Pharmabiotics, Phocaeicola dorei, ameliorates cholestatic liver fibrosis by alleviating macrophage efferocytosis of neutrophils

Phocaeicola dorei has been reported to ameliorate metabolic diseases. Its role in liver fibrosis remains unclear. We evaluated the hepatoprotective effect of P. dorei in liver fibrosis. Fecal samples were collected from healthy controls and patients (n = 285) to assess the clinical relevance of P. dorei. In male mice models (3,5-diethoxycarbonyl-1.4-dihydrocollidine [DDC] diet), P. dorei (109 CFU/g twice/week) was orally administered. Primary HSCs, LX-2, THP-1, and HL-60 cell lines were used for mechanical validation. The relative abundance of P. dorei increased with worsing liver disease in human. P. dorei administration significantly reduced neutrophil degranulation and efferocytosis pathways (Ly6g and F4/80). The dysregulated expression of neutrophil-associated chemokines (Cx3cl1 and Cx3cr1) was restored by P. dorei. P. dorei culture supernatant inhibited macrophage-mediated efferocytosis. P. dorei attenuates liver fibrosis by suppressing neutrophil and macrophage infiltration and disrupting efferocytosis. Our results identify P. dorei as a potential microbiome-based therapeutic candidate for cholestatic liver fibrosis. This study reveals that the gut bacterium Phocaeicola dorei reduces liver fibrosis by regulating immune cell clearance of neutrophils.