scholarly journals Long-Term Cholic Acid Therapy in Zellweger Spectrum Disorders

2018 ◽  
Vol 12 (2) ◽  
pp. 360-372 ◽  
Author(s):  
James E. Heubi ◽  
Kenneth D.R. Setchell ◽  
Kevin E. Bove
Keyword(s):  
Bile Acid ◽  
Liver Function ◽  
Bile Acids ◽  
Cholic Acid ◽  
Feedback Inhibition ◽  
Oral Treatment ◽  
Acid Therapy ◽  
Spectrum Disorders ◽  
Zellweger Spectrum Disorders

Zellweger spectrum disorders (ZSDs), a subgroup of peroxisomal biogenesis disorders, have a generalized defect in peroxisome function. Liver disease in ZSDs has been linked to accumulation of C27-bile acid intermediates due to the lack of peroxisomal β-oxidation of these intermediates to form primary C24-bile acids. Oral treatment with primary bile acid, cholic acid (CA), inhibits formation of hepatotoxic C27-bile acids by restoring normal physiologic feedback inhibition on bile acid synthesis. We present the long-term CA treatment and liver-related outcomes for 3 pediatric patients with ZSDs who have received CA treatment for ≥15 years. Ongoing CA treatment was associated with stabilized liver function, as shown by serum biochemistries and liver histopathology, and no treatment-related adverse effects were observed. All 3 patients have attended regular school with classroom accommodations and attained a good quality of life. Our patient outcomes suggest that early and ongoing CA therapy may sustain liver function in patients with ZSDs.

scholarly journals Long-Term Cholic Acid Treatment in a Patient with Zellweger Spectrum Disorder

2018 ◽  
Vol 12 (3) ◽  
pp. 661-670 ◽  
Author(s):  
James E. Heubi ◽  
Warren P. Bishop
Keyword(s):  
Liver Disease ◽  
Bile Acid ◽  
Liver Biopsy ◽  
Cholic Acid ◽  
Feedback Inhibition ◽  
Hepatocellular Cancer ◽  
Acid Synthesis ◽  
Adjunctive Treatment ◽  
Acid Therapy

Zellweger spectrum disorders (ZSDs) are a subgroup of peroxisomal biogenesis disorders with a generalized defect in peroxisome function. Liver disease in ZSDs has been associated with the lack of peroxisomal β-oxidation of C27-bile acid intermediates to form primary C24-bile acids, which prevents normal physiologic feedback and leads to accumulation of hepatotoxic bile acid intermediates. Primary bile acid therapy, oral cholic acid (CA), as adjunctive treatment for ZSDs, restores physiologic feedback inhibition on bile acid synthesis and inhibits formation of hepatotoxic bile acid intermediates. Our patient is a Caucasian male diagnosed with moderately severe ZSD at age 5 months, and he received long-term CA therapy from age 16 months through 19 years old. CA treatment was well tolerated, with no reports of adverse events. His liver biopsy prior to CA therapy showed cholestasis, periportal inflammation, and bridging fibrosis. Following 5 months of CA therapy, his liver biopsy showed improvement in inflammation and no change in fibrosis. Serum liver enzymes during CA therapy improved compared to pre-therapy levels but frequently were above the upper limit of normal. At age 19 years, following several years with clinical cirrhosis with severe portal hypertension, he presented with worsening jaundice, and he was diagnosed with hepatocellular cancer (HCC). Early-onset advanced liver disease associated with ZSD and natural disease progression that is not completely suppressed with CA treatment likely caused HCC in our patient. Greater awareness is needed of the possibility of development of HCC in patients with moderately severe ZSD who survive past childhood.

scholarly journals Cholic acid therapy in Zellweger spectrum disorders

2016 ◽  
Vol 39 (6) ◽  
pp. 859-868 ◽  
Author(s):  
Kevin Berendse ◽  
Femke C. C. Klouwer ◽  
Bart G. P. Koot ◽  
Elles M. Kemper ◽  
Sacha Ferdinandusse ◽  
...  
Keyword(s):  
Cholic Acid ◽  
Acid Therapy ◽  
Spectrum Disorders ◽  
Zellweger Spectrum Disorders

Radioimmunoassay of conjugated cholic acid, chenodeoxycholic acid, and deoxycholic acid from human serum, with use of 125I-labeled ligands.

