Huang-Lian-Jie-Du decoction enhances Capecitabine-Oxaliplatin efficacy via Akkermansia muciniphila and CD8+ T cells in colorectal cancer.

BACKGROUND: The Capecitabine plus Oxaliplatin (XELOX) regimen is a first-line chemotherapy for colorectal cancer (CRC), but drug resistance remains a major therapeutic challenge. Our clinical observations suggest a positive correlation between fecal Akkermansia muciniphila bundance and chemotherapy responsiveness. Huang-Lian-Jie-Du Decoction (HLJDD), a traditional Chinese medicine with gut microbiota-modulating properties, may serve as a chemosensitizer, though its mechanisms are unclear.

PURPOSE: This study aimed to evaluate whether HLJDD enhances XELOX efficacy in CRC and to elucidate the role of gut microbiota, particularly A. muciniphila, in this synergistic effect.

METHODS: CRC patients receiving XELOX were analyzed for fecal A. muciniphila levels and treatment response. In MC38 and CT26 tumor-bearing mice, HLJDD was administered alone or combined with XELOX. Gut microbiota composition (16S rRNA sequencing), serum metabolites (untargeted metabolomics), and tumor immune infiltration (immunohistochemistry) were assessed. Co-housing experiments and direct A. muciniphila supplementation were conducted to validate microbiota-mediated mechanisms.

RESULTS: Higher baseline A. muciniphila abundance correlated with improved XELOX response in CRC patients. HLJDD selectively promoted A. muciniphila proliferation in vitro and in vivo. In murine models, HLJDD synergized with XELOX, significantly suppressing tumor growth vs. XELOX alone. Multi-omics analyses revealed HLJDD-driven enrichment of tryptophan metabolism and increased 5-hydroxytryptophan levels, accompanied by enhanced CD8+ T cell infiltration and interferon-γ upregulation in tumors. Cohousing with HLJDD-treated mice or direct A. muciniphila gavage recapitulated the chemosensitizing effects, confirming gut microbiota's pivotal role.

CONCLUSION: This study unveils a novel and multi-faceted therapeutic strategy: HLJDD overcomes XELOX resistance by specifically remodeling gut microbiota to expand A. muciniphila, which subsequently activates tryptophan metabolism and anti-tumor immunity. Our findings provide robust preclinical evidence for combining HLJDD with XELOX as a promising innovative approach to overcome CRC chemoresistance, with A. muciniphila serving as a predictive biomarker and potential therapeutic target.