Total Bile Acid Pool Size Research Articles

Gly-β-MCA is a potent anti-cholestasis agent against “human-like” hydrophobic bile acid-induced biliary injury in mice

Cholestasis is a chronic liver disease with limited therapeutic options. Hydrophobic bile acid-induced hepatobiliary injury is a major pathological driver of cholestasis progression. This study investigates the anti-cholestasis efficacy and mechanisms of action of glycine-conjugated β-muricholic acid (Gly-β-MCA). We use female Cyp2c70 KO mice, a rodent cholestasis model that does not produce endogenous muricholic acid (MCA) and exhibits a “human-like” hydrophobic bile acid pool and female-dominant progressive hepatobiliary injury and portal fibrosis. The efficacy of Gly-β-MCA and ursodeoxycholic acid (UDCA), the first line drug for cholestasis, on cholangiopathy and portal fibrosis are compared. At a clinically relevant dose, Gly-β-MCA shows comparable efficacy as UDCA in reducing serum transaminase, portal inflammation and ductular reaction, and better efficacy than UDCA against portal fibrosis. Unlike endogenous bile acids, orally administered Gly-β-MCA is absorbed at low efficiency in the gut and enters the enterohepatic circulation mainly after microbiome-mediated deconjugation, which leads to taurine-conjugated MCA enrichment in bile that alters enterohepatic bile acid pool composition and reduces bile acid pool hydrophobicity. Gly-β-MCA also promotes fecal excretion of endogenous hydrophobic bile acids and decreases total bile acid pool size, while UDCA treatment does not alter total bile acid pool. Furthermore, Gly-β-MCA treatment leads to gut unconjugated MCA enrichment and reduces gut hydrophobic lithocholic acid (LCA) exposure. In contrast, UDCA treatment drives a marked increase of LCA flux through the large intestine. In conclusion, Gly-β-MCA is a potent anti-cholestasis agent with potential clinical application in treating human cholestasis.

IBAT inhibitors in pediatric cholestatic liver diseases: Transformation on the horizon?

Historically, the therapeutic options available to hepatologists managing cholestasis have been limited. Apart from bile acid--binding resins and the choleretic ursodeoxycholic acid, the medical management of cholestasis in children has been predominately focused on managing the complications of cholestasis, namely pruritus, malnutrition, fat-soluble vitamin deficiencies, and portal hypertension. As such, invasive surgical procedures such as biliary diversion and liver transplantation may become the only options for progressive and unremitting cases of cholestasis. Particularly in the pediatric population, where debilitating pruritus is a common indication for a liver transplant, effective anti-cholestatic medications have the potential to prolong native liver survival without the need for biliary diversion. Ileal bile acid transporter (IBAT) inhibitors are a relatively new class of drugs which that target the ileal re-uptake of bile acids, thus interrupting the enterohepatic circulation and reducing the total bile acid pool size and exposure of the liver. Oral, minimally absorbed IBAT inhibitors have been demonstrated to reduce serum bile acid levels and pruritus with a minimal side effect profile in clinical trials in Alagille Ssyndrome and progressive familial intrahepatic cholestasis, leading to FDA and EMA approval. The indications for IBAT inhibitors will likely expand in the coming years as clinical trials in other adult and pediatric cholestatic conditions are ongoing. This review will summarize the published clinical and pre-clinical data on IBAT inhibitors and offer providers guidance on their practical use.

Glycine-β-Muricholic Acid Improves Liver Fibrosis and Gut Barrier Function by Reducing Bile Acid Pool Size and Hydrophobicity in Male Cyp2c70 Knockout Mice.

