Gut-derived succinic acid potentiates high-altitude-related spermatogenesis dysfunction

Exposure to high altitude (HA) is linked to male spermatogenesis impairment and microbial imbalance; however, the association and underlying mechanisms remain unexplored. Herein, we demonstrate that HA-induced gut microbiota changes in humans and mice lead to reduced sperm quality. Specifically, we observe an increase in intestinal Clostridium symbiosum colonization in HA human populations and mice exposed to HA-mimicking conditions. Furthermore, C. symbiosum causes a decline in sperm quality through succinic acid (su) production. Mechanistically, su targets G-protein-coupled receptor 91(GPR91) to activate the TRPV4/Ca²⁺ signaling pathway in testicular macrophages (TMs), driving their polarization into inflammatory CD68⁺CD163^- subsets, and ultimately promoting TM-mediated apoptosis of spermatogenic cells. Notably, the influence of C. symbiosum or su on sperm quality is dependent on TRPV4 signaling. Our study reveals a disrupted microbiota-immune axis within the testis under HA exposure, offering potential therapeutic avenues for HA-induced sperm impairment based on gut microbiota manipulation.