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Background <p>Gut microbiota (GM) regulates the tumor microenvironment through microbial metabolites. Indole 3-propionic acid (3-IPA) is one such metabolite that regulates gastrointestinal barrier function. In this study, we investigated the effects of 3-IPA on the progression of lymph node metastasis of gastric cancer (GC) and the molecular mechanisms that underlie them.</p> Methods <p>The microbial metabolites were identified using a fecal metabolomic assay in GC patients. Lymphangiogenesis was evaluated using tube formation and wound healing assays in vitro. The expression of aryl hydrocarbon receptor (AHR), CYP1A1, and vascular endothelial growth factor receptor 3 (VEGFR3) were assayed using quantitative real-time PCR (qRT-PCR) and western blot (WB) analyses. Matrigel plug and popliteal lymph node metastasis model were employed to validate the influence on lymphangiogenesis and lymph node metastasis in vivo.</p> Results <p>Fecal metabolomic and microbiome profiling was drastically different between GC patients with lymph node metastasis (GC-LM) and those without metastasis. The GC-LM group showed high 3-IPA expression in the feces; 3-IPA had no significant effect on GC cells; Human lymphatic endothelial cells showed greater tube formation and promoted migration after 3-IPA administration. Also, upregulation of AHR, CYP1A1, and VEGFR3 was observed. Moreover, administration of the AHR inhibitor suppressed tube formation and lymph node metastasis both in vitro and in vivo.</p> Conclusions <p>Our findings suggest that gut microbiota-derived 3-IPA functions as a lymph node metastasis promoter through the AHR/CYP1A1–VEGFR3 axis in GC. 3-IPA could serve as a prognostic biomarker and conceivably a therapeutic target for GC lymph node metastasis.</p>

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Gut microbiota-derived indole-3-propionic acid promotes lymph node metastasis in gastric cancer via the aryl-hydrocarbon receptor signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Mingfei Wang,
  • Yan Wang,
  • Mingshuai Bai,
  • Qifan Peng,
  • Qishuan Wu,
  • Zhou Shang,
  • Guangrui Chen,
  • Zhengjun Zhang,
  • Shilong Yang,
  • Leping Li,
  • Feng Tian,
  • Changqing Jing

摘要

Background

Gut microbiota (GM) regulates the tumor microenvironment through microbial metabolites. Indole 3-propionic acid (3-IPA) is one such metabolite that regulates gastrointestinal barrier function. In this study, we investigated the effects of 3-IPA on the progression of lymph node metastasis of gastric cancer (GC) and the molecular mechanisms that underlie them.

Methods

The microbial metabolites were identified using a fecal metabolomic assay in GC patients. Lymphangiogenesis was evaluated using tube formation and wound healing assays in vitro. The expression of aryl hydrocarbon receptor (AHR), CYP1A1, and vascular endothelial growth factor receptor 3 (VEGFR3) were assayed using quantitative real-time PCR (qRT-PCR) and western blot (WB) analyses. Matrigel plug and popliteal lymph node metastasis model were employed to validate the influence on lymphangiogenesis and lymph node metastasis in vivo.

Results

Fecal metabolomic and microbiome profiling was drastically different between GC patients with lymph node metastasis (GC-LM) and those without metastasis. The GC-LM group showed high 3-IPA expression in the feces; 3-IPA had no significant effect on GC cells; Human lymphatic endothelial cells showed greater tube formation and promoted migration after 3-IPA administration. Also, upregulation of AHR, CYP1A1, and VEGFR3 was observed. Moreover, administration of the AHR inhibitor suppressed tube formation and lymph node metastasis both in vitro and in vivo.

Conclusions

Our findings suggest that gut microbiota-derived 3-IPA functions as a lymph node metastasis promoter through the AHR/CYP1A1–VEGFR3 axis in GC. 3-IPA could serve as a prognostic biomarker and conceivably a therapeutic target for GC lymph node metastasis.