Veillonella dispar triggers dual-hits in the pathogenesis of autoimmune hepatitis and primary biliary cholangitis via testosterone depletion-BAFF-B cell axis and Th17 cell activation

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) often appear as overlapping conditions, sharing sexual dimorphism and increased Veillonella dispar (V. dispar) levels. Researchers sought to understand how V. dispar contributes to the distinct pathologies of AIH and PBC. Using clean-grade and germ-free mice, they induced AIH and PBC by introducing V. dispar orally or via injection of liver antigens. Single-cell analysis, metabolomics, microscopy, and flow cytometry were used to decipher the mechanisms.

V. dispar caused liver inflammation by reducing systemic arginine levels, leading to apoptosis of gonadal stromal cells and decreased testosterone. Lower testosterone weakened its inhibitory effect on BAFF secretion, amplifying B cell-mediated responses. In the presence of S100 or PDC-E2, V. dispar also triggered Th17 cell activation, dictating the specific pathology of AIH or PBC.

Clinical data showed both AIH and PBC patients had higher V. dispar abundance and lower arginine and testosterone levels. Elevated serum BAFF and IL-17 were also noted.

The study concludes that V. dispar drives AIH and PBC pathogenesis through reduced testosterone and increased BAFF, expanding B cells in the liver. The presence of S100 and PDC-E2 further matures these B cells and activates Th17 cells, determining whether the condition is AIH or PBC.