Lactic acid enhances cadmium to promote the progression of hepatocellular carcinoma

High dietary intake of environmental cadmium (Cd) has been associated with increased risk of gastrointestinal cancer, although the mechanisms by which Cd affects cancer susceptibility remain to be determined. Here, we demonstrate lactic acid enhances the ability of Cd exposure to promote the initiation and progression of hepatocellular carcinoma (HCC). The tumor-promoting effect of long-term Cd exposure in hepatoma H22-bearing mice was abolished by depletion of the gut microbiome using oral antibiotics, which also elevated the tumor Zn/Cd ratio. Moreover, administration of lactic acid enhanced the ability of Cd to increase the severity of the histological features of fibrosis, shifted gut microbiota composition leading to combined deficiency of beneficial bacteria, and altered liver mRNA expression profiles in diethylnitrosamine (DEN)-treated rats at 10 weeks, which accelerated the development of HCC and led to a lower Zn/Cd ratio at 30 weeks. Notably, fecal transfer from HCC rats administered lactic acid and Cd to healthy rats was sufficient to transmit the deleterious effects of Cd exposure. Moreover, administration of lactic acid enhanced enterohepatic recycling of Cd. Collectively, lactic acid enhances the ability of Cd to accelerate the initiation and progression of HCC by altering the liver Zn/Cd ratio and gut microbiome.