Aging-associated modification of intestinal homeostasis and barrier function: Role of microbiota, iNOS and innate immunity

几项研究的结果表明，肠道微生物群和屏障功能可能主要影响健康维持和寿命，从而也调节健康寿命。此外，肠道屏障功能的损害，肠道微生物群组成的变化和TH 1/TH 2细胞平衡的改变以及肠道中的氧化还原状态被讨论为在老年人中经常发现的低度炎症的发展中至关重要。我们最近发现，小鼠的衰老与肠道菌群组成的变化和肠道屏障功能的损害有关，这与小肠上部iNOS和促炎介质的表达水平降低有关。然而，肠道微生物群，屏障功能，免疫系统和衰老相关的退化和衰退之间的相互作用仅部分了解。从这一背景出发，本研究项目的目的是使用小鼠模型（1）描述肠道稳态和屏障功能在什么年龄发生改变，以及这些变化是否与肠道微生物群组成和NO生物利用度的改变以及小肠和大肠组织中的TH 1细胞流行率相关，和（2）确定通过iNOS的NO合成在肠道微生物群组成和屏障功能的老化相关修饰中的作用。在此，我们将特别关注膳食组成和能量生物利用度的作用，以及确定新的靶向策略，以防止肠道微生物群组成和屏障功能的老化相关改变。因此，我们的目标也是增加对微生物-宿主相互作用的基本原理的理解。

Results of several studies suggest that intestinal microbiota and barrier function may majorly impact health maintenance and longevity thereby also modulating healthy life-span. Furthermore, impairments of intestinal barrier function, changes in intestinal microbiota composition and alterations of the TH1/TH2 cell balance as well as redox status in the gut are discussed to be critical in the development of the low-grade inflammation frequently found in elderly. We recently found that old age in mice is associated with changes of intestinal microbiota composition and impairments of intestinal barrier function which went alongwith decreased expression levels of iNOS and proinflammatory mediators in the upper parts of the small intestine. However, the interaction between intestinal microbiota, barrier function, immune system and aging-associated degeneration and decline is only partially understood. Starting from this background, using mouse models the aim of the present research project is (1) to delineate at what age modifications of intestinal homeostasis and barrier function set in and if these changes are associated with alterations of intestinal microbiota composition and NO bioavailability as well as TH1 cells prevalence in small and large intestinal tissue, and (2) to determine the role of NO-synthesis through iNOS in aging-associated modifications of intestinal microbiota composition and barrier function. Herein, we will especially focus on the role of dietary composition and energy bioavailability as well as the identification of novel targeting strategies to prevent aging-associated alterations of intestinal microbiota composition and barrier function. We thereby also aim to add to the understanding of the fundamental principles of microbe-host interaction.