Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial...

Area of Science:

• Immunology
• Hepatology
• Microbiology

Background:

• Bacterial infection is increasingly implicated in the pathogenesis of primary biliary cirrhosis (PBC).
• Previous studies detected bacterial lipoteichoic acid at inflammatory sites in PBC livers and high antibody titers against streptococcal histone-like protein in PBC patients.
• The direct role of chronic bacterial exposure in triggering PBC-like pathology remains to be fully elucidated.

Purpose of the Study:

• To investigate whether chronic bacterial exposure can induce primary biliary cirrhosis (PBC)-like epithelial cell damage in normal mice.
• To determine if bacterial inoculation leads to the development of autoantibodies associated with PBC.
• To explore the potential involvement of bacteria in the pathogenesis of PBC and related multifocal epithelial inflammation.

Main Methods:

• BALB/c mice were repeatedly inoculated with various bacteria, including Streptococcus intermedius (S.i.), for 8 weeks.
• Liver and salivary gland samples were collected at 1 week and 3-20 months post-inoculation for histological analysis.
• Sera were analyzed for the presence of autoantibodies (anti-HuCCT1, anti-nuclear, anti-gp210, anti-mitochondrial) and antibodies against S.i. histone-like protein (S.i.-HLP).

Main Results:

• S.i. inoculation induced cellular infiltration around bile ducts in the liver (Group 1) and portal inflammation with periductal infiltrates in salivary glands (Group 2).
• Sera from S.i.-inoculated mice showed antibodies against HuCCT1 biliary epithelial cells, anti-nuclear, and anti-gp210 antibodies, but not anti-mitochondrial antibodies.
• Anti-S.i.-HLP antibodies were detected and shown to bind to synthetic gp210 peptide, indicating molecular mimicry.

Conclusions:

• Chronic bacterial exposure, particularly S.i., can trigger PBC-like cholangitis and multifocal epithelial inflammation in mice.
• The study demonstrates bacteria-induced autoantibody production, including against gp210, a known PBC autoantigen.
• These findings strongly suggest that bacteria play a significant role in the pathogenesis of primary biliary cirrhosis and associated inflammatory conditions.