Dietary fat effects on gut microbes, host immune state and experimental colitis

描述(由申请人提供)：不幸的是，遗传背景和某些煽动性共生细菌的定居结合在一起，可能导致遗传易感个体发展为炎症性肠病(IBD)。由于目前几乎没有办法纠正遗传易感性，以可预测和可持续的方式改变IBD患者的肠道菌群是一个切实和实用的解决方案。我们认为，这可以通过饮食控制肠道微生物区系来实现。将检验两个假设：(1)在“西方饮食”中得到很好代表的某些饮食脂肪能够通过对肠道微生物群的作用(目标1)来沉淀或预防/改善结肠炎，以及(2)通过脂肪酸补充剂或提高短链脂肪酸的生物利用度的饮食干预可以重塑致病肠道微生物群，以降低风险或改善IBD，从而为未来的临床应用奠定基础。例如，我们表明，高饱和乳源性脂肪的饮食可以显著增加IL-10KO小鼠患结肠炎的风险，这种脂肪促进了免疫原性三角洲蛋白细菌的繁殖，而三角洲蛋白细菌是肠道微生物群“稀有生物圈”的一部分。我们还表明，几种形式的饮食补充可以重塑和改变饱和脂肪引起的肠道微生物区系变化的免疫原性。这些研究将利用依赖培养和独立的方法以及DDRCC宿主-微生物核心的生物信息分析服务。此外，还将使用微生物区系转移和灵知生物群动物技术来确定饮食诱导的肠道微生物区系变化是否在造成免疫失衡和不良风险后果方面起到因果作用。综上所述，我们将确定饮食如何影响并可用于操纵肠道微生物区系，以恢复免疫稳态，降低复杂免疫介导性疾病的风险和严重性。通过这些研究获得的知识将为IBD的病因提供基本的见解，并有助于确定通过操纵肠道微生物区系来预防或改善IBD的饮食策略。

DESCRIPTION (provided by applicant): The unfortunate combination of genetic background and colonization by certain inciting commensal bacteria, can result in the development of inflammatory bowel diseases (IBD) in genetically susceptible individuals. Because little can be done presently to correct genetic susceptibility, changing the gut flora of IBD patients in a predictable and sustainable way represents a tangible and practical solution. We believe this can be accomplished through dietary manipulation of the enteric microbiota. Two hypotheses will be tested: (1) that certain dietary fats which that are well represented in "Western diets" ar capable of either precipitating or preventing/ameliorating colonic inflammation through their actions on the enteric microbiome (Aim 1), and (2) that dietary intervention with fatty acid supplements or increased short chain fatty acid bioavailability can reshape disease-causing enteric microbiomes to reduce risk or ameliorate IBD, thus setting the stage for future clinical application. We show, for instance, that risk for developing colitis in IL-10 KO mice can be significantly increased by diets high in saturated, milk-derived fat, which promote the bloom of immunogenic Deltaproteobacteria that are part of the "rare biosphere" of the enteric microbiome. We also show that several forms of dietary supplementation can reshape and alter the immunogenicity of saturated fat-induced changes in the enteric microbiota. These studies will take advantage of cultivation-dependent and -independent approaches and the bioinformatic analysis services of DDRCC Host-Microbe Core. In addition, microbiota transfer and gnotobiotic animal technologies will be used to determine if there is causal role of diet-induced changes of the enteric microbiota in creating immune imbalances and adverse risk outcomes. In summary, we will determine how diet affects and can be used to manipulate the enteric microbiota to restore immune homeostasis and reduce risk and severity of complex immune-mediated disorders. The knowledge gained through these studies will provide fundamental insights into the cause of IBD and help define dietary strategies to prevent or ameliorate IBD through manipulation of the enteric microbiota.