Anti–Cholestatic Therapy with Obeticholic Acid Improves Short-Term Memory in Bile Duct–Ligated Mice

Lucy M.V. Gee, Ben Barron-Millar, Jack Leslie, Claire Richardson, Marco Y.W. Zaki, Saimir Luli, Rachel A. Burgoyne, Rainie I.T. Cameron, Graham R. Smith, John G. Brain, Barbara Innes, Laura Jopson, Jessica K. Dyson, Katherine R.C. McKay, Alexandros Pechlivanis, Elaine Holmes, Rolando Berlinguer-Palmini, Stella Victorelli, George F. Mells, Richard N. SandfordJeremy Palmer, John A. Kirby, Christos Kiourtis, Joao Mokochinski, Zoe Hall, Thomas G. Bird, Lee A. Borthwick, Christopher M. Morris, Peter S. Hanson, Diana Jurk, Elizabeth A. Stoll, Fiona E.N. LeBeau, David E.J. Jones, Fiona Oakley

Research output: Contribution to journalArticlepeer-review


Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.

Original languageEnglish (US)
Pages (from-to)11-26
Number of pages16
JournalAmerican Journal of Pathology
Issue number1
StatePublished - Jan 2023

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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