Exploring Advanced Therapies for Primary Biliary Cholangitis: Insights from the Gut Microbiota-Bile Acid-Immunity Network

Abstract

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota-bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

Keywords: bile acid; gut microbiota; primary biliary cholangitis.

Figure 1

Interactions between bile acids and gut microbiota, bile acid metabolism, and circulation. Gut microbiota participates in the synthesis and metabolism of bile acids, impacting the composition of the bile acid pool. Bile acids affect the abundance and composition of gut microbiota through their antimicrobial activity. Primary bile acids chenodeoxycholic acid (CDCA) and cholic acid (CA) are synthesized from cholesterol in the liver; they then bind to glycine or taurine to form conjugated hydrophilic bile acids. Through the bile salt export protein (BSEP), these bile acids are secreted into the bile and then released into the duodenum; approximately 95% of them are reabsorbed mainly by enterocyte apical sodium-dependent bile acid transporter (ASBT) and effluxed into the portal circulation by the organic solute transporter α and β heterodimer (OSTα/β), finally taken up by hepatocytes via Na⁺-dependent taurocholate cotransport peptide (NTCP) and organic anion-transporters (OATP). The unabsorbed bile acids enter the colon and interact with gut microbiota, forming secondary bile acids such as deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) by deconjugation, dehydrogenation, 7α-dehydroxylation, and epimerization of primary bile acids. Created by Biorender.com (accessed on 9 March 2024).