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<p>Deoxycholic acid (DCA), a microbial-derived secondary bile acid, plays a multifunctional role in gastrointestinal (GI) carcinogenic through various molecular and cellular mechanisms. Mechanistically, DCA causes disruption of epithelial barrier function by occludin, downregulation of claudin-5, and disruption of ERK signaling, increasing permeability and inflammation. DCA initiates DNA damage by reactive oxygen species (ROS), production of hydroxyl radicals, and degradation of p53, triggering Poly (ADP-ribose) polymerase (PARP)-mediated DNA repair signals. DCA triggers pro-oncogenic signaling such as β-catenin, M3 muscarinic receptor (M3R) transactivation of Epidermal Growth Factor Receptor (EGFR), and Nuclear factor kappa B (NF-κB), promoting cell proliferation, synthesis of Mucin 2 (MUC2), and pro-inflammatory cytokine release (e.g., Interleukin-8 (IL-8), Interferon gamma (IFN-γ)). DCA also inhibits antitumor immunity by blocking Ca<sup>2</sup>⁺-Nuclear factor of activated T-cell (NFAT) 2 signaling in CD8⁺ T cells, thus disrupting cytotoxicity. DCA causes intestinal metaplasia and trans-differentiation in gastric and esophageal epithelial cells via KLF Transcription Factor 5 (KLF5)-caudal-related homeobox transcription factor 2 (CDX2) signaling. While acute levels of DCA induce apoptosis by mitochondrial membrane depolarization and caspase-9 activation, chronic accumulation leads to tumorigenesis through chronic inflammation, disruption of barrier function, and immune escape. DCA-heparin conjugates are antiangiogenic and chemo-sensitizing and offer new therapeutic windows. Taken together, these data provide evidence for the dualistic action of DCA and its central position as a microbial metabolite linking diet, barrier function, immunity, and GI carcinogenesis.</p>

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Multifaceted roles of microbiota-derived deoxycholic acid in gastrointestinal cancers: from barrier disruption to therapeutic implications

  • 期刊论文

  • 发表日期：

    2025年10月10日

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  • Hai Zhao,
  • Fan Yang,
  • Jiaxin Yang,
  • Sheng Yang

摘要

Deoxycholic acid (DCA), a microbial-derived secondary bile acid, plays a multifunctional role in gastrointestinal (GI) carcinogenic through various molecular and cellular mechanisms. Mechanistically, DCA causes disruption of epithelial barrier function by occludin, downregulation of claudin-5, and disruption of ERK signaling, increasing permeability and inflammation. DCA initiates DNA damage by reactive oxygen species (ROS), production of hydroxyl radicals, and degradation of p53, triggering Poly (ADP-ribose) polymerase (PARP)-mediated DNA repair signals. DCA triggers pro-oncogenic signaling such as β-catenin, M3 muscarinic receptor (M3R) transactivation of Epidermal Growth Factor Receptor (EGFR), and Nuclear factor kappa B (NF-κB), promoting cell proliferation, synthesis of Mucin 2 (MUC2), and pro-inflammatory cytokine release (e.g., Interleukin-8 (IL-8), Interferon gamma (IFN-γ)). DCA also inhibits antitumor immunity by blocking Ca2⁺-Nuclear factor of activated T-cell (NFAT) 2 signaling in CD8⁺ T cells, thus disrupting cytotoxicity. DCA causes intestinal metaplasia and trans-differentiation in gastric and esophageal epithelial cells via KLF Transcription Factor 5 (KLF5)-caudal-related homeobox transcription factor 2 (CDX2) signaling. While acute levels of DCA induce apoptosis by mitochondrial membrane depolarization and caspase-9 activation, chronic accumulation leads to tumorigenesis through chronic inflammation, disruption of barrier function, and immune escape. DCA-heparin conjugates are antiangiogenic and chemo-sensitizing and offer new therapeutic windows. Taken together, these data provide evidence for the dualistic action of DCA and its central position as a microbial metabolite linking diet, barrier function, immunity, and GI carcinogenesis.