Angiotensin (1-7) [Ang (1-7)] is an active heptapeptide of the non-canonical arm of the renin-angiotensin system that modulates molecular signaling pathways associated with vascular and cellular inflammation, vasoconstriction and fibrosis. Pre-clinical 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-weeks of intervention, the 16S mRNA microbiome analysis revealed a main effect of probiotic treatment within and between groups. The probiotic treatment enhanced alpha diversity (Inverse Simpson (F[2,56] = 4.44; p = 0.02); Shannon-Wiener (F[2,56] = 4.27; p = 0.02)) and beta-diversity (F[2,56] = 2.66; p = 0.01) amongst rats receiving our GMP. The analysis of microbes’ composition revealed 3 genera’s altered by our GMP (Enterorhabdus, Muribaculaceae unclassified and Faecalitalea). The mRNA multi-tissue data analysis showed that our combined intervention upregulated neuro-remodeling 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. Lastly, the integrative network analysis detected different communities of tightly (|r| > 0.8 and p < 0.05) correlated metabolites, genera’s and genes in these tissues.