中国科学技术大学朱书等研究人员合作发现，肠道微生物群改变的胆汁酸通过抑制CD8⁺ T细胞效应功能促进结直肠癌生长。该研究于2024年3月12日在线发表于国际一流学术期刊《免疫》。

研究人员筛选了一个肠道微生物群衍生代谢产物库，发现脱氧胆酸（DCA）是CD8⁺ T细胞效应功能的负调控因子。从机理上讲，DCA通过靶向质膜Ca²⁺ ATP酶（PMCA）抑制Ca²⁺-活化T细胞核因子（NFAT）2信号传导来抑制CD8⁺ T细胞反应。在结直肠癌（CRC）患者中，CD8⁺ T细胞效应功能与DCA浓度和细菌DCA生物合成基因的表达呈负相关。

携带DCA生物合成基因的细菌会抑制CD8⁺ T细胞的效应功能，并促进小鼠肿瘤的生长。通过胆汁酸螯合、细菌DCA生物合成途径基因消减或特异性噬菌体，来破坏胆汁酸代谢可消除这种效应。这项研究证明了微生物DCA代谢与CRC抗肿瘤CD8⁺ T细胞反应之间的因果关系，为抗肿瘤治疗提供了潜在的方向。

据悉，在CRC患者体内，次级胆汁酸DCA的浓度异常升高，但对其后果仍知之甚少。

附：英文原文

Title: Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions

Author: Jingjing Cong, Pianpian Liu, Zili Han, Wei Ying, Chaoliang Li, Yifei Yang, Shuling Wang, Jianbo Yang, Fei Cao, Juntao Shen, Yu Zeng, Yu Bai, Congzhao Zhou, Lilin Ye, Rongbin Zhou, Chunjun Guo, Chunlei Cang, Dennis L. Kasper, Xinyang Song, Lei Dai, Linfeng Sun, Wen Pan, Shu Zhu

Issue&Volume: 2024-03-12

Abstract: Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantlyelevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood.Here, we screened a library of gut microbiota-derived metabolites and identified DCAas a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expressionof a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressedCD8+ T cells effector function and promoted tumor growth in mice. This effect was abolishedby disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterialDCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.

DOI: 10.1016/j.immuni.2024.02.014

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00090-6