To investigate the direct effect of growth differentiation factor 9 (GDF9) on androgen production in human theca cells. Experimental study. Tertiary hospital-based research laboratory. Women who underwent in vitro fertilization and intracytoplasmic sperm injections at our clinic were included in this study. Primary cultured human theca cells from women undergoing in vitro fertilization and intracytoplasmic sperm injection treatment were treated with GDF9, an activin receptor-like kinase 5 (ALK5) inhibitor, and a SMAD4 agonist. The expression of androgen synthesis-related genes StAR, CYP17A1, and LHCGR, levels of androstenedione and testosterone, phosphorylation of SMAD2/3, and the interaction between bone morphogenic protein-activated type II receptor and ALK5 were evaluated using reverse transcription-quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assays, and coimmunoprecipitation assays, respectively. Growth differentiation factor 9 decreased StAR, CYP17A1, and LHCGR expression levels in human theca cells, which was prevented by treatment with the ALK5 inhibitor, and suppressed production of androgen in human theca cells. Growth differentiation factor 9 increased SMAD2/3 phosphorylation, and the ALK5 inhibitor also suppressed this effect. Bone morphogenic protein-activated type II receptor and ALK5 bound to each other after GDF9 stimulation. The SMAD4 agonist kartogenin also decreased messenger RNA levels of StAR and CYP17A1 and protein levels of StAR in human theca cells. Growth differentiation factor 9 can activate the bone morphogenic protein-activated type II receptor-ALK5-SMAD2/3 signaling pathway, suppress CYP17A1 expression, and decrease androgen production in human theca cells.

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 million people worldwide, and despite the availability of anti-seizure medications (ASMs), approximately 30% of patients develop drug-resistant epilepsy. Current ASMs primarily suppress seizures rather than prevent disease progression, highlighting the need for alternative therapeutic strategies. In this context, increasing evidence supports a role for microbiota-dependent pathways in modulating seizure activity and treatment responsiveness. However, the mechanistic basis of these interactions remains incompletely understood. Methods: This narrative review synthesizes findings from the existing literature to examine the role of microbiota-derived metabolites, including neurotransmitters, vitamins, and the polyphenol metabolite S-equol, in gut–brain communication relevant to epilepsy. Evidence was drawn from both preclinical animal models and clinical studies to provide an integrated, mechanistic perspective on how these pathways may influence central nervous system function and seizure susceptibility. Emphasis was placed on studies describing molecular, metabolic, and signaling mechanisms linking the gut microbiome to epileptogenesis and treatment response. Results: Current evidence indicates that communication between the gut and CNS occurs through neural pathways, such as the vagus nerve, as well as through circulating microbial metabolites. These metabolites can cross the intestinal barrier and, in some cases, the blood–brain barrier (BBB), serving as key mediators of host–microbiota signaling. Emerging studies suggest that while some microbial metabolites may directly influence neuronal hyperexcitability and seizure susceptibility, others likely exert secondary or modulatory effects through broader metabolic and immune pathways. However, the precise mechanisms underlying these interactions remain incompletely understood. Conclusions: Some microbial-derived metabolites may serve as promising biomarkers and mechanistic mediators of epilepsy; however, further investigation is needed to define the molecular and cellular pathways through which these metabolites influence seizure susceptibility and epileptogenesis.

Viral infections of the central nervous system (CNS) pose a significant risk for seizures, and in some cases, long‐term epileptogenesis. Seizure development following viral infection involves diverse CNS mechanisms, with emerging evidence that peripheral factors, including gut microbiome composition and immune‐inflammatory responses, also contribute. The gut microbiome is a multifaceted ecosystem with important roles in CNS health, and advances in sequencing have enabled investigation of host and microbial genomic changes associated with seizure development. While both animal and human studies link gut dysbiosis to epilepsy, including infection‐induced epilepsy, the specific effects of viral‐induced seizures on the gut microbiome remain unclear. Moreover, the influence of virus‐triggered epileptogenesis is not well understood. This review summarizes current knowledge on viral infections linked to seizures and highlights the limited but growing evidence for gut microbial changes in this context. We focus on Zika virus (ZIKV), West Nile virus (WNV), and herpes simplex virus‐1 (HSV‐1), all implicated in human epileptogenesis, though direct microbiome–seizure connections are still limited. We also discuss severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), which causes neurological symptoms without consistently inducing seizures in rodent models despite neurological involvement, and Theiler's murine encephalomyelitis virus (TMEV), a murine virus widely used as a model of infection‐induced seizures because it induces strain‐dependent seizures in mice. Current evidence suggests associations among viral infections, gut microbiome alterations, and seizure occurrence; however, further causative studies are needed to define their roles and elucidate underlying mechanisms.