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

Area of Science:

• Reproductive Biology
• Microbiome Research
• High Altitude Physiology

Background:

• High altitude (HA) exposure is associated with impaired male fertility and altered gut microbiota.
• The specific mechanisms linking HA, gut microbes, and sperm quality are not well understood.

Purpose of the Study:

• To investigate the association between HA-induced gut microbiota changes and male reproductive health.
• To elucidate the underlying molecular mechanisms of HA-induced sperm impairment.

Main Methods:

• Comparative analysis of gut microbiota in human populations at high altitude and mice under HA-mimicking conditions.
• Identification of specific bacterial species and their metabolites affecting sperm quality.
• Investigation of signaling pathways involved in testicular inflammation and apoptosis.

Main Results:

• HA exposure led to increased intestinal Clostridium symbiosum colonization in humans and mice.
• C. symbiosum produced succinic acid (su), which reduced sperm quality.
• Succinic acid activated the TRPV4/Ca2+ pathway in testicular macrophages, promoting inflammation and apoptosis of spermatogenic cells.

Conclusions:

• HA-induced gut dysbiosis, specifically C. symbiosum overgrowth, contributes to reduced sperm quality.
• Succinic acid acts as a key mediator, disrupting testicular immune homeostasis via the GPR91-TRPV4 pathway.
• Targeting gut microbiota may offer therapeutic strategies for high altitude-induced male infertility.