Division of Gerontology, Geriatrics and Palliative Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States.
Research Center for Physical Activity, Health and Leisure, Faculty of Sport, University of Porto, Porto, Portugal.
J Appl Physiol (1985). 2023 May 1;134(5):1135-1153. doi: 10.1152/japplphysiol.00508.2022. Epub 2023 Mar 9.
Angiotensin (1-7) [Ang (1-7)] is an active heptapeptide of the noncanonical arm of the renin-angiotensin system that modulates molecular signaling pathways associated with vascular and cellular inflammation, vasoconstriction, and fibrosis. Preclinical evidence suggests that Ang (1-7) is a promising therapeutic target that may ameliorate physical and cognitive function in late life. However, treatment pharmacodynamics limits its clinical applicability. Therefore, this study explored the underlying mechanisms altered by a genetically modified probiotic (GMP) that expresses Ang (1-7) combined with and without exercise training in an aging male rat model as a potential adjunct strategy to exercise training to counteract the decline of physical and cognitive function. We evaluated cross-tissue (prefrontal cortex, hippocampus, colon, liver, and skeletal muscle) multi-omics responses. After 12 wk of intervention, the 16S mRNA microbiome analysis revealed a main effect of probiotic treatment within- and between groups. The probiotic treatment enhanced α diversity (Inverse Simpson ([2,56] = 4.44; = 0.02); Shannon-Wiener ([2,56] = 4.27; = 0.02)) and β-diversity ([2,56] = 2.66; = 0.01) among rats receiving our GMP. The analysis of microbes' composition revealed three genera altered by our GMP (, , and ). The mRNA multi-tissue data analysis showed that our combined intervention upregulated neuroremodeling pathways on prefrontal cortex (i.e., 140 genes), inflammation gene expression in the liver (i.e., 63 genes), and circadian rhythm signaling on skeletal muscle. Finally, the integrative network analysis detected different communities of tightly (|| > 0.8 and < 0.05) correlated metabolites, , and genes in these tissues. This manuscript uses a multiomics approach (i.e., microbiome, metabolomics, and transcriptomics) to explore the underlying mechanisms driven by a genetically modified probiotic (GMP) designed to express angiotensin (1-7) combined with moderate exercise training in an aged male rat model. After 12 wk of intervention, our findings suggest that our GMP enhanced gut microbial diversity while exercise training altered the transcriptional response in relevant neuroremodeling genes, inflammation, and circadian rhythm signaling pathways in an aging animal model.
血管紧张素 (1-7) [Ang (1-7)] 是肾素-血管紧张素系统非经典途径的一种活性七肽，可调节与血管和细胞炎症、血管收缩和纤维化相关的分子信号通路。临床前证据表明，Ang (1-7) 是一种很有前途的治疗靶点，可能改善老年动物的身体和认知功能。然而，治疗的药效学限制了其临床应用。因此，本研究探讨了一种表达 Ang (1-7) 的基因工程益生菌 (GMP) 联合和不联合运动训练在衰老雄性大鼠模型中改变的潜在机制，作为一种潜在的辅助策略来对抗身体和认知功能下降。我们评估了跨组织（前额叶皮层、海马体、结肠、肝脏和骨骼肌）多组学反应。干预 12 周后，16S mRNA 微生物组分析显示益生菌治疗在组内和组间均有主要作用。益生菌治疗增强了接受我们 GMP 治疗的大鼠的 α 多样性（逆辛普森 ([2,56] = 4.44; = 0.02)；香农-威纳 ([2,56] = 4.27; = 0.02)）和 β 多样性 ([2,56] = 2.66; = 0.01)。微生物组成分析显示，我们的 GMP 改变了三个属（，，和）。多组织 mRNA 数据分析显示，我们的联合干预上调了前额叶皮层的神经重塑途径（即 140 个基因）、肝脏的炎症基因表达（即 63 个基因）和骨骼肌的昼夜节律信号。最后，整合网络分析检测到这些组织中紧密相关（|| > 0.8 和 < 0.05）的代谢物、和基因的不同群落。本研究使用多组学方法（即微生物组学、代谢组学和转录组学）来探索一种基因工程益生菌（GMP）设计用于表达血管紧张素 (1-7)，并联合中等强度运动训练在衰老雄性大鼠模型中的潜在机制。干预 12 周后，我们的研究结果表明，我们的 GMP 增强了肠道微生物多样性，而运动训练改变了衰老动物模型中相关神经重塑基因、炎症和昼夜节律信号通路的转录反应。
