Butyrate ameliorates acute‐on‐chronic liver failure by regulating macrophage polarization

ABSTRACT Gut microbiota dysbiosis and its metabolite disorders may drive the progression of hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) through the gut–liver axis, but the specific mechanisms and intervention targets remain unclear. Blood and stool samples were collected from 50 patients with liver disease at different stages and subjected to metagenomic, metabolomic, and transcriptomic sequencing to elucidate the microbiota–metabolism–immune characteristics of HBV‐ACLF. We evaluated changes in gut microbiota composition, short‐chain fatty acids, intestinal barrier integrity, liver injury, and immune cell function following fecal microbiota transplantation or butyrate supplementation, and explored specific regulatory mechanisms in ACLF mouse models and RAW264.7 cells. HBV‐ACLF was associated with loss of beneficial gut microbes, reduced butyrate, a weakened intestinal barrier, and increased leakage of bacterial components into the bloodstream, which further exacerbated liver inflammation. Butyrate strengthened the intestinal barrier, reduced lipopolysaccharide leakage, and suppressed M1 macrophage polarization, further improving ACLF disease progression. Mechanistic analysis revealed that butyrate inhibited the phosphorylation of the mitogen‐activated protein kinase signaling pathway within macrophages, thereby suppressing their polarization towards the pro‐inflammatory M1 phenotype. These findings support a chain linking gut microbes, short‐chain fatty acids, and immune dysregulation in ACLF, and highlight butyrate‐based modulation as a potential therapeutic strategy for ACLF.