The Role of the Gut Microbiota in Female Reproductive and Gynecological Health: Insights into Endometrial Signaling Pathways
Abstract
:1. Introduction
2. Determinants of Gut Microbial Composition and Its Implications for Endometrial Function
2.1. Microbial Trajectories Across the Lifespan: Impact on Reproductive Immunity and Estrogen Homeostasis
2.2. Environmental Modulators of the Gut Microbiota and Their Influence on Systemic Metabolic and Immune Responses
2.3. Host Genetic Control of Gut Microbiota: Relevance for Endometrial Signaling Pathways
3. The Gut Microbiome as an Endocrine Modulator of Reproductive Signaling
3.1. Estrobolome-Driven Estrogen Recycling: Molecular Links to Endometrial Receptivity
3.2. Microbial Modulation of Metabolic Hormones: Downstream Effects on Implantation and Uterine Function
4. Microbiota-Mediated Mechanisms Underlying Endometrial Dysfunction in Gynecological Disorders
4.1. Endometriosis Pathogenesis Through Gut-Driven Inflammatory and Estrogenic Dysregulation
4.2. Gut Microbial Dysbiosis in PCOS: Crosstalk Between Inflammation, Hormonal Imbalance, and Endometrial Disruption
4.3. Actions of Gut–Immune–Endometrial Axis in Recurrent Implantation Failure (RIF) and Recurrent Pregnancy Loss (RPL)
- (1)
- The disruption of microbial diversity and ecological stability;
- (2)
- The skewing of immune cell polarization and cytokine networks;
- (3)
- The dysregulation of microbiota-derived metabolites crucial for immune tolerance;
- (4)
- Immunogenetic susceptibility, which is mediated by molecular mimicry and autoimmune activation.
4.3.1. Microbial Diversity Collapse and Taxonomic Shifts in RPL and RIF
4.3.2. Microbiota-Driven Autoimmunity and Molecular Mimicry in Endometrial Rejection
4.4. Gut Microbial Dysbiosis in Preterm Birth: Immune Activation and Barrier Dysfunction at the Maternal–Fetal Interface
4.5. Gut-Endometrial Crosstalk in Preeclampsia: Microbial Influences on Vascular Inflammation and Placental Signaling
5. Microbial Dysbiosis Beyond Classical Gynecological Disorders: Endocrine–Immune Disruption and Endometrial Signaling
5.1. Bacterial Vaginosis and the Gut–Vaginal Axis: Microbial Crosstalk and Endometrial Consequences
5.2. Uterine Fibroids: Estrogen Dysregulation and Immune Modulation Mediated by the Gut Microbiota
5.3. Gynecologic Cancers: Gut Microbiota, Inflammation, and Hormone-Driven Oncogenesis
5.4. Gut Dysbiosis-Driven Immune Priming and Hormonal Imbalance in Reproductive Dysfunction
6. Gut Microbiota and Endometrial Biology in Reproductive Function: Mechanistic Insights and Future Perspectives
- (1)
- Immune dysregulation, characterized by elevated IL-6, TNF-α, and IL-1β; increased Th17 cells; and reduced Tregs [118];
- (2)
- The activation of inflammatory signaling pathways, including NF-κB, TLR4–LPS, and NLRP3 inflammasome [118];
- (3)
- (4)
- (5)
- (6)
- Maladaptive microbial–endometrial crosstalk involving translocated microbial metabolites, local immune activation, and shifts in the endometrial microbial community [74].
- (1)
- The mechanistic dissection of SCFA- and tryptophan-mediated gene regulation;
- (2)
- An investigation into the inflammatory and fibrotic consequences of microbial DNA and viable microbe translocation;
- (3)
- The identification of reproducible microbial and metabolic biomarkers across fertility-relevant conditions;
- (4)
- The development of precision microbiota-based therapies tailored to specific immunoendocrine profiles.
