Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy

Cihan Yurdaydin, Thomas J. Walsh, Howard D. Engler, Jeoung Hee Ha, Yong Li, E. Anthony Jones, Anthony S. Basile

Research output: Contribution to journalArticlepeer-review

Abstract

Benzodiazepine receptor (BZR) ligands are elevated in animals and humans with fulminant hepatic failure (FHF) and contribute to the pathogenesis of the associated hepatic encephalopathy (HE). As gut factors are proposed to play a role in the pathogenesis of HE, we investigated gut flora as a source of BZR ligands. Rats received daily oral neomycin, vancomycin and metronidazole (AB +) or saline (AB -) before and concurrent with the induction of FHF with thioacetamide. BZR ligands were extracted from brain and plasma and quantified using radiometric techniques. Plasma BZR ligand concentrations in AB(+) and AB(-) rats with HE were higher than AB(+) and AB(-) control rats. Brain BZR ligand concentrations increased in AB(+) and AB(-) rats with HE. Stool cultures from antibiotic treated rats with HE indicated the presence of multidrug resistantAcinetobacter lwoffii. Although no significant concentrations of BZR ligands were detected in culture media inoculated withA. lwoffii, administeringA. lwoffii to normal rats significantly elevated BZR ligand levels in brain, but not plasma. Thus, antibiotic treatment of rats is associated with the growth of a resistant strain of bacterium which produces an inactive BZR ligand precursor. BZR ligands may be synthesized from these precursors in the brain and efficiently cleared by a normal liver following brain-to-plasma transfer. Impairment of this clearance process in FHF facilitates their accumulation, enabling agonist BZR ligands to contribute to the pathogenesis of HE by further enhancing GABAergic neurotransmission.

Original languageEnglish (US)
Pages (from-to)42-48
Number of pages7
JournalBrain research
Volume679
Issue number1
DOIs
StatePublished - May 8 1995

Keywords

  • Acinetobacter
  • Antibiotic
  • Benzodiazepine receptor
  • Brain
  • Hepatic encephalopathy
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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