Cyp2c70 knockout mice lack the enzyme that produces muricholic acids and show a "human-like" hydrophobic bile acid pool-induced hepatobiliary injury. In this study, we investigated the potential anti-cholestasis effect of glycine-conjugated β muricholic acid (G-β-MCA) in male Cyp2c70 KO mice based on its hydrophilic physiochemical property and signaling property as an farnesoid X receptor (FXR) antagonist. Our results showed that G-β-MCA treatment for 5 weeks alleviated ductular reaction and liver fibrosis and improved gut barrier function. Analysis of bile acid metabolism suggested that exogenously administered G-β-MCA was poorly absorbed in the small intestine and mostly deconjugated in the large intestine and converted to taurine-conjugated MCA (T-MCA) in the liver, leading to T-MCA enrichment in the bile and small intestine. These changes decreased the biliary and intestine bile acid hydrophobicity index. Furthermore, G-β-MCA treatment decreased intestine bile acid absorption via unknown mechanisms, resulting in increased fecal bile acid excretion and a reduction in total bile acid pool size. In conclusion, G-β-MCA treatment reduces the bile acid pool size and hydrophobicity and improves liver fibrosis and gut barrier function in Cyp2c70 KO mice.

Invited Commentary for Disruption of Enterohepatic Circulation of Bile Acids Ameliorates Small Bowel Resection Associated Hepatic Injury

In this issue, Tecos et al [ 1 Tecos ME Steinberger AE Guo J Rubin DC Davidson NO Warner BW Disruption of enterohepatic circulation of bile acids ameliorates small bowel resection associated hepatic injury. J Pediatr Surg. 2023; (in press) Google Scholar ] expand on their previous demonstration that parenteral nutrition (PN)-independent hepatoxicity in a murine small bowel resection (SBR) model is region dependent and may be mitigated by tauroursodeoxycholic acid (TUDCA) supplementation. Interestingly, these results contradict a previous report from their own group as to the impact of proximal vs. distal resection, seemingly due to the presence or absence of the ileocecal valve (ICV) and adjacent bowel, which differed between the two studies [ 2 Barron LK Gayer GP Roberts A Golden JM Aladegbami BG Guo J Erwin CR Warner BW Liver steatosis induced by small bowel resection is prevented by oral vancomycin. Surgery. 2016; 160: 1485-1495 Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar ]. Dr. Warner’s group was the first to report liver injury in a PN-independent murine SBR model [ 3 Chiang JYL Bile acid metabolism and signaling in liver disease and therapy. Liver Res. 2017 Jun; 1: 3-9 Crossref PubMed Scopus (140) Google Scholar ]. In this latest study, they reveal that proximal SBR results in greater oxidative stress in the liver as evidenced by elevated mRNA transcripts for tumor necrosis factor-α, nicotininamide adenine dinucleotide phosphate oxidase, and glutathione synthetase with a greater compensatory antioxidant response consisting of elevated lipocalin 2. Furthermore, distal SBR demonstrated decreased hepatic bile acid content, smaller total bile acid pool size, and significant changes in bile acid composition, such as a decrease in the most insoluble, toxic, and hydrophobic bile acids, as well as an increase in de novo bile acid synthesis of physiologic, less toxic, hydrophilic bile acids. Equally compelling, the hepatotoxicity and injurious bile acid profile observed in proximal SBR was mitigated by exogenous TUDCA supplementation. In addition to these intriguing observations, the authors propose a mechanism for this difference. Distal SBR results in disruption of enterohepatic bile acid recycling, leading to amplified production of more physiologic, less toxic, and more hydrophilic bile acids, resulting in less oxidative stress to the liver and ultimately decreased liver injury. While TUDCA had similar hepatoprotective effects to distal SBR, they were not identical, and thus, the authors suggest it may differ in mechanism of action. Regardless, this study expands on the identification of therapeutic targets for intestinal failure-associated liver disease.

Time‐related changes in nutrient digestibility and faecal bile acid loss of rainbow trout ( Oncorhynchus mykiss ) as affected by dietary fat level and non‐starch polysaccharide level

Time-related changes in apparent digestibility coefficients (ADC) and faecal bile acid loss as affected by dietary fat level and non-starch polysaccharide (NSP) level were studied in rainbow trout (Oncorhynchus mykiss). Low-Fat versus High-Fat and Low-NSP versus High-NSP diets were formulated. Fish were fed for 6 weeks to apparent satiation and faeces were sampled in week 2, 4 and 6. Most nutrient ADC increased with time and increases were consistently larger for the High-Fat and High-NSP diets. Nevertheless, time of adaptation was equal between diets/nutrients and steady-state digestion was reached at week 3. Although faecal bile acid loss was affected by diet, the observed time-related decrease in faecal bile acid loss was mainly driven by a decrease in feed intake and faeces production. Fat ADC improved over time regardless of NSP level, which does not support the hypothesis that enhanced faecal bile acid loss (related to satiation feeding of high-NSP diets) causes a depletion of the total body bile acid pool size that is critical for proper fat digestion. The high-fat diets consistently resulted in the lowest Fat ADC, which might have been related to a lower availability of bile acids relative to the level of dietary fat.

