Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria.
Institute of Animal Science, University of Hohenheim, Stuttgart, Germany.
Int J Med Microbiol. 2021 May;311(4):151500. doi: 10.1016/j.ijmm.2021.151500. Epub 2021 Mar 29.
The number of people above the age of 60 years is raising world-wide being associated with an increase in the prevalence of aging-associated impairments and even diseases. Recent studies suggest that aging is associated with alterations in bacterial endotoxin levels and that these changes may add to low-grade inflammation, the so-called 'inflammaging', and aging-associated liver degeneration. However, mechanisms involved, and especially, the interaction of intestinal microbiota and barrier in the development of aging-associated inflammation and liver degeneration have not been fully understood.
The aim of the present study was to determine if intestinal microbiota composition changes with age and if these alterations are associated with changes of markers of intestinal barrier function and the development of inflammation and liver degeneration.
Blood, liver, small and large intestinal tissue of male 2-, 15-, 24- and 30-months old C57BL/6 mice fed standard chow were obtained. Intestinal microbiota composition, expression levels of antimicrobial peptides in small intestine and markers of intestinal barrier function were measured. Furthermore, indices of liver damage, inflammation and expression levels of lipopolysaccharide binding protein (Lbp) as well as of toll-like receptors (Tlr) 1-9 in liver tissue were assessed.
Pairwise comparisons of the microbial community in the small intestine showed differences between 2- and 24-, 15- and 24-, as well as 15- and 30-months old animals while Shannon's diversity, species richness and evenness indexes did not differ in both small and large intestine, respectively, between age groups. Concentrations of nitric oxide were significantly lower in small intestine of 15-, 24- and 30-months old mice compared to 2-months old mice while mRNA expression of the antimicrobial peptides defensin alpha 1 and lysozyme 1 was unchanged. In contrast, in liver tissue, older age of animals was associated with increasing inflammation and the development of fibrosis in 24- and 30-months old mice. Numbers of inflammatory foci and neutrophils in livers of 24- and 30-months old mice were significantly higher compared to 2-months old mice. These alterations were also associated with higher endotoxin levels in plasma as well as an increased mRNA expression of Lbp and Tlr1, Tlr2, Tlr4, Tlr6 and Tlr9 in livers in older mice.
Despite no consistent and robust changes of microbiota composition in small and/or large intestine of mice of different age were observed, our data suggest that alterations of markers of intestinal barrier function in small intestine are associated with an induction of several Tlrs and beginning hepatic inflammation in older mice and increase with age.
全球 60 岁以上人口数量增加，与衰老相关损伤甚至疾病的患病率增加有关。最近的研究表明，衰老与细菌内毒素水平的改变有关，这些变化可能会导致低水平炎症，即所谓的“炎症衰老”，以及与衰老相关的肝脏退化。然而，涉及的机制，特别是肠道微生物群和屏障在衰老相关炎症和肝脏退化发展中的相互作用，尚未完全理解。
本研究旨在确定肠道微生物群组成是否随年龄而变化，以及这些变化是否与肠道屏障功能标志物的变化以及炎症和肝脏退化的发生有关。
获取 2、15、24 和 30 月龄雄性 C57BL/6 小鼠的血液、肝脏、小肠和大肠组织。测量肠道微生物群组成、小肠中抗菌肽的表达水平以及肠道屏障功能的标志物。此外，还评估了肝损伤、炎症的指标以及肝组织中脂多糖结合蛋白（Lbp）和 toll 样受体（TLR）1-9 的表达水平。
小肠微生物群落的两两比较显示，2 月龄和 24 月龄、15 月龄和 24 月龄以及 15 月龄和 30 月龄动物之间存在差异，而小、大肠微生物群落的香农多样性、物种丰富度和均匀度指数在不同年龄组之间均无差异。与 2 月龄小鼠相比，15、24 和 30 月龄小鼠的小肠中一氧化氮浓度显著降低，而抗菌肽防御素 alpha 1 和溶菌酶 1 的 mRNA 表达不变。相反，在肝脏组织中，动物年龄的增加与 24 月龄和 30 月龄小鼠的炎症和纤维化的发展有关。与 2 月龄小鼠相比，24 月龄和 30 月龄小鼠肝脏中的炎症灶和中性粒细胞数量明显增加。这些变化还与血浆中内毒素水平的升高以及肝脏中 Lbp 和 TLR1、TLR2、TLR4、TLR6 和 TLR9 的 mRNA 表达增加有关。
尽管在不同年龄的小鼠的小、大肠中没有观察到一致且显著的微生物群落组成变化，但我们的数据表明，小肠中肠道屏障功能标志物的改变与几个 TLR 的诱导以及老年小鼠的肝脏炎症早期发生有关，并随年龄的增长而增加。
