Lei Jin

Background and Objective: Infertility affects approximately 8–12% of couples worldwide, with male factors accounting for nearly half of all cases. The gut microbiota is widely recognized as a key regulator of host physiology, yet its specific role in male reproductive health remains to be elucidated. This narrative review synthesizes current evidence on the “gut microbiota-testis axis” and provides a critical evaluation of the strength of evidence derived from different study designs. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE up to May 2026 using Boolean search strategies combining terms related to the gut microbiota (e.g., “Gastrointestinal Microbiome”, “gut microbiota”, “gut microbiome”) with terms related to male reproduction (e.g., “Semen Analysis”, “Spermatozoa”, “Infertility, Male”, “semen quality”, “sperm quality”). Separate search strategies were developed for human and animal studies. Literature screening and data extraction were performed independently by two reviewers according to predefined inclusion and exclusion criteria. Key Content and Findings: Although human studies remain preliminary, several genera, including Anaerotruncus, Bacteroides, and Faecalibacterium prausnitzii, have been reproducibly associated with semen quality, with microbial metabolites such as butyrate, trimethylamine-N-oxide (TMAO), and succinate potentially serving as important mediators. At the mechanistic level, microbiota-derived metabolic and inflammatory signals act on Leydig cells, Sertoli cells, and germ cells, thereby influencing testosterone synthesis and spermatogenesis. Fecal microbiota transplantation (FMT) experiments in animal models have provided direct evidence for these causal links. Conclusions: The gut microbiota-testis axis has emerged as a critical physiological pathway linking the microbiome to male reproductive function. This review provides an evidence-based framework for understanding this axis and highlights key knowledge gaps that must be addressed. Future research should integrate large-scale longitudinal cohorts, mechanistic exploration, and randomized controlled trials with fertility outcomes as primary endpoints to advance the field from descriptive correlations toward mechanism-driven clinical translation.

While serum luteinizing hormone (LH) on the day of trigger is a conventional predictor of in vitro fertilization (IVF) outcomes, its clinical utility remai

Background: The sphingolipid rheostat – the interconversion between pro-apoptotic ceramide (Cer) and pro-survival sphingosine-1-phosphate (S1P) – governs female reproductive homeostasis. This review integrates mechanistic evidence across the reproductive continuum to elucidate how compartmentalised disruptions of this axis drive divergent pathologies. Methods: A systematic search up to 2026 across PubMed and Web of Science identified molecular mechanisms and translational models linking sphingolipid signalling to ovarian ageing, polycystic ovary syndrome (PCOS), endometriosis, adenomyosis and uterine fibroids. Results: Pathological Cer accumulation drives mitochondrial outer membrane permeabilisation (MOMP) and cytochrome c release, accelerating follicular atresia in primary ovarian insufficiency (POI). Conversely, PCOS is associated with heterogeneous remodeling of follicular-fluid sphingolipids, compromising oocyte competence. Within uterine and peritoneal microenvironments, a hyper-activated S1P axis operating via S1PR1–3 networks acts as a core pathogenic engine. This axis exhibits a threshold-dependent dual nature: low thresholds promote homeostatic survival, whereas high thresholds drive M2 macrophage polarisation for immune evasion and cross-link with TGF-β/Smad and Activin A cascades to stimulate fibroblast-to-myofibroblast transdifferentiation (FMT) and extracellular matrix deposition in endometriosis and fibroids. Additionally, the SphK/S1P axis amplifies chronic pelvic pain by modulating nerve growth factor (NGF) and transient receptor potential vanilloid 4 channels. Conclusions: The sphingolipid axis constitutes a unifying molecular rheostat in reproductive medicine. Mapping these compartmentalised lipidomic signatures enables high-resolution diagnostics, while targeted sub-receptor antagonists and non-hormonal drug repurposing offer promising, fertility-preserving therapeutic frontiers. However, successfully translating these lipid-targeted interventions into clinical practice demands addressing key bottlenecks regarding systemic off-target toxicities and engineering advanced, tissue-specific delivery platforms.

The age‐related decline in oocyte quality constitutes a major cause of reduced female fertility. In this study, we investigated the potential of stromal cell‐derived factor‐1 (SDF‐1) to counteract oocyte deterioration during reproductive aging. We observed a significant negative correlation between SDF‐1 levels and aging in both human follicular fluid/oocytes and murine ovarian tissues. Utilizing aged mouse models, we found that SDF‐1 supplementation, both in vitro and in vivo, was associated with the amelioration of multiple aging‐associated oocyte defects, including restored meiotic spindle morphology, improved chromosomal alignment, normalized distribution of cortical granules and mitochondria, enhanced mitochondrial membrane potential, and reduced oxidative stress. Consequently, SDF‐1 treatment improved fertilization competence, embryonic developmental potential, and fertility restoration in aged female mice. Mechanistically, transcriptomic and functional analyses suggested that SDF‐1 ameliorates oocyte aging primarily by enhancing autophagic activity, which was associated with clearance of accumulated stress granules and mitigation of oxidative damage. Pharmacological inhibition of autophagy attenuated the beneficial effects of SDF‐1. In conclusion, our findings point to a previously underexplored role for SDF‐1 in alleviating age‐related oocyte decline, potentially through autophagy‐enhanced stress granule scavenging, positioning SDF‐1 as a promising candidate for therapeutic intervention in reproductive aging, although further investigations are warranted in the future.

Extracellular vesicles (EVs) in the mammalian oviduct constitute a key maternal regulatory system that maintains redox balance during early embryogenesis, yet their molecular cargo and functional relevance in human embryos remain poorly defined. Here, we show that human Fallopian tube‐derived EVs (oEVs) are rapidly internalized by human preimplantation embryos and improve developmental quality in vitro, increasing high‐quality Day 3 embryo formation and blastocyst development. Label‐free proteomics identified 6505 oEV proteins, with metabolic, antioxidant and stress‐response pathways strongly enriched. Cross‐reference with four independent datasets revealed a conserved protein subset shared across secretory‐phase oviduct fluid, pluripotent stem cell‐derived EVs and in‐vivo‐developed embryos; among these, YWHAZ was prioritized for functional validation because of its abundance in oEVs, its presence across embryo‐related datasets, and its known involvement in stress‐response pathways. We found that Ywhaz ‐deficient mouse embryos exhibit elevated oxidative and apoptotic stress, transcriptional signatures of impaired glutathione metabolism, and failure to survive to birth despite normal blastocyst morphology. Recombinant YWHAZ protein alone failed to enter intact embryos, whereas engineered YWHAZ‐loaded EVs were efficiently internalized and significantly reduced intracellular ROS and apoptosis, restoring redox status towards in vivo levels without compromising implantation or foetal growth. Taken together, these findings identify YWHAZ protein as a conserved vesicle‐delivered regulator of redox homeostasis and demonstrate that EV‐mediated molecular delivery can partially rescue the oxidative stress burden characteristic of in vitro embryo culture. This work provides mechanistic insight into the maternal redox support system of the oviduct and establishes a foundation for EV‐based engineering of next‐generation embryo culture strategies.