Parvimonas micra promotes carcinogenesis of colorectal cancer through phenyllactic acid-induced DNA damage

Recent studies have demonstrated the significance of gut microbiota in the colorectal cancer (CRC) pathogenesis. But their role in carcinogenesis remains to be established. Thus, we established a clinical cohort and the faecal samples from CRC and healthy control were collected. Our metagenomic analysis found that the presence of Parvimonas micra exhibited the most significant relationship with the occurrence of CRC. Increased colonisation of P. micra in CRC was validated with analysis of 1379 faecal metagenomes from eight public cohorts. Untargeted metabolomics subsequently identified an accumulation of phenyllactic acid (PLA) in faecal samples from CRC patients. Higher concentration of PLA was detected in the supernatant from our isolated P. micra. Whole-genome sequencing confirmed that a series of genes associated with PLA biosynthesis such as pdhD were observed in the P. micra genome. Importantly, both P. micra and PLA-induced carcinogenesis in Apc^Min/+ and azoxymethane/dextran sulphate sodium salt mice model. The roles of P. micra and PLA in CRC development were associated with DNA damage. Engineered Escherichia coli BL21 that encoded the heterologous pdhD from P. micra could also induce DNA damage. Mechanically, PLA-induced DNA damage and CRC carcinogenesis were significantly alleviated in Ahr^-/- mice. Aryl hydrocarbon receptor (AHR) inhibitor exhibited a therapeutic potential to reduce mice carcinogenesis. These findings established the role of P. micra and its metabolite, therefore providing diagnostic and therapeutic targets for treating CRC.