Akkermansia muciniphila supports anti-PD-1 therapy in colorectal cancer: Butyrate-associated metabolic changes and...

Colorectal cancer (CRC) exhibits limited response to immune checkpoint blockade (ICB) therapy. Akkermansia muciniphila has been linked to immune regulation; however, whether its administration during anti-PD-1 treatment is associated with greater antitumor activity and related metabolic and immune changes in CRC remains unclear.

Azoxymethane/dextran sulfate sodium (AOM/DSS)-induced and subcutaneous models were established, with A. muciniphila gavage combined with anti-PD-1 treatment. Tumor growth, short-chain fatty acids (SCFAs), and ENO1 expression were detected. Clinical data of CRC patients receiving anti-PD-1 were analyzed.

A. muciniphila combined with anti-PD-1 alleviated weight loss, prolonged colon length, reduced colonic polyp number, and lowered histological scores. In the subcutaneous model, the anti-PD-1 plus A. muciniphila group showed reduced tumor growth, lower Ki-67/PCNA expression, and increased TUNEL-positive apoptotic cells compared with anti-PD-1 monotherapy. Intestinal acetate, propionate, and butyrate were elevated, with butyrate significantly correlating with all tumor-related indicators. In patients, responders had higher A. muciniphila abundance and butyrate concentration. Low ENO1 expression was associated with higher response rate and longer overall survival. Combined assessment of fecal A. muciniphila abundance and tumor ENO1 expression tended to separate responders from non-responders in exploratory clustering analysis.

The findings suggest that A. muciniphila administration during anti-PD-1 treatment is associated with greater antitumor activity than anti-PD-1 monotherapy. The experimental evidence supports a butyrate-associated ENO1 component contributing to tumor-cell metabolic and EMT-related changes, together with a distinct in vivo CD8⁺ T-cell immune component. These data do not establish formal synergy or a single uninterrupted causal pathway. Clinical associations require prospective validation in larger independent cohorts.