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Background: Cftr(-/-tm1Unc) mice develop progressive hepato-biliary pathology. We hypothesize that this liver pathology is related to alterations in biliary bile hydrophobicity and bile salt metabolism in Cftr(-/-tm1Unc) mice., Methods: We determined bile production, biliary and fecal bile salt- and lipid compositions and fecal bacterial composition of C57BL/6J Cftr(-/-tm1Unc) and control mice., Results: We found no differences between the total biliary bile salt or lipid concentrations of Cftr(-/-) and controls. Compared to controls, Cftr(-/-) mice had a ~30% higher bile production and a low bile hydrophobicity, related to a ~7 fold higher concentration of the choleretic and hydrophilic bile salt ursocholate. These findings coexisted with a significantly smaller quantity of fecal Bacteroides bacteria., Conclusions: Liver pathology in Cftr(-/-tm1Unc) is not related to increased bile hydrophobicity. Cftr(-/-) mice do however display a biliary phenotype characterized by increased bile production and decreased biliary hydrophobicity. Our findings suggest Cftr dependent, alterations in intestinal bacterial biotransformation of bile salts., (Copyright © 2014. Published by Elsevier B.V.)

Polyethylene glycol (PEG) is a frequently used osmotic laxative that accelerates gastrointestinal transit. It has remained unclear, however, whether PEG affects intestinal functions. We aimed to determine the effect of PEG treatment on intestinal sterol metabolism. Rats were treated with PEG in drinking water (7%) for 2 wk or left untreated (controls). We studied the enterohepatic circulation of the major bile salt (BS) cholate with a plasma stable isotope dilution technique and determined BS profiles and concentrations in bile, intestinal lumen contents, and feces. We determined the fecal excretion of cholesterol plus its intestinally formed metabolites. Finally, we determined the cytolytic activity of fecal water (a surrogate marker of colorectal cancer risk) and the amount and composition of fecal microbiota. Compared with control rats, PEG treatment increased the pool size (+51%; P < 0.01) and decreased the fractional turnover of cholate (-32%; P < 0.01). PEG did not affect the cholate synthesis rate, corresponding with an unaffected fecal primary BS excretion. PEG reduced fecal excretion of secondary BS and of cholesterol metabolites (each P < 0.01). PEG decreased the cytolytic activity of fecal water [54 (46-62) vs. 87 (85-92)% erythrocyte potassium release in PEG-treated and control rats, respectively; P < 0.01]. PEG treatment increased the contribution of Verrucomicrobia (P < 0.01) and decreased that of Firmicutes (P < 0.01) in fecal flora. We concluded that PEG treatment changes the intestinal bacterial composition, decreases the bacterial dehydroxylation of primary BS and the metabolism of cholesterol, and increases the pool size of the primary BS cholate in rats.

Hypercholesterolemia is an important risk factor for cardiovascular disease. It is caused by a disturbed balance between cholesterol secretion into the blood versus uptake. The pathways involved are regulated via a complex interplay of enzymes, transport proteins, transcription factors and non-coding RNA's. The last two decades insight into underlying mechanisms has increased vastly but there are still a lot of unknowns, particularly regarding intracellular cholesterol transport. After decades of concentration on the liver, in recent years the intestine has come into focus as an important control point in cholesterol homeostasis. This review will discuss current knowledge of cholesterol physiology, with emphasis on cholesterol absorption, cholesterol synthesis and fecal excretion, and new (possible) therapeutic options for hypercholesterolemia., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)