Bile acid malabsorption in inflammatory bowel disease

Leníček, Martin; Ďuricová, Dana; Komarek, Viktor; Gabrysova, Bronislava; Lukáš, Milan; Šmerhovský, Zdeněk; Vı́tek, Libor

doi:10.1002/ibd.21502

Cited by 110 publications

(105 citation statements)

References 29 publications

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“…Two recent studies showed slightly increased 24 or rather unchanged 25 FGF19 serum concentrations in patients with UC in comparison with healthy controls. Interestingly, however, the same studies consistently showed that patients with CD had significantly lower levels of FGF19 in serum.…”

Section: Discussionmentioning

confidence: 94%

“…In this regard, Lenicek et al 25 reported that FGF19 down-regulation only appeared in cases with a significant ileal involvement because CD patients with Crohn's colitis had normal FGF19 serum levels and only those with ileitis had significantly decreased FGF19 levels compared with controls. Consistently, in the study of Iwamoto et al, 24 the only patient with CD and a colonic inflammation had higher FGF19 levels than other CD patients.…”

Section: Discussionmentioning

confidence: 99%

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Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

Rau

Stieger²,

Monte

et al. 2016

Inflammatory Bowel Diseases

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BACKGROUND: Fibroblast growth factor (FGF) 15/19 is part of the gut-liver crosstalk accounting for bile acid (BA) metabolism regulation. Dysregulation of fibroblast growth factor 15/19 signaling is observed in different pathological conditions, for example, in gastrointestinal diseases such as inflammatory bowel disease (IBD). To understand the molecular bases, we analyzed the enterohepatic regulation of Fgf15-mediated pathway in 2 different inflammatory bowel disease mouse models. METHODS: Target genes of the BA-farnesoid-X-receptor (Fxr)-Ffg15 axis were quantified by RT-PCR or western blotting in gut and liver of dextran sulfate sodium (DSS)-treated and IL10 mice. Serum Fgf15 levels were analyzed by ELISA. Biliary and fecal BA composition was differentiated by HPLC-MS/MS. RESULTS: Dextran sulfate sodium-treated mice with ileum-sparing colitis showed higher Fgf15 serum levels. In contrast, IL10 mice with ileitis had a trend toward decreased Fgf15 serum levels compared with controls and increased expression of Asbt as a negative Fxr-target gene. In hepatic tissue of both models, no histological changes, but higher interleukin 6 (IL-6) mRNA expression and down-regulation of Fxr and Cytochrom P450 7a1 mRNA expression were observed. Fibroblast growth factor receptor 4 up-regulation was in line with higher Fgf15 serum levels in dextran sulfate sodium-treated mice. A distinct fecal BA profile was observed in both models with significantly higher levels of taurine-conjugated BA in particular tauro--muricholic acid in IL10 mice. CONCLUSIONS: Ileum-sparing colitis is characterized by activation of Fxr-Fgf15 signaling with higher expression of Fxr-target gene Fgf15, whereas ileal inflammation showed no signs of Fxr-Fgf15 activation. Abundance of BA such as T--MCA may be important for intestinal Fxr activation in mice.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

Rau

Stieger²,

Monte

et al. 2016

Inflammatory Bowel Diseases

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“…12,13,15,36,37 Recently, in patients with idiopathic bile acid-induced diarrhoea, FGF19 and 7a-hydroxy-4-cholesten-3-one were shown to correlate negatively and FGF19 was proposed to serve as diagnostic marker for this disease. 16 Furthermore, in diabetic patients undergoing Roux-en-Y gastric bypass, lower FGF19 levels were significantly correlated with increased hepatic expression of the CYP7A1 gene, modulating bile acid production.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of hepatic bile acid synthesis via fibroblast growth factor 19 is defective in gallstone disease but functional in overweight individuals

et al. 2014

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Background: Fibroblast growth factor 19 (FGF19) is an enteric hormone regulating bile acid de novo synthesis by sensing ileal bile acid flux. However, the role of FGF19 in cholelithiasis has not yet been elucidated and therefore is investigated in the present study. Methods: Total mRNA and protein were isolated from ileal biopsies and used for tissue expression analysis. FGF19, 7a-hydroxycholesterol (7a-OH-Chol), 27-hydroxycholesterol (27-OH-Chol), and different bile acids were determined in the blood samples. Results: FGF19 serum levels did not differ between gallstone carriers and controls but were significantly decreased in the overweight individuals (À32%, p ¼ 0.0002), irrespective of gallstone status (normalweight to overweight controls À29%, p ¼ 0.0017; normalweight to overweight gallstone carriers À44%, p ¼ 0.0338), and correlated inversely with bodyweight (p < 0.0001, r ¼ À0.3317). Compared to non-overweight controls, apical sodium-dependent bile acid transporter expression was significantly diminished in the non-overweight gallstone carriers (À42%, P mRNA ¼ 0.0393; À52%, p protein ¼ 0.0169) as well as in the overweight controls (À24%, P mRNA ¼ 0.0148; À43%, p protein ¼ 0.0017). FGF19 expression varied widely and was similar in all groups. A significant negative correlation was noted between 7a-OH-Chol, 27-OH-Chol, and FGF19 serum levels (p < 0.01; r 7a-OH-Chol ¼ À0.2155; r 27-OH-Chol ¼ À0.2144) in obesity. Conclusion: Upregulation of hepatic bile acid synthesis via FGF 19 is defective in gallstone disease but functional in overweight individuals.

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“…IBD is associated with diarrhea, malnutrition, and weight loss through inhibited absorption of nutrients, electrolytes, and water (Sands, 2007). BAM in ileal CD was also observed in surgically untreated CD (Meihoff and Kern, 1968;Tougaard et al, 1986;Lenicek et al, 2011). However, exact molecular mechanisms for BAM in IBD are incompletely understood (Nolan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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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Bile acid malabsorption in inflammatory bowel disease

Cited by 110 publications

References 29 publications

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation

Upregulation of hepatic bile acid synthesis via fibroblast growth factor 19 is defective in gallstone disease but functional in overweight individuals

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

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