Search Results (60)

Adverse pregnancy outcomes (APOs), including preterm birth, preeclampsia, low birth weight, recurrent miscarriage, gestational diabetes mellitus, and fetal growth restriction, remain major threats to maternal and offspring health. Increasing evidence links the maternal microbiome to pregnancy health, but most studies have examined individual microbial niches rather than their interactions. The oral cavity and gut are anatomically and immunologically connected and form a bidirectional oral–gut microbiota axis through microbial trafficking, immune signaling, and metabolite-mediated feedback. Emerging studies suggested that oral dysbiosis, periodontal inflammation, and gut microbial remodeling were associated with APOs, although direct causal evidence in human pregnancy remains limited. This review summarizes pregnancy-related remodeling of the oral–gut microbiota axis, evaluates clinical and experimental evidence linking oral and gut dysbiosis to APOs, and discusses potential mechanisms, including microbial translocation, immune and inflammatory activation, metabolic remodeling, epigenetic regulation, and outer membrane vesicle-mediated signaling. Candidate biomarkers, probiotic and dietary intervention strategies, and current translational limitations are also discussed. Overall, the oral–gut microbiota axis offers a useful framework for understanding microbiome-associated APOs, but standardized sampling, longitudinal cohorts, and mechanistic validation are required before clinical application. Full article

Gestational diabetes mellitus (GDM) is an increasingly prevalent metabolic disorder of pregnancy, driven by rising maternal age, obesity, and complex metabolic–inflammatory interactions. Emerging evidence implicates the maternal microbiome as a key modulator of metabolic adaptation during gestation; however, its precise role in GDM pathogenesis remains incompletely defined. This narrative review synthesizes current knowledge on microbiome alterations across gut, vaginal, and oral niches, focusing on their contribution to insulin resistance, metabolic endotoxemia, and immune dysregulation. GDM is consistently associated with reduced microbial diversity, depletion of beneficial taxa (e.g., Akkermansia, Bifidobacterium, Faecalibacterium), and expansion of pro-inflammatory pathobionts, which collectively may impair intestinal barrier integrity and promote low-grade systemic inflammation. These mechanisms are linked to altered insulin signaling and adverse maternal–fetal outcomes. In parallel, microbiome-derived metabolites and early taxonomic signatures have been proposed as potential biomarkers for first-trimester risk stratification, offering an opportunity to overcome the limitations of late diagnostic approaches such as the oral glucose tolerance test. Despite these advances, most available evidence remains associative, with substantial heterogeneity across studies and limited mechanistic validation. The clinical utility of microbiome-based interventions—including dietary modulation, prebiotics, and probiotics—remains promising but inconclusive, with outcomes highly dependent on individual, microbial, and methodological factors. Overall, the maternal microbiome represents a compelling but still evolving target in GDM research. Future progress will depend on standardized methodologies, longitudinal multi-omics studies, and the development of precision medicine approaches capable of integrating microbial, metabolic, and host data. Such advances may enable earlier diagnosis, targeted prevention, and ultimately the disruption of intergenerational metabolic risk. Full article

Oocyte formation occurs successfully within a meticulously controlled follicular environment characterized by well-documented endocrine, metabolic, and paracrine signals. Yet, the immunological landscape of the follicle and its role in influencing oocyte competency has received less attention in research. Growing research indicates that the ovarian follicle functions as an immunological-active niche necessitating a precise equilibrium between controlled inflammation and targeted immune tolerance. The programmed cell death-1 (PD-1) receptor and its ligand PD-L1 constitute a crucial immune checkpoint pathway, essential for sustaining peripheral immunological tolerance and averting excessive immune activation. Despite their comprehensive research in cancer biology and maternal–fetal interactions, their possible function in the follicular microenvironment remains mostly unexamined. We propose that PD-1/PD-L1 signaling may facilitate the formation of a localized immune-tolerant milieu inside the follicle to safeguard the developing oocyte from inflammatory injury and immune-mediated stress. The disturbance of this suggested equilibrium may lead to a pro-inflammatory follicular environment, compromised granulosa cell function, and modified oocyte maturation, hence affecting fertilization and embryonic developmental potential. In clinical contexts with immunological dysregulation, such as endometriosis, polycystic ovarian syndrome, and unexplained IVF failure, such processes may be especially significant. The purpose of this narrative review is to assimilate the current comprehension of immune regulation in the follicle with the established biology of PD-1/PD-L1 and to investigate a potential correlation between immune checkpoint signaling, oocyte competence, and assisted reproductive outcomes. Considering the follicle as an immune-regulated microenvironment offers a new paradigm for comprehending infertility and identifying novel indicators or therapeutic targets. Full article