Mechanisms of Altered Bile Acid Homeostasis in Offspring Exposed to Maternal Obesogenic Diet

BackgroundNon‐alcoholic fatty liver disease (NAFLD) affects approximately one‐quarter of the global population with increasing prevalence in the pediatric population. There is currently no standard medical therapy and no diagnostic study capable of predicting which patients will develop severe disease. Recent evidence in both humans and animal models show that maternal obesity is a risk factor for the development of NAFLD and progression to NASH. We have shown in a murine model of maternal obesity the offspring develop periportal fibrosis and inflammation with associated changes in bile acid (BA) homeostasis. In this study we define the mechanisms of changes in BA homeostasis.MethodsFemale C57Bl6 mice were fed chow (CON) or HF/HS diet for 6 weeks to induce obesity and bred with lean males. Offspring were fed chow diet from the time of weaning until tissue collection. BA pool size and levels of specific intrahepatic bile acid species were measured. RT‐PCR was performed to evaluate gene expression of factors involved in bile acid metabolism and signaling. 16S sequencing was performed for evaluation of offspring microbiome. Levels of stool BAs were quantified and timed BA excretion performed.ResultsOffspring from the maternal HF/HS (mHF/HS) lineage exhibited an increase in total BA pool size with associated changes in expression of genes involved in bile acid metabolism (increased Cyp7a1, Cyp27a1). Measurement of specific bile acids in liver showed a shift in the intrahepatic BA pool composition (decreased deoxycholic acid, increased muricholic acid) in offspring from the mHF/HS lineage. Decreased BA excretion was observed in mHF/HS lineage offspring. Fecal microbiome analysis showed a decrease in alpha diversity and shifts in the abundance of particular phyla (increased Bacteroidetes, decreased Proteobacteria) and genera (increased Barnesiella, decreased Clostridium). Measurement of cecal BA levels showed an increase in abundance of muricholic acid (FXR antagonist) and a decrease in abundance of deoxycholic acid (FXR agonist) in mHF/HS lineage offspring.ConclusionsMaternal HF/HS diet exposure leads to pathologic changes in the offspring including periportal fibrosis and inflammation, which is associated with changes in BA homeostasis. Several factors are involved in the BA homeostasis changes including BA metabolism and excretion. Vertical transmission of gut dysbiosis may be a primary factor in driving changes in BA homeostasis in offspring exposed to maternal obesogenic diet.

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Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice

G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) is a novel G protein-coupled receptor for bile acid. Tissue distribution and cell-type specificity of Gpbar1 mRNA suggest a potential role for the receptor in the endocrine system; however, the precise physiological role of Gpbar1 still remains to be elucidated. To investigate the role of Gpbar1 in vivo, the Gpbar1 gene was disrupted in mice. In homozygous mice, total bile acid pool size was significantly decreased by 21-25% compared with that of the wild-type mice, suggesting that Gpbar1 contributes to bile acid homeostasis. In order to assess the impact of Gpbar1 deficiency in bile acid homeostasis more precisely, Gpbar1 homozygous mice were fed a high-fat diet for 2 months. As a result, female Gpbar1 homozygous mice showed significant fat accumulation with body weight gain compared with that of the wild-type mice. These findings were also observed in heterozygous mice to the same extent. Although the precise mechanism for fat accumulation in female Gpbar1 homozygous mice remains to be addressed, these data indicate that Gpbar1 is a potential new player in energy homeostasis. Thus, Gpbar1-deficient mice are useful in elucidating new physiological roles for Gpbar1.

Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice.

