The anti-tumor effect of different F. prausnitzii strains were evaluated using classic azoxymethane plus dextran sulfate sodium (AOM/DSS) and Apcmin/+ colorectal tumorigenesis mouse models, which allowed us to identify the bioactive component in the potent F. prausnitzi. With the classic tumor coculture model, we found that F. prausnitzii extracts induced strongest anti-tumor effects comparing to F. prausnitzii lysate and the culture supernatant. We next confirmed that the bioactive component was protein in nature as demonstrated by its loss of activity upon protease digestion and further verified that it was enriched in the fraction with molecular weight greater than 30 kDa. Interestingly, different treatment approaches revealed that pre-treating MC38 tumor cells with F. prausnitzii extracts elicited the strongest anti-tumor response, compared to pre-treating splenocytes or direct coculture. Extracted protein was analyzed by mass spectrum (MS) and F. prausnitzii-originated PRPS was further identified.