7. Conclusions: Integrating Microbial, Immune, and Hormonal Networks in Fertility Research
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AhR | Aryl hydrocarbon receptor |
BAs | Bile acids |
BV | Bacterial vaginosis |
CRP | C-reactive protein |
EMT | Epithelial–mesenchymal transition |
EDCs | Endocrine-disrupting chemicals |
FGT | Female genital tract |
FMT | Fecal microbiota transplantation |
FXR | Farnesoid X receptor |
GPBAR1 | G protein-coupled bile acid receptor 1 (also known as TGR5) |
GPCR | G protein-coupled receptor |
GLP-1 | Glucagon-like peptide-1 |
HPG axis | Hypothalamic–pituitary–gonadal axis |
HDAC | Histone deacetylase |
IL | Interleukin |
IPA | Indolepropionic acid |
IVF | In vitro fertilization |
KP | Kynurenine pathway |
LPS | Lipopolysaccharide |
MMT | Mesothelial–mesenchymal transition |
MR | Mendelian randomization |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NK cells | Natural killer cells |
PCOS | Polycystic ovary syndrome |
PE | Preeclampsia |
PID | Pelvic inflammatory disease |
PYY | Peptide YY |
RIF | Recurrent implantation failure |
RPL | Recurrent pregnancy loss |
ROS | Reactive oxygen species |
SCFA | Short-chain fatty acid |
SRC-1 | Steroid receptor coactivator-1 |
TAGLN | Transgelin |
Th | T helper (cell) |
TGF-β | Transforming growth factor beta |
TLR | Toll-like receptor |
TNF-α | Tumor necrosis factor alpha |
Treg | Regulatory T cell |
ZO-1 | Zonula occludens-1 |
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Hormone | Primary Source | Microbial Influence | Physiological Function | Therapeutic Potential |
---|---|---|---|---|
GLP-1 | Intestinal L-cells | SCFAs (butyrate and propionate) upregulate secretion via GPR41/GPR43 | Enhances insulin secretion; promotes satiety | Prebiotics and SCFA-promoting probiotics enhance GLP-1 for glycemic control and satiety |
PYY | Intestinal L-cells | Stimulated by SCFAs; influenced by microbial density | Inhibits appetite; slows gastric emptying | Prebiotic fibers modulate PYY via SCFA production to reduce appetite and improve weight management |
Ghrelin | Stomach X/A-like cells (in fundus) | Modulated by gut microbiota composition; lower in SCFA-rich profiles | Stimulates appetite; regulates energy balance | Microbial modulation (e.g., Akkermansia) may suppress ghrelin to reduce food intake and aid obesity management |
Leptin | Adipocytes | Indirectly influenced via gut barrier integrity and systemic signals | Regulates satiety and energy expenditure | Gut barrier restoration via probiotics may enhance leptin sensitivity and reduce inflammation-associated resistance |
Insulin | Pancreatic β-cells | Enhanced via SCFA-mediated GLP-1 secretion; impacted by bile acids | Regulates blood glucose levels | SCFA-driven incretin release and bile acid signaling can improve insulin sensitivity and glucose regulation |
Neuropeptide Y (NPY) | Hypothalamic arcuate nucleus neurons. (AgRP/NPY neurons) | Suppressed by SCFA signaling and the microbial modulation of CNS | Promotes feeding behavior and energy storage | Diet and microbiota interventions targeting SCFA-NPY pathways may help control appetite and metabolic diseases |
Orexin | Lateral hypothalamic area (LHA neurons) | Indirect modulation through microbiota–brain axis | Regulates arousal, wakefulness, and appetite | The probiotic modulation of the gut–brain axis may regulate orexin and improve sleep, mood, and appetite patterns |
Regulatory Pathways | Microbial Drivers | Molecular Mediators | Target System | Action on Maternal Immune Interface | Key References |
---|---|---|---|---|---|
Immune Homeostasis | Faecalibacterium prausnitzii, Roseburia, Bifidobacterium spp. | SCFAs (butyrate, acetate), IL-10, TGF-β | CD4+ T cells (↑ Treg, ↓ Th17), NK cells | Promotes immune tolerance; suppresses pro-inflammatory cytokines | [42,43] |
Inflammatory Regulation | Dysbiotic expansion: Prevotella, Erysipelotrichaceae, Enterococcus | LPS, IL-6, IL-1β, TNF-α, IL-17A | TLR4/NF-κB signaling in endometrium and periphery | Induces Th17-skewed inflammation; trophoblast apoptosis | [44,45] |
Metabolite Signaling | ↓ Akkermansia, Anaerostipes, Ruminococcaceae | ↓ Bile acids (HDCA, LCA), ↑ Imidazolepropionic acid | FXR/GPBAR1, oxidative stress; epithelial integrity | Disrupted mucosal tolerance; elevated cytokines | [43,46] |
Barrier Function | Lactobacillus spp., Akkermansia muciniphila | Mucin; tight junction proteins (ZO-1, claudins) | Intestinal and uterine epithelia | Reduced LPS translocation; protects from “leaky gut” | [42,47] |
Endocrine Modulation | Clostridium scindens, Bacteroides spp. | Estrobolome (β-glucuronidase), steroid-modulating enzymes | Estrogen/progesterone bioavailability | Impacts endometrial receptivity; decidualization | [2,48] |
Autoimmune Susceptibility | Dysbiotic networks in HLA-DQ2/DQ8+ hosts | Molecular mimicry, cross-reactive antigens | Autoantibodies, complement system | Increased maternal immune rejection of fetal cells | [42,44] |
