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

Abstract

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.

Keywords

carcinogenesis / colorectal cancer / DNA damage / metabolomics / microbiota

References

[1] Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025; 75(1): 10-45.

[2] Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022; 12(1): 31-46.

[3] Cullin N, Azevedo Antunes C, Straussman R, Stein-Thoeringer CK, Elinav E. Microbiome and cancer. Cancer Cell. 2021; 39(10): 1317-1341.

[4] Jiang SS, Chen YX, Fang JY. Fusobacterium nucleatum: ecology, pathogenesis and clinical implications. Nat Rev Microbiol. 2026;24:197-214.

[5] Lee SM, Donaldson GP, Mikulski Z, Boyajian S, Ley K, Mazmanian SK. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature. 2013; 501(7467): 426-429.

[6] Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, et al. Mutational signature in colorectal cancer caused by genotoxic pks(+) E. coli. Nature. 2020; 580(7802): 269-273.

[7] He Z, Yu J, Gong J, et al. Campylobacter jejuni-derived cytolethal distending toxin promotes colorectal cancer metastasis. Cell Host Microbe. 2024; 32(12): 2080-2091.e6.

[8] Long X, Wong CC, Tong L, et al. Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity. Nat Microbiol. 2019; 4(12): 2319-2330.

[9] Wang X, Jia Y, Wen L, et al. Porphyromonas gingivalis promotes colorectal carcinoma by activating the hematopoietic NLRP3 inflammasome. Cancer Res. 2021; 81(10): 2745-2759.

[10] Liu Y, Wong CC, Ding Y, et al. Peptostreptococcus anaerobius mediates anti-PD1 therapy resistance and exacerbates colorectal cancer via myeloid-derived suppressor cells in mice. Nat Microbiol. 2024; 9(6): 1467-1482.

[11] Piccinno G, Thompson KN, Manghi P, et al. Pooled analysis of 3,741 stool metagenomes from 18 cohorts for cross-stage and strain-level reproducible microbial biomarkers of colorectal cancer. Nat Med. 2025; 31(7): 2416-2429.

[12] Okumura S, Konishi Y, Narukawa M, et al. Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion. Nat Commun. 2021; 12(1): 5674.

[13] Cui W, Guo M, Liu D, et al. Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition. Nat Cell Biol. 2024; 26(1): 124-137.

[14] Liu C, Lai P, Hu J, et al. Lactobacillus johnsonii synthesizes chenodeoxycholic acid to reduce susceptibility to high-fat diet-induced colorectal cancer. Cancer Res. 2025; 85(23): 4600-4615.

[15] Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15): 2114-2120.

[16] Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4): 357-359.

[17] Franzosa EA, McIver LJ, Rahnavard G, et al. Species-level functional profiling of metagenomes and metatranscriptomes. Nat Methods. 2018; 15(11): 962-968.

[18] Wood DE, Lu J, Langmead B. Improved metagenomic analysis with Kraken 2. Genome Biol. 2019; 20(1): 257.

[19] Wu J, Zeng W, Xie H, et al. Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease. Cell Host Microbe. 2024; 32(11): 1927-1943.e9.

[20] Cheng Q, Hou M, Li M, et al. Effects of sour soup on silage fermentation performance and bacterial community of Broussonetia papyrifera. BMC Microbiol. 2025; 25(1): 761.

[21] Feng Q, Liang S, Jia H, et al. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat Commun. 2015; 6: 6528.

[22] Gupta A, Dhakan DB, Maji A, et al. Association of Flavonifractor plautii, a flavonoid-degrading bacterium, with the gut microbiome of colorectal cancer patients in India. mSystems. 2019; 4(6):e00438-19.

[23] Thomas AM, Manghi P, Asnicar F, et al. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat Med. 2019; 25(4): 667-678.

[24] Wirbel J, Pyl PT, Kartal E, et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat Med. 2019; 25(4): 679-689.

[25] Yachida S, Mizutani S, Shiroma H, et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nat Med. 2019; 25(6): 968-976.

[26] Yu J, Feng Q, Wong SH, et al. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut. 2017; 66(1): 70-78.

[27] Zeller G, Tap J, Voigt AY, et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol. 2014; 10(11): 766.

[28] Coker OO, Liu C, Wu WKK, et al. Altered gut metabolites and microbiota interactions are implicated in colorectal carcinogenesis and can be non-invasive diagnostic biomarkers. Microbiome. 2022; 10(1): 35.

[29] He Z, Gharaibeh RZ, Newsome RC, et al. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut. 2019; 68(2): 289-300.

[30] Hu J, Chen J, Xu X, Hou Q, Ren J, Yan X. Gut microbiota-derived 3-phenylpropionic acid promotes intestinal epithelial barrier function via AhR signaling. Microbiome. 2023; 11(1): 102.

[31] Neilands J, Davies JR, Bikker FJ, Svensäter G. Parvimonas micra stimulates expression of gingipains from Porphyromonas gingivalis in multi-species communities. Anaerobe. 2019; 55: 54-60.

[32] Qi H, Gao H, Li M, et al. Parvimonas micra promotes oral squamous cell carcinoma metastasis through TmpC‒CKAP4 axis. Nat Commun. 2025; 16(1): 2305.

[33] Bergsten E, Mestivier D, Donnadieu F, et al. Parvimonas micra, an oral pathobiont associated with colorectal cancer, epigenetically reprograms human colonocytes. Gut Microbes. 2023; 15(2):2265138.

[34] Chang Y, Huang Z, Hou F, et al. Parvimonas micra activates the Ras/ERK/c-Fos pathway by upregulating miR-218-5p to promote colorectal cancer progression. J Exp Clin Cancer Res. 2023; 42(1): 13.

[35] Liu J, Geng W, Sun H, et al. Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma. Gut. 2022; 71(6): 1203-1213.

[36] Laursen MF, Sakanaka M, von Burg N, et al. Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut. Nat Microbiol. 2021; 6(11): 1367-1382.

[37] Jiang YH, Ying JP, Xin WG, LY Yang, Li XZ, Zhang QL. Antibacterial activity and action target of phenyllactic acid against Staphylococcus aureus and its application in skim milk and cheese. J Dairy Sci. 2022; 105(12): 9463-9475.

[38] Liang X, Weng J, You Z, et al. Oxidative stress in cancer: from tumor and microenvironment remodeling to therapeutic frontiers. Mol Cancer. 2025; 24(1): 219.

[39] Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 2006; 6(12): 947-960.

RIGHTS & PERMISSIONS

2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.