2. Academic Validation
  3. Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

  • Sci Rep. 2021 May 27;11(1):11107. doi: 10.1038/s41598-021-90687-5.
Lori W E van der Schoor 1 2,  Henkjan J Verkade 1 2,  Anna Bertolini 1,  Sanne de Wit 1,  Elvira Mennillo 3,  Eva Rettenmeier 3,  André A Weber 3,  Rick Havinga 1,  Petra Valášková 4,  Jana Jašprová 4,  Dicky Struik 1,  Vincent W Bloks 1,  Shujuan Chen 3,  Andrea B Schreuder 1 2,  Libor Vítek 4,  Robert H Tukey 5,  Johan W Jonker 6
Affiliations

Affiliations

  • 1 Section of Molecular Metabolism and Nutrition, Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
  • 2 Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
  • 3 Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA, 92093, USA.
  • 4 Fourth Department of Internal Medicine and Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 5 Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA, 92093, USA. [email protected].
  • 6 Section of Molecular Metabolism and Nutrition, Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. [email protected].
PMID: 34045606 DOI: 10.1038/s41598-021-90687-5
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.

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