Mechanistic Domain | Microbial Features | Key Mediators | Immunological/Metabolic Consequences | References |
---|---|---|---|---|
1. Microbial Diversity Collapse | ↓ Faecalibacterium, Bifidobacterium, Akkermansia, SCFA-producing Lactobacillus spp. ↑ Prevotella, Bacteroides, Enterococcus, Erysipelotrichaceae | LPS, peptidoglycan, flagellin TLR4 → NF-κB → IL-1β, IL-6, TNF-α | Increased gut permeability; systemic inflammation; impaired maternal–fetal tolerance | [42,43,44] |
2. Th17/Treg Imbalance | ↓ SCFA-producers (Roseburia, Anaerostipes, Blautia) ↑ Prevotella, Escherichia/Shigella | ↓ Tregs, ↑ Th17 IL-17A, IL-6, IL-8, IFN-γ | Impaired decidualization; abnormal NK cell recruitment; pro-inflammatory uterine environment | [43,75,76] |
3. Metabolite Dysregulation | ↓ Butyrate and bile acid-producing genera (Eubacterium, Clostridium XIVa) ↑ Histidine-metabolizing bacteria | ↓ SCFAs, ↓ HDCA and isoLCA ↑ Imidazolepropionic acid | Oxidative stress; barrier dysfunction; altered IL-10/IL-17 signaling | [43,45,52,77] |
4. Immunogenetic Susceptibility | HLA-DQ2/DQ8+genotype ↑ Firmicutes, Proteobacteria, Prevotella | Autoantibodies (ANA, aPL), complement activation | Cross-reactivity to fetal antigens; immune rejection; recurrent miscarriage | [42,44,78,79] |
Microbial Taxa | Abundance in Pe | Associated Metabolites | Host Pathways Affected | Proposed Mechanism in Pe Pathophysiology | Key References |
---|---|---|---|---|---|
Escherichia/Shigella (Proteobacteria) | ↑ Increased | LPS (endotoxin) | TLR4 → NF-κB → IL-6, TNF-α | Promotes systemic inflammation; endothelial dysfunction | [42,98] |
Blautia (Firmicutes) | ↓ Decreased | Butyrate and valerate | GPCR41/43 signaling; HDAC inhibition | Anti-inflammatory, vasodilatory; protects endothelial barrier | [98] |
Eubacterium hallii | ↓ Decreased | Butyrate | SCFA receptor activation; mitochondrial support | Improves vascular tone; reduces oxidative stress | [98] |
Bifidobacterium spp. | ↓ Decreased | Acetate and lactate | Enhances mucosal barrier integrity; immune modulation | Loss may increase gut permeability and LPS leakage | [43,98] |
Subdoligranulum | ↓ Decreased | Butyrate | Treg induction; anti-inflammatory cytokines | Supports immune tolerance; depletion linked to Th17 shift | [98] |
Enterobacter | ↑ Increased | LPS and TMA precursors | TLR4 activation; endothelial stress | Associated with hypertension and cytokine elevation | [98] |
Akkermansia muciniphila | ↓ Decreased | Mucin-degradation products | Mucin layer maintenance; gut barrier protection | Depletion leads to “leaky gut” and metabolic inflammation | [42,99] |
General SCFA Producers (Roseburia, Faecalibacterium) | ↓ Decreased | Butyrate, acetate, and propionate | GPR109A; Treg expansion | Critical for immune balance and endothelial protection | [43,46] |
Condition | Microbial Features | Key Immune Mediators | Pathophysiological Impact | References |
---|---|---|---|---|
Bacterial Vaginosis (BV) | ↓ Lactobacillus, ↑ anaerobes (Gardnerella, etc.) | IL-6, IL-1β, TNF-α | Vaginal inflammation, biofilm formation, ↑ PID, miscarriage, preterm birth risk | [30] |
Uterine Fibroids | ↑ β-glucuronidase (Clostridia) → ↑ estrogen | IL-6, M1 macrophages | Estrogen-driven fibroid growth, immune cell infiltration, fibrosis | [104] |
Gynecologic Cancers | ↑ Fusobacterium, Bacteroides, E. coli | IL-6, TNF-α, ROS, ↓ NK cells | Chronic inflammation, immune evasion, mucosal breakdown, tumor promotion | [105,106] |
Pelvic Inflammatory Disease (PID) | ↑ Gardnerella, Mycoplasma, Bacteroides | IL-1β, IL-8, TNF-α | Persistent pelvic inflammation, tubal scarring, infertility | [30] |
Menstrual Irregularities | ↓ diversity, ↑ Bacteroides, Clostridium | IL-6, CRP, β-glucuronidase | Hormonal imbalance, anovulation, cycle disruption | [8] |
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Escorcia Mora, P.; Valbuena, D.; Diez-Juan, A. The Role of the Gut Microbiota in Female Reproductive and Gynecological Health: Insights into Endometrial Signaling Pathways. Life 2025, 15, 762. https://doi.org/10.3390/life15050762
Escorcia Mora P, Valbuena D, Diez-Juan A. The Role of the Gut Microbiota in Female Reproductive and Gynecological Health: Insights into Endometrial Signaling Pathways. Life. 2025; 15(5):762. https://doi.org/10.3390/life15050762
Chicago/Turabian StyleEscorcia Mora, Patricia, Diana Valbuena, and Antonio Diez-Juan. 2025. "The Role of the Gut Microbiota in Female Reproductive and Gynecological Health: Insights into Endometrial Signaling Pathways" Life 15, no. 5: 762. https://doi.org/10.3390/life15050762
APA StyleEscorcia Mora, P., Valbuena, D., & Diez-Juan, A. (2025). The Role of the Gut Microbiota in Female Reproductive and Gynecological Health: Insights into Endometrial Signaling Pathways. Life, 15(5), 762. https://doi.org/10.3390/life15050762