Lactarius hatsudake Tanaka Polysaccharides Inhibit Hepatocellular Carcinoma by Modulating the Gut Microbiota and Its Metabolites

We previously reported that Lactarius hatsudake Tanaka polysaccharide (LHP) can inhibit hepatocellular carcinoma, but the mechanism remains unclear especially gut microbe-mediated antitumor immunity. This research found that LHP and fecal microbiota transplantation were associated with reduced tumor growth. The ratio of CD8+/CD4+ T cells and levels of interferon-γ were increased following LHP intervention in the tumor, spleen, and blood. Additionally, in vivo and in vitro microbiome analyses indicated that LHP treatment significantly increased beneficial bacteria such as Bifidobacterium animalis while reducing Lactobacillus murinus. Furthermore, metabolomic analyses suggested that LHP may be metabolized into propionate via the succinate pathway, accompanied by changes in the microbial composition, which significantly inhibit the arginine and tryptophan metabolic pathways. These microbial and metabolite changes paralleled improvements in the tumor immune microenvironment and coincided with attenuated hepatocellular carcinoma progression. These findings suggest that LHP-induced gut microbiota remodeling is associated with antitumor immune modulation.