Treating colon cancer by regulating intestinal immunity through microbial metabolism

项目摘要 结直肠癌（CRC）受到肠道免疫系统和肠道微生物组的深刻影响， 其可以发挥与细胞内在突变事件一起起作用的促癌和抗癌作用。免疫 细胞产生有助于上皮诱变和增殖的反应性分子和细胞因子， 免疫细胞浸润发展中肿瘤并影响对化疗和抗肿瘤的反应 免疫疗法治疗性调节免疫系统具有改变CRC结果的潜力， 但是这种干预必须精确地针对特定的信号传导途径、免疫细胞类型，理想地， 在当地交付。这种精确的免疫调节靶点的一个有希望的来源是产生的代谢物 肠道微生物组，最近已被证明对特定的免疫细胞产生强大的影响， 肠内的类型。开发微生物代谢物的治疗潜力需要：1）基础知识 2）安全有效的代谢产物定位方法 递送，和3）用于限定的治疗环境的经验证的靶标。在本提案中，我们将解决这三个问题 关键差距，统一关注肠道中抗炎T细胞的关键群体：RORgt+调节 T细胞（RORgt+ TcR）。在目标1中，我们将剖析一种以前未知的微生物代谢物的机制， 微生物组和膳食色氨酸通过其调节肠道RORgt+ Treg群体的免疫途径。 在目标2中，我们将设计大肠杆菌的益生菌菌株，作为局部递送 治疗代谢物;我们的初步目标是通过过量生产短链脂肪酸来提高RORgt+ TcR 丁酸盐。在目标3中，我们将评估升高RORgt+ TdR（通过饮食丁酸盐）对关键结局的疗效 散发性与结肠炎相关CRC的体内比较。这个项目将加深我们对代谢的理解 免疫调节，开发用于治疗代谢物递送的新型益生菌菌株，并评估 是CRC中重要的抗炎细胞类型。

PROJECT SUMMARY Colorectal cancer (CRC) is profoundly affected by the intestinal immune system and the intestinal microbiome, which can exert both pro- and anti-cancer effects that operate alongside cell-intrinsic mutational events. Immune cells produce reactive molecules and cytokines which contribute to epithelial mutagenesis and proliferation, and immune cells infiltrate developing tumors and influence response to chemotherapy and anti-tumor immunotherapy. Therapeutically modulating the immune system holds potential for transforming CRC outcomes, but such interventions must be precisely targeted to specific signaling pathways, immune cell types and, ideally, delivered locally. One promising source for such precision immunomodulatory targets are metabolites produced by the intestinal microbiome, which have recently been shown to exert powerful effects on specific immune cell types in the intestine. Exploiting the therapeutic potential of microbial metabolites requires: 1) basic knowledge of the diet-microbe-metabolite-immune signaling network, 2) safe and effective means for localized metabolite delivery, and 3) validated targets for defined therapeutic contexts. In this proposal, we will address these three key gaps, with a unifying focus on a key population of anti-inflammatory T cells in the intestine: RORgt+ regulatory T cells (RORgt+ Tregs). In Aim 1, we will dissect the mechanism of a previously unknown microbome-metabolite- immune pathway by which the microbiome and dietary tryptophan regulate intestinal RORgt+ Treg populations. In Aim 2, we will engineer a probiotic strain of E coli to serve as a general platform for localized delivery of therapeutic metabolites; our initial goal will be to boost RORgt+ Tregs by overproducing the short-chain fatty acid butyrate. In Aim3, we will evaluate the efficacy of elevating RORgt+ Tregs (via dietary butyrate) on key outcomes for sporadic vs colitis-associated CRC in vivo. This project will deepen our understanding of metabolic immunoregulation, develop novel probiotic strains for therapeutic metabolite delivery, and evaluate the role of an important anti-inflammatory cell type in CRC.