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Lipid and Bile Acid Dysmetabolism in Crohn's Disease.

ABSTRACT: Crohn's disease is one of the systemic autoimmune diseases. It commonly affects the small intestine and colon but may involve any portion of the gastrointestinal tract from the mouth to the anus. The most affected area by Crohn's disease is the distal part of the small intestine, in which the bile acid molecules are most efficiently reabsorbed. Bile acids form mixed micelles together with fatty acids, which function as a transport vehicle to deliver fatty acids to the apical membrane of enterocytes for absorption. Therefore, if the terminal ileum is impaired, bile acid malabsorption may occur, which may cause congenital diarrhoea in Crohn's disease. Similarly, the impairment of the terminal ileum also induces fatty acid malabsorption, which may influence the role of fatty acids in Crohn's disease. In contrast, a recent study reported that multidrug resistance protein 1 (MDR1) regulated effector T-cell function in the ileum from bile acid-driven oxidative stress and MDR1 loss of function in a subset of patients with Crohn's disease. However, the role of consumption of fatty acids in Crohn's disease remains to be fully elucidated. This review is aimed at providing an overview of some recent developments in research of Crohn's disease from comprehensive perspective with a focus on the connection between disease location and behaviour, lipid diets, and bile acid malabsorption.

SUBMITTER: Uchiyama K

PROVIDER: S-EPMC6191959 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Lipid and Bile Acid Dysmetabolism in Crohn's Disease.

Uchiyama Koji K Kishi Hisashi H Komatsu Wataru W Nagao Masanori M Ohhira Shuji S Kobashi Gen G

Journal of immunology research 20181001

Crohn's disease is one of the systemic autoimmune diseases. It commonly affects the small intestine and colon but may involve any portion of the gastrointestinal tract from the mouth to the anus. The most affected area by Crohn's disease is the distal part of the small intestine, in which the bile acid molecules are most efficiently reabsorbed. Bile acids form mixed micelles together with fatty acids, which function as a transport vehicle to deliver fatty acids to the apical membrane of enterocy ...[more]

PMID: 30402511

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Project description:Background & aimsPatients with Crohn's disease (CD) often have bile acid diarrhea (BAD), due to bile acid malabsorption following ileal resection (IR). Bile acid malabsorption increases production of 7α-hydroxy-4-cholesten-3-one (C4), a bile acid precursor. We investigated relationships between serum concentrations of C4 and BAD in patients with CD.MethodsWe collected demographic data, serum samples, and information on the presence of diarrhea (>3 liquid bowel movements/day), as well as clinical, endoscopic, and histologic scores from 26 patients with CD and IR, 21 patients with CD without IR, and 37 patients with ulcerative colitis (UC). We compared serum concentrations of C4 and fibroblast growth factor 19 (FGF19) between groups. We performed area under the receiver operating characteristic curve (AUROC) analysis to identify the optimal cutoff C4 concentrations for the diagnosis of diarrhea attributable to bile acid malabsorption (BAD), defined as diarrhea and a serum concentration of FGF19 <60 pg/mL.ResultsPatients with UC had a median serum C4 concentration of 11.8 ng/mL, whereas patients with CD and IR with ileitis (documented endoscopically) had a median concentration of 100.0 ng/mL (P compared to UC < .0001) and patients with CD and IR without ileitis had a median concentration of 51.6 ng/mL (P compared to UC < .001). Patients with CD without IR did not have a significantly higher median concentration of C4 than patients with UC (P = .71), regardless of ileitis (P = .34). When endoscopic findings were confirmed histologically, similar results were found to analyses using endoscopic findings alone. A higher proportion of patients with active UC had diarrhea (72.0% vs 0 patients with inactive UC; P < .001), but their median concentrations of C4 did not differ significantly from that of patients with inactive UC (12.1 ng/mL vs 9.7 ng/mL; P = .3). A cutoff concentration of C4 of 48.3 ng/mL or greater identified patients with diarrhea attributable to bile acid malabsorption with 90.9% sensitivity, 84.4% specificity, and an AUROC 0.94. A significantly higher proportion of patients with concentrations of C4 above this cutoff had BAD (50.0%) than below this cutoff (1.8%) (P < .001). When we analyzed only patients with diarrhea, a C4 cutoff of 48.3 ng/mL identified those with low FGF19 concentrations (<60 pg/mL) with 91% sensitivity and 95.5% specificity (AUROC, 0.99). Above this cutoff, 83.3% of patients had a serum concentration of FGF19 <60 pg/mL compared to 4.5% below this threshold (P < .0001). C4 concentrations correlated with the number of daily bowel movements (r = 0.41; P = .004) and correlated inversely with FGF19 concentrations (r = -0.72; P<.0001).ConclusionWe observed significantly increased serum concentrations of C4 in patients with CD with IR, compared to patients with UC. A cutoff concentration of C4 above 48.3 ng/mL identifies patients with diarrhea likely attributable to bile acid malabsorption (BAD) with an AUROC value of 0.94. Increased serum levels of bile acid precursors identify patients with diarrhea and a low serum concentration of FGF19, and concentrations of C4 correlate with daily liquid bowel movements and correlate inversely with FGF19 concentrations. C4 may be a biomarker to identify patients with diarrhea attributable to bile acid malabsorption.

Project description:IntroductionCholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis.AimTo investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions.MethodsHepG2.rNtcp cells were preconditioned (24 h) with sub-apoptotic concentrations (0.1-50 ?M) of various bile acids, the superoxide donor menadione, TNF-? or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 ?M for 4 h), menadione (50 ?M, 6 h) or cytokine mixture (CM; 6 h). Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11) and bile acid sensors, as well as intracellular GCDCA levels were analyzed.ResultsPreconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauro)ursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-? potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA-preconditioning.ConclusionsSub-toxic concentrations of bile acids in the range that occur under normal physiological conditions protect HepG2.rNtcp cells against GCDCA-induced apoptosis, which is independent of FXR-controlled changes in bile acid transport.

Dataset Information

Lipid and Bile Acid Dysmetabolism in Crohn's Disease.

Publications

Lipid and Bile Acid Dysmetabolism in Crohn's Disease.

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