Enterococcus faecalis-induced bystander effect causes epigenetic alterations leading to aberrant TGF-β signaling and epithelial-mesenchymal transition.
1/5 보강
[BACKGROUND] promotes colorectal cancer (CRC) in murine models through the microbiota-induced bystander effect (MIBE), but its potential to induce epigenetic changes remains unexplored.
APA
Xu L, Li T, et al. (2026). Enterococcus faecalis-induced bystander effect causes epigenetic alterations leading to aberrant TGF-β signaling and epithelial-mesenchymal transition.. Cell communication and signaling : CCS, 24(1). https://doi.org/10.1186/s12964-026-02735-0
MLA
Xu L, et al.. "Enterococcus faecalis-induced bystander effect causes epigenetic alterations leading to aberrant TGF-β signaling and epithelial-mesenchymal transition.." Cell communication and signaling : CCS, vol. 24, no. 1, 2026.
PMID
41680783
Abstract
[BACKGROUND] promotes colorectal cancer (CRC) in murine models through the microbiota-induced bystander effect (MIBE), but its potential to induce epigenetic changes remains unexplored. This study investigates how -infected macrophages induce epigenetic alterations contributing to CRC pathogenesis.
[METHODS] RAW264.7 macrophages were infected with OG1RF (superoxide-producing), WY84 (superoxide-deficient), or PBS. Conditioned media were collected and used to treat IEC-6 intestinal epithelial cells. Genome-wide H3 acetylation was assessed using chromatin immunoprecipitation sequencing (ChIP-seq). Western blotting and immunofluorescence staining were employed to investigate -induced histone H3 acetylation and associated signaling pathways. Furthermore, colonic organoid cultures and -colonized mouse models were utilized to validate the in vitro findings.
[RESULTS] Conditioned medium (CM) from -infected macrophages significantly increased histone H3 acetylation at lysines 27 and 9 (H3K27ac/H3K9ac) in IEC-6 intestinal epithelial cells and murine colonic organoids, with similar findings validated in vivo in -colonized mice. ChIP-seq revealed genome-wide alterations in H3K27ac in cells treated with CM from -infected macrophages, leading to activation of CRC-associated signaling pathways. Metabolomic analysis identified 12-hydroxyeicosatetraenoic acid (12-HETE), produced by -infected macrophages, as a mediator of bystander effect promoting H3 acetylation. Furthermore, CM from -infected macrophages and 12-HETE decreased E-cadherin and increased vimentin expression in IEC-6 cells, indicating epithelial-mesenchymal transition—a finding corroborated by reduced E-cadherin levels in intestinal biopsies from -colonized mice.
[CONCLUSION] Our results indicate that -infected macrophages produce 12-HETE, which promotes epigenetic alterations and induces EMT in intestinal epithelial cells via a bystander effect. These findings strengthen the link between gut microbiota and innate immunity in CRC development, highlighting potential targets for innovative prevention and therapeutic strategies.
[TRIAL REGISTRATION] Not applicable.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12964-026-02735-0.
[METHODS] RAW264.7 macrophages were infected with OG1RF (superoxide-producing), WY84 (superoxide-deficient), or PBS. Conditioned media were collected and used to treat IEC-6 intestinal epithelial cells. Genome-wide H3 acetylation was assessed using chromatin immunoprecipitation sequencing (ChIP-seq). Western blotting and immunofluorescence staining were employed to investigate -induced histone H3 acetylation and associated signaling pathways. Furthermore, colonic organoid cultures and -colonized mouse models were utilized to validate the in vitro findings.
[RESULTS] Conditioned medium (CM) from -infected macrophages significantly increased histone H3 acetylation at lysines 27 and 9 (H3K27ac/H3K9ac) in IEC-6 intestinal epithelial cells and murine colonic organoids, with similar findings validated in vivo in -colonized mice. ChIP-seq revealed genome-wide alterations in H3K27ac in cells treated with CM from -infected macrophages, leading to activation of CRC-associated signaling pathways. Metabolomic analysis identified 12-hydroxyeicosatetraenoic acid (12-HETE), produced by -infected macrophages, as a mediator of bystander effect promoting H3 acetylation. Furthermore, CM from -infected macrophages and 12-HETE decreased E-cadherin and increased vimentin expression in IEC-6 cells, indicating epithelial-mesenchymal transition—a finding corroborated by reduced E-cadherin levels in intestinal biopsies from -colonized mice.
[CONCLUSION] Our results indicate that -infected macrophages produce 12-HETE, which promotes epigenetic alterations and induces EMT in intestinal epithelial cells via a bystander effect. These findings strengthen the link between gut microbiota and innate immunity in CRC development, highlighting potential targets for innovative prevention and therapeutic strategies.
[TRIAL REGISTRATION] Not applicable.
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12964-026-02735-0.
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