Potential Role of Bile Acids in the Pathogenesis and Treatment of PBC
DOI:
https://doi.org/10.53469/jcmp.2025.07(02).19Keywords:
Primary Biliary Cholangitis, Bile Acid, TherapyAbstract
Primary biliary cholangitis (PBC) is a chronic cholestatic disease whose pathogenesis involves a complex interplay of genetic predisposition, environmental triggers, and aberrant activation of the immune system. It is characterized by immune-mediated bile duct injury and chronic intrahepatic cholestasis, which ultimately leads to biliary cirrhosis and even liver failure. Cholestasis is an important pathogenetic feature and pathophysiological alteration of PBC, in which toxicity accumulation, inflammatory activation, fibrosis drive, and immunomodulatory abnormalities combine to drive disease progression. In addition, targeted bile acid (bile acid) therapy has shown therapeutic efficacy in improving liver biochemistry and survival in the majority of patients, and the current first-line therapy for PBC is bile acid therapy, with bile acids thought to play an important role in disease progression and treatment. This review focuses on the potential impact of bile acids in the disease process of PBC and its treatment, and discusses the current state of research with a view to informing further studies in PBC.
References
Etherington RE, Millar B, Innes BA, Jones D, Kirby JA, Brain JG. Bile acid receptor agonists in primary biliary cholangitis: regulation of the cholangiocyte secretome and downstream T cell differentiation. FASEB Bioadv. 2019. 1(5): 332-343.
Sun Y, Haapanen K, Li B, Zhang W, Van de Water J, Gershwin ME. Women and primary biliary cirrhosis. Clin Rev Allergy Immunol. 2015. 48(2-3): 285-300.
Trivella J, John BV, Levy C. Primary biliary cholangitis: epidemiology, prognosis, and treatment. Hepatol Commun. 2023. 7(6): e0179.
Davies SP, Ronca V, Wootton GE, et al. Expression of E-cadherin by CD8(+) T cells promotes their invasion into biliary epithelial cells. Nat Commun. 2024. 15(1): 853.
Zhao SX, Li WC, Fu N, et al. Emperipolesis mediated by CD8(+) T cells correlates with biliary epithelia cell injury in primary biliary cholangitis. J Cell Mol Med. 2020. 24(2): 1268-1275.
EASL Clinical Practice Guidelines: the diagnosis and management of patients with primary biliary cholangitis. j Hepatol. 2017. 67(1): 145-172.
Hirschfield GM, Dyson JK, Alexander G, et al. The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines. gut. 2018. 67(9): 1568-1594.
Tang R, Wei Y, Li Y, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. gut. 2018. 67(3): 534 -541.
Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. gastroenterology. 2015. 148(4): 751-61. e8.
Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem.. 2003. 72: 137-74.
Chiang JY. Bile acid metabolism and signaling. Compr Physiol. 2013. 3(3): 1191-212.
Castellanos-Jankiewicz A, Guzmán-Quevedo O, Fénelon VS, et al. Hypothalamic bile acid-TGR5 signaling protects from obesity. Cell Metab. 2021. 33(7). 1483-1492.e10.
Wang MQ, Zhang KH, Liu FL, et al. Wedelolactone alleviates cholestatic liver injury by regulating the FXR-bile acid-NF-κB/NRF2 axis to reduce bile acid accumulation and its subsequent inflammation and oxidative stress. Phytomedicine. 2024. 122: 155124.
Li J, Zhu X, Zhang M, et al. Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism. j Hepatol. 2021. 75(2): 400-413.
Zheng C, Wang L, Zou T, et al. Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8(+) T cells. j Hepatol. 2024. 80(5): 764-777.
Schramm C, Wedemeyer H, Mason A, et al. Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis. jHEP Rep. 2022. 4(11): 100544.
Chen W, Wei Y, Xiong A, et al. Comprehensive Analysis of Serum and Fecal Bile Acid Profiles and Interaction with Gut Microbiota in Primary Biliary Cholangitis. Clin Rev Allergy Immunol. 2020. 58(1): 25-38.
Kennedy L, Carpino G, Owen T, et al. Secretin alleviates biliary and liver injury during late-stage primary biliary cholangitis via restoration of secretory processes. j Hepatol. 2023. 78(1): 99-113.
Farooqui N, Elhence A, Shalimar. A Current Understanding of Bile Acids in Chronic Liver Disease. J Clin Exp Hepatol. 2022. 12(1): 155-173.
Abdulazeez MA, Jasim HA, Bashir M, Ross K, Fatokun AA. Peristrophe bicalyculata (Retz) Nees contains principles that are cytotoxic to cancer cells and induce caspase-mediated, intrinsic apoptotic death through oxidative stress, mitochondrial depolarization and DNA damage. Biomed Pharmacother. 2022. 147: 112597.
