sciences, School of Medicine, University of Bologna, Italy.
| | - Christine Feinle-Bisset
- University of Adelaide Discipline of Medicine, and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide Discipline of Medicine, Adelaide, South Australia
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Eamonn M Quigley
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA
| | - Javier Santos
- Lab Neuro-immune-gastroenterology, Digestive System Research Unit, Department of Gastroenterology, Institut de Recerca Vall d'Hebron, Hospital Vall d'Hebron, Barcelona, Spain
| | - Steve Vanner
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Nathalie Vergnolle
- Inserm, U1220, Toulouse, France; Université de Toulouse, UPS, Institut de Recherche en Santé Digestive (IRSD), Toulouse, France
| | - Erwin G Zoetendal
- Laboratory of Microbiology, Department of Agrotechnology and Food Sciences, Wageningen University, the Netherlands
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Abstract
Irritable bowel syndrome (IBS) affects about 15 % of the US population and results in significant morbidity and health care costs. There remains a significant unmet need for effective treatments particularly for the pain component of IBS and other functional gastrointestinal disorders (FGIDs). Progress made in our understanding of pathophysiological mechanisms such as the role of altered bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and secretory properties of the gut has led to advancements in therapeutic armamentarium for IBS. This review discusses the new drugs for constipation and diarrhea-predominant IBS subtypes that have been tested or have been under investigation over the last 3-4 years. Overall, there is a promising pipeline of investigational drugs for the future treatment of IBS and related FGIDs.
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Affiliation(s)
- Akhilesh Wadhwa
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Madhusudan Grover
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Zhou H, Zhou S, Gao J, Zhang G, Lu Y, Owyang C. Upregulation of bile acid receptor TGR5 and nNOS in gastric myenteric plexus is responsible for delayed gastric emptying after chronic high-fat feeding in rats. Am J Physiol Gastrointest Liver Physiol 2015; 308:G863-73. [PMID: 25540233 PMCID: PMC4437020 DOI: 10.1152/ajpgi.00380.2014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 12/19/2014] [Indexed: 01/31/2023]
Abstract
Chronic high-fat feeding is associated with functional dyspepsia and delayed gastric emptying. We hypothesize that high-fat feeding upregulates gastric neuronal nitric oxide synthase (nNOS) expression, resulting in delayed gastric emptying. We propose this is mediated by increased bile acid action on bile acid receptor 1 (TGR5) located on nNOS gastric neurons. To test this hypothesis, rats were fed regular chow or a high-fat diet for 2 wk. Rats fed the high-fat diet were subjected to concurrent feeding with oral cholestyramine or terminal ileum resection. TGR5 and nNOS expression in gastric tissue was measured by immunohistochemistry, PCR, and Western blot. Gastric motility was assessed by organ bath and solid-phase gastric emptying studies. The 2-wk high-fat diet caused a significant increase in neurons coexpressing nNOS and TGR5 in the gastric myenteric plexus and an increase in nNOS and TGR5 gene expression, 67 and 111%, respectively. Enhanced nonadrenergic, noncholinergic (NANC) relaxation, deoxycholic acid (DCA)-induced inhibition in fundic tissue, and a 26% delay in gastric emptying accompanied these changes. A 24-h incubation of whole-mount gastric fundus with DCA resulted in increased nNOS and TGR5 protein expression, 41 and 37%, respectively. Oral cholestyramine and terminal ileum resection restored the enhanced gastric relaxation, as well as the elevated nNOS and TGR5 expression evoked by high-fat feeding. Cholestyramine also prevented the delay in gastric emptying. We conclude that increased levels of circulatory bile acids induced by high-fat feeding upregulate nNOS and TGR5 expression in the gastric myenteric plexus, resulting in enhanced NANC relaxation and delayed gastric emptying.
