Validation of Metformin as a Microbiome-targeted intervention for Endometriosis
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
By directly targeting microbial dysbiosis, hormonal imbalances, and inflammation, metformin not only validates the clinical relevance of the endometriosis microbiome signature but also positions itself as an effective therapeutic option for the condition.
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Karen Pendergrass
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
Overview 
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References Overview
Metformin, a widely used anti-diabetic medication, demonstrates significant therapeutic potential for endometriosis by targeting both microbial imbalances and the inflammatory pathways central to the condition. Its capacity to reduce the abundance of key Major Microbial Associations (MMAs) in endometriosis, such as Escherichia coli and Streptococcus agalactiae, [1] along with its ability to suppress estrogen production and alleviate endometriosis-associated symptoms, [2] validates its utility as a microbiome-targeted intervention (MBTI). Furthermore, these microbial and biochemical effects strengthen confidence in the clinical relevance and accuracy of the endometriosis microbiome signature.
Validation of Metformin as an MBTI
Metformin addresses microbial imbalances in endometriosis by suppressing key MMAs (Escherichia coli and Streptococcus agalactiae), rebalancing the microbiome, and mitigating inflammation. It inhibits estrogen production in ovarian tissue and endometriotic lesions, reducing endometrial cell proliferation. Clinically, metformin alleviates symptoms such as chronic pelvic pain, dysmenorrhea, and dyspareunia, aligning with both the pathological and microbial hallmarks of the disease.
Hormonal and Symptom Modulation: Metformin inhibits estrogen synthesis in both ovarian tissue and endometriotic lesions, reducing the proliferation of endometrial cells. Clinically, metformin significantly lessens endometriosis-associated symptoms, such as pelvic pain, dysmenorrhea, and dyspareunia.
Microbial Modulation: Metformin decreases populations of Escherichia coli and Streptococcus agalactiae, two key microbial taxa elevated in the endometriosis microbiome signature. It also has indirect effects on the broader microbial ecosystem, fostering a microbial environment that mitigates inflammation and dysbiosis.
Validation of the Microbiome Signature of Endometriosis
The endometriosis microbiome signature is characterized by a dysbiotic profile, including elevated levels of Escherichia coli and Streptococcus agalactiae. These microbial taxa exacerbate inflammatory pathways and tissue damage, contributing to the progression of the disease. The ability of metformin to specifically target and reduce the abundance of these microbes provides a direct link between the microbiome signature and clinical outcomes. This alignment between metformin’s targeted microbial effects and the dysbiotic pattern in endometriosis supports the validity of the microbiome signature as a representation of the condition. The reduction in microbial MMAs correlates with improvements in symptoms and estrogen regulation, further confirming the clinical relevance of the signature.
| Key Features of the Microbiome Signature | Observed Effects of Metformin |
|---|---|
| Increased Escherichia coli | Metformin reduces the abundance of this MMA. |
| Increased Streptococcus agalactiae | Metformin suppresses this dysbiotic taxon. |
Dual Validation of MBTI and Microbiome Signature
Metformin’s ability to influence both microbial dysbiosis and endometriosis-associated pathology highlights its dual role as an MBTI and as a tool for validating the microbiome signature of the condition. By reducing Escherichia coli and Streptococcus agalactiae—key MMAs—while simultaneously improving hormonal and inflammatory profiles, metformin demonstrates the interconnectedness of microbial and systemic processes in endometriosis.
If the microbiome signature were not representative of the disease, the targeted effects of metformin on E. coli and S. agalactiae would not correlate with its observed clinical benefits, such as reduced symptoms and suppressed estrogen production. This dual validation reinforces confidence in the microbiome signature’s accuracy while establishing metformin as a promising MBTI for endometriosis.
Conclusion
Metformin exemplifies the potential of MBTIs to address both microbial and systemic aspects of endometriosis. By directly targeting microbial dysbiosis, hormonal imbalances, and inflammation, metformin not only validates the clinical relevance of the endometriosis microbiome signature but also positions itself as an effective therapeutic option for the condition. This dual validation underscores the critical role of microbiome-targeted strategies in advancing our understanding and treatment of endometriosis.
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High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin
March 9, 2023
Hyperglycemia weakens placental immunity in GDM, increasing bacterial invasiveness. Metformin reduces bacterial counts of E. coli and S. agalactiae, providing protective benefits beyond insulin. Cytokine tolerization under hyperglycemia highlights the need for enhanced therapeutic interventions.
What Was Studied?
This study explored the effects of hyperglycemia on inflammation and the innate defense mechanisms of the placenta against Escherichia coli (E. coli) and Streptococcus agalactiae (S. agalactiae). It also evaluated the roles of insulin and metformin in mitigating these effects. Placental explants were cultured in hyperglycemic environments and challenged with these bacteria to assess inflammatory cytokine secretion, beta defensin production, bacterial counts, and tissue invasiveness.
Who Was Studied?
The research used placental explants from 35 normoevolutive, term pregnancies (37.2–40 weeks). The placental tissues were exposed to varying glucose concentrations, insulin, and metformin in vitro. Pathogenic strains of E. coli and S. agalactiae were used to test bacterial growth and invasion under hyperglycemic and treated conditions.
What Were the Most Important Findings?
Hyperglycemia significantly increased placental secretion of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) while reducing beta defensin (HBD1-4) production, weakening innate immunity. These changes promoted greater bacterial counts and invasiveness, especially for E. coli, which exhibited a strong tropism for capillaries. The study found that insulin reduced bacterial invasiveness by fortifying the placental barrier, but did not affect bacterial counts. Metformin, on the other hand, significantly reduced bacterial counts of both E. coli and S. agalactiae in addition to mitigating bacterial invasiveness. Despite these protective effects, neither treatment restored beta defensin synthesis. Furthermore, hyperglycemia combined with bacterial infection induced "cytokine tolerization," resulting in a pