Gut microbiota: implications in pathogenesis and potential therapeutic target in primary biliary cholangitis

Primary Biliary Cholangitis (PBC) is a chronic, progressive autoimmune liver disease characterized by the immune-mediated destruction of small intrahepatic bile ducts, leading to cholestasis, fibrosis, and potentially cirrhosis. While the first-line treatment, ursodeoxycholic acid (UDCA), improves long-term outcomes, a significant portion of patients exhibit a suboptimal response.

The etiology of PBC involves a complex interplay of genetic susceptibility and environmental triggers. Recently, the gut microbiota has emerged as a critical factor at this interface, influencing disease onset, progression, and therapeutic response.

READ MORE: Propionate from gut bacterium Akkermansia mitigates liver fibrosis

READ MORE: Scientists find a microbial molecule that restores liver and gut health

This review, published in Journal of Clinical and Translational Hepatology, synthesizes current evidence on gut microbiota dysbiosis in PBC, elucidates its pathogenic mechanisms, and explores its potential as both a diagnostic biomarker and a novel therapeutic target.

Characteristic dysbiosis in PBC

A consistent theme across multiple studies from China and Japan is a significant alteration in the gut microbial composition of PBC patients compared to healthy individuals. This dysbiosis is characterized by:

• Reduced Diversity: Overall microbial diversity, richness, and evenness are decreased.

• Imbalanced Flora: There is a notable decrease in beneficial bacteria, such as Faecalibacterium, Sutterella, and Oscillospira, which are known for producing anti-inflammatory metabolites like short-chain fatty acids (SCFAs).

• Pathogen Enrichment: Conversely, potential pathogens like Veillonella, Streptococcus, Klebsiella, and Enterobacteriaceae are often increased.

Furthermore, specific microbial signatures correlate with disease severity. For instance, advanced liver fibrosis is associated with higher levels of Weissella, and patients with more severe liver dysfunction show an increase in Streptococcus and a decrease in beneficial Lachnospira. The gut microbiome is also dynamic; UDCA treatment can partially restore a healthier microbial profile, and distinct baseline microbiota (e.g., low Clostridia abundance) are linked to poor UDCA response.

Pathogenic mechanisms linking gut dysbiosis to PBC

The gut microbiota contributes to PBC pathogenesis through several interconnected mechanisms:

1. Immune Dysregulation and Molecular Mimicry: A hallmark of PBC is the presence of anti-mitochondrial antibodies (AMA) that target the pyruvate dehydrogenase complex (PDC-E2). Bacteria from the Enterobacteriaceae order (e.g., Escherichia coli) possess enzymes structurally similar to human PDC-E2. This “molecular mimicry” is hypothesized to trigger a cross-reactive autoimmune response, breaking tolerance and initiating bile duct injury. Additionally, the reduction in SCFA-producing bacteria diminishes the availability of these critical immunomodulatory metabolites, which normally help suppress inflammation and maintain immune homeostasis.

2. Intestinal Barrier Disruption: Dysbiosis can compromise the integrity of the intestinal wall. Enrichment of bacteria with “invasion of epithelial cells” pathways and a shift in microbial metabolism from anaerobic to aerobic respiration are indicators of a damaged gut barrier. This increased permeability allows bacterial products and pro-inflammatory molecules to translocate to the liver via the portal vein, exacerbating local inflammation and injury.

3. Bile Acid (BA) Metabolic Dysregulation: The gut microbiota plays a vital role in the enterohepatic circulation of BAs by converting primary BAs into secondary BAs. In PBC, dysbiosis disrupts this process, leading to a deficiency in secondary BAs and an accumulation of toxic, hydrophobic primary BAs. This imbalance not only directly damages cholangiocytes but also impairs the Farnesoid X receptor (FXR) signaling pathway, which is crucial for feedback inhibition of BA synthesis, thereby worsening cholestasis.

Gut microbiome as a clinical tool

The gut microbiota holds immense promise as a non-invasive biomarker for PBC. Specific microbial profiles can aid in diagnosis, stratify patients based on prognosis (e.g., anti-gp210 positive patients have distinct microbiota), and predict response to UDCA therapy. Integrating microbiome data with metabolomic profiles could lead to powerful models for personalized management, allowing clinicians to identify high-risk patients early and adjust treatment strategies accordingly.

The recognition of the gut-liver axis in PBC has opened new avenues for treatment:

• Probiotics and Metabolites: Supplementation with probiotics like Lactobacillus or direct administration of protective metabolites like butyrate has shown promise in animal models by reducing liver injury and inflammation.

• Fecal Microbiota Transplantation (FMT): While not yet tested in human PBC trials, FMT from healthy donors could theoretically restore a healthy microbial ecosystem, as evidence from mouse models shows that transferring PBC patient microbiota can induce disease-like features.

• Bacteriophage Therapy: This approach uses viruses that specifically target and lyse pathogenic bacteria (e.g., Klebsiella) without disrupting the commensal flora. Although nascent, its success in other liver diseases makes it a compelling future strategy.

• Synergy with Existing Drugs: UDCA itself modulates the gut microbiota. Future therapies may involve combining UDCA or second-line agents (like FXR agonists) with targeted microbiome interventions to enhance efficacy, especially in non-responders.

Gut microbiota dysbiosis is a pivotal factor in the pathogenesis of Primary Biliary Cholangitis, contributing to the disease through immune activation, barrier dysfunction, and disrupted bile acid metabolism. The analysis of gut microbial profiles offers a valuable, non-invasive means for diagnosis, prognosis, and predicting treatment response. Looking forward, therapeutic strategies aimed at restoring a healthy gut microbiome—whether through probiotics, FMT, bacteriophages, or adjunctive therapies—represent a highly promising frontier for improving outcomes for patients with PBC.