An integrated study of gut microbiota and serum metabolites in T2DM-ED rats after fecal microbiota transplantation.

Erectile dysfunction (ED) is a highly prevalent and refractory complication of type 2 diabetes mellitus (T2DM), with penile cavernosal dysfunction, inflammation, apoptosis, and fibrosis as core pathological features. Here we identify gut microbiota dysbiosis and its downstream metabolite arachidonic acid (AA) as critical mediators of T2DM-associated erectile dysfunction (T2DM-ED) through a systemic gut-penis axis. Gut dysbiosis is sufficient to induce an ED phenotype, as demonstrated by fecal microbiota transplantation (FMT) from T2DM-ED rats into pseudo-germ-free recipients, which successfully transferred the erectile impairment with significantly decreased ICP/MAP ratios. Recipient rats showed impaired colonic barrier integrity, mucosal damage, goblet cell depletion, and downregulated tight junction proteins (Occludin, Claudin-4). Multi-omics integration of 16S rRNA sequencing and serum metabolomics identified AA as a key elevated metabolite that drives inflammatory signaling via the HIF-1α and NF-κB pathways. In penile corpus cavernosum tissue, ED-FMT rats displayed smooth muscle loss, fibrosis, increased apoptosis, and hyperactivation of the TLR4-MyD88-NF-κB-HIF-1α axis. In primary corpus cavernosum smooth muscle cells (CCSMCs), AA stimulation recapitulated pathological activation, including a pro-apoptotic shift in the Bax/Bcl-2 ratio, elevated Cleaved Caspase-3, reduced α-SMA, increased COX-2, stabilized HIF-1α, and excessive PGE2 production; these effects were abolished by pharmacological inhibition of NF-κB. Mechanistically, gut dysbiosis-induced systemic AA accumulation triggers inflammatory damage, apoptosis, and functional impairment in penile smooth muscle via the TLR4-MyD88-NF-κB/HIF-1α cascade. These findings define a gut-AA-NF-κB-penis axis that drives T2DM-ED pathogenesis, highlighting AA and its downstream signaling as promising therapeutic targets for diabetic erectile dysfunction.