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

人们普遍认为，我们与肠道微生物群生活在共生稳态中，而改变肠道微生物群数量或组成的扰动会导致胃肠道不适。最近，我们体内微生物群体内平衡的改变与肥胖、糖尿病和炎症性肠病（IBD）等疾病有关。在IBD的病例中，临床证据表明慢性炎症是由环境/微生物因素结合患者遗传易感性背景引起的。这种关系背后的机制尚不清楚，但存在两种可能性，我们试图研究：1)存在遗传上定义的，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)肠道微生物群组成的改变触发遗传易感个体的病理反应（微生物群触发）。哪一种在引起IBD中起主要作用尚不清楚，因为几乎所有的研究都是在发病后进行的。关于不同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体易患IBD或使病情恶化，我们所知的就更少了。我在正常老鼠身上的初步数据表明，高饱和脂肪的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。我们实验室的数据也表明，高饱和脂肪饮食显著增加结肠炎的发生率在遗传易感小鼠模型。相反，在许多研究中，鱼油补充剂已被证明可以缓解IBD的症状，但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，该项目的目的是通过改变肠道微生物环境，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结肠炎小鼠模型（IL10-/-）和完全缺乏肠道微生物群的新型IL10-/-无菌（GF）小鼠来实现，这将阐明微生物群的直接因果作用。分析将包括高通量焦磷酸测序和代谢组学分析改变的微生物物种和随后的宿主炎症反应。目的1：在已建立的结肠炎小鼠模型中，确定膳食中添加I-3和I-6对肠道微生物群和炎症标志物微生物产生的影响。目的2：在常规和无菌il - 10-/-小鼠模型中，确定膳食中补充I-3和I-6对宿主对微生物群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.