Type 2 diabetes (T2DM) clinically exhibits a higher incidence of hepatocellular carcinoma (HCC), contributing to a lousy prognosis in patients harboring both diseases. Microflora-based therapy draws attention with low side effects. Accumulating evidence shows thatLactobacillus breviscan improve blood glucose and body weight of the T2DM mice model and reduce several cancer incidences. However, the therapeutic effect ofLactobacillus brevisin affecting the prognosis of T2DM+HCC remains unknown. In this study, we aim to explore this questionviaan established T2DM+HCC mice model. We observed a significant alleviation after the probiotic intervention.Lactobacillus brevisimproves blood glucose and insulin resistance and ameliorates Mechanically. Combined with a multi-omics approach including 16SrDNA, GC-MS, and RNA-seq, we identified distinct intestinal microflora composition and metabolites afterLactobacillus brevisintervention. Furthermore, we found thatLactobacillus brevisdelayed disease progression by regulating MMP9 and NOTCH 1 signaling pathways, potentially through gut microflora and BA interaction. This study indicates thatLactobacillus brevismay improve the prognosis of T2DM + HCC, providing novel therapeutic opportunitiesviatargeting intestinal flora for patients with T2DM+HCC.