Atractylodes macrocephala polysaccharide (PAMK) inhibits colorectal tumor growth via gut microbiota-spleen immune axis

Colorectal cancer (CRC) is a prevalent global malignancy, with advanced stages often entangled in a gut microbiota-metabolism-immunity vicious cycle that demands early intervention. Current therapeutic strategies frequently face challenges in fully restoring immune balance or addressing the complex interplay between the gut microbiome and systemic immunity. Investigating natural compounds that can modulate this intricate axis offers a promising avenue for novel CRC immunotherapies, particularly those that can act as immune adjuvants to enhance host defenses against tumor progression.

Researchers investigated the anti-CRC effects of Atractylodes macrocephala polysaccharide (PAMK) in CT26 tumor-bearing mice. The study explored PAMK's impact on tumor growth and overall quality of life. To dissect the role of the gut microbiota, a cohort of mice underwent antibiotic-induced microbiota depletion (AIMD). The therapeutic effects of PAMK were then re-evaluated in these AIMD mice. Furthermore, fecal microbiota transplantation (FMT) was performed to determine if the microbiota-dependent effects of PAMK could be restored. Multi-omics analyses, including transcriptomics and qPCR, were employed to assess metabolic, circadian, and immune pathway modulation in the spleen.

PAMK significantly inhibited tumor growth and improved the quality of life in CT26 tumor-bearing mice by enhancing antitumor immunity. This immune enhancement included increased NK cell infiltration and NKG2D expression, elevated CD4⁺:CD8⁺ ratios, and higher serum IFN-γ levels. Crucially, PAMK's therapeutic benefits were completely absent in antibiotic-induced microbiota depletion (AIMD) mice, highlighting the essential role of the gut microbiome. PAMK effectively alleviated tumor-induced gut microbiota dysbiosis, characterized by an enriched g_Alistipes, and remodeled both fatty acid and steroid metabolism. This metabolic shift was strongly associated with the observed enhanced antitumor immunity, suggesting a potent microbiota-metabolism-immunity axis.

Following fecal microbiota transplantation (FMT), the therapeutic effects of PAMK were largely restored, confirming the gut microbiota's critical role in its anti-tumor action. Integrative multi-omics analysis further revealed that PAMK modulated multiple metabolic, circadian, and immune pathways in the spleen. The study concluded that a synergistic gut microbiota-metabolite-spleen gene axis mediates PAMK's anti-CRC effects.