Seminal dysbiosis in idiopathic male infertility: toward a seminal dysbiosis–inflammatory/oxidative endophenotype–SDF axis
TL;DR
This approach provides a falsifiable structure for IMI and provides a template for future trial designs based on SD×IO stratification, which may reduce effect dilution across mixed populations and make the hypothesis more directly testable.
Abstract
Idiopathic male infertility (IMI) usually refers to abnormal semen parameters after known causes have been excluded. However, its clinical stratification and intervention evidence remain difficult to reconcile. Based on low biomass in semen, this review proposes an SD–IO–SDF axis linking seminal dysbiosis (SD), inflammatory/oxidative endophenotype (IO), and sperm DNA fragmentation (SDF) in subsets of IMI. It integrates three mechanisms of evidence strength: (i) inflammation–oxidative injury pathway (leukocyte-dependent); (ii) leukocyte-independent redox imbalance; and (iii) a metabolic–epigenetic route (SAM cycle, butyrate) as a testable hypothesis. Existing evidence suggests that the association between SD and SDF concentrates in specific IO activation states and IMI subtypes. IO stratification may reduce effect dilution across mixed populations and make the hypothesis more directly testable. For research implementation, we propose IO indicators grouped by measurement type (inflammatory: leukocytospermia and/or PMN-elastase; oxidative: sORP), with validation against SDF platforms as a subsequent step. This approach provides a falsifiable structure for IMI and provides a template for future trial designs based on SD×IO stratification.