Effect of W-3 supplementation on IBD via alterations in the enteric microbiome

人们普遍认为，我们与肠道微生物区系处于共生状态，而改变这些微生物区系的数量或组成的扰动会导致胃肠道不适。最近，我们的微生物区系的动态平衡改变与肥胖、糖尿病和炎症性肠病(IBD)等疾病有关。就IBD而言，临床证据表明，慢性炎症是环境/微生物因素与患者遗传易感性背景相结合的结果。这种关系背后的机制尚不清楚，但存在两种可能性，我们试图检查：1)存在基因定义的对正常肠道菌群的异常宿主反应，促进持续的粘膜炎症和损伤(宿主触发)，或2)肠道微生物区系组成的变化引发遗传易感个体的病理反应(微生物区系触发)。由于几乎所有的研究都是在疾病发作后进行的，所以目前还不清楚哪一种疾病是导致IBD的主要原因。更不知道各种饮食成分对肠道细菌种类的影响，以及这些种类的变化如何使个人容易患上IBD或恶化病情。我在正常小鼠身上的初步数据显示，高饱和脂肪饮食会导致一种细菌的大量繁殖，这种细菌与一系列炎症性疾病有关。我们实验室的数据还显示，高饱和脂肪饮食显著增加了遗传易感小鼠模型的结肠炎发病率。相反，在许多研究中，补充鱼油已被证明可以缓解IBD的症状，然而这些结果仍然是间接的，因为没有机制研究来解释这种相关性。因此，本项目的目标是通过肠道微生物环境的改变，为补充I-3鱼油对IBD的影响提供新的见解。这一目标将通过使用已建立的遗传易感性结肠炎(IL10-/-)小鼠模型和完全没有肠道微生物区系的新的IL10/-无菌(GF)小鼠来实现，这将阐明微生物区系的直接因果作用。分析将包括高通量焦磷酸测序和对改变的微生物物种的代谢分析以及随后的宿主炎症反应。该项目的目标将在以下具体目标中进行审查：目标1：确定饮食中补充I-3和I-6对已建立的结肠炎小鼠模型中肠道微生物区系和炎症标志物微生物产生的影响。目的2：在常规和无菌IL10-/-小鼠模型中，明确饮食中补充I-3和I-6对宿主对微生物区系改变的炎症反应的影响。

It is accepted that we live in symbiotic homeostasis with our intestinal microbiota and perturbations that alter the quantity or makeup of this microbiota can cause gastrointestinal distress. Recently, altered homeostasis with our microbiota has been linked to diseases including obesity, diabetes, and inflammatory bowel diseases (IBD). In the case of IBD, clinical evidence suggests the chronic inflammation results from a combination of environmental/microbial factors on a patient background of genetic susceptibility. The mechanisms that underlie this relationship are unknown, however two possibilities exist which we seek to examine: 1) There is a genetically-defined, abnormal host response to the normal enteric flora that promotes sustained mucosal inflammation and injury (host triggering), or 2) alterations in the composition of gut microbiota trigger a pathologic response from genetically susceptible individuals (microbiota triggering). Which one plays the major role in causing IBD is not known because virtually all studies have been performed after the onset of disease. Even less is known about the effect of various dietary compositions on the species of bacteria in our gut and how changes in these species may predispose individuals to IBD or worsen the condition. My preliminary data in normal mice show that a diet high in saturated fat induce a bloom of a bacterial strain implicated in an array of inflammatory disorders. Data from our lab also show that a high saturated fat diet dramatically increases incidence of colitis in genetically susceptible mouse model. Conversely, fish oil supplementation has been shown to relieve symptoms of IBD in numerous studies, however these results remain circumstantial as no mechanistic studies exist to explain the correlation. Thus, the objective of this project is to provide new insight into the impact of I-3 fish oil supplementation on IBD via alterations in the intestinal microbial environment. This objective will be achieved by using an established mouse model of genetically susceptible colitis (IL10-/-) and the novel IL10-/- germ-free (GF) mouse completely devoid of enteric microbiota which will elucidate a direct cause-effect role of the microbiota. Analyses will include high-throughput pyrosequencing and metabolomic analysis of altered microbial species and subsequent host inflammatory responses. The project objective will be examined in the following specific aims: Aim 1: Define the effects of dietary I-3 and I-6 supplementation on the enteric microbiota and microbial production of inflammatory markers in an established mouse model of colitis. Aim 2: Define the effects of dietary I-3 and I-6 supplementation on the host inflammatory response to altered microbiota in conventional and germ-free IL10-/- mouse models.