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Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia.

ABSTRACT: Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10-14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

SUBMITTER: van der Schoor LWE

PROVIDER: S-EPMC8160219 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia.

van der Schoor Lori W E LWE Verkade Henkjan J HJ Bertolini Anna A de Wit Sanne S Mennillo Elvira E Rettenmeier Eva E Weber André A AA Havinga Rick R Valášková Petra P Jašprová Jana J Struik Dicky D Bloks Vincent W VW Chen Shujuan S Schreuder Andrea B AB Vítek Libor L Tukey Robert H RH Jonker Johan W JW

Scientific reports 20210527 1

Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humaniz ...[more]

PMID: 34045606

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Project description:Neonatal hyperbilirubinemia (jaundice) is common in infants, with extremely preterm infants (EPT, <28 weeks gestational age) being at high risk for bilirubin-induced neurotoxicity, resulting in neurodevelopmental impairment. Hyperbilirubinemia is treated using phototherapy to lower unconjugated bilirubin levels. However, the benefits and risks of phototherapy in EPTs have not been well studied, and bilirubin at low levels may be protective as an antioxidant. Phototherapy is associated with markers of oxidative stress in the plasma, but the effects of phototherapy on the hippocampus (HPC) are not known. Bilirubin and insults associated with EPTs impair hippocampal development, a brain structure critical for cognitive function, but their underlying mechanisms remain unknown. The effects of hyperbilirubinemia and phototherapy on the HPC were studied using a Gunn rat model. Jaundiced (jj) and non-jaundiced (Nj) pups were subjected to phototherapy from postnatal day 4 (P4) through P6. The HPC was harvested and processed for RNA sequencing. Serum bilirubin levels were elevated in jj compared to Nj control rats. Phototherapy significantly lowered serum bilirubin levels in jj rats. Compared to Nj rats, 1294 genes were differentially expressed in the jj hippocampal transcriptome and mapped onto the nervous system development, inflammation, and ferroptosis signaling pathways. Phototherapy induces 3297 differentially-expressed genes (DEGs) in rat hippocampal transcriptome compared to untreated rats. These DEGs were annotated to pathways regulating synaptogenesis, long-term potentiation, and neurogenesis. Both hyperbilirubinemia and phototherapy altered expression of 407 genes, which mapped onto hippocampal plasticity functions, including neuritogenesis and long-term potentiation. Our study demonstrates a model for investigating molecular effects of hyperbilirubemia and phototherapy in an EPT-equivalent Gunn rat pup. Our data revealed the effects of hyperbilirubinemia and phototherapy on signaling pathways critical for hippocampal development and plasticity.

Project description:ObjectiveTo investigate the changes in bile acid (BA) metabolites within the follicular fluid (FF) of patients with diminished ovarian reserve (DOR) and to identify novel diagnostic markers that could facilitate early detection and intervention in DOR patients.DesignA total of 182 patients undergoing assisted reproductive technology (ART) were enrolled and categorized into the normal ovarian reserve (NOR) group (n = 91) or the DOR group (n = 91) to measure BA levels in FF. To identify the changes in granulosa cells (GCs), we collected GCs from an additional 7 groups of patients for transcriptome sequencing.SettingReproductive medicine center within a hospital and university research laboratory.PopulationA total of 182 patients undergoing assisted reproductive technology were enrolled and categorized into the NOR group (n = 91) or the DOR group (n = 91).MethodsIn this study, BA metabolites in FF of DOR and NOR patients were analyzed in detail by targeted metabolomics, and the correlation between BA levels in FF and clinical indicators was discussed. Then, we constructed a diagnostic model for DOR using the random forest algorithm based on five different BAs. Additionally, we performed a functional enrichment analysis on differentially expressed genes (DEGs) in GCs from both DOR and NOR patients.Main outcome measuresBA levels in FF and their correlation with clinical indicators; the areas under the curve (AUCs) of the random forest diagnostic model for DOR; and the DEGs and corresponding functional enrichment results of GC RNA analysis.Result (s)The levels of lithocholic acid, chenodeoxycholic acid, ursodeoxycholic acid, deoxycholic acid and cholic acid in FF of DOR group were lower than those of NOR group. And significant reductions in total, primary, secondary, and unconjugated BA levels were observed in the DOR group. The above five BAs levels were closely related to indicators of ovarian reserve. The AUC of the diagnostic model based on the above five BAs was 0.964. Based on transcriptome sequencing data from two groups of GCs, a total of 482 up-regulated and 654 down-regulated DEGs were identified. Gene ontology analysis revealed that the metabolic and biosynthetic processes of fatty acids, steroids, and cholesterol were enriched in these DEGs, whereas Kyoto Encyclopedia of Genes and Genomes analysis indicated enrichment of fatty acid and ovarian steroidogenesis.Conclusion(s)The levels of multiple BA metabolites in FF are significantly lower than those in patients with DOR and are closely related to the evaluation of ovarian reserve function.

Dataset Information

Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia.

Publications

Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia.

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