Fertility

Infertility affects one in six people, but the underlying mechanisms remain unclear. We show that the microbiota governs female reproductive longevity in mice. Germ-free mice have fewer primordial follicles, increased atresia, and ovarian fibrosis, leading to smaller litters, fewer offspring, and a shorter reproductive lifespan. Germ-free mice are born with a similar ovarian reserve but display excessive activation, impaired progression, and increased atresia during post-natal development. Microbiome colonization during a critical post-natal window rescues premature ovarian reserve loss by normalizing follicle kinetics and gene expression patterns. These changes parallel increased short-chain fatty acids (SCFAs), and SCFA administration mitigates ovarian dysfunction in germ-free mice. Similar oocyte dysfunction occurred in conventionally raised mice fed a high-fat diet, but additional dietary fiber helped preserve oocyte quality and embryo competence. Thus, host-microbe interactions shape female fertility, and microbiota-targeted interventions may offer strategies to address reproductive disorders.

BackgroundMale infertility accounts for approximately 50% of all infertility cases, and its pathogenesis is highly complex. Beyond traditional factors such as genetics, endocrine disorders, and infections, growing evidence indicates that dysregulation of immunometabolism plays a pivotal role in the onset and progression of male reproductive dysfunction.ObjectiveThis review aims to systematically elucidate the role of immunometabolism in male reproductive health, focusing on the complex interplay among inflammation, oxidative stress, and metabolic imbalance. Additionally, it seeks to summarize potential therapeutic targets and outline future research directions.MethodsA narrative review was conducted in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines. Relevant studies published between January 2010 to March 2025 were retrieved from PubMed, Embase, and Web of Science using keywords such as "immunometabolism," "testis," "male infertility," and "oxidative stress."ResultsTesticular immune homeostasis depends on the metabolic coordination among Sertoli cells, Leydig cells, and local immune cells. Aberrant immunometabolism disrupts the blood-testis barrier and endocrine balance by enhancing glycolysis, suppressing oxidative phosphorylation, and promoting the accumulation of reactive oxygen species (ROS), thereby impairing spermatogenesis and testosterone synthesis. Systemic metabolic inflammation induced by obesity, diabetes, and gut microbiota dysbiosis further exacerbates testicular dysfunction through the mTOR/HIF-1α signaling axis and the "gut-immune-gonadal axis." Pharmacological modulation of key immunometabolic regulators, including AMPK, SIRT1, and PPARγ, has been shown to improve sperm quality and hormone levels in experimental models.ConclusionImmunometabolism serves as a crucial mechanistic bridge linking inflammation, oxidative stress, and the decline of male fertility. Future studies integrating multi-omics and spatial analysis technologies are expected to delineate immunometabolic phenotypes associated with male infertility, paving the way for precision diagnosis and personalized therapeutic interventions.

According to the World Health Organization, infertility has emerged as a critical public health issue, affecting approximately 48 million couples and 186 million individuals worldwide. Ovarian aging-defined by the progressive depletion and functional deterioration of the primordial follicle pool-accounts for a major proportion of female-factor infertility and has profound socioeconomic consequences. It is characterized by a decline in follicle quantity and quality, which significantly influences infertility. This phenomenon is multifaceted, involving genetic predisposition, hormonal fluctuations, mitochondrial dysfunction, oxidative stress, and ovarian microenvironment alterations. This review explores the biological mechanisms of ovarian aging, evaluates current therapeutic advances, and identifies strategies to maintain ovarian function and prolong reproductive lifespan. Recent advancements-including antioxidant and mitochondria-targeted therapies, hormonal modulation, growth factor interventions (e.g., platelet-rich plasma), mitochondrial transfer, and in vitro follicle activation-show promise for maintaining ovarian reserve. Fertility preservation strategies, such as ovarian tissue cryopreservation and transplantation, and pharmacological inhibition of follicle depletion, have expanded therapeutic options. The development of personalized treatments, refined biomarkers, and integrative strategies combining antioxidants, hormonal therapies, and novel fertility preservation techniques is essential. Therefore, translational research utilizing animal models remains crucial for validating efficacy and safety prior to clinical application. Future research should prioritize validating these emerging therapies through larger clinical trials to ensure safe, effective, and practical translation into clinical practice, ultimately prolonging reproductive lifespan and enhancing quality of life for aging women.

The human endometrium undergoes dynamic changes across the menstrual cycle to establish a receptive state for embryo implantation. Using bulk and single-cell RNA-Seq, we characterized gene expression dynamics in the cycling endometrium and the decidua from early pregnancy. We demonstrated that during the mid-secretory phase - the period encompassing the window of implantation - secretory glandular epithelial cells undergo notable transcriptional changes and alterations in cell-cell communication. Through comprehensive analyses, we identified the glandular epithelium receptivity module (GERM) signature, comprising 556 genes associated with endometrial receptivity. This GERM signature was consistently perturbed across datasets of endometrial samples from women with impaired fertility, validating its relevance as a marker of receptivity. In addition to epithelial changes, we observed shifts in stromal cell populations, notably involving decidual and senescent subsets, which also play key roles in modulating implantation. Together, these findings provide a high-resolution transcriptomic atlas of the receptive and early pregnant endometrium and shed light on key molecular pathways underlying successful implantation.