Akkermansia muciniphila administration during anti-PD-1 treatment is associated with greater antitumor activity than anti-PD-1 monotherapy, with experimental evidence supporting 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.
Key Findings
Results
A. muciniphila combined with anti-PD-1 treatment alleviated colitis-associated tumor burden in the AOM/DSS mouse model compared to anti-PD-1 monotherapy.
The combination treatment alleviated weight loss and prolonged colon length in AOM/DSS-induced colorectal cancer mice.
Reduced colonic polyp number was observed in the combination group.
Histological scores were lower in the A. muciniphila plus anti-PD-1 group compared to anti-PD-1 alone.
A. muciniphila was administered via gavage concurrent with anti-PD-1 treatment in the experimental models.
Results
In the subcutaneous tumor model, the anti-PD-1 plus A. muciniphila group showed reduced tumor growth and increased apoptosis compared with anti-PD-1 monotherapy.
The combination group exhibited lower Ki-67 and PCNA expression, indicating reduced tumor cell proliferation.
Increased TUNEL-positive apoptotic cells were found in the combination group relative to anti-PD-1 monotherapy.
A subcutaneous tumor model was used alongside the AOM/DSS-induced model to assess antitumor effects.
Results
Intestinal short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, were elevated with A. muciniphila treatment, with butyrate significantly correlating with all tumor-related indicators.
Acetate, propionate, and butyrate levels were all elevated in the A. muciniphila-treated groups.
Butyrate showed the strongest and most significant correlation with all measured tumor-related indicators among the SCFAs.
The findings support a butyrate-associated component contributing to tumor-cell metabolic and EMT-related changes.
Results
In clinical CRC patients receiving anti-PD-1 therapy, responders had higher A. muciniphila abundance and butyrate concentration compared to non-responders.
Analysis of clinical data from CRC patients receiving anti-PD-1 therapy was performed.
Responders demonstrated higher fecal A. muciniphila abundance than non-responders.
Responders also had higher fecal butyrate concentrations than non-responders.
These clinical associations require prospective validation in larger independent cohorts.
Results
Low tumor ENO1 expression was associated with higher anti-PD-1 response rate and longer overall survival in CRC patients.
ENO1 expression in tumor tissue was assessed in clinical CRC patients receiving anti-PD-1 therapy.
Patients with low ENO1 expression had a higher response rate to anti-PD-1 treatment.
Patients with low ENO1 expression also had longer overall survival.
ENO1 is implicated in a butyrate-associated metabolic and EMT-related pathway in tumor cells.
Results
Combined assessment of fecal A. muciniphila abundance and tumor ENO1 expression tended to separate responders from non-responders in exploratory clustering analysis.
An exploratory clustering analysis was performed integrating both biomarkers.
The combined biomarker approach showed a tendency to discriminate anti-PD-1 responders from non-responders.
The authors describe this as an exploratory finding, and formal validation in larger prospective cohorts is noted as required.
This represents a potential composite biomarker strategy for patient stratification.
Results
The experimental evidence supports a distinct in vivo CD8+ T-cell immune component associated with A. muciniphila and anti-PD-1 combination treatment.
CD8+ T-cell responses were identified as a component of the antitumor immune activity in the experimental models.
The CD8+ T-cell component is described as distinct from the butyrate-associated ENO1 metabolic component.
The authors note that 'these data do not establish formal synergy or a single uninterrupted causal pathway' between these components.
What This Means
This research suggests that a gut bacterium called Akkermansia muciniphila, when given alongside immune checkpoint therapy (specifically anti-PD-1 treatment), may improve treatment outcomes in colorectal cancer. In mouse models of colorectal cancer, combining A. muciniphila with anti-PD-1 therapy reduced tumor growth, decreased markers of cancer cell proliferation, and increased cancer cell death compared to anti-PD-1 therapy alone. The study also found that this bacterium was linked to higher levels of short-chain fatty acids in the gut—particularly butyrate—which correlated with better tumor control and appears to influence how tumor cells behave metabolically and whether they spread (a process called EMT). A protein called ENO1 appears to play a role in this pathway, and tumors with lower ENO1 expression responded better to treatment.
In colorectal cancer patients receiving anti-PD-1 therapy, those who responded to treatment had higher amounts of A. muciniphila and butyrate in their stool, and lower ENO1 expression in their tumors was linked to better response rates and longer survival. An exploratory analysis suggested that looking at both A. muciniphila levels and tumor ENO1 expression together might help identify which patients are more likely to respond to immunotherapy.
This research suggests that the gut microbiome—specifically A. muciniphila—may play an important role in how well colorectal cancer patients respond to immunotherapy, potentially through butyrate production and effects on immune cells (particularly CD8+ T cells that attack tumors). However, the authors caution that the clinical findings are preliminary associations that need to be confirmed in larger prospective studies, and that the data do not prove a single direct cause-and-effect chain between these biological components.
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Cheng Z, Xu M, Yan W, Li H, Zhang C, Wang X. (2026). Akkermansia muciniphila supports anti-PD-1 therapy in colorectal cancer: Butyrate-associated metabolic changes and CD8⁺ T-cell responses.. Pathology, research and practice. https://doi.org/10.1016/j.prp.2026.156667