Young Human-Derived Microbiota Ameliorates Cognitive Decline and Reproductive Senescence in Aged Mice.

Background/Objectives: Age-related gut microbiota dysbiosis leads to systemic oxidative stress, chronic inflammation, and multi-organ functional decline. However, there is limited evidence supporting microbiota-based therapies for aging. This study aimed to examine the effect of gut microbiota from young donors, particularly those with increasing Bifidobacteria levels through dietary intervention, on age-related declines in fertility, cognition, and reproduction. Methods: We conducted experiments using gut microbiota from young human donors, with or without pre-conditioning with barley leaves (BL), to transplant into aged male mice. Hippocampal metabolome and behavioral assessments were used to identify differences in recognitive regulation during aging. Moreover, testis tissue, semen quality, and offspring studies were determined to investigate the beneficial effects on fertility and underlying mechanism. Conclusions: This preliminary dietary treatment promotes the growth of Bifidobacterium in aged recipient mice. Aged male mice received young fecal microbiota transplants (yFMTs), BL-conditioned yFMTs (BLyFMTs), and a combined treatment of BLyFMT plus recipient BL supplementation. The combined approach significantly increased intestinal Bifidobacterium levels and effectively restored hippocampal metabolomic profiles and cognitive behavior. Additionally, yFMT-based treatments mitigated structural damage to the seminiferous tubules and prevented the germ cell depletion. Consistently, those interventions improved sperm quality and mechanistically enhanced hypothalamic-pituitary-gonadal (HPG) axis activity in aged recipients. These findings highlight Bifidobacterium as a key factor in microbiome-driven rejuvenation, enhancing the effectiveness of yFMTs in addressing aging-related declines.