Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms
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Background The blood brain barrier tightly regulates the passage of molecules into the brain and becomes leaky following obstructive cholestasis. The aim of this study was to determine if increased serum bile acids observed during cholestasis permeabilize the blood brain barrier.Methods Rats underwent bile duct ligation or deoxycholic or chenodeoxycholic acid injections and blood brain barrier permeability assessed. In vitro, the permeability of rat brain microvessel endothelial cell monolayers, the expression and phosphorylation of occludin, ZO-1 and ZO-2 as well as the activity of Rac1 was assessed after treatment with plasma from cholestatic rats, or bile acid treatment, in the presence of a Rac1 inhibitor.Results Blood brain barrier permeability was increased in vivo and in vitro following bile duct ligation or treatment with bile acids. Associated with the bile acid-stimulated increase in endothelial cell monolayer permeability was elevated Rac1 activity and increased phosphorylation of occludin. Pretreatment of endothelial cell monolayers with a Rac1 inhibitor prevented the effects of bile acid treatment on occludin phosphorylation and monolayer permeability.Conclusions These data suggest that increased circulating serum bile acids may contribute to the increased permeability of the blood brain barrier seen during obstructive cholestasis via disruption of tight junctions.
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Bile duct ligation increases blood-brain barrier permeability.
“Bile duct ligation alters the GM composition, and increases the permeability of the BBB (328, 329).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [328]
Bile duct ligation alters gut microbiota composition.
“Bile duct ligation alters the GM composition, and increases the permeability of the BBB (328, 329).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [328]
In rats, bile acids increase permeability of the blood-brain barrier, which could increase the flow of other neuroactive metabolites or neurotoxins into the brain and affect brain function and behavior.
“In rats, bile acids were also demonstrated to increase permeability of the BBB (412), which could increase the flow of other neuroactive metabolites or neurotoxins into the brain and affect brain function and behavior.”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [412]
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“Studies have found that some BAs may show increased BBB permeability both in vitro and in vivo through Rac1-dependent phosphorylation mechanisms of tight junction protein [117], which may be related to the activation of FXR and TGR5 [118 – 120].”
RetractedLinking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling
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- Authors
- Quinn, M., McMillin, M., Galindo, C., Frampton, G., Pae, H. Y., & DeMorrow, S.
- Affiliations
- Texas A&M Health Science Center (US)
- Corresponding author
- DeMorrow, Sharon
- Venue
- Digestive and Liver Disease
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 46
- Issue
- 6
- Pages
- 527-534
- ISSN
- 1590-8658 (ISSN-L)
- PMC
- PMC4065628
- OpenAlex
- W2051089741
- Cited by
- 259
- References
- 49
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 43 · 2023: 33 · 2022: 37 · 2021: 26 · 2020: 17 · 2019: 11 · 2018: 9 · 2017: 8 · 2016: 7 · 2015: 9 · 2014: 1
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Digestive and Liver Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Binus University
- National Institute of Diabetes and Digestive and Kidney Diseases (DK082435, R01DK082435, K01DK078532)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- bile acids, blood-brain barrier permeability, obstructive cholestasis, bile duct ligation, Rac1, occludin phosphorylation, tight junctions, endothelial permeability, deoxycholic acid, chenodeoxycholic acid, ZO-1, ZO-2
- MeSH terms
- Aminoquinolines, Animals, Bile Ducts, Blood-Brain Barrier, Chenodeoxycholic Acid, Cholestasis, Deoxycholic Acid, Disease Models, Animal, Ligation, Male, Permeability, Phosphorylation, Pyrimidines, RNA, Messenger, Rats, Sprague-Dawley, Tight Junctions, rac1 GTP-Binding Protein, Endothelial Cells, Tissue Culture Techniques, Rats, Microvessels, Occludin, Zonula Occludens-1 Protein, Zonula Occludens-2 Protein
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