Although the physiological roles of the individual bile acid synthetic enzymes have been extensively examined, relatively little is known regarding the function of intracellular bile acid-binding proteins. Male L-FABP (liver fatty-acid-binding protein) gene-ablated mice were used to determine a role for L-FABP, the major liver bile acid-binding protein, in bile acid and biliary cholesterol metabolism. First, in control-fed mice L-FABP gene ablation alone increased the total bile acid pool size by 1.5-fold, especially in gall-bladder and liver, but without altering the proportions of bile acid, cholesterol and phospholipid. Loss of liver L-FABP was more than compensated by up-regulation of: other liver cytosolic bile acid-binding proteins [GST (glutathione S-transferase), 3alpha-HSD (3alpha-hydroxysteroid dehydrogenase)], key hepatic bile acid synthetic enzymes [CYP7A1 (cholesterol 7alpha-hydroxylase) and CYP27A1 (sterol 27alpha-hydroxylase)], membrane bile acid translocases [canalicular BSEP (bile salt export pump), canalicular MRP2 (multidrug resistance associated protein 2), and basolateral/serosal OATP-1 (organic anion transporting polypeptide 1)], and positive alterations in nuclear receptors [more LXRalpha (liver X receptor alpha) and less SHP (short heterodimer partner)]. Secondly, L-FABP gene ablation reversed the cholesterol-responsiveness of bile acid metabolic parameters such that total bile acid pool size, especially in gall-bladder and liver, was reduced 4-fold, while the mass of biliary cholesterol increased 1.9-fold. The dramatically reduced bile acid levels in cholesterol-fed male L-FABP (-/-) mice were associated with reduced expression of: (i) liver cytosolic bile acid-binding proteins (L-FABP, GST and 3alpha-HSD), (ii) hepatic bile acid synthetic enzymes [CYP7A1, CYP27A1 and SCP-x (sterol carrier protein-x/3-ketoacyl-CoA thiolase)] concomitant with decreased positive nuclear receptor alterations (i.e. less LXRalpha and more SHP), and (iii) membrane bile acid transporters (BSEP, MRP2 and OATP-1). These are the first results suggesting a physiological role for the major cytosolic bile acid-binding protein (L-FABP) in influencing liver bile metabolic phenotype and gall-bladder bile lipids of male mice, especially in response to dietary cholesterol.

Mechanism of serum cholesterol reduction by oat bran

Nine normolipidemic young men consumed a constant diet for 2 mo into which oat bran was incorporated during the second month so that we might test the hypotheses that oats lower serum cholesterol concentrations by decreasing bile acid and fat absorption and increasing bile acid synthesis. Bile acid kinetics were determined by measuring the 13C enrichment of serum cholic and chenodeoxycholic acids. Oat bran consumption decreased serum cholesterol levels (p < 0.01) and cholic acid pool size (p < 0.05). Deoxycholic acid pool size (p < 0.01) and the synthesis and fractional turnover rates of both primary bile acids (p < 0.05) increased. Total bile acid pool size did not change. Fecal excretion of total bile acids, the two secondary bile acids and fat increased significantly. The results demonstrate that oat bran lowers serum cholesterol levels in part by altering bile acid metabolism. In addition, the substantial increase in the proportion of the total bile acid pool that was deoxycholic acid is consistent with the hypothesis that oat bran also decreases cholesterol synthesis.

Bile Acid Pool Size and Gallbladder Storage Capacity in Gallstone Disease

Gallstone patients have a reduced total bile acid pool size. To analyze mechanisms behind this, the relation between gallbladder storage capacity and bile acid pool size was studied in 20 gallstone patients, 15 women and 5 men. At cholecystectomy bile was aspirated from the gallbladders, and the volume of bile and concentration of bile acids were recorded. The total bile acid pool size was at the same time estimated by an isotope dilution technique. A significant positive correlation between gallbladder volume and bile acid pool size was found (r = 0.45). The correlation between bile acid concentration in the gallbladders and pool size was, however, not significant (r = 0.24). It is suggested that gallbladder storage capacity may be a determinant of bile acid pool and that a diminished pool size, as seen in gallstone disease, may to some extent be caused by gallbladder fibrosis and shrinkage.