1979 ◽  
Vol 25 (2) ◽  
pp. 264-268 ◽  
Author(s):  
O Mäentausta ◽  
O Jänne
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Chenodeoxycholic Acid ◽  
Deoxycholic Acid ◽  
Serum Samples ◽  
Analytical Recovery ◽  
Hepatobiliary Diseases ◽  
Polyethylene Glycol Precipitation ◽  
Free Serum

Abstract We describe a method for radioimmunoassay of conjugated cholic acid, chenodeoxycholic acid, and deoxycholic acid in serum. In the method, 125I-labeled bile acid conjugates are used as the tracers along with antibodies raised against individual bile acid-bovine serum albumin conjugates. Antibody-bound and free bile acids were separated by polyethylene glycol precipitation (final concentration, 125 g/L). Before radioimmunoassay, 0.1-mL serum samples were precipitated with nine volumes of ethanol, and portions from the supernate were used in the assays. The lowest measurable amounts of the bile acids, expressed as pmol/tube, were: cholic acid conjugates, 2; chenodeoxycholic acid conjugates, 0.5; and deoxycholic acid conjugates. 2. Analytical recovery of bile acids added to bile acid-free serum ranged from 85 to 110%; intra-assay and inter-assay CVs ranged from 3.2 to 5.3% and from 5.3 to 12.2%, respectively. Concentrations (mean +/- SD) of the bile acid conjugates in serum from apparently healthy women and men (in mumol/L) were: cholic acid conjugates, 0.43 +/- 0.17 (n = 126); chenodeoxycholic acid conjugates, 0.47 +/- 0.23 (n = 111); and deoxycholic acid conjugates, 0.33 +/- 0.11 (n = 96). The values for primary bile acids were greatly increased in patients with various hepatobiliary diseases.

Interaction between bile acids and staphylococcal polysaccharide: inhibition of capsule formation in encapsulated mutant strains (taurine+, taurine−) of Staphylococcus aureus

1983 ◽  
Vol 29 (12) ◽  
pp. 1653-1660 ◽  
Author(s):  
Toshichika Ohtomo
Keyword(s):  
Staphylococcus Aureus ◽  
Bile Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Taurocholic Acid ◽  
Polysaccharide Antigen ◽  
Capsule Formation ◽  
Mutant Strains ◽  
Bile Acid Derivatives ◽  
Capsular Material

In a previous paper, we showed that bile acid derivatives inhibit capsule formation as well as taurine biosynthesis in a taurine+ (Tau+) encapsulated strain of Staphylococcus aureus. In the present study, binding of [14C]cholic acid ([14C]CA) and [14C]taurocholic acid ([14C]TA) to the staphylococcal polysaccharide antigen (SPA) of the capsular fraction was examined. The bile acids were found to bind with SPA via taurine of the Tau+ cells. [14C]CA bound with the SPA fraction of the Tau+ strain within 10–30 min, whereas 60–120 min was required in the binding of [14C]TA. Various bile acids competed with cholic acid binding to Tau+ cells which was shown by the inhibition of binding with cholic acid or taurocholic acid but not with glycholic acid. Binding of bile acid derivatives to a Tau− encapsulated mutant or to capsular material from this mutant was not observed.

scholarly journals Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

2017 ◽  
Vol 83 (7) ◽  
Author(s):  
Lien Van den Bossche ◽  
Pieter Hindryckx ◽  
Lindsey Devisscher ◽  
Sarah Devriese ◽  
Sophie Van Welden ◽  
...  
Keyword(s):  
Community Structure ◽  
Bile Acid ◽  
Bile Acids ◽  
Experimental Colitis ◽  
Acid Therapy ◽  
Content Type ◽  
Bile Acid Therapy ◽  
Inflammatory Bowel ◽  
The Impact ◽  
Secondary Bile Acids

ABSTRACT The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes. Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD. IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we studied the alterations in the fecal microbial abundance in colitic mice following the administration of secondary bile acids. Our results show that secondary bile acids reduce the severity of colitis and ameliorate colitis-associated fecal dysbiosis at the phylum level. This study indicates that secondary bile acids might act as a safe and effective drug for inflammatory bowel disease.

scholarly journals Metabolism of Oxo-Bile Acids and Characterization of Recombinant 12α-Hydroxysteroid Dehydrogenases from Bile Acid 7α-Dehydroxylating Human Gut Bacteria

2018 ◽  
Vol 84 (10) ◽  
Author(s):  
Heidi Doden ◽  
Lina A. Sallam ◽  
Saravanan Devendran ◽  
Lindsey Ly ◽  
Greta Doden ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Bile Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Deoxycholic Acid ◽  
Gut Bacteria ◽  
Dietary Lipids ◽  
Human Gut ◽  
Content Type ◽  
Low Activity

