Dietary regulation of type 2 immunity and inflammation in the gut

项目摘要 了解环境因素的作用，包括来自饮食和微生物群的信号， 改善包括炎症性肠病在内的胃肠道疾病的治疗和干预策略 疾病（IBD）和炎症相关的结直肠癌（CRC）。膳食纤维可发挥免疫调节作用 通过微生物发酵产物，包括短链脂肪酸（SCFA）的影响。然而，影响 膳食纤维对大多数微生物群衍生代谢产物的影响及其在免疫调节中的作用仍不清楚。在 在新的初步研究中，我发现富含菊粉的高纤维饮食会引发微生物群中的结肠嗜酸性粒细胞增多症， 在肠损伤的鼠模型中， 炎症相关的CRC。这些饮食诱导的2型炎症反应与 微生物群来源的胆汁酸的上调和间充质基质细胞（MSC）的活化，以及组2 先天淋巴样细胞（ILC 2）。然而，宿主和代谢产物中的细胞和分子成分 微生物群中介导饮食对肠道炎症的影响的途径仍然不清楚。在目标1中， 我将确定胆汁酸如何调节2型细胞因子和嗜酸性粒细胞增多症在高纤维饮食诱导的肠 炎症在目标2中，我将研究膳食纤维诱导的嗜酸性粒细胞如何导致肠道损伤。 在目标3中，我将采用细菌遗传学和知菌方法来确定微生物代谢途径 高纤维饮食引起的肠道炎症。在成功实现拟议目标后，我 期望有助于从根本上对膳食纤维的生物学、微生物来源的 代谢产物和基质细胞在调节2型炎症中的作用，这可能有助于合理设计饮食- 和基于微生物群的治疗方法。我的首要职业目标是成为一名独立的 研究人员和一个鼓舞人心的导师在一个领先的学术机构，并研究机制， 环境因素调节肠道炎症和胃肠道疾病。完成我的研究 本计划的目标将使我能够发展各种科学，专业和个人技能， 成为一名成功的独立调查员。这些将包括获得各领域的专业知识，包括 代谢组学分析和遗传工程的帮助下，我的合作者，以及发展技能， 写作、指导、交流和实验室管理。我将在以下实验室进行K99阶段： 博士大卫阿蒂斯，在粘膜免疫学和宿主微生物群相互作用领域的世界领导者。的 实验室可以使用完成拟议目标所需的所有仪器和设施，包括 gnotobiotic动物设施，并提供了一个优秀的环境和培训计划，以支持博士后 研究人员除了我的导师和共同导师，我还得到了几位杰出研究人员的支持 作为顾问和合作者，他们拥有丰富的专业知识，这将极大地促进我的实验的完成 在K99阶段，我将成为一名独立调查员。

PROJECT SUMMARY Understanding the role of environmental factors including signals derived from the diet and microbiota is key to improving therapeutic and intervention strategies for gastrointestinal disorders including inflammatory bowel diseases (IBD) and inflammation-associated colorectal cancer (CRC). Dietary fiber can exert immunoregulatory effects through microbial fermentation products including short chain fatty acids (SCFAs). However, the influence of dietary fiber on most microbiota-derived metabolites and their role in immunoregulation remain unclear. In new preliminary studies, I identified that an inulin-rich high fiber diet triggers colonic eosinophilia in a microbiota- dependent manner which exacerbates disease outcomes in murine models of intestinal damage and inflammation-associated CRC. These diet-induced type 2 inflammatory responses are associated with upregulation of microbiota-derived bile acids and activation of mesenchymal stromal cells (MSCs) and group 2 innate lymphoid cells (ILC2s). However, the cellular and molecular components in the host and the metabolic pathways in the microbiota that mediate the dietary effects on intestinal inflammation remain unclear. In Aim 1, I will determine how bile acids regulate type 2 cytokines and eosinophilia during high fiber diet-induced intestinal inflammation. In Aim 2, I will investigate how dietary fiber-induced eosinophils contribute to intestinal damage. In Aim 3, I will employ bacterial genetics and gnotobiotic approaches to identify the microbial metabolic pathways required for high fiber diet-induced intestinal inflammation. Upon successful completion of the proposed aims, I expect to contribute to a fundamentally new understanding of the biology of dietary fiber, microbiota-derived metabolites, and stromal cells in regulating type 2 inflammation which could contribute to rational design of diet- and microbiota-based therapeutic approaches. My overarching career goals are to become an independent investigator and an inspirational mentor at a leading academic institution and to study the mechanisms by which environmental factors regulate intestinal inflammation and gastrointestinal diseases. Completion of my research aims in this proposal will allow me to develop various scientific, professional, and personal skills critical to become a successful independent investigator. These will include acquiring expertise in various fields including metabolomic analyses and genetic engineering with help of my collaborators, as well as developing skills in writing, mentoring, communicating and laboratory management. I will perform the K99 phase in the laboratory of Dr. David Artis, a world leader in the fields of mucosal immunology and host-microbiota interactions. The laboratory has access to all instruments and facilities necessary to complete the proposed aims including a gnotobiotic animal facility and provides an outstanding environment and training program to support postdoctoral researchers. In addition to my mentor and co-mentor, I have support from several distinguished investigators with extensive expertise as advisors and collaborators that will greatly facilitate the completion of my experiments during the K99 phase as I progress to become an independent investigator.