Preterm birth is a major cause of neonatal morbidity and mortality, and many spontaneous cases remain idiopathic. Increasing evidence suggests that intrauterine inflammation may occur in the absence of detectable infection, leading to the recognition of sterile intrauterine inflammation as an important mechanism contributing to threatened preterm labor and spontaneous preterm birth. This review summarizes current knowledge regarding the role of damage-associated molecular patterns (DAMPs), alarmins, pattern recognition receptors, inflammasome activation, cellular senescence, and pyroptosis in the initiation of sterile inflammatory pathways associated with labor. Key mediators including HMGB1, IL-1α, fetal cell-free DNA, platelet-activating factor, and S100 proteins appear to promote inflammatory activation within fetal membranes and the amniotic cavity. The review also discusses the emerging contribution of fetal immune activation, maternal–fetal immune dysregulation, maternal microchimerism, and epigenetic mechanisms to idiopathic preterm birth. Current diagnostic and therapeutic options remain limited, and no targeted treatment for sterile intrauterine inflammation has yet been established. Future approaches may include precision biomarkers, multiomics-based risk stratification, targeted immunomodulatory therapies, and modulation of maternal–fetal immune interactions. Improved understanding of sterile inflammatory mechanisms may ultimately support development of personalized strategies to prevent preterm birth and improve perinatal outcomes. Full article

Drug exposure during pregnancy and early life is typically considered a short-term clinical intervention rather than a determinant of long-term pharmacological outcomes. Consequently, the developmental context is largely absent from drug discovery and drug development paradigms, where efficacy, safety and target engagement are evaluated predominantly in adult, steady-state systems. This disconnect may contribute to unexplained variability in drug response and toxicity later in life. Pregnancy is accompanied by dynamic remodeling of the maternal gut microbiota and its metabolic output, generating bioactive microbial metabolites that regulate immune tone, metabolic homeostasis and the expression of drug-metabolizing enzymes and transporters. These microbial signals intersect with pharmacological interventions across gestation, shaping maternal pharmacokinetics, placental regulation and fetal drug exposure during developmentally sensitive windows. Importantly, microbiota–drug interactions initiated during pregnancy do not terminate at birth. Instead, they extend into infancy through vertical microbial transmission, breast milk-mediated metabolic signaling, and the immaturity of neonatal drug-handling systems, collectively contributing to developmental programming of drug responsiveness beyond early life. In this review, we propose a microbiota-informed framework that reframes perinatal drug exposure as a developmentally embedded signal operating across a maternal–placental–infant continuum. This perspective introduces a missing developmental dimension into drug discovery and highlights new opportunities to improve translational predictability and precision pharmacotherapy across the life course. Full article

Endocrine-disrupting chemicals (EDCs) are a diverse group of environmental pollutants capable of interfering with hormonal and immune system regulation. In recent years, increasing concern has been raised about the effects of chemicals, including bisphenols, phthalates, per- and polyfluoroalkyl substances (PFAS), insecticides, and parabens, on maternal and fetal health, primarily due to their widespread exposure in human populations. Pregnancy represents a critical window characterized by tightly regulated hormonal and immunological adaptations. Emerging evidence suggests that EDC exposure during this period may alter maternal microbiota, disrupt immune responses, and interfere with endocrine signaling. These changes may increase susceptibility to bacterial and viral infections, including bacterial vaginosis, urinary tract infections, and intrauterine infections, all of which are associated with adverse pregnancy outcomes. This review summarizes the current evidence on the sources and mechanisms of exposure to endocrine disruptors during pregnancy and examines the potential biological pathways linking endocrine disruption to the development of infections. Particular emphasis is placed on the interactions between immune regulation, hormonal signaling, and changes in the microbiome, which may contribute to increased susceptibility to infections. A deeper understanding of these complex mechanisms is critical to improve risk assessment, develop effective public health strategies, and ultimately protect maternal and fetal health in an environment of increasing chemical exposure. A literature search was conducted using PubMed/MEDLINE, Scopus, and Web of Science, including studies published up to January 2026. Full article

