Nighttime-restricted feeding disrupts spermatogenesis in mice via gut microbiota-derived KYNA homeostasis

Time-restricted feeding (TRF) may modulate metabolic homeostasis through circadian rhythms, but its effects on male fertility remain unclear. This study investigates how different TRF schedules influence testicular homeostasis and spermatogenesis, focusing on the gut-testis axis. Mice are subjected to daytime (DRF) or nighttime (NRF) restricted feeding, compared with ad libitum controls. The results show that NRF reduces testicular index and sperm quality, while DRF shows no adverse effects. Histological analysis confirms decreased numbers of spermatocytes and spermatozoa in the NRF group. 16S rRNA sequencing reveals altered gut microbiota composition in NRF mice, and metabolomics identify elevated levels of kynurenic acid (KYNA), a tryptophan metabolite. KYNA administration inhibits spermatogenesis in a dose-dependent manner, mimicking the NRF phenotype. These findings suggest that feeding timing influences male reproductive health, with gut-derived metabolites like KYNA potentially mediating TRF effects, offering new targets for fertility interventions.