Contribution of phytochemicals to gut symbiont colonization and synthesis of immunomodulatory sphingolipids

植物化学物质对肠道共生体定植和免疫调节鞘脂合成的贡献

基本信息

批准号：
10339335
负责人：
Sungwhan F Oh
金额：
$ 40.28万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339335
关键词：
Adult Affect Agonist Anabolism Animal Model Animals Anti-Inflammatory Agents Antibiotics Bacteria Bacteroides fragilis Biochemical Biochemical Pathway Body Surface Branched-Chain Amino Acids Cell physiology Chemicals Colitis Colon Communities Complex Consensus Cytotoxic T-Lymphocytes Development Diet Dietary Component Dietary Factors Disease Disease susceptibility Dissection Ecosystem Environmental Exposure Essential Amino Acids Gastrointestinal tract structure Genes Genetic Genome Germ-Free Glycosphingolipids Gnotobiotic Goals Growth Health Health Benefit Human Human Development Human Genome Human Microbiome Immune Immune system Immunologics In Vitro Individual Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Investigation Knock-out Knowledge Life Mass Spectrum Analysis Mediating Mediator of activation protein Metabolic Metabolic Pathway Metagenomics Methodology Microbe Microbiology Modeling Molecular Mus Nutrient Oligosaccharides Organ Organism Outcome Pathway interactions Physiology Phytochemical Plants Predisposition Probiotics Production Regulatory T-Lymphocyte Research Resistance Sphingolipids Structure T cell regulation T-Cell Development Testing United States National Institutes of Health antagonist bacterial genetics commensal bacteria commensal microbes competitive environment density dietary fitness germ free condition gut microbiota host microbiome host microbiota human microbiota immunoregulation in vivo interest lipid structure metabolomics metagenome microbial microbiome microbiome research microbiota microorganism mouse model multidisciplinary mutant novel novel therapeutics nutrient metabolism postnatal prebiotics symbiont synergism tool working group

项目摘要

Project summary Recent findings in studies of the human microbiome have added a layer of complexity to research on the impact of the diet on health. While the health benefits of certain classes of diet-derived molecules are well appreciated, the molecular mechanisms underlying these benefits have been only partially elucidated. The diet provides nutrients not only to the host but also to the microorganisms that make up the gut microbiota. The commensal metagenome, which numerically exceeds the host genome by >100-fold, contributes enormous chemical diversity to nutrient metabolism. Dietary metabolites attributable to specific gut commensals, have been identified as key effector molecules of host health and disease in several studies. At the tripartite juncture of host, diet, and microbiota, we have been investigating a unique class of sphingolipids of the gut commensal Bacteroides fragilis (BfaGCs) and their host immunomodulatory functions. BfaGCs regulate the proliferation of invariant natural killer T (NKT) cells in the host's colon, which determines disease susceptibility in the NKT cell–mediated murine model of inflammatory bowel disease. This colonic NKT-cell regulation by B. fragilis occurs only when colonization takes place during the first few days of life in mice. This observation indicates that early postnatal exposure of the gut immune system to the microbiota is crucial in establishing the number of gut NKT cells throughout life. Further studies have shown that terminal branching in the glycosphingolipid structure is crucial in directing either agonism or antagonism of NKT cells functions. It is of considerable interest that dietary branched-chain amino acids (BCAAs) can dictate the lipid structure of BfaGCs. This observation suggests a novel concept in symbiotic mediator synthesis: direct incorporation of dietary factors into bacterial biochemical pathways, where they are further converted into bioactive mediators. BCAAs are essential amino acids for humans and are primarily produced by plants. Many BCAA-rich diets of plant origin are also rich in plant oligosaccharides (POs), some of which are metabolized exclusively by B. fragilis and confer this a survival advantage to this organism in the competitive environment of the gut. We hypothesize that these phytochemicals (BCAAs and POs) act synergistically to help induce colonization by B. fragilis and promote the production of NKT cell–regulatory BfaGCs that protect the host from NKT cell–mediated colitis. Using multi-pronged approaches (bacterial genetics, gnotobiotic mouse models, and high-sensitivity analytical platforms), we propose (1) to characterize critical genes in the BCAA-derived sphingolipid biosynthetic pathway in B. fragilis and investigate their colonic NKT cell modulatory functions and (2) to determine the impact of phytochemicals on immunomodulatory BfaGC production, postnatal NKT cell development, and colitis resistance in adulthood. We expect to acquire molecular-level information on how dietary factors can synergize growth of beneficial bacteria and bacterial production of symbiotic factors.

项目摘要人类微生物组研究的最新发现增加了一层复杂性来研究影响健康饮食。虽然对某些类别的饮食衍生分子的健康益处得到了很好的赞赏，但这些益处的分子机制仅部分阐明了。饮食提供不仅是宿主的营养素，而且还针对构成肠道菌群的微生物。共生元基因组在数值上超过宿主基因组> 100倍，贡献了巨大的化学物质已经鉴定出可归因于特定肠道的饮食代谢产物作为宿主健康和疾病的关键效应分子。在宿主，饮食和微生物群的三方关头，我们一直在研究一类独特的鞘脂肠道共生菌落fragilis（BFAGC）及其宿主免疫调节功能。 bfagcs 调节宿主结肠中不变天然杀伤剂（NKT）细胞的扩散，该细胞决定疾病 NKT细胞介导的炎症性肠病的鼠模型中的敏感性。这个结肠NKT细胞脆弱的B. fragilis的调节仅在生命的头几天发生在小鼠生命的头几天中时才发生。这观察表明，肠道免疫系统早期暴露于微生物群中至关重要在一生中确定肠道NKT细胞的数量。进一步的研究表明，末端分支糖磷脂结构对于指导NKT细胞功能的激动剂或拮抗作用至关重要。它是饮食中分支链氨基酸（BCAA）可以决定BFAGC的脂质结构。该观察结果暗示了共生介体合成中的一个新概念：直接纳入饮食因素进入细菌生化途径，在那里它们进一步转化为生物活性介体。 BCAA是人类必需的氨基酸，主要由植物产生。许多BCAA富含BCAA的饮食植物起源也富含植物寡糖（POS），其中一些是由B. fragilis代谢的并在肠道的竞争环境中对这个组织具有生存优势。我们假设这些生理化学物质（BCAA和POS）协同作用，以帮助影响B.b。b.and of Fragilis和促进保护宿主免受NKT细胞介导的结肠炎的NKT细胞调节BFAGC的产生。使用多管齐的方法（细菌遗传学，gnotobiotic小鼠模型和高敏性分析平台），我们建议（1）表征BCAA衍生的鞘脂生物合成途径中的关键基因在Fragilis中，研究其结肠NKT细胞调节功能，（2）确定关于免疫调节的BFAGC产生，产后NKT细胞发育和结肠炎的植物化学物质成年。我们希望获得有关饮食因素如何协同增长的分子级信息有益细菌和共生因子的细菌产生。