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Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

ABSTRACT: BACKGROUND:Oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects, which are rare and severe genetic liver diseases. To date there has been no report of the effects of this therapy in children reaching adulthood. The aim of the study was to evaluate the long-term effectiveness and safety of CA therapy. METHODS:Fifteen patients with either 3?-hydroxy-?5-C27-steroid oxidoreductase (3?-HSD) (n?=?13) or ?4-3-oxosteroid 5?-reductase (?4-3-oxo-R) (n?=?2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed prospectively. RESULTS:The median age at last follow-up and the median time of follow-up with treatment were 24.3 years (range: 15.3-37.2) and 21.4 years (range: 14.6-24.1), respectively. At last evaluation, physical examination findings and blood laboratory test results were normal in all patients. Liver sonograms were normal in most patients. Mean daily CA dose was 6.9 mg/kg of body weight. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites remained low or traces in amount with CA therapy. Liver fibrosis scored in liver biopsies or assessed by elastography in 14 patients, after 10 to 24 years with CA therapy, showed a marked improvement with disappearance of cirrhosis (median score?

SUBMITTER: Gonzales E

PROVIDER: S-EPMC6206929 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

Gonzales Emmanuel E Matarazzo Lorenza L Franchi-Abella Stéphanie S Dabadie Alain A Cohen Joseph J Habes Dalila D Hillaire Sophie S Guettier Catherine C Taburet Anne-Marie AM Myara Anne A Jacquemin Emmanuel E

Orphanet journal of rare diseases 20181029 1

<h4>Background</h4>Oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects, which are rare and severe genetic liver diseases. To date there has been no report of the effects of this therapy in children reaching adulthood. The aim of the study was to evaluate the long-term effectiveness and safety of CA therapy.<h4>Methods</h4>Fifteen patients with either 3β-hydroxy-Δ<sup>5</sup>-C<sub>27</sub>-steroid oxidoreductase (3β-HSD ...[more]

PMID: 30373615

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Project description:Bile acids (BAs) are steroid-derived molecules with important roles in digestion, the maintenance of host metabolism, and immunomodulation. Primary BAs are synthesized by the host, while secondary BAs are produced by the gut microbiome through transformation of the former. The regulation of microbial production of secondary BAs is not well understood, particularly the production of 7-dehydroxylated BAs, which are the most potent agonists for host BA receptors. The 7-dehydroxylation of cholic acid (CA) is well established and is linked to the expression of a bile acid-inducible (bai) operon responsible for this process. However, little to no 7-dehydroxylation has been reported for other host-derived BAs (e.g., chenodeoxycholic acid, CDCA or ursodeoxycholic acid, UDCA). Here, we demonstrate that the 7-dehydroxylation of CDCA and UDCA by the human isolate Clostridium scindens is induced when CA is present, suggesting that CA-dependent transcriptional regulation is required for substantial 7-dehydroxylation of these primary BAs. This is supported by the finding that UDCA alone does not promote expression of bai genes. CDCA upregulates expression of the bai genes but the expression is greater when CA is present. In contrast, the murine isolate Extibacter muris exhibits a distinct response; CA did not induce significant 7-dehydroxylation of primary BAs, whereas BA 7-dehydroxylation was promoted upon addition of germ-free mouse cecal content in vitro. However, E. muris was found to 7-dehydroxylate in vivo. The distinct expression responses amongst strains indicate that bai genes are regulated differently. CA promoted bai operon gene expression and the 7-dehydroxylating activity in C. scindens strains. Conversely, the in vitro activity of E. muris was promoted only after the addition of cecal content and the isolate did not alter bai gene expression in response to CA. The accessory gene baiJ was only upregulated in the C. scindens ATCC 35704 strain, implying mechanistic differences amongst isolates. Interestingly, the human-derived C. scindens strains were also capable of 7-dehydroxylating murine bile acids (muricholic acids) to a limited extent. This study shows novel 7-dehydroxylation activity in vitro resulting from the presence of CA and suggests distinct bai gene expression across bacterial species.

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Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

Publications

Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood.

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