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

High-altitude exposure in humans and mice is associated with reduced sperm quality and gut microbiota changes.

• HA-induced gut microbiota changes were observed in both human populations residing at high altitude and mice exposed to HA-mimicking conditions.
• The study demonstrates a link between microbial imbalance and male spermatogenesis impairment under HA conditions.
• Both human and mouse models showed consistent associations between HA exposure and sperm quality decline.

Clostridium symbiosum colonization is increased in the intestines of high-altitude human populations and HA-exposed mice.

• C. symbiosum was specifically identified as the key bacterium elevated under HA conditions.
• The increase in C. symbiosum was observed in both human HA populations and mice exposed to HA-mimicking conditions.
• C. symbiosum colonization was causally linked to a decline in sperm quality.

Clostridium symbiosum impairs sperm quality through the production of succinic acid.

• Succinic acid (su) was identified as the specific metabolite produced by C. symbiosum responsible for sperm quality decline.
• The influence of C. symbiosum on sperm quality was shown to be mediated through succinic acid production.
• This finding identifies a gut metabolite as a key mediator linking microbiota changes to testicular dysfunction.

Succinic acid targets GPR91 to activate TRPV4/Ca2+ signaling in testicular macrophages, driving inflammatory polarization.

• Succinic acid targets G-protein-coupled receptor 91 (GPR91) in testicular macrophages (TMs).
• GPR91 activation by succinic acid activates the TRPV4/Ca2+ signaling pathway.
• This signaling cascade drives polarization of testicular macrophages into inflammatory CD68+CD163- subsets.
• The inflammatory macrophage polarization ultimately promotes TM-mediated apoptosis of spermatogenic cells.

The effects of C. symbiosum and succinic acid on sperm quality are dependent on TRPV4 signaling.

• The influence of C. symbiosum on sperm quality was shown to be dependent on TRPV4 signaling.
• The influence of succinic acid on sperm quality was also shown to be dependent on TRPV4 signaling.
• This dependency establishes TRPV4 as a critical node in the gut microbiota-testicular immune axis.

The study reveals a disrupted microbiota-immune axis within the testis under high-altitude exposure.

• The authors describe this as a 'disrupted microbiota-immune axis within the testis under HA exposure.'
• The findings offer 'potential therapeutic avenues for HA-induced sperm impairment based on gut microbiota manipulation.'
• The mechanistic pathway spans from gut microbiota composition to testicular macrophage function and spermatogenic cell survival.