Role of Dietary Fiber-Microbiota Interactions in the development and function

膳食纤维-微生物群相互作用在发育和功能中的作用

• 批准号: 10632834
• 负责人: Luisa Cervantes Barragan
• 金额: $ 6.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10632834
• 关键词: Abdominal Pain; Affect; Award; Bacteria; Bromodeoxyuridine; Cell Adhesion Molecules; Cell Communication; Cells; Cellulose; Chronic; Chronic diarrhea; Complement; Consumption; Crohn' s disease; Development; Diet; Diet therapy; Dietary Fiber; Dietary Intervention; E-Cadherin; Energy-Generating Resources; Environment; Environmental Risk Factor; Epithelial; Epithelial Cells; Etiology; Fiber; Flow Cytometry; Gastrointestinal tract structure; Genetic; Goals; Grant; Growth; Hemorrhage; Histology; Homeostasis; Immune; Immune system; Immunoglobulin A; Impairment; Incidence; Individual; Inflammation; Inflammatory Bowel Diseases; Intestines; Life; Measures; Mediating; Molecular; Mucosal Immune Responses; Mucosal Immune System; Mucous Membrane; Mus; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Production; Quality of life; Regulatory T-Lymphocyte; Risk; Role; Severity of illness; Small Intestines; Source; Structure; Symptoms; T-Cell Development; T-Lymphocyte; Tamoxifen; Testing; Therapeutic; Ulcerative Colitis; base; common symptom; conditional knockout; dietary; disorder control; gut inflammation; gut microbiome; gut microbiota; immunoregulation; improved outcome; in vivo Model; intestinal epithelium; intraepithelial; member; microbiome; microbiome components; microbiome composition; microbiota; mouse model; parent grant; prevent; receptor; rectal; success; transcriptome; transcriptome sequencing

SUMMARY Global incidence of Inflammatory Bowel Disease (IBD) has increased 6% in the past 30 years, reducing quality of life for more than 6.8 million individuals. IBD is characterized by chronic inflammation of the gastrointestinal tract, resulting in Crohn’s Disease (CD) or Ulcerative Colitis (UC). Although its etiology is unknown, IBD is thought to be the result of abnormal mucosal immune responses caused by genetic factors, the microbiome, and the environment. Dietary interventions have been proposed as therapeutic measures for IBD. However, studies that delineate the mechanism of how dietary fiber impacts microbiome composition and development of the mucosal immune response are still very scarce. Such studies are needed to discover diet-microbiota-immune system interactions that can be harnessed to control disease. Results obtained from the parent award R01DK129950- 01 of this application, showed a relationship between dietary fiber, Segmented filamentous bacteria, and CD4+CD8αα+ IEL T cells (DP IELs), a population of intestinal T cells with local regulatory functions in the small intestine. The main aim of this Diversity Supplement Application is to delineate the molecular mechanism of the intestinal epithelial cells-SFB-DP IEL interaction and constitutes a new direction different from the aims proposed in the parent grant. To accomplish this, we propose to determine the effects of fiber and SFB on small intestinal epithelial cells (sIECs) using RNAseq, qPCR and flow cytometry, and determine the role of SFB-dependent expression of MHC II on sIECs cells on the development and turnover of DP IELs using genetically modified in vivo models to remove MHC II expression on intestinal epithelial cells. The studies in this proposal will identify interactions between small intestine epithelial cells and SFB that are necessary for the development of DP IELs and how the absence of fermentable fiber affects these interactions. Our proposed studies will complement and extend the studies proposed in the parent R01 grant, which long-term goal is to identify how the consumption of dietary fiber affects interactions between members of the microbiota and the immune system. These studies will further our understanding of the mucosal immune system to aid in the development and implementation of dietary therapeutic measures that will improve the outcomes of IBD patients.

总结 炎症性肠病（IBD）的全球发病率在过去30年中增加了6%， 超过680万人的生命。IBD的特征是胃肠道的慢性炎症 肠道，导致克罗恩病（CD）或溃疡性结肠炎（UC）。虽然其病因不明，但IBD被认为是 是由遗传因素、微生物组和细胞因子引起的异常粘膜免疫应答的结果。 环境饮食干预已被提议作为IBD的治疗措施。然而，研究表明， 描述膳食纤维如何影响微生物组组成和粘膜发育的机制 免疫反应仍然非常缺乏。这些研究需要发现饮食-微生物群-免疫系统 可以用来控制疾病的相互作用。从母公司获得的结果R 01 DK 129950- 01，显示了膳食纤维、分节丝状细菌和 CD 4 + CD 8 αα+ IEL T细胞（DP IEL）是一群在小肠中具有局部调节功能的肠道T细胞。 肠子本多样性补充申请的主要目的是描述 肠上皮细胞-SFB-DP IEL的相互作用，构成了一个新的方向不同的目的提出 在父母补助金里为了实现这一目标，我们建议确定纤维和SFB对小肠的影响， 使用RNAseq、qPCR和流式细胞术检测上皮细胞（sIEC），并确定SFB依赖性 使用基因修饰的人源化细胞，sIEC细胞上MHC II的表达对DP IEL的发育和周转的影响。 体内模型，以去除肠上皮细胞上的MHC II表达。本提案中的研究将确定 小肠上皮细胞和SFB之间的相互作用是DP IEL发育所必需的 以及可发酵纤维的缺乏如何影响这些相互作用。我们建议的研究将补充和 扩展在父R 01补助金中提出的研究，其长期目标是确定如何消费 膳食纤维影响微生物群成员与免疫系统之间的相互作用。这些研究将 进一步了解粘膜免疫系统，以帮助开发和实施膳食补充剂， 改善IBD患者预后的治疗措施。