ABSTRACTBile acids are important cholesterol-derived nutrient signaling hormones, synthesized in the liver, that act as detergents to solubilize dietary lipids. Bile acid 7α-dehydroxylating gut bacteria generate the toxic bile acids deoxycholic acid and lithocholic acid from host bile acids. The ability of these bacteria to remove the 7-hydroxyl group is partially dependent on 7α-hydroxysteroid dehydrogenase (HSDH) activity, which reduces 7-oxo-bile acids generated by other gut bacteria. 3α-HSDH has an important enzymatic activity in the bile acid 7α-dehydroxylation pathway. 12α-HSDH activity has been reported for the low-activity bile acid 7α-dehydroxylating bacteriumClostridium leptum; however, this activity has not been reported for high-activity bile acid 7α-dehydroxylating bacteria, such asClostridium scindens,Clostridium hylemonae, andClostridium hiranonis. Here, we demonstrate that these strains express bile acid 12α-HSDH. The recombinant enzymes were characterized from each species and shown to preferentially reduce 12-oxolithocholic acid to deoxycholic acid, with low activity against 12-oxochenodeoxycholic acid and reduced activity when bile acids were conjugated to taurine or glycine. Phylogenetic analysis suggests that 12α-HSDH is widespread amongFirmicutes,Actinobacteriain theCoriobacteriaceaefamily, and human gutArchaea.IMPORTANCE12α-HSDH activity has been established in the medically important bile acid 7α-dehydroxylating bacteriaC. scindens,C. hiranonis, andC. hylemonae. Experiments with recombinant 12α-HSDHs from these strains are consistent with culture-based experiments that show a robust preference for 12-oxolithocholic acid over 12-oxochenodeoxycholic acid. Phylogenetic analysis identified novel members of the gut microbiome encoding 12α-HSDH. Future reengineering of 12α-HSDH enzymes to preferentially oxidize cholic acid may provide a means to industrially produce the therapeutic bile acid ursodeoxycholic acid. In addition, a cholic acid-specific 12α-HSDH expressed in the gut may be useful for the reduction in deoxycholic acid concentration, a bile acid implicated in cancers of the gastrointestinal (GI) tract.

scholarly journals Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats

1991 ◽  
Vol 280 (2) ◽  
pp. 373-377 ◽  
Author(s):  
S Dueland ◽  
J Reichen ◽  
G T Everson ◽  
R A Davis
Keyword(s):  
Bile Acid ◽  
Bile Duct ◽  
Liver Function ◽  
Urinary Excretion ◽  
Bile Acids ◽  
Bile Duct Ligation ◽  
Microsomal Cytochrome ◽  
Duct Ligation ◽  
Cytochrome P 450

We examined how total blockage of biliary excretion, the major pathway through which cholesterol and bile acids are removed from the body, affects liver function, cholesterol and bile acid metabolism and homoeostasis. After 4 weeks of bile-duct ligation, rats showed impaired liver function, as documented by elevations in serum bilirubin and alkaline phosphatase activity. Moreover, bile-duct ligation decreased by about 30% both the amount of microsomal cytochrome P-450 in the liver and the elimination of aminopyrine in vivo, a reliable index in vivo of microsomal mixed-function oxidase activity. Cholesterol and bile acid contents in livers of bile-duct-ligated rats were doubled compared with sham-operated controls. Despite the increase in the contents of cholesterol and bile acids in liver, activities of the respective rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol 7 alpha-hydroxylase, were doubled. Serum concentrations of bile acids and free cholesterol increased 25- and 4-fold respectively. The large increase in serum bile acids was associated with a 380-fold increase in the urinary excretion of bile acids. Although there is a general decrease in cytochrome P-450 content and drug metabolism involving cytochrome P-450-containing hydroxylases, the activity of cholesterol 7 alpha-hydroxylase, also a cytochrome P-450-containing enzyme, is actually increased. These data show that complete obstruction of the bile duct results in the selective impairment of microsomal cytochrome P-450. Increased activity of 7 alpha-hydroxylase, bile acid synthesis and urinary excretion provides an alternative excretory pathway that helps to maintain cholesterol homoeostasis when the biliary excretory pathway is eliminated.

scholarly journals Studies on the origin of biliary phospholipid. Effect of dehydrocholic acid and cholic acid infusions on hepatic and biliary phospholipids

1990 ◽  
Vol 270 (3) ◽  
pp. 691-695 ◽  
Author(s):  
F Chanussot ◽  
H Lafont ◽  
J Hauton ◽  
B Tuchweber ◽  
I Yousef
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Bile Flow ◽  
Normal Values ◽  
Specific Radioactivity ◽  
Regulatory Effect ◽  
Experimental Protocol ◽  
Dehydrocholic Acid ◽  
Cellular Organelles

The correlation between the secretion of biliary phospholipid (PL) and bile acid suggests a regulatory effect of bile acid on PL secretion. Bile acids may influence PL synthesis and/or the mobilization of a preformed PL pool. The objective of this study was to determine the contribution of these two sources to biliary PL, by using an experimental protocol in which dehydrocholic acid (DHCA) and cholic acid (CA) were infused to manipulate biliary PL secretion. In control rats, there was a steady state in bile flow. PL secretion and the biliary secretion of newly synthesized phosphatidylcholine (PC). The specific radioactivity of PC in bile was significantly higher than in plasma, microsomes and canalicular membranes. DHCA infusion decreased biliary PC secretion rate by 80%, and secretion returned to normal values at the transport maximum of CA. The specific radioactivity of biliary PC was decreased by 30% by DHCA infusion and reached normal values during CA infusion. There were no significant changes in the specific radioactivity of PC in plasma or cellular organelles during infusion of bile acids. These data indicate that: (1) newly synthesized PC contributes a small percentage to biliary PC; thus a preformed pool (microsomal and extrahepatic) is a major source of biliary PL; (2) the contribution of the extrahepatic pool to the biliary PL may be more important than the microsomal pool.

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