Colitis Ameliorates Murine Autoimmune Cholangitis Through Polarization of M2 Macrophages and Inhibition of CD8⁺...

Primary biliary cholangitis (PBC) is a form of chronic autoimmune cholangitis of enigmatic etiology and pathogenesis. While numerous studies indicate an association between inflammatory bowel disease (IBD) and PBC, the bidirectional impact on disease progression remains unclear. This study investigated the role of colitis in PBC progression using a mouse model of IBD-PBC.

Acute experimental colitis was induced using dextran sodium sulfate in transgenic mice with PBC to establish an IBD-PBC model. Colon and liver tissues were analyzed by histopathology, flow cytometry, and immunostaining. Inflammatory mediators and metabolomic changes were further evaluated using quantitative real-time polymerase chain reaction and untargeted metabolomics.

We found that acute experimental colitis exacerbated colonic injury in PBC mice but concurrently attenuated hepatic inflammation. This hepatic effect was characterized by reduced liver-infiltrating lymphocytes (particularly CD8⁺ T-cells) and reduced levels of key inflammatory mediators, including interleukin-1 beta, tumor necrosis factor alpha, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10. Further analysis revealed colitis triggered a qualitative shift in hepatic macrophage polarization from the pro-inflammatory M1 phenotype towards the anti-inflammatory M2 phenotype, without altering total macrophage numbers. Untargeted metabolomics identified several metabolites linked to immune regulation, including oxopalmitoylcarnitine, linoleoylcarnitine, and 3-hydroxydecanoic acid.

Collectively, these findings suggest that experimental acute colitis may promote hepatic M2 macrophage polarization in mice with PBC, potentially through modulation of specific metabolites, thereby inhibiting CD8⁺ T-cells and alleviating cholangitis. This study provides novel insights into the complex connection between IBD and PBC and offers a compelling rationale for future clinical research into multi-organ treatment strategies for PBC.