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

• Published in: Cell metabolism Vol. 35; no. 6; pp. 943 - 960.e9
• Main Authors: Zhang, Qingqing, Zhao, Qing, Li, Tao, Lu, Longya, Wang, Fei, Zhang, Hong, Liu, Zhi, Ma, Huihui, Zhu, Qihui, Wang, Jingjing, Zhang, Xuemei, Pei, Yang, Liu, Qisha, Xu, Yuyu, Qie, Jinlong, Luan, Xiaoting, Hu, Zhibin, Liu, Xingyin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.06.2023
• Subjects: Animals; Carcinogenesis; CD8-Positive T-Lymphocytes; colorectal cancer; Colorectal Neoplasms; Epigenesis, Genetic; epigenetic regulation; ILA; indole-3-lactic acid; Lactobacillus plantarum; Lactobacillus plantarum - physiology; Mice; Lactobacillus plantarum; colorectal cancer; indole-3-lactic acid; epigenetic regulation; ILA
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2023.04.015

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. [Display omitted] •L. plantarum L168 and its derived ILA ameliorate colorectal tumorigenesis•ILA accelerates IL12a production in DCs to prime anti-tumor immunity of CD8+ T cells•ILA enhances function of CD8+ T cells through epigenetic mechanisms•ILA inhibits expression of Saa3 in CD8+ T cells to reduce tumor growth of CRC The underlying anti-tumor immune mechanisms for probiotics preventing colorectal cancer remain largely unknown. Zhang et al. report that a strain of probiotics, L. plantarum L168 and its derived metabolite, indole-3-lactic acid, ameliorate colorectal tumorigenesis through contributing to anti-tumor immunity of CD8+ T cell via epigenetic regulation.