Pregnancy represents a distinct immunological and physiological state that modifies maternal susceptibility to SARS-CoV-2 and influences the clinical and biological course of COVID-19. Accumulating evidence indicates that the interaction between viral entry determinants, gestation-specific immune modulation, placental endocrine–angiogenic pathways, and systemic inflammatory responses underlies the characteristic manifestations of SARS-CoV-2 infection during pregnancy. This review consolidates current understanding of SARS-CoV-2 viral structure, receptor biology, and the gestational regulation of key entry cofactors, including ACE2, TMPRSS2, NRP1, CTSL and FURIN, within reproductive and placental tissues. The review further integrates documented mechanisms of cytokine-mediated immune dysregulation, endothelial injury, thrombo-inflammation, and steroidogenic alteration observed in affected pregnancies, and examines their contribution to placental malperfusion, preeclampsia-like presentations, fetal growth abnormalities and preterm birth. Published molecular and computational studies characterising trophoblast antiviral defenses, receptor expression patterns, and structural determinants of Spike–ACE2 affinity are synthesised to contextualise the biological basis of placental susceptibility and the rarity of confirmed transplacental transmission. Current evidence on maternal clinical outcomes, fetal and neonatal consequences, vaccination efficacy, therapeutic considerations and contemporary management guidelines is also critically reviewed. By integrating molecular, immunological, pathological and clinical insights, this article provides a comprehensive framework for understanding the interaction between SARS-CoV-2 infection and pregnancy-specific physiology, with implications for risk assessment, preventive strategies and maternal–fetal care. Full article

Chronic kidney disease (CKD) represents a major global health burden, with growing evidence indicating that its origins extend back to early developmental stages. This narrative review integrates epidemiological, clinical, and mechanistic experimental evidence to position inflammation as a life-course driver of kidney vulnerability rather than a late-stage consequence. Inflammation has emerged as a central mechanistic link connecting adverse prenatal and postnatal exposures to lifelong kidney vulnerability. We highlight the translational potential by identifying pathways amenable to early-life interventions that could modify disease trajectory. During fetal development, maternal nutritional status, metabolic stress, and inflammatory exposures influence nephron endowment, immune maturation, and epigenetic regulation, thereby shaping long-term CKD risk. In childhood, early immune dysregulation and low-grade inflammation contribute to disease initiation, defining critical windows for preventive and renoprotective interventions that can be implemented in at-risk populations. In adulthood and aging, persistent activation of cytokine signaling, inflammasomes, oxidative stress pathways, autophagy–mitophagy imbalance, and cellular senescence drives progressive kidney injury, further amplified by gut microbiota dysbiosis and renin–angiotensin system interactions. Emerging life-course strategies include maternal nutrition optimization, early-life risk stratification, targeted anti-inflammatory and immunomodulatory therapies, and microbiota-directed interventions tailored to developmental stage and individual risk profile. By emphasizing inflammation as a developmentally programmed and preventable process, this review underscores opportunities for early-life and transgenerational CKD prevention, translating mechanistic insights into actionable strategies for preventive medicine and public health. Full article

Background/Objectives: Pregnancy loss is a common and multifactorial complication of human reproduction, traditionally attributed to fetal chromosomal abnormalities, maternal anatomical and endocrine disorders, and immune dysfunction. Growing evidence now indicates that the maternal microbiome, particularly within the reproductive tract, plays a critical role in implantation, placental development, and the maintenance of immune tolerance during early pregnancy. Importantly, the influence of the microbiome on miscarriage appears to be strongly modulated by host genetic background and immune regulation. Methods: This narrative review summarizes current evidence linking alterations in the vaginal, endometrial, placental, and gut microbiomes to miscarriage, with a specific focus on host genetics and immune–microbial interactions. Results: We discuss how genetic variation in innate and adaptive immune pathways, inflammatory signaling, and mucosal barrier function may shape host responses to microbial communities, thereby influencing susceptibility to PL. In addition, we highlight emerging data on microbiome-driven regulation of gene expression and epigenetic modifications in the endometrium and decidua, emphasizing the role of microbial metabolites in immune tolerance and placental function. Conclusions: By integrating findings from microbiome research, host genomics, immunology, and epigenetics, this review proposes a framework in which miscarriage is viewed as a consequence of disrupted host–microbe crosstalk rather than isolated pathology. Finally, we address key methodological challenges and outline future research directions aimed at advancing mechanistic understanding and translational applications. Full article