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Affiliation(s)
- Hui Zhou
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; and ,2Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shiyi Zhou
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; and
| | - Jun Gao
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; and
| | - Guanpo Zhang
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; and
| | - Yuanxu Lu
- 1Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; and
| | - Chung Owyang
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; and
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Le Pluart D, Sabaté JM, Bouchoucha M, Hercberg S, Benamouzig R, Julia C. Functional gastrointestinal disorders in 35,447 adults and their association with body mass index. Aliment Pharmacol Ther 2015; 41:758-67. [PMID: 25728697 DOI: 10.1111/apt.13143] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2014] [Revised: 12/11/2014] [Accepted: 02/06/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Functional gastrointestinal disorders' (FGIDs) associations with body mass index (BMI) have not been thoroughly investigated in the general population. AIM To investigate the overlap between functional dyspepsia (FDy), irritable bowel syndrome (IBS), functional constipation (FC) and functional diarrhoea (FDh) and the relationship between BMI and those diagnoses in a large French adult population. METHODS Subjects participating in the Nutrinet-Santé cohort study completed a questionnaire based on Rome III criteria. Anthropometrics, socio-demographical and lifestyle data were collected via self-administered questionnaires. Associations between BMI and FGIDs were investigated with multivariate logistic regression. RESULTS A total of 35 447 subjects were included in the analysis. Among subjects with FGIDs, 10.4% presented more than one disorder. [FDy coexisted with IBS (23.6%) and FC (15.1%)]. Associations between BMI and FDy differed according to sex. In females, higher odds were observed for underweight and obesity subgroups (OR = 1.26 (95% CI: 0.99-1.59), OR = 1.35 (1.08-1.69), OR = 1.20 (0.81-1.77), OR = 1.47 (0.89-2.42) for underweight, class I, II and III obesity respectively compared with normal BMI), forming a U-shaped relationship confirmed with nonlinear model (P < 0.001). In females, FDh was associated with BMI [OR = 1.05 (1.03-1.07), P < 0.001]. In males, a negative association between BMI and IBS was observed [OR = 0.97 (0.94-0.99), P=0.04]. Other associations were not significant. CONCLUSIONS Our study showed an important overlap in FGIDs, supporting the contention of common pathophysiological mechanisms. Relationships between BMI and FGIDs appeared to be sex-dependent. Interaction by sex in the association between BMI and FGIDs should therefore be further explored.
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Affiliation(s)
- D Le Pluart
- Université Paris 13, Sorbonne Paris Cité, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Biostatistiques (CRESS), UMR 1153 Inserm, U1125 Inra, Cnam, COMUE Sorbonne Paris Cité, Bobigny, France
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Lazaraki G, Chatzimavroudis G, Katsinelos P. Recent advances in pharmacological treatment of irritable bowel syndrome. World J Gastroenterol 2014; 20:8867-8885. [PMID: 25083060 PMCID: PMC4112893 DOI: 10.3748/wjg.v20.i27.8867] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 03/13/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent functional disorder that reduces patients’ quality of life. It is a chronic disorder characterized by abdominal pain or discomfort associated with disordered defecation in the absence of identifiable structural or biochemical abnormalities. IBS imposes a significant economic burden to the healthcare system. Alteration in neurohumoral mechanisms and psychological factors, bacterial overgrowth, genetic factors, gut motility, visceral hypersensitivity, and immune system factors are currently believed to influence the pathogenesis of IBS. It is possible that there is an interaction of one or more of these etiologic factors leading to heterogeneous symptoms of IBS. IBS treatment is predicated upon the patient’s most bothersome symptoms. Despite the wide range of medications and the high prevalence of the disease, to date no completely effective remedy is available. This article reviews the literature from January 2008 to July 2013 on the subject of IBS peripherally acting pharmacological treatment. Drugs are categorized according to their administration for IBS-C, IBS-D or abdominal pain predominant IBS.
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Jones ML, Martoni CJ, Ganopolsky JG, Labbé A, Prakash S. The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention. Expert Opin Biol Ther 2014; 14:467-82. [PMID: 24479734 DOI: 10.1517/14712598.2014.880420] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Recent evidence indicates that the human gut microbiome plays a significant role in health and disease. Dysbiosis, defined as a pathological imbalance in a microbial community, is becoming increasingly appreciated as a 'central environmental factor' that is both associated with complex phenotypes and affected by host genetics, diet and antibiotic use. More recently, a link has been established between the dysmetabolism of bile acids (BAs) in the gut to dysbiosis. AREAS COVERED BAs, which are transformed by the gut microbiota, have been shown to regulate intestinal homeostasis and are recognized as signaling molecules in a wide range of metabolic processes. This review will examine the connection between BA metabolism as it relates to the gut microbiome and its implication in health and disease. EXPERT OPINION A disrupted gut microbiome, including a reduction of bile salt hydrolase (BSH)-active bacteria, can significantly impair the metabolism of BAs and may result in an inability to maintain glucose homeostasis as well as normal cholesterol breakdown and excretion. To better understand the link between dysbiosis, BA dysmetabolism and chronic degenerative disease, large-scale metagenomic sequencing studies, metatranscriptomics, metaproteomics and metabolomics should continue to catalog functional diversity in the gastrointestinal tract of both healthy and diseased populations. Further, BSH-active probiotics should continue to be explored as treatment options to help restore metabolic levels.
