Chronic stress drives oligoasthenozoospermia via gut microbiota-vitamin-Sting1/Slc9c2 axis

Male infertility is linked to chronic psychological stress, however, the mechanisms underlying chronic stress-induced oligoasthenozoospermia (OAZS) remain incompletely elucidated. Here, we establish a chronic forced swim stress (CFSS) rat model and identify a gut microbiota-testis/epididymis axis as the mediator. CFSS activates the HPA axis, leading to elevated corticosterone levels. The excessed glucocorticoid compromises gut barrier integrity via glucocorticoid receptor signaling, resulting in depletion of Lactobacillus and disruption of vitamins A/E metabolism. These deficits promote upregulation of Sting1. Concurrently, epididymal transcriptomics analysis reveals downregulation of Slc9c2 as the basis for impaired sperm motility. Notably, restoration of Lactobacillus and dietary supplementation with vitamins A/E ameliorate OAZS phenotypes. Genetic targeting Sting1/Slc9c2 in CFSS model rats treated with vitamins A/E, validating the involvement of vitamin A/E metabolism-Sting1/Slc9c2 axis in mediating CFSS-induced OAZS. These findings redefines OAZS as a multisystem disorder driven by gut microbial-metabolic-testis/epididymis axis dysregulation and proposes microbiota-targeted therapies for chronic stress-induced infertility.