Metabolic modeling reveals the aging-associated decline of host-microbiome metabolic interactions in mice

Aging is the predominant cause of morbidity and mortality in industrialized countries. The specific molecular mechanisms that drive aging are poorly understood, especially the contribution of the microbiota in these processes. Here, we combined multi-omics with metabolic modeling in mice to comprehensively characterize host-microbiome interactions and how they are affected by aging. Our findings reveal a complex dependency of host metabolism on microbial functions, including previously known as well as novel interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome, which we attribute to reduced beneficial interactions in the microbial community and a reduction in the metabolic output of the microbiome. These microbial changes coincided with a corresponding downregulation of key host pathways predicted by our model that are crucial for maintaining intestinal barrier function, cellular replication, and homeostasis. Our results elucidate potential microbiome-host interactions that may influence host aging processes, focusing on microbial nucleotide metabolism as a pivotal factor in aging dynamics. total-RNA with Illumina's TruSeq stranded kit, with polyA enrichment, 100bp or 75bp paired end sequencing of 52 samples each from male mice's (C57BL/6J/Ukj) colons, livers, brains at different ages: 2 (n = 10), 9 (n = 10), 15 (n = 10), 24 (n = 10), and 30 (n = 12) months.衰老是工业化国家人群发病与死亡的首要诱因。目前学界对驱动衰老的特异性分子机制尚缺乏深入认知，尤以微生物群（microbiota）在衰老进程中的调控作用为甚。 本研究以小鼠为模型，将多组学技术（multi-omics）与代谢建模（metabolic modeling）相结合，全面解析宿主-微生物组（microbiome）互作关系及其受衰老的影响机制。 研究结果揭示了宿主代谢对微生物功能的复杂依赖性，涵盖既往已报道与全新发现的互作模式。我们观察到衰老状态下微生物组的代谢活性显著降低，该现象可归因于微生物群落内有益互作的减弱以及微生物组整体代谢产出的下降。 上述微生物组的变化与我们模型预测的关键宿主通路的下调高度吻合，这些通路对维持肠道屏障功能、细胞增殖及体内稳态至关重要。 本研究阐明了可能影响宿主衰老进程的潜在微生物组-宿主互作机制，并聚焦微生物核苷酸代谢作为衰老动态调控的关键因素。 本研究采用Illumina TruSeq链特异性建库试剂盒进行总RNA（total-RNA）建库，辅以polyA富集（polyA enrichment），对不同周龄雄性C57BL/6J/Ukj小鼠的结肠、肝脏、脑组织样本开展100bp或75bp双端测序（paired end sequencing），共纳入52份样本：2月龄（n=10）、9月龄（n=10）、15月龄（n=10）、24月龄（n=10）及30月龄（n=12）。