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Affiliation(s)
- Mitchell L Jones
- McGill University, Artificial Cells and Organs Research Centre, Department of Biomedical Engineering and Physiology, Biomedical Technology and Cell Therapy Research Laboratory, Faculty of Medicine , 3775 University Street, Montreal, Quebec, H3A2B4 , Canada +1 514 398 3676 ; +1 514 398 7461 ;
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Abstract
Bile acids (BA) are actively reabsorbed in the terminal ileum by the apical Na(+)-dependent bile salt transporter. This review addresses the epidemiology, pathophysiology, diagnosis and treatment of BA diarrhea (BAD). BAD is typically caused by ileal resection or disease; 25-33% of patients with chronic functional diarrhea or irritable bowel syndrome-diarrhea (IBS-D) have BAD, possibly from deficiency in the ileal hormone, FGF-19, which normally provides feedback inhibition of BA synthesis. Diagnosis of BAD is typically based on reduced BA retention of radiolabeled BA ((75)SeHCAT), increased BA synthesis (serum C4) or increased fecal BA loss. In clinical practice, diagnosis is often based on response to BA sequestrants (e.g., cholestyramine or colesevelam). Diagnostic tests for BA malabsorption (BAM) need to be used more extensively in clinical practice. In the future, farnesoid X receptor agonists that stimulate ileal production of FGF-19 may be alternative treatments of BAD.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, 200 First St. S.W., Charlton Bldg., Rm. 8-110, Rochester, MN 55905, USA
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Reigstad CS, Kashyap PC. Beyond phylotyping: understanding the impact of gut microbiota on host biology. Neurogastroenterol Motil 2013; 25:358-72. [PMID: 23594242 PMCID: PMC4524550 DOI: 10.1111/nmo.12134] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 03/19/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Microbial constituents of the gut microbiome interact with each other and the host to alter the luminal environment and impact development, motility, and homeostasis of the gut. Powerful methods are becoming available to investigate connections between the gut microbiome and human health. While high-throughput sequencing of 16S rRNA genes can be used to identify and enumerate microbes in the gut, advances in several techniques (e.g., metagenomics, metatranscriptomics, metabolomics, and metaproteomics) are providing a clearer view as to the specific activities of the microbiota in the context of functional host-microbe interactions. Testing emergent hypotheses regarding microbial effects on host biology, which arise from analyses of 'Big Data' generated from massive parallel high-throughput sequencing technology and spectroscopic techniques, to guide translational research is an important goal for the future. Insights regarding the fundamental operating principles of the gut microbiota should lay the foundation for rational manipulation of the microbiota to promote human health. PURPOSE In this review, we provide an overview of current research on the gut microbiome emphasizing current state-of-the-art technologies, approaches, and directions for improvement of our understanding of the impact of the gut microbiota with specific focus on gastrointestinal motility disorders.
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Affiliation(s)
- Christopher S. Reigstad
- Department of Gastroenterology and Hepatology; Enteric Neuroscience Program; Mayo Clinic; Rochester; MN; USA
| | - Purna C. Kashyap
- Department of Gastroenterology and Hepatology; Enteric Neuroscience Program; Mayo Clinic; Rochester; MN; USA
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Abu-Hayyeh S, Papacleovoulou G, Williamson C. Nuclear receptors, bile acids and cholesterol homeostasis series - bile acids and pregnancy. Mol Cell Endocrinol 2013; 368:120-8. [PMID: 23159988 DOI: 10.1016/j.mce.2012.10.027] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 08/28/2012] [Accepted: 10/26/2012] [Indexed: 12/19/2022]
Abstract
Bile acids have been traditionally thought of as having an important role in fat emulsification. It is now emerging that they act as important signalling molecules that not only autoregulate their own synthesis but also influence lipid and glucose metabolism. Although, the mechanisms that underlie the regulation of bile acid homeostasis have been well characterised in normal physiology, the impact of pregnancy on bile acid regulation is still poorly understood. This review summarises the main regulatory mechanisms underlying bile acid homeostasis and discusses how pregnancy, a unique physiological state, can modify them. The fetoplacental adaptations that protect against fetal bile acid toxicity are reviewed. We highlight the importance of bile acid regulation during gestation by discussing the liver disease of pregnancy, intrahepatic cholestasis of pregnancy (ICP) and how genetic, endocrine and environmental factors contribute to the disease aetiology at a cellular and molecular level.
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Affiliation(s)
- Shadi Abu-Hayyeh
- Institute of Reproductive and Developmental Biology, Dept. of Surgery and Cancer, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom
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Abstract
IBS is a common disorder that affects approximately 5-20% of the populations of Western countries; the main symptoms are abdominal pain and erratic, altered bowel habits, often accompanied by bloating. Despite an array of available pharmacological and nonpharmacological treatments aimed at a wide variety of gastrointestinal and brain targets, many patients do not report adequate symptom relief. The effect of IBS on an individual can be enormous, and the societal and financial costs overall are high, which is indicative of an unmet need for effective IBS treatments. Intense research efforts are ongoing that range from the development of new molecules for pharmacological therapies to testing the utility of internet technology to facilitate widespread delivery of efficacious behavioural therapy. This Review discusses the latest treatments for IBS, including novel nonpharmacological and pharmacological approaches. We have included estimates of the number needed to treat and the number needed to harm for selected treatments. Emerging and potential future treatments are included, with the data supporting an optimistic view about the future of IBS therapeutics. The ability to optimize therapy by individualizing management whilst also avoiding harm remains the key to achieving the best possible outcomes with currently available therapeutics.
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