Alcohol and high-fat diet aggravate colitis-induced liver injury via glucocorticoid/IL-6-SAA1 axis in mice

Colitis-associated liver injury rarely causes acute mortality, but whether alcohol and a high-fat diet (HFD) aggravate hepatic injury during colitis remains unclear. Here, dextran sulfate sodium (DSS)-induced colitic mice were exposed to alcohol, HFD, or both. Compared with DSS alone, combined HFD and alcohol exposure (DSSHA) caused greater body-weight loss, poorer body condition, and reduced survival. These effects were linked mainly to liver rather than intestinal deterioration, as shown by an increased liver/body-weight ratio, elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and severe hepatic steatosis, whereas colon length, colon weight, and intestinal histological injury were not further aggravated. Mechanistically, alcohol-HFD co-exposure impaired the gut-liver axis, reduced intestinal tight-junction proteins, increased gut permeability and circulating lipopolysaccharide (LPS), and promoted hepatic macrophage and neutrophil infiltration with increased interleukin-6 (IL-6). Transcriptomics identified serum amyloid A1 (SAA1) as a highly upregulated acute-phase gene and revealed Toll-like receptor 4 (TLR4) pathway enrichment. TLR4 inhibition TAK-242 significantly improved survival and attenuated liver injury. Multi-omics further showed increased hepatic cortisol and corticosterone, which cooperated with IL-6 to induce SAA1 expression in HepG2 cells. Thus, an IL-6/glucocorticoid-SAA1-TLR4 axis drives alcohol-HFD-aggravated liver injury in colitis and may represent a therapeutic target.