Gut Inflammation from Emulsifier Perturbations of Microbiota-Host Interactions

 描述(申请人提供)：肠道中有一大片不同的细菌群落，统称为肠道微生物区系。当以稳定的方式与肠道上皮细胞保持适当的安全距离时，微生物区系为宿主提供了好处，特别是在能量获取、病原体排斥和促进免疫发展方面。然而，在这笔赠款下进行的研究让我们假设，在遗传和非遗传因素的推动下，微生物区系-宿主关系的紊乱可以导致慢性肠道炎症，可能表现为炎症性肠病(IBD)或代谢综合征。最近完成的拨款，其资金这项申请寻求恢复，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，在过去的60年里，在相对恒定的遗传学中，包括IBD和代谢综合征在内的许多慢性炎症性疾病的发病率急剧增加，这突显了了解非遗传因素可能改变微生物群-宿主关系以促进肠道炎症的机制的重要性。因此，这一更新应用的目标是调查一类普遍存在的食品添加剂对微生物群-宿主关系的干扰，即乳化剂，其在世界食品供应中的渗透性与慢性炎症性疾病的增加大致相同。我们对乳化剂的关注是基于这样一个概念，即这些洗涤剂样分子被建议促进细菌在肠道粘膜中的移位，此外，我们最近的发现是，在小鼠中，通过饮食给予2种常见的合成乳化剂，即聚山梨酸酯80(P80)和羧甲基纤维素(CMC)，其浓度低于它们被批准用于加工食品的浓度，会促进具有这种疾病遗传易感性(IL-10-/-和TLR5-/-)的小鼠的结肠炎，此外，还会在2个不同的WT小鼠品系(C57BL/6和Swiss-Webster)中驱动代谢综合征。这种乳化剂诱导的代谢综合征需要微生物区系的存在，因为P80和CMC都不会促进无菌小鼠的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)最终将需要确定乳化剂在推动IBD和代谢综合征发病率增加方面的作用，但我们认为，了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，还可以广泛地增强我们对任何扰乱微生物区系-肠道关系的因素可以促进慢性炎症性疾病的基本机制的理解。因此，这项提议试图调查我们的假设，即乳化剂促进病原体穿透粘液层，从而诱导炎症，从而改变微生物区系组成，进一步推动炎症及其后果。

 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.