Targeting Gut Microbiota for the Treatment of Primary Biliary Cholangitis: From Bench to Bedside

Abstract

Primary biliary cholangitis (PBC) is a complex cholestatic liver disease with an unresolved etiology. The gut microbiota is composed of a dynamic community of bacteria, archaea, fungi, and viruses that have a key role in physiological processes related to nutrition, immunity, and host defense responses. A number of recent studies found that the composition of the gut microbiota of PBC patients was significantly altered, and reported that gut dysbiosis might arise during PBC development because of the close interactions of the liver and the gut. In light of the growing interest in this topic, the focus of this review is to characterize PBC gut microbiota alterations, the correlation between PBC pathology and the gut microbiota, and prospective therapies that target the altered gut microbiota, such as probiotics and fecal microbiota transplantation.

Causal associations between gut microbiota and primary biliary cholangitis: a bidirectional two-sample Mendelian randomization study

“…The human gut microbiome, comprised of a diverse array of microorganisms, performs a vital function in metabolic processes, immune regulation, and the preservation of gut integrity ( Hou et al, 2022 ). An increasing body of evidence indicates that imbalances in the gut microbiota may play a role in the onset and advancement of PBC ( Zhang L. et al, 2023 ). This connection arises from the linkage between the liver and intestine through the portal vein, forming a gut-liver axis ( Wang et al, 2021 ).…”

Current Perspectives on the Molecular and Clinical Relationships between Primary Biliary Cholangitis and Hepatocellular Carcinoma

“…The role of BAs in HCC development is further supported by the observation that the relative amount of primary and conjugated BAs is altered in preclinical models and patients with HCC. The increased conversion of primary to secondary conjugated BAs has been linked to the alteration of gut microbiota [41,48,49]. Notably, these microbiotaassociated dysregulations of BAs have been correlated to immune-related alterations in the liver, for example, downregulation of the Chemokine (C-X-C motif) ligand 16 (CXCL16), a chemotactic cytokine with a peculiar role in cancer [50].…”

“…Interestingly, the CXCL16 downregulation reduces hepatic CXCR6+ natural killer T (NKT) cells, immune cells involved in immune surveillance [40,51]. Recently, many studies have observed that the gut microbiota is significantly altered in PBC patients, and dysbiosis could act as a promoter of HCC development [49]. Moreover, the increased bacterial abundance observed in the hepatic tissue of cirrhotic patients due to the so-called leaky gut induces transcriptional changes, leading to the activation of fibro-inflammatory pathways and the modulation of the hepatic inflammatory microenvironment towards cancer cell immune escape and promoting HCC development (Figure 2).…”

Sequence of events leading to primary biliary cholangitis

“…Aromaticivorans compared to E. Coli and the ubiquity of this bacteria is demonstrated by its presence in 25% of fecal samples from both PBC patients or control[ 19 ]. Regarding the mechanism linking bacteria to PBC progression, also a role for intestinal dysbiosis has been claimed[ 20 ]. This may increase intestinal permeability and lipopolysaccharide flux toward the liver, thus resulting in an enhanced immune/inflammatory response.…”