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

补充 W-3 通过改变肠道微生物组对 IBD 产生影响

• 批准号: 7912766
• 负责人: Suzanne Devkota
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912766
• 关键词: Bacteria; Bioinformatics; Chronic; Clinical; Colitis; Data; Diabetes Mellitus; Diet; Disease; Distress; Enteral; Environment; Fish Oils; Genetic Predisposition to Disease; Germ-Free; Homeostasis; Immune response; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Interleukin-10; Intestines; Life; Link; Mucositis; Mus; Nature; Obesity; Onset of illness; Pathogenesis; Pathologic; Patients; Play; Production; Role; Supplementation; Symptoms; gastrointestinal; gut microbiota; inflammatory marker; insight; metabolomics; microbial; microbiome; mouse model; novel; prevent; public health relevance; response; saturated fat

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The insights gained through these studies will provide clues to the fundamental nature of inflammatory bowel diseases pathogenesis. Accordingly, this information will help define complementary or alternative strategies to restore intestinal microbiota or host immune responses to non-inflammatory state, thereby preventing or treating inflammatory bowel diseases.

描述（由申请人提供）：公认的是，我们与肠道微生物群生活在共生体内平衡中，改变这种微生物群的数量或组成的扰动可能导致胃肠道不适。最近，我们的微生物群的稳态改变与肥胖，糖尿病和炎症性肠病（IBD）等疾病有关。在IBD的情况下，临床证据表明慢性炎症是由遗传易感性患者背景上的环境/微生物因素组合引起的。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）存在对正常肠道植物群的遗传定义的异常宿主反应，其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）。哪一个在引起IBD中起主要作用尚不清楚，因为几乎所有的研究都是在疾病发作后进行的。关于各种饮食组合物对我们肠道中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，我们所知甚少。我对正常小鼠的初步数据显示，高饱和脂肪饮食会诱导一种与一系列炎症性疾病有关的细菌菌株大量繁殖。来自我们实验室的数据还表明，高饱和脂肪饮食显著增加了遗传易感小鼠模型中结肠炎的发病率。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，因为没有机制研究可以解释这种相关性。因此，本项目的目的是通过改变肠道微生物环境，为I-3鱼油补充剂对IBD的影响提供新的见解。这一目的将通过使用建立的遗传易感性结肠炎（IL 10-/-）小鼠模型和完全缺乏肠道微生物群的新型IL 10-/-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。项目目标将在以下具体目标中进行检查：目标1：确定饮食I-3和I-6补充剂对肠道微生物群和炎症标记物在已建立的小鼠结肠炎模型中的微生物产生的影响。 目标二：在常规和无菌IL 10-/-小鼠模型中，确定膳食补充I-3和I-6对宿主对改变的微生物群的炎症反应的影响。 公共卫生关系：通过这些研究获得的见解将为炎症性肠病发病机制的基本性质提供线索。因此，这些信息将有助于定义补充或替代策略，以恢复肠道微生物群或宿主免疫应答至非炎症状态，从而预防或治疗炎症性肠病。