Effect of Chronic Ursocholic Acid Administration on Bile Lipid Composition and Bile Acid Pool Size in Gallstone Patients

We assessed the effect of chronic (4-6 weeks) administration of ursocholic acid (UCA) (15 mg/kg/day), a natural bile acid with poor detergent capacity, on biliary lipid composition of gallbladder bile (n = 26) and bile acid pool size (n = 5) in gallstone patients. During treatment the biliary molar percentage UCA increased from trace values to 28% (p less than 0.001). This effect was accompanied by an increase in molar percentage deoxycholic acid from 16% to 33% (p less than 0.001). Total bile acid pool size remained unchanged during UCA administration; cholic acid and chenodeoxycholic acid pool sizes decreased from 1.0 to 0.6 mmol (p less than 0.05) and from 1.6 to 0.9 mmol (p less than 0.05), respectively. The molar percentage cholesterol of gallbladder bile decreased from 9.8% to 7.0% (p less than 0.001) during UCA, but bile remained supersaturated with cholesterol in 21 patients. The weak effect on biliary lipid composition and the increase of potentially toxic deoxycholic acid in bile suggest that UCA is unlikely to replace ursodeoxycholic and chenodeoxycholic acid for medical treatment of gallstones.

Effect of ursodeoxycholic acid administration on biliary lipid secretion in primary biliary cirrhosis.

Ursodeoxycholic acid (UDCA) has been reported to improve liver function tests when administered to patients with cholestatic liver diseases, such as primary biliary cirrhosis (PBC). However, its effects on biliary lipid metabolism in patients with PBC are still unknown. In this study we report the effect that UDCA (600 mg/day, for four weeks) had on biliary cholesterol saturation index, biliary bile acid pattern and pool size, and biliary lipid output in seven female patients (ages 34-58 years) with PBC, stages I to III. A significant improvement of liver function tests was observed after four weeks of treatment. Saturation index was significantly decreased from 1.23 +/- 0.1 to 0.7 +/- 0.08 (P less than 0.02); this effect was due to the significant decrease of biliary cholesterol concentration from 6.7 +/- 0.36 to 3.6 +/- 0.37 percent molar (P less than 0.02). A significant decrease of cholesterol output (from 88 +/- 9 to 55 +/- 10 mumol/hr, P less than 0.02) was also observed. The amount of cholic acid, the predominant bile acid in bile, significantly decreased (from 47.3 +/- 3.5 to 35.4 +/- 2.6 percent molar, P less than 0.02), as did amounts of chenodeoxycholic and deoxycholic acids, while the amount of UDCA rose from 1.6 +/- 1.0 to 34.0 +/- 1.3 percent molar (P less than 0.02). Total bile acid pool size was not affected by UDCA, but the evaluation of individual bile acid pool sizes showed an increased proportion of UDCA relative to the endogenous bile acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Biliary lipids, bile acid metabolism, gallbladder motor function and small intestinal transit during ingestion of a sub-fifty oral contraceptive

The risk of developing gallstone disease while using low dose oral contraceptives (OC) has been incompletely explored in man. In this study, biliary lipid composition, bile acid conjugation, primary bile acid kinetics, gallbladder storage and emptying by quantitative cholescintigraphy, and small intestinal transit by breath hydrogen analysis are reported in a group of non-obese healthy young women, both after 3-5 months OC, using 30 micrograms ethinyl oestradiol daily, and during an adjacent control period. OC use was associated with a significant rise of biliary cholesterol saturation in gallbladder bile. Total bile acid pool size did not change; however, mean cholic acid pool size was 36% greater than in the control period (P less than 0.001), due to its enhanced synthesis rate, at the expense of chenodeoxycholic acid and deoxycholic acid pool sizes (P less than 0.05). A rise in taurine conjugation of biliary bile acids was apparent in all subjects (P less than 0.0001). Gallbladder motor function was not influenced by ingestion of OC, whereas only a minor retardation of small intestinal transit was found. The findings show an effect of this sub-50 OC on biliary lipid composition and cholesterol saturation that is comparable with that of conventional OC. The predominance of more hydrophilic bile acid conjugates during oral contraception is in keeping with a hepatic effect of this preparation on bile acid metabolism.

