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

描述（由申请人提供）：遗传背景和某些刺激性肠道细菌定植的不幸组合可导致遗传易感个体发生炎症性肠病（IBD）。由于目前几乎无法纠正遗传易感性，因此以可预测和可持续的方式改变IBD患者的肠道植物群是一种切实可行的解决方案。我们相信这可以通过对肠道微生物群的饮食控制来实现。将检验两个假设：（1）在“西方饮食”中得到充分代表的某些膳食脂肪能够通过其对肠道微生物组的作用来促进或预防/改善结肠炎症（目标1），以及（2）用脂肪酸补充剂或增加的短链脂肪酸生物利用度的膳食干预可以重塑致病肠道微生物组以降低风险或改善IBD，从而为将来的临床应用奠定了基础。例如，我们表明，在IL-10 KO小鼠中发生结肠炎的风险可以通过富含饱和乳源性脂肪的饮食显着增加，这促进了免疫原性Deltaproteobacteria的大量繁殖，这些细菌是肠道微生物组的“稀有生物圈”的一部分。我们还表明，几种形式的膳食补充剂可以重塑和改变饱和脂肪诱导的肠道微生物群变化的免疫原性。这些研究将利用依赖于培养和非依赖于培养的方法以及DDRCC Host-Microbe Core的生物信息学分析服务。此外，微生物群转移和gnotobiotic动物技术将用于确定饮食诱导的肠道微生物群变化是否在产生免疫失衡和不良风险结果中起因果作用。总之，我们将确定饮食如何影响并可用于操纵肠道微生物群以恢复免疫稳态并降低复杂免疫介导疾病的风险和严重程度。通过这些研究获得的知识将为IBD的病因提供基本的见解，并帮助确定通过操纵肠道微生物群来预防或改善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.