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Gut microbiota-derived indole-3-propionic acid promotes lymph node metastasis in gastric cancer via the
Mingfei Wang1,2, Yan Wang1,3, Mingshuai Bai1
1Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China.
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.
Insights
Gut microbiota metabolite indole 3-propionic acid (3-IPA) promotes gastric cancer lymph node metastasis by activating the aryl hydrocarbon receptor (AHR)/CYP1A1-VEGFR3 pathway. 3-IPA may serve as a therapeutic target and prognostic biomarker for gastric cancer.
Area of Science:
- Oncology
- Microbiome Research
- Molecular Biology
Background:
- Gut microbiota influences the tumor microenvironment via metabolites.
- Indole 3-propionic acid (3-IPA) is a gut microbial metabolite affecting gastrointestinal barrier function.
Purpose of the Study:
- Investigate the effect of 3-IPA on gastric cancer (GC) lymph node metastasis.
- Elucidate the underlying molecular mechanisms involving the aryl hydrocarbon receptor (AHR) pathway.
Main Methods:
- Fecal metabolomic and microbiome profiling in GC patients.
- In vitro assays (tube formation, wound healing) for lymphangiogenesis.
- In vivo models (Matrigel plug, lymph node metastasis) in mice.
- Gene and protein expression analysis (qRT-PCR, WB) for AHR, CYP1A1, and VEGFR3.
Main Results:
- Distinct fecal metabolomic profiles in GC patients with and without lymph node metastasis (GC-LM).
- Elevated fecal 3-IPA in GC-LM patients; 3-IPA promoted lymphatic endothelial cell tube formation and migration.
- Upregulation of AHR, CYP1A1, and VEGFR3 expression observed.
- AHR inhibition suppressed lymphangiogenesis and lymph node metastasis in vitro and in vivo.
Conclusions:
- Gut microbiota-derived 3-IPA promotes GC lymph node metastasis via the AHR/CYP1A1-VEGFR3 axis.
- 3-IPA shows potential as a prognostic biomarker and therapeutic target for GC lymph node metastasis.
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