Lactobacillus plantarum-derived indole-3-lactic acid ameliorates colorectal tumorigenesis via epigenetic regulation of CD8+ T cell immunity

Abstract

Previous studies have shown that Lactobacillus species play a role in ameliorating colorectal cancer (CRC) in a mouse model. However, the underlying mechanisms remain largely unknown. Here, we found that administration of a probiotic strain, Lactobacillus plantarum L168 and its metabolite, indole-3-lactic acid, ameliorated intestinal inflammation, tumor growth, and gut dysbiosis. Mechanistically, we indicated that indole-3-lactic acid accelerated IL12a production in dendritic cells by enhancing H3K27ac binding at the enhancer regions of IL12a that contributed to priming CD8⁺ T cell immunity against tumor growth. Furthermore, indole-3-lactic acid was found to transcriptionally inhibit Saa3 expression related to cholesterol metabolism of CD8⁺ T cells through changing chromatin accessibility and subsequent enhancing function of tumor-infiltrating CD8⁺ T cells. Together, our findings provide new insights into the epigenetic regulation of probiotics-mediated anti-tumor immunity and suggest the potential of L. plantarum L168 and indole-3-lactic acid to develop therapeutic strategies for patients with CRC.

Keywords: ILA; Lactobacillus plantarum; colorectal cancer; epigenetic regulation; indole-3-lactic acid.