Female reproductive tract (FRT) disorders such as maternal conditions and gynecological cancers represent a significant global health burden. However, women’s health, and particularly locally acting therapies targeting the FRT, has historically been underprioritized in drug development and translational research. Developing safe and effective therapies requires a clear understanding of drug transport across FRT barriers. Conventional in vitro culture systems and animal studies fail to recapitulate the physiological complexity of the human FRT, including stratified mucosal architecture, functional mucus barriers, microbiome interactions, as well as dynamic hormonal regulation. Recently, organ-on-chip (OoC) microfluidic platforms, integrating human cells with precisely controlled perfusion, have emerged as advanced in vitro systems capable of recreating dynamic physiological microenvironments. This review summarizes the major anatomical and physiological barriers of the FRT, including the vagina, cervix, endometrium, and placenta, and discusses critical design considerations for the development of FRT-on-chip models. We highlight the advanced OoC developed to study infection, drug permeation, hormonal responses, and maternal–fetal interface dynamics. Finally, future perspectives are outlined, including the integration of immune components, vascularization strategies, and multi-organ systems to better simulate inter-organ communication. Collectively, these advances underscore the potential of FRT-on-chip models as predictive platforms for preclinical drug screening, toxicity evaluation, and personalized medicine. Full article

Maternal immune tolerance and controlled inflammatory responses are essential for fetal development and successful pregnancy. Regulatory T cells (Tregs) and B cells with regulatory properties (Bregs) maintain this balance by limiting excessive immune activation through the secretion of anti-inflammatory and tolerogenic cytokines, such as IL-10, TGF-β, and IL-35. Moreover, alterations in the costimulatory potential of antigen-presenting cells (APCs), including B cells, modulate the activation and differentiation of T cells. Toll-like receptors (TLRs), particularly TLR9, influence B-cell antigen presentation and cytokine production, thereby affecting the balance between pro-inflammatory and tolerogenic responses at the maternal–fetal interface. TLR9 overexpression has been observed in several pregnancy-related disorders in both humans and murine models. In this study, we examine whether blocking TLR9 shortly after mating could improve pregnancy outcomes and modulate the regulatory and antigen-presenting functions of B cells, as well as their interactions with T cells. Using an abortion-prone murine model (CBA/J × DBA/2J), we show that intraperitoneal administration of a TLR9 antagonist (ODN 2088) shortly after mating increases embryo resorption in CBA/J females compared to controls without affecting implantation. Flow cytometry analysis further reveals that mice receiving the TLR9 antagonist are characterized by downregulation of CD80 and upregulation of CD86 on B cells, accompanied by reduced expression of CD40L and CD28 on T cells, as well as a lower percentage of Tregs and activated T cells. In conclusion, blocking TLR9 signaling shortly after mating does not improve pregnancy outcomes; conversely, it exacerbates pregnancy loss in the CBA/J × DBA/2J abortion-prone model, while altering the costimulatory phenotype of B and T cells and impairing Treg development during pregnancy. Full article

Obesity, type 2 diabetes (T2D), and insulin resistance are pervasive metabolic disorders marked by chronic low-grade inflammation and systemic metabolic disorders. The emerging field of immunometabolism highlights how interactions between immune processes and metabolic pathways in adipose tissue, liver, muscle, and pancreatic islets contribute to disease pathogenesis. Lipid dysregulation plays a central role in these processes, with distinct lipid molecules identified in obese patients as compared to lean patients that correlate with insulin resistance, inflammation, and vascular dysfunction. This Special Issue compiles a multidisciplinary body of research aimed at elucidating molecular mechanisms, identifying novel biomarkers, and exploring innovative therapeutic strategies. Key contributions include studies on omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) and their differential associations with neurocognitive development; the potential of beta-defensin 2 as a biomarker linking gut-derived inflammation and metabolic dysfunction; and the promotion of adipocyte browning by Carnosic acid via AMPK activation and GSK3β inhibition. Additionally, reviews of phytochemicals underscore their multisystem therapeutic potential, while investigations into sodium–glucose cotransporter-2 (SGLT2) inhibitors suggest possible metabolic and neuroprotective benefits beyond glucose control. Maternal lipid metabolism during pregnancy and its impact on maternal fetal health further emphasize the clinical complexity of lipid dysregulation. Despite promising insights, significant gaps remain regarding causality versus correlation in lipid biomarkers, standardization of analytical methodologies, tissue heterogeneity, and unintended effects of metabolic interventions. Collectively, these studies underscore the necessity of integrative, mechanism-driven research to bridge fundamental biology with translational and clinical applications, ultimately advancing precision therapies for metabolic diseases. Full article

