Gut Inflammation from Emulsifier Perturbations of Microbiota-Host Interactions

微生物群与宿主相互作用的乳化剂扰动引起肠道炎症

• 批准号: 8986401
• 负责人: Andrew T Gewirtz
• 金额: $ 33.86万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986401
• 关键词: Automobile Driving; Bacteria; Bacterial Translocation; Biological Assay; Biological Models; Carboxymethylcellulose; Cardiovascular Diseases; Chronic; Colitis; Communities; Data; Detergents; Development; Diabetes Mellitus; Diet; Disease; Disease Clusterings; Epidemic; Epithelial; Epithelial Cells; Epithelium; Exclusion; Exhibits; Fatty Liver; Flagellin; Food Additives; Food Processing; Food Supply; Functional disorder; Funding; Gene Expression; Genetic; Goals; Grant; Harvest; Healthcare Systems; Human; Humanities; Hyperglycemia; Hyperlipidemia; Immune; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Insulin Resistance; Interleukin-10; Intestines; Life; Liver Dysfunction; Mastigophora; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic syndrome; Mouse Strains; Mucous Membrane; Mucous body substance; Mus; Obesity; Penetrance; Penetration; Persons; Phenotype; Polysorbate 80; Process; Public Health; Reporting; Research; Risk; Role; Security; Signal Transduction; Testing; Tissues; Toll-Like Receptor 5; Transplantation; base; gut microbiota; insight; non-genetic; pathogen; protein function; public health relevance; receptor

 DESCRIPTION (provided by applicant): The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. When maintained in a stable manner, at an appropriately safe distance from gut epithelial cells, the microbiota provides a benefit to the host, especially in terms of energy harvest, pathogen exclusion, and promotion of immune development. However, research performed under this grant has led to us hypothesize that disturbance of the microbiota-host relationship, promoted by genetic and non-genetic factors, can drive chronic gut inflammation that can manifest as inflammatory bowel disease (IBD) or metabolic syndrome. The recently completed grant whose funding this application seeks to reinstate, has largely focused on understanding how a genetic innate immune deficiency can result in chronic gut inflammation. Yet, the dramatic increase in incidence of numerous chronic inflammatory diseases, including IBD and metabolic syndrome over the last 60 years amidst relatively constant genetics highlights the importance of understanding mechanisms by which non-genetic factors might alter the microbiota-host relationship to promote gut inflammation. Hence, the goal of this renewal application is to investigate disturbance of the microbiota-host relationship by a ubiquitous class of food additives, namely emulsifiers, whose penetrance in the world's food supply roughly parallel's increases in chronic inflammatory diseases. Our focus on emulsifiers is based on the notion that these detergent-like molecules have been suggested to promote bacterial translocation across gut mucosa and, moreover, our recent findings that, in mice, administration of 2 common synthetic emulsifiers, namely polysorbate 80 (P80) and carboxymethylcellulose (CMC), via diet, at concentrations below that which they are approved for use in processed foods, promote colitis in mice with a genetically predisposed to this disorder (IL-10-/- and TLR5-/-) and, moreover, drive metabolic syndrome in 2 distinct WT mouse strains (C57BL/6 and Swiss-Webster). Such emulsifier-induced metabolic syndrome requires the presence of a microbiota in that neither P80 nor CMC promote low-grade inflammation or metabolic syndrome in germfree mice. While human studies (that we will propose elsewhere) will ultimately be required to define the role of emulsifiers in driving the increased incidence of IBD and metabolic syndrome, we submit that understanding mechanisms by which emulsifiers promote inflammatory diseases in our model systems can guide such studies and, moreover, broadly enhance our understanding of fundamental mechanisms by which any factor that disturbs the microbiota-gut relationship can promote chronic inflammatory diseases. Hence, this proposal seeks to investigate our hypothesis that emulsifiers promote pathobiont penetration through the mucus layer thus inducing inflammation that changes microbiota composition to further drive inflammation and its consequences.

 描述（由申请人提供）：肠道中居住着大量不同的细菌群落，统称为肠道微生物群。当以稳定的方式保持在与肠道上皮细胞适当的安全距离时，微生物群为宿主提供益处，特别是在能量收获、病原体排除和促进免疫发育方面。然而，在这项资助下进行的研究使我们假设，由遗传和非遗传因素促进的微生物-宿主关系的紊乱可以驱动慢性肠道炎症，这些炎症可以表现为炎症性肠病（IBD）或代谢综合征。最近完成的拨款，其资金本申请寻求恢复，主要集中在了解遗传先天免疫缺陷如何导致慢性肠道炎症。然而，在过去60年中，在相对恒定的遗传学中，许多慢性炎症性疾病（包括IBD和代谢综合征）的发病率急剧增加，这突出了理解非遗传因素可能改变微生物-宿主关系以促进肠道炎症的机制的重要性。因此，该更新申请的目标是研究普遍存在的一类食品添加剂（即乳化剂）对微生物-宿主关系的干扰，乳化剂在世界食品供应中的比例大致与慢性炎症性疾病的增加平行。我们对乳化剂的关注是基于这样的观点：这些洗涤剂样分子被认为可以促进细菌穿过肠道粘膜的移位，此外，我们最近的发现是，在小鼠中，以低于批准用于加工食品的浓度，通过饮食给予2种常见的合成乳化剂，即聚山梨酯80（P80）和羧甲基纤维素（CMC），在具有遗传易感性的小鼠中促进结肠炎（IL-10-/-和TLR 5-/-），此外，在2种不同的WT小鼠品系（C57 BL/6和Swiss-Webster）中驱动代谢综合征。这种代谢综合征需要微生物群的存在，因为P80和CMC都不会在无菌小鼠中促进低度炎症或代谢综合征。虽然人类研究（我们将在其他地方提出）最终将被要求定义乳化剂在推动IBD和代谢综合征发病率增加中的作用，我们认为理解乳化剂在我们的模型系统中促进炎症性疾病的机制可以指导此类研究，此外，广泛地增强了我们对基本机制的理解，任何干扰微生物-肠道关系的因素都可以促进慢性炎症性疾病。因此，该提案旨在研究我们的假设，即乳化剂促进致病菌渗透通过粘液层，从而诱导炎症，改变微生物群组成以进一步驱动炎症及其后果。