Gut microbiota derived indole-3-acetic acid ameliorates precancerous inflammatory intestinal milieu to inhibit tumorigenesis through IL-35

Background Gut microbiota can significantly alter the risk or progression of cancer by maintaining gut immune system homeostasis. However, the exact mechanism by which the gut microbiota and its metabolites influence colorectal tumorigenesis is unclear. Methods The roles of tryptophan metabolite indole-3-acetic acid (IAA) in inflammation and tumor development were investigated in dextran sodium sulfate (DSS) and azoxymethane (AOM)-DSS mouse models with or without IAA supplementation and with or without Lactobacillus reuteri -produced IAA. Pregnane X receptor (PXR) knockout (KO) mice and aryl hydrocarbon receptor KO mice were used to explore the mechanism by which IAA regulates interleukin (IL)-35 expression. IL-35 + immune cells were stimulated in vitro and analyzed by flow cytometry. Additionally, metabolites were analyzed by liquid chromatography-mass spectrometry. Results We found that IAA, a metabolite of tryptophan produced in the gut by L. reuteri , can inhibit the development of colitis by inducing IL-35 expression in immunosuppressant cells. HuREG3α IECtg mice had high levels of intestinal microbiota-derived IAA, and these mice were resistant to AOM-DSS-induced cancer. Patients with colorectal cancer also had low peripheral blood levels of IAA. Further studies revealed that IAA-producing L. reuteri alleviated colitis symptoms and inhibited colon tumors by inducing macrophages, T cells, and B cells to produce IL-35. Finally, PXR KO completely abolished the effects of IAA on immune cells. Conclusion We demonstrate that gut microbiota-derived IAA can improve the precancerous colon inflammatory environment through IL-35, thereby inhibiting tumorigenesis, suggesting that IAA may be a preventive factor for colitis-related cancers.