Bifidobacterium bifidum-derived nanoparticles attenuate alcoholic liver disease via enhanced hepatic phagocytosis and gastrointestinal homeostasis.

Alcohol-associated liver disease (ALD) has limited therapeutic options due to its complex pathogenesis. This study demonstrates the ALD-protective effects of extracellular nanoparticles derived from Bifidobacterium bifidum (BNPs), focusing on the concept of gut microbiota-derived nanoparticles (GNPs) in disease pathogenesis. When isolated BNPs were administered in an ALD mouse model, they upregulated Vsig4 receptor expression in liver macrophages, improving phagocytic clearance of harmful GNPs that contained bacterial DNA. GNPs activated liver inflammation via the cGAS-STING pathway, exacerbating ALD and liver fibrosis in Vsig4-deficient mice. BNP treatment suppressed the inflammatory cascade, modulated macrophage polarization, and reduced hepatic steatosis and liver injury, while also restoring the balance of the gut microbiota and enhancing intestinal barrier function. These findings reveal the role of GNPs in ALD pathogenesis and present targeted microbial nanoparticle postbiotics as potential therapeutics for treatment of alcohol-associated and other liver diseases.