Enterococcus faecalis-Induced Bystander Effect Drives Histone Acetylation Leading to Epithelial-Mesenchymal Transition via TGF-β Signaling

ABSTRACT: Objective: Enterococcus faecalis has been implicated in the development of colorectal cancer (CRC) in murine models through the microbiota-induced bystander effect (MIBE). This study aimed to investigate whether this commensal bacterium induces epigenetic alterations via MIBE. Methods: Murine macrophage RAW264.7 cells were treated with either superoxide-producing E. faecalis OG1RF or superoxide-deficient WY84. Conditioned medium (CM) was then collected and used to treat IEC-6 rat intestinal epithelial cells. Histone acetylation states and related signaling pathways were analyzed using immunoblotting, immunofluorescent staining, and chromatin immunoprecipitation sequencing (ChIP-seq). Results: CM derived from E. faecalis-infected macrophages significantly induced histone H3 acetylation at lysine 27 and 9 (H3K27ac/H3K9ac) in IEC-6 cells compared to controls. Furthermore, this CM inhibited histone deacetylases, which contributed to the increased in H3 acetylation. ChIP-seq analysis revealed widespread alterations in H3K27ac across the genome in cells treated with E. faecalis-infected macrophage-derived CM. Additionally, these changes were associated with aberrantly activated TGF-β signaling, leading to epithelial-mesenchymal transition (EMT). Targeted metabolomic analysis indicated that E. faecalis activated arachidonate lipoxygenase-12 (Alox12) in macrophages, resulting in the production of 12-hydroxyeicosatetraenoic acid (12-HETE), which induces H3 acetylation via the bystander effect (BSE). Conclusion: Infection with E. faecalis activates Alox12 in macrophages, leading to the production of 12-HETE that subsequently induces H3 acetylation through the BSE. This aberrant H3 acetylation alters gene expression associated with TGF-β signaling, promoting EMT. These findings elucidate the mechanisms by which commensal bacteria may initiate and promote CRC, potentially providing insights for the development of novel strategies for CRC prevention and treatment.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE281011 | GEO | 2026/03/25

REPOSITORIES: GEO