Treating colon cancer by regulating intestinal immunity through microbial metabolism

项目总结 结直肠癌(CRC)深受肠道免疫系统和肠道微生物群的影响， 它可以发挥促癌和抗癌的作用，与细胞固有的突变事件同时发生。免疫 细胞产生有助于上皮细胞突变和增殖的活性分子和细胞因子，以及 免疫细胞渗入发展中肿瘤及其对化疗和抗肿瘤疗效的影响 免疫疗法。免疫系统的治疗性调节有可能改变结直肠癌的结果， 但这种干预必须精确地针对特定的信号通路、免疫细胞类型，理想情况下， 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。 通过肠道微生物群，最近被证明对特定的免疫细胞有强大的作用 在肠子里打字。开发微生物代谢物的治疗潜力需要：1)基本知识 饮食-微生物-代谢产物-免疫信号网络；2)安全有效的代谢产物定位手段 交付，以及3)确定的治疗环境的验证目标。在这项提案中，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+Tregs)。在目标1中，我们将剖析一种以前未知的微生物代谢产物的机制-- 微生物群和饮食色氨酸调节肠道RORgt+Treg种群的免疫途径。 在目标2中，我们将设计一种益生菌菌株，作为本地化输送的通用平台 治疗代谢物；我们的最初目标将是通过过度生产短链脂肪酸来促进RORgt+Tregs 丁酸盐。在Aim3中，我们将评估提高RORgt+Tregs(通过饮食丁酸)对关键结局的效果 用于体内散发性与结肠炎相关的结直肠癌。这个项目将加深我们对新陈代谢的理解 免疫调节，开发用于治疗代谢物输送的新型益生菌菌株，并评价 结直肠癌中一种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.