Disappearing gastrointestinal microbiota in epidemic obesity.

描述（由申请人提供）：在美国和其他发达国家，肥胖症的发病率正在迅速上升。我们的假设是，由于包括抗生素暴露在内的现代化，古老起源的本地微生物种群正在发生变化。我们的假设是，这些微生物组组成的变化至少在一定程度上导致了肥胖发病率的增加。更具体地说，我们还假设常见的抗生素治疗偶然导致代谢活跃的胃肠道细菌群的组成发生变化，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群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，胃上皮产生参与能量稳态的激素（瘦素和胃饥饿素）。我们提出了5项研究。研究A1将评估目前在荷兰登记的队列中母亲幽门螺杆菌状态与儿童肥胖发展的关系。研究A2将研究儿童幽门螺杆菌状态与胃激素、炎症和免疫生理的关系。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人激素和代谢表型的变化。研究B1将从代谢和激素表型方面评估低剂量持续给药对幼鼠的影响。研究B2将检查单胎和双胞胎出生后第一年肠道微生物群的发育，并将评估抗生素干扰对发育过程的影响。总之，这些研究将检验胃和结肠细菌种群组成变化与代谢表型的关系，并为进一步探索提供机会。

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.