Effect of ursodeoxycholate and its taurine conjugate on bile acid synthesis and cholesterol absorption

Six male subjects with normal gastroenterologic function were studied to determine the effects of ursodeoxycholic (15 mg/kg · day) and tauroursodeoxycholic (20 mg/kg · day) acid feeding on bile acid synthesis and cholesterol absorption. Each bile acid was fed for 1 mo and withheld for the next month. Subjects remained on a metabolic ward and consumed a constant diet of 500 mg of cholesterol mixed with solid and liquid formulas. Before the study started, each subject received 50 μCi of [4-14C]cholesterol intravenously. During the study, stools were collected for the determination of 24-h fecal acidic and neutral sterol excretion, and blood was drawn twice weekly for determination of serum cholesterol specific activity. At the end of each month an intestinal perfusion study was performed to measure total bile acid pool size and hourly biliary secretion rates of cholesterol, phospholipid, and bile acid. From these data, the percentage of cholesterol absorption and total endogenous bile acid synthesis could be calculated. Neither ursodeoxycholic nor tauroursodeoxycholic acid feeding decreased endogenous bile acid synthesis. During bile acid feeding periods, the percentage of cholesterol absorption was decreased.

Lack of effect of experimental ascorbic acid deficiency on bile acid metabolism, sterol balance, and biliary lipid composition in man.

Extensive studies in animal models indicate that subclinical ascorbic acid deficiency impairs the conversion of cholesterol to bile acid, elevates plasma cholesterol levels, and predisposes to development of cholesterol cholelithiasis. The present study was designed to see if this is also true in man. Five normal volunteers were hospitalized in a metabolic ward and placed on a controlled diet containing 3-4 mg of ascorbic acid each day. Ascorbic acid supplementation was given as follows: control period I (days 1-33), 75 mg/day; deficient period (days 34-96), 0 mg/day; and repletion period (days 97-101), 1000 mg/day. In addition, three of the subjects were studied during a second control period (days 102-139) during which they were given 75 mg/day of ascorbic acid. Ascorbate levels at the end of both control periods were 0.87-1.34 mg/dl in plasma and 19.4-29.5 micrograms/10(8) cells in leukocytes. At the end of the deficient period these levels were 0.09-0.15 mg/dl in plasma and 6.2-10.0 micrograms/10(8) cells in leukocytes, levels approaching those seen in scurvy. There was no effect of ascorbic acid deficiency on plasma cholesterol and triglycerides; plasma cholesterol in high, very low, and low density lipoprotein fractions; biliary lipid composition and saturation index of gallbladder bile; synthesis, fractional turnover, or pool size of either cholic or chenodeoxycholic acids; output of fecal acid or neutral sterols; and fecal sterol balance. Total bile acid pool size calculated by the one-sample technique was reduced 11% in the deficient period compared to control period I (P less than 0.005), and increased to 98.7% of the baseline levels in control period II. However, total bile acid pool calculated by the Lindstedt method did not change during deficiency. These data demonstrate that short-term subclinical ascorbic acid deficiency near the scorbutic range has no significant effect on bile acid and cholesterol metabolism in man.

Effect of bile acid conjugation pattern on bile acid metabolism in normal humans

Six male subjects were fed taurine 0.5 g six times daily for 2 wk to determine the effect of a shift in bile acid conjugation pattern upon bile acid metabolism. Duodenal bile acids were analyzed, and bile acid pool size, daily fecal excretion, and biliary excretion rate were quantified. In addition, daily biliary excretion rate of cholesterol and phospholipid were quantified, and biliary saturation with cholesterol was estimated. The dose of taurine caused reversal of the bile acid glycine-to-taurine conjugation ratio. Total bile acid pool size decreased, as did the pool size of chenodeoxycholic acid. Pool sizes of cholic and deoxycholic acids did not change. Daily fecal bile acid excretion decreased slightly. Biliary secretion rates of cholesterol, phospholipid, and bile acids did not change, nor did biliary cholesterol saturation. Pool size can decrease because of increased bile acid catabolism or decreased synthesis. The fact that bile acid excretion failed to increase, and actually decreased slightly, suggests that the effect is upon bile acid synthesis. In normal humans, the effect is small and probably physiologically unimportant. In special cases, however, such as during ursodeoxycholic acid therapy, the effect of shifting conjugation pattern may become important.

