Parvimonas micra-derived SirTM: An ADP-ribosyltransferase as a novel driver in colorectal cancer progression.

[INTRODUCTION] Gut microbiota is a key player in colorectal cancer (CRC) proliferation. Parvimonas micra (P. micra), an obligate anaerobic bacterium that colonizes the oral cavity and gastrointestinal tract, has been implicated in CRC development. However, its virulence factors and pathogenic mechanisms remain poorly understood.

[OBJECTIVES] We aimed to explore the strain-level differences of P. micra in promoting the development of CRC, and the role of the virulence factor SirTM in pathogenic mechanisms.

[METHODS] Utilizing an optimized culturomics approach, we isolated 99 strains of P. micra from the mucosal surfaces of CRC tissues. Through APC mouse model experiments and whole genome sequencing of the strains, the role of virulence factors in promoting CRC development was explored. Protein mass spectrometry, transcriptome sequencing, and CUT&Tag combined analysis were used to investigate the pathogenic mechanism of virulence factors in P. micra.

[RESULTS] We isolated 99 strains of P. micra from the mucosal surfaces of CRC tissues post-surgery, revealing strain-level variations in CRC promotion through whole genomics analysis and experiments. We identified SirTM of P. micra, a potential virulence factor possessing ADP-ribosyltransferase activity, which was experimentally validated to drive CRC progression. Further investigation determined that SirTM targets histone H2B, and their interaction facilitates CRC development via the CEBPβ/SAA1/IL-17C signaling pathway. Moreover, SirTM was evaluated as a potential biomarker target, and SAA1 as a potential therapeutic target in clinical CRC samples.

[CONCLUSION] P. micra can enter CRC cells to release SirTM and modify H2B with ADP-ribosylation, thereby promoting the development of CRC through the CEBPβ/SAA1/IL-17C pathway.