A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis

Walters, Julian R.F.; Tasleem, Ali M.; Omer, Omer Serhan; Brydon, W. G.; Dew, Tracy; Roux, Carel W. le

doi:10.1016/j.cgh.2009.04.024

Cited by 286 publications

(296 citation statements)

References 30 publications

(36 reference statements)

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“…Patients suffering from primary BAM (as with ASBT mutation) are not able to sufficiently reabsorb BA in the gut; diarrhea-predominant irritable bowel syndrome (IBS) patients have BAM with high intraluminal BA levels due to missing FGF-19-mediated repression of hepatic BA biosynthesis (Walters et al, 2009). Depending on their concentrations within the colonic lumen, BA can have, via FXR signaling, not only a prosecretory but also an anitsecretory effect (Keating et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in both copies of ASBT lead to primary (congenital) BA-induced malabsorption (BAM) with diarrhea, steatorrhea, and hypocholesterolemia (Oelkers et al, 1997). Patients with diarrhea-predominant irritable bowel syndrome (IBS) seem to suffer from BAM due to impaired FGF-19 feedback inhibition, resulting in excessive BA synthesis with overloaded capacity for ileal reabsorption (Walters et al, 2009). Secondary BAM results from ileal resection [e.g., due to Crohn's disease (CD)] with consequently reduced ileal BA reabsorption and presumable missing FGF-19-mediated suppression of hepatic BA synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

et al. 2014

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The enterohepatic circulation of bile acids (BAs) critically depends on absorption of BA in the terminal ileum and colon, which can be affected by inflammatory bowel disease (IBD). Diarrhea in IBD is believed to result in part from BA malabsorption (BAM). We explored whether IBD alters mRNA expression of key intestinal BA transporters, BA detoxifying systems, and nuclear receptors that regulate BA transport and detoxification. Using real-time polymerase chain reaction, mucosal biopsy specimens from the terminal ileum in Crohn's disease (CD) patients and from the descending colon in ulcerative colitis (UC) patients were assessed for mRNA expression. Levels were compared with healthy controls. The main ileal BA uptake transporter, the apical sodium dependent bile acid transporter, was downregulated in active CD and UC and in CD in remission. Other significant changes such as repression of breast cancer-related protein and sulphotransferase 2A1 were seen only during active disease. In UC, pancolitis (but not exclusively left-sided colitis) was associated with altered expression of major BA transporters [multidrug resistance-associated protein 3 (MRP3), MRP4, multidrug resistance gene 1, organic solute transporter a/b] and nuclear receptors (pregnane X receptor, vitamin D receptor) in the descending colon. UC pancolitis leads to broad changes and CD ileitis to selective changes in intestinal BA transporter expression. Early medical manipulation of intestinal BA transporters may help prevent BAM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

et al. 2014

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“…FGF15 is secreted into the portal circulation and in the liver represses via a receptor mediated process the biosynthesis of bile salts [55,258]. In humans, reduced serum levels of FGF19 lead to bile salt induced diarrhea, which highlights the importance of a tight control of the bile salt pool [132,335]. In addition to its tight regulation, bile acid biosynthesis undergoes diurnal variation, as exemplified by a diurnal rhythm of biliary bile salt and lipid secretion [234].…”

Section: Physiology Of Bile Formationmentioning

confidence: 99%

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

Stieger

2010

Handbook of Experimental Pharmacology

245

260

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“…11 In the latter case, evidence suggests that TI absorption of bile acids is normal or increased, 12 but impaired negative feedback of bile acids on fibroblast growth factor-19 (FGF-19) leads to dysregulation of the enterohepatic circulation and excessive bile acid synthesis. 13 A relatively simple and highly sensitive method of testing for BAD is via the 75 selenium homocholic acid taurine ( 75 SeHCAT) test, where retention of radio-labelled bile acids of less than 10-15% after 7 days is abnormal. 14,15 The…”

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confidence: 99%

High Prevalence of Idiopathic Bile Acid Diarrhea Among Patients With Diarrhea-Predominant Irritable Bowel Syndrome Based on Rome III Criteria

Aziz

Mumtaz

Bholah

et al. 2015

Clinical Gastroenterology and Hepatology

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Abstract:Background & Aims: Some studies have found that patients with idiopathic bile acid diarrhea (BAD) present with symptoms of diarrhea-predominant irritable bowel syndrome (D-IBS). However, these studies were either retrospective, did not define D-IBS according to current criteria, or included patients with chronic functional diarrhea. We performed a prospective study of the prevalence of idiopathic BAD in consecutive patients fulfilling the Rome III criteria for D-IBS. Methods:We analyzed data from 118 consecutive adult patients who fulfilled the Rome III criteria for D-IBS (mean age, 41.7 years; 72.9% female), seen at 2 gastroenterology clinics in the UK. We excluded patients with risk factors for BAD (previous history of cholecystectomy, terminal ileal C celiac disease, or microscopic colitis). Participants completed questionnaires at baseline (on demographics, hospital anxiety, somatization, and depression, as well as the patient health questionnaire-12 and the short form-36 [SF-36]), and then received the 75 selenium homocholic acid taurine retention test. Retention of 75 selenium homocholic acid taurine 7 days after administration BAD BAD BAD BAD Results: Twenty-eight were found to have BAD (23.7% of total), with similar percentages at each study site (25.3% and 20%; P=.54). Eight patients had mild BAD (28.6%), 8 had moderate BAD (28.6%), and 12 had severe BAD (42.8%). There was no statistical difference in age or sex, or depression, patient health questionnaire-12, or SF-36 scores, between individuals with vs without BAD. However, patients with BAD had a higher mean body mass index than those without BAD (31.6 vs. 26.4; P=.003). Physical activity (based on the SF-36) was significantly lower in subjects with moderate (43.8) or severe BAD (41.7), compared to patients with mild BAD (87.5) (P=.046). Conclusion:Almost 25% of patients presenting with D-IBS have idiopathic BAD; most cases are moderate to severe. Guidelines should advocate testing to exclude BAD before patients are diagnosed with D-IBS.

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A New Mechanism for Bile Acid Diarrhea: Defective Feedback Inhibition of Bile Acid Biosynthesis

Abstract: Patients with BAM have reduced serum FGF19 which may be useful in diagnosis. We propose a mechanism whereby impaired FGF19 feedback inhibition causes excessive bile acid synthesis that exceeds the normal capacity for ileal reabsorption, producing bile acid diarrhea.

Cited by 286 publications

References 30 publications

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation

High Prevalence of Idiopathic Bile Acid Diarrhea Among Patients With Diarrhea-Predominant Irritable Bowel Syndrome Based on Rome III Criteria

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