Rowachol and Ursodeoxycholic Acid in Hamsters with Cholesterol Gallstones

Rowachol, a mixture of 6 terpenes in olive oil and under investigation for dissolution of gallstones in humans, was compared with UDCA in hamsters with induced cholesterol gallstones. Eighty hamsters were allocated to eight groups of ten animals each. One group received only standard rodent chow. The other seven groups received the lithogenic regime (standard chow containing ethinyl estradiol and increased cholesterol), either alone or with 20 mg/kg/day of UDCA, or 5, 10, or 20 mg/kg/day of mixed terpenes in olive oil or 10 mg (of terpenes) kg/day of Rowachol or 0.2 cc/day of olive oil. The animals were sacrificed after 12 weeks. Two additional groups of six hamsters each received the lithogenic regime for 12 weeks, and then were switched to the standard diet, alone or with 10 mg/kg/day of Rowachol for eight weeks at the end of which time they were sacrificed. Rowachol decreased HMGCoA reductase activity 18%, but did not dissolve gallstones. Neither the terpenes nor Rowachol altered the biliary cholesterol saturation index, bile acid pool size or the activity of cholesterol 7-alpha hydroxylase or prevented formation of gallstones. UDCA unsaturated bile, increased the total bile acid pool size 38%, depressed the activity of HMGCoA reductase 29%, and prevented formation of gallstones.

Bile acid absorption kinetics in Crohn's disease on elemental diet after oral administration of a stable-isotope tracer with chenodeoxycholic-11, 12-d2 acid.

A non-radioactive tracer, deuterium, incorporated in chenodeoxycholic acid, was used to study bile acid absorption kinetics employing gas chromatography-mass fragmentography for its analysis. Eight patients with Crohn's disease and four control volunteers were administered chenodeoxycholic-11, 12-d2 acid. In order to obtain constant dietary conditions, they were fed by an elemental diet during the study. There were significant reductions of the biological half-life of chenodeoxycholic-11, 12-d2 acid, the pool size of chenodeoxycholic acid, and the total bile acid pool size in patients with Crohn's disease as compared with those in normal subjects. There was a marked increase in the relative concentration of ursodeoxycholic acid with a concomitant decrease of deoxycholic acid in patients with Crohn's disease, although such differences did not reach statistical significance. The present study confirms that there are some impairments of enterohepatic circulation of bile acids in patients with Crohn's disease.

Effect of the selective expansion of cholic acid pool on bile lipid composition: Possible mechanism of bile acid induced biliary cholesterol desaturation

The effect of cholic acid pool expansion on biliary lipid composition was investigated in 21 subjects with cholesterol gallstones. All subjects were fed cholic acid (15 mg/kg/day) and ampicillin (2 g/day) in order to depress the intestinal degradation of cholic to deoxycholic acid. Five additional subjects were given ampicillin alone. The treatment lasted 2–3 wk. Parameters investigated included biliary and plasma lipid, biliary bile acid composition, and total and individual bile acid pool size. In 11 of 21 subjects (group I) cholic acid pool expanded two-threefold, whereas deoxycholic acid pool increased only slightly. In this group mean saturation index fell from 1.32 ± 0.27 (mean ± SD) to 0.93 ± 0.25 (p < 0.001), and plasma cholesterol increased from 185 ± 45 mg/dl before to 213 ± 37 after treatment (p < 0.01). In the remaining 10 subjects (group II) the increase of the deoxycholic acid pool far exceeded that of cholic acid, and in these subjects the saturation index rose from a mean value of 1.07 ± 0.27 to 1.42 ± 0.22 after treatment (p < 0.01). In this group plasma cholesterol tended to decrease (from 213 ± 57 to 197 ± 51 after treatment). In the 5 subjects treated with ampicillin alone deoxycholic acid pool was greatly reduced, and the saturation index fell from 1.25 ± 0.25 to 0.95 ± 0.35. The results suggest that cholic acid pool expansion reduces bile cholesterol saturation, whereas the increase of deoxycholic acid pool tends to supersaturate the bile. It is concluded that a determinant of bile cholesterol saturation might be the detergent power of the bile acid pool.