Iruzubieta P, Goikoetxea-Usandizaga N, Barbier-Torres L, et al. Boosting mitochondria activity by silencing MCJ overcomes cholestasis-induced liver injury. jHEP Rep. 2021. 3(3): 100276.
Rust C, Karnitz LM, Paya CV, Moscat J, Simari RD, Gores GJ. The bile acid taurochenodeoxycholate activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. j Biol Chem. 2000. 275(26): 20210-6.
Arenas F, Hervías I, Sáez E, et al. Promoter hypermethylation of the AE2/SLC4A2 gene in PBC. JHEP Rep. 2019. 1(3): 145-153.
Hisamoto S, Shimoda S, Harada K, et al. Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis. J Autoimmun. 2016. 75: 150-160.
Banales JM, Sáez E, Uriz M, et al. Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis. Hepatology. 2012. 56(2): 687-97.
Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol. 2011. 178(1): 175-86.
Zhuang Y, Ortega-Ribera M, Thevkar Nagesh P, et al. Bile acid-induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis-induced liver and kidney injury via regulation of ZBP1. Hepatology. 2024. 79(4): 752-767.
Guo C, Xie S, Chi Z, et al. Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. Immunity. 2016. 45(4): 802- 816.
Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 2004. 39(3): 779-91.
Chen RR, Li YJ, Zhou XM, et al. The association between bile salt export pump single-nucleotide polymorphisms and primary biliary cirrhosis susceptibility and ursodeoxycholic acid response. dis Markers. 2014. 2014: 350690.
Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology. 2008. 48(5): 1632-43.
Hang S, Paik D, Yao L, et al. Bile acid metabolites control T(H)17 and T(reg) cell differentiation. nature. 2019. 576(7785): 143-148.
Liu Q, Huang B, Zhou Y, et al. Gut microbiome pattern impacts treatment response in primary biliary cholangitis. med. 2025. 6(1): 100504.
Umemura M, Honda A, Yamashita M, et al. High-fat diet modulates bile acid composition and gut microbiota, affecting severe cholangitis and cirrhotic change in murine primary biliary cholangitis. J Autoimmun. 2024. 148: 103287.
Tanaka A. New Therapies on the Horizon for Primary Biliary Cholangitis. drugs. 2024. 84(1): 1-15.
Namisaki T, Fujinaga Y, Moriya K, Yoshiji H. The association of histological progression with biochemical response to ursodeoxycholic acid in primary biliary cholangitis. Hepatol Res. 2021. 51(1): 31-38.
Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. j Hepatol. 2015. 62(1 Suppl): s25-37.
Yu K, Li P, Xu T, et al. Decreased infiltration of CD4(+) Th1 cells indicates a good response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis Pathol Res Pract. 2021. 217: 153291.
Liang TJ, Yuan JH, Tan YR, et al. Effect of ursodeoxycholic acid on TGF beta1/Smad signaling pathway in rat hepatic stellate cells. chin Med J (Engl). 2009. 122(10): 1209-13.
You H, Duan W, Li S, et al. Guidelines on the Diagnosis and Management of Primary Biliary Cholangitis (2021). J Clin Transl Hepatol. 2023. 11(3): 736-746.
Chascsa D, Lindor KD. Emerging therapies for PBC. J Gastroenterol. 2020. 55(3): 261-272.
Trivedi PJ, Hirschfield GM, Gershwin ME. Obeticholic acid for the treatment of primary biliary cirrhosis. Expert Rev Clin Pharmacol. 2016. 9(1): 13-26.
Murillo Perez CF, Fisher H, Hiu S, et al. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls. gastroenterology. 2022. 163(6): 1630-1642.e3.
Zhang Y, Jackson JP, St Claire RL 3rd, Freeman K, Brouwer KR, Edwards JE. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes. Pharmacol Res Perspect. 2017. 5(4): e00329.
Li X, Lu W, Kharitonenkov A, Luo Y. Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases. J Intern Med. 2024. 295(3): 292 -312.
Li X, Liao M, Pan Q, et al. Combination therapy of obeticholic acid and ursodeoxycholic acid in patients with primary biliary cholangitis who respond incompletely to ursodeoxycholic acid: a systematic review. Eur J Gastroenterol Hepatol. 2020. 32(9): 1116-1122.
Karatza E, Swift B, Carreño F, et al. Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat. Liver Int. 2024. 44(9): 2293-2302.
Kremer AE, Mayo MJ, Hirschfield GM, et al. Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis. Hepatology. 2024. 80(1): 27-37.
Al-Dury S, Wahlström A, Wahlin S, et al. Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis. Sci Rep. 2018. 8(1): 6658.
Han W, Song T, Huang Z, Liu Y, Xu B, Huang C. Distinct signatures of gut microbiota and metabolites in primary biliary cholangitis with poor biochemical response after ursodeoxycholic acid treatment. Cell Biosci. 2024. 14(1): 80.
Kennedy L, Francis H, Invernizzi P, et al. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis. faseb j. 2019. 33(9): 10269-10279.
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