Reproductive aging represents a critical physiological bottleneck characterized by a progressive decline in tissue homeostasis and physiological function. While the gut microbiota is known to shift during host aging, the ecological forces governing the assembly of the reproductive microbiota and its functional feedback on uterine homeostasis remain poorly understood. We demonstrated that uterine aging drives a transition from stochastic to deterministic microbial community assembly, selecting for a microbiota enriched in Rhodococcus in aged laying hens. Multi-omics analyses revealed that this deterministic shift acts as a compensatory mechanism to counteract age-related energy metabolism decline in the uterus. Mechanistically, the aged uterus suffered from oxidative phosphorylation impairment due to PARP1-mediated NAD+ depletion in response to accumulated DNA damage. However, the specific colonization of Rhodococcus ruber, or the administration of its metabolite spermidine, rescued this phenotype. Spermidine improved uterine energy metabolism by inducing PINK1/Parkin-mediated mitophagy, thereby restoring mitochondrial quality control and ATP production essential for eggshell biomineralization. This study uncovers a previously unrecognized role of the microbiota in reproductive aging: resident microbes enhance oxidative phosphorylation in the aged uterus through the metabolite spermidine, which induces mitophagy. This process alleviates cellular energy deficiency caused by PARP1-mediated NAD + depletion, elucidating a key mechanism of host–microbe interaction in maintaining uterine energy homeostasis during aging.
Dai et al. (Fri,) studied this question.