Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, necessitating the development of novel therapeutic strategies. Poria cocos polysaccharides (PCP), bioactive components of the traditional medicinal fungus Poria cocos, exhibit significant anticancer potential. This study investigates the protective effects of PCP against azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC in mice, with a focus on its impact on intestinal microbiota composition, intestinal barrier integrity, and inflammatory responses. PCP treatment significantly reduced tumor incidence, tumor size, and tumor burden while improving histopathological features and inhibiting Ki67-positive cell proliferation. Mechanistically, PCP enhanced intestinal barrier function by restoring tight junction proteins (E-cadherin, ZO-1, Claudin-3) and mucin secretion (MUC2), thereby reducing intestinal permeability and systemic lipopolysaccharide (LPS) levels. Furthermore, PCP exhibited potent anti-inflammatory effects by downregulating pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and upregulating the anti-inflammatory cytokine IL-10. 16S rRNA sequencing results revealed that PCP modulated the intestinal microbiota, decreasing pathogenic bacteria such as Helicobacter and Eisenbergiella while promoting beneficial taxa including Limosilactobacillus, Paraprevotella, and Muribaculum. Fecal microbiota transplantation (FMT) further confirmed the microbiota-mediated protective effects of PCP, as FMT from PCP-treated donors significantly suppressed tumorigenesis, restored intestinal barrier integrity, and alleviated inflammation in CRC mice. Additionally, PCP demonstrated a favorable safety profile, with no adverse effects on major organs. These findings highlight PCP as promising natural agents for CRC prevention and therapy, acting through modulation of the intestinal microbiota, enhancement of intestinal barrier function, and suppression of inflammation.
