Disappearing gastrointestinal microbiota in epidemic obesity.

描述(申请人提供)：肥胖症的发病率在美国和其他发达国家一直在迅速增加。我们的假设是，由于包括抗生素暴露在内的现代化，起源于古老的本土微生物种群正在发生变化。我们的假设是，微生物群组成的这些变化至少在一定程度上对肥胖率的增加起到了作用。更具体地说，我们还假设，常见的抗生素治疗顺便引起代谢活跃的胃肠道细菌种群组成的变化，并且这种影响可能是连续的，母体的变化随后被下一代遗传。我们将通过研究结肠微生物区系和幽门螺杆菌来验证这一假设，幽门螺杆菌是与胃上皮相互作用的主要胃细菌，胃上皮产生的激素(瘦素和胃促生长素)参与能量稳态。我们提出了5项研究。研究A1将评估母亲幽门螺杆菌状况与荷兰目前登记的队列中儿童肥胖症发展的关系。研究A2将研究幽门螺杆菌感染儿童与胃激素、炎症和免疫的生理学之间的关系。研究A3将评估由于临床指示根除幽门螺杆菌而导致的年轻成年人激素和代谢表型的变化。研究B1将评估持续给予低剂量抗生素对小鼠代谢和激素表型的影响。研究B2将检查单胞胎和双胞胎出生后第一年肠道微生物区系的发育，并将评估抗生素扰动对发育过程的影响。总之，这些研究将检验胃和结肠细菌种群组成的变化与代谢表型的关系，并提供进一步探索的机会。 与公共健康相关：在美国和其他发达国家，肥胖症的发病率正在迅速增加。我们将探索这样一种假设，即胃肠道古老的内源性微生物区系的组成和活动的变化在肥胖的发展中发挥了作用。我们将专注于母体和抗生素对胃和结肠细菌种群组成的影响，以及它们对代谢的影响。

DESCRIPTION (provided by applicant): The incidence of obesity has been rapidly increasing in the United States and other developed countries. Our hypothesis is that changes are occurring in the indigenous microbial populations that are of ancient origin, due to modernization including antibiotic exposure. Our hypothesis is that these changes in the composition of the microbiome are at least in part playing a role in the increasing incidence of obesity. More specifically, we also hypothesize that common antibiotic treatments are incidentally causing changes in the composition of metabolically active gastrointestinal bacterial populations, and that the effects may be sequential in which maternal changes are then inherited by the next generation. We will test this hypothesis by studying both the colonic microbiota, and Helicobacter pylori, the dominant gastric bacteria that interact with gastric epithelium, which produces hormones (leptin and ghrelin) that are involved in energy homeostasis. We propose 5 studies. Study A1 will be to assess the association of maternal H. pylori status on the development of childhood obesity in a presently enrolled cohort in The Netherlands. Study A2 will examine the relationship in children of H. pylori status and the physiology of gastric hormones, inflammation, and immunity. Study A3 will assess the changes in hormonal and metabolic phenotypes in young adults due to clinically indicated eradication of H. pylori. Study B1 will assess the effects on young mice of the continuous administration of low antibiotic doses in terms of metabolic and hormonal phenotypes. Study B2 will examine the development of the intestinal microbiota over the first year of life in singletons and twins, and will assess the effects of antibiotic perturbation on the developmental process. In total, these studies will examine the relationship changing gastric and colonic bacterial population composition with metabolic phenotypes, and provide opportunities for further exploration. PUBLIC HEALTH RELEVANCE: The incidence of obesity is rapidly increasing in the United States and other developed countries. We will explore the hypothesis that changes in the composition and activity of the ancient endogenous microbiota of the gastrointestinal tract is playing a role in the development of obesity. We will focus on both maternal and antibiotic effects on the composition of the gastric and colonic bacterial populations, and their metabolic effects.