Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation

Abrahamsson, Hasse; Östlund-Lindqvist, Ann-Margret; Nilsson, Ralf; Simrén, Magnus; Gillberg, Per‐Göran

doi:10.1080/00365520802321212

Cited by 56 publications

(46 citation statements)

References 8 publications

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“…Walters et al (113) provided evidence that impaired feedback inhibition of bile acid synthesis by the ileal hormone FGF-19 plays a role in bile acid-associated diarrhea. Conversely, patients with C-IBS and functional constipation had altered diurnal rhythm with no serum 7␣C4 peak at lunchtime (1). These data might suggest that alterations in genes that regulate bile acid metabolism and feedback may contribute to abnormal bowel pattern and symptoms in IBS.…”

Section: Genetic Predisposition To Bile Acid Malabsorption In Ibsmentioning

confidence: 83%

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Camilleri

Katzka

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

103

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The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, ␣ 2-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNF␣, GN␤3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT3 genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klotho␤ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published. adrenergic; serotonergic; solute carrier 6A4; 5-hydroxytryptamine transporter-linked polymorphic region; inflammation; susceptibility; klotho␤; bile acid malabsorption EPIDEMIOLOGICAL STUDIES of familial aggregation (57, 99) and twins (7,70,72,82,83) suggest a genetic contribution to irritable bowel syndrome (IBS). While the data are conflicting, they are generally consistent with the hypothesis that IBS may be a complex genetic disorder. Understanding of genetic variation and its influence on gut motility, secretion, sensation, and inflammation, as it is applied to IBS, has the potential to help elucidate mechanisms of control of a poorly understood syndrome. Similarly, the impact of genetic variation on the targets of therapy in IBS may enhance the efficacy of pharmacological therapies. These targets include receptors and regulators of gut function and variations in drug metabolism.This review addresses the available literature on the role of genetics in IBS. There are no published genome-wide association studies in functional gastrointestinal (GI) or motility disorders specifically focusing on genetic epidemiology and pharmacogenetics. Genetic Epidemiology of IBS: Candidate Gene ApproachAs the general approach followed in genotype association studies (Fig. 1), investigators have sought the relationship between genotype and clinical phenotype, while appreciating that intermediaries, such as th...

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Section: Genetic Predisposition To Bile Acid Malabsorption In Ibsmentioning

confidence: 83%

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Camilleri

Katzka

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

103

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“…Several recent studies have demonstrated bile acid malabsorption in a subset of patients with IBS (1,29,93,192). Furthermore, reduced ileal absorption and excess of bile acid in the colon can lead to acceleration of colonic transit by stimulating motility and secretion (8,109).…”

Section: Microbiota and Enteric Sensorimotor Functionmentioning

confidence: 99%

Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome

Ringel

Maharshak

2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ringel Y, Maharshak N.Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 305: G529-G541, 2013. First published July 25, 2013; doi:10.1152/ajpgi.00207.2012.-The pathophysiology of irritable bowel syndrome (IBS) is believed to involve alterations in the brain-gut axis; however, the etiological triggers and mechanisms by which these changes lead to symptoms of IBS remain poorly understood. Although IBS is often considered a condition without an identified "organic" etiology, emerging evidence suggests that alterations in the gastrointestinal microbiota and altered immune function may play a role in the pathogenesis of the disorder. These recent data suggest a plausible model in which changes in the intestinal microbiota and activation of the enteric immune system may impinge upon the brain-gut axis, causing the alterations in gastrointestinal function and the clinical symptoms observed in patients with IBS. This review summarizes the current evidence for altered intestinal microbiota and immune function in IBS. It discusses the potential etiological role of these factors, suggests an updated conceptual model for the pathogenesis of the disorder, and identifies areas for future research.inflammation; gastrointestinal; microbiota IRRITABLE BOWEL SYNDROME (IBS) is the most common and best studied condition of a larger group of functional gastrointestinal (GI) disorders. Functional GI disorders refer to the presence of a variable combination of chronic or recurrent GI symptoms not explained by structural or biochemical abnormalities (130,159). IBS is characterized by chronic or recurring abdominal pain or discomfort that is associated with altered bowel habits (53, 99). The condition is often associated with other GI symptoms (e.g., bloating, distention, and gas), other functional GI disorders (e.g., functional dyspepsia), other non-GI disorders (e.g., fibromyalgia, interstitial cystitis, migraine headache), and psychological disorders (e.g., depression, anxiety, somatization) (96,146,167). Traditionally, IBS has been subtyped on the basis of the patient's predominant symptom/stool pattern (99). These subtypes include diarrhea predominant (IBS-D), constipation predominant (IBS-C), and mixed type (IBS-M), in which patients experience alternating periods of diarrhea and constipation. Unlike other conditions that can be associated with abdominal pain and abnormal bowel patterns such as inflammatory bowel diseases (IBD), IBS is not associated with any overt histopathology, structural, or biochemical abnormalities. IBS has been generally considered to be caused by alterations in the brain-gut axis (the bidirectional communication network involving the enteric nervous system, the autonomic nervous system, and the central nervous system) (60,108,125), and the pathophysiological mechanisms behind this condition remain unclear. Traditionally, IBS is considered to be a multifactorial condition in which multiple environmental, genetic, physiological, ...

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“…In another recent study, the normal lunchtime increase in C4 levels was not detected in 82% of functional constipation and irritable bowel syndrome constipation (IBS-C) patients with delayed colonic transit compared with 17% of those with normal transit (p < 0.001). The authors concluded that alterations in diurnal bile acid metabolism might play a role in the pathogenesis of constipation [10].…”

Section: How Might Bile Acids Be Related To Constipation?mentioning

confidence: 99%

Targeting bile acids in the treatment of constipation

Maneerattanaporn

Chey

2011

Expert Review of Gastroenterology & Hepatology

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Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation

Abstract: Patients with IBS-C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.

Cited by 56 publications

References 8 publications

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome

Targeting bile acids in the treatment of constipation

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