Gestational diabetes mellitus (GDM) is a multifactorial metabolic disorder arising from impaired insulin sensitivity and altered maternal–fetal energy regulation. Beyond classical mechanisms involving β-cell dysfunction and pregnancy-induced insulin resistance, emerging evidence suggests a bidirectional interaction between the maternal gut microbiota and the placenta, forming a dynamic placenta–gut axis. Microbial dysbiosis alters levels of metabolites, inflammatory mediators, and bile acids, which influence placental signaling, trophoblast metabolism, immune activation, and nutrient transport. Conversely, the placenta secretes hormones, cytokines, lipids, and exosomal miRNAs that shape maternal metabolism and potentially modulate the gut microbiota. This review synthesizes current mechanistic insights underlying the placenta–gut microbiota axis in GDM, describes immune and metabolic crosstalk, and highlights therapeutic opportunities targeting this inter-organ communication system. Addressing these interactions may advance precision strategies for managing GDM and improving outcomes across generations. Full article

Preeclampsia (PE) is an obstetric disorder with significant risks to both maternal and fetal health, characterized by hypertension and multi-organ dysfunction. Central to its pathogenesis is the impaired differentiation and function of trophoblast cells, leading to abnormal placental development and defective uterine vascular remodeling. This dysfunctional placentation triggers a cascade of oxidative stress, systemic inflammation, and immune dysregulation, collectively exacerbating disease severity. The trophoblast regulates maternal–fetal interactions through complex and tightly controlled gene expression networks, in which non-coding RNAs such as microRNAs (miRNAs) and circular RNAs (circRNAs) play essential regulatory roles. Here, we summarize current findings on transcriptomic alterations associated with trophoblast anomalies in PE and discuss their potential translational applications. Understanding these molecular mechanisms may enhance early diagnosis, improve clinical outcomes, and pave the way for precision medicine and individualized therapeutic strategies in PE. Full article

Background: Autism Spectrum Disorder (ASD) is a multifactorial neurodevelopmental condition in which genetic predisposition interacts with environmental factors. Among these, the gut microbiota has emerged as a crucial modulator of the microbiota–gut–brain axis (MGBA), influencing neuroinflammation, neurotransmission, and behavior. This review aims to provide an updated and integrative overview of the relationship between gut microbiota, diet, and neurodevelopment in ASD. Methods: A comprehensive search was conducted in PubMed, Scopus, and Web of Science for articles published between 2010 and 2025. Original studies, systematic reviews, and meta-analyses in English were included. Results: Evidence from human and animal studies supports a strong association between gut dysbiosis and ASD-related behaviors. Alterations in microbial composition, characterized by reduced Bifidobacterium and Prevotella and increased Clostridium spp., have been linked to impaired intestinal barrier function, chronic inflammation, and altered production of microbial metabolites such as short-chain fatty acids and tryptophan derivatives. Discussion: Maternal dysbiosis, nutritional imbalances, and perinatal stressors may further modulate fetal neurodevelopment through immune and epigenetic pathways. Emerging data suggest that dietary modulation, targeted nutritional interventions, functional foods, prebiotics, probiotics, and postbiotics could help restore microbial balance and improve neurobehavioral outcomes. Conclusions: The gut microbiota represents a key biological interface between environment, metabolism, and neurodevelopment. It is, therefore, necessary to transform current knowledge about the microbiota and neurodevelopment into clinical, social, and health actions that offer real solutions to people with ASD and their families. From this perspective, focusing on prevention, promoting healthy lifestyles, and integrating new technologies represent the true tools for building a more sustainable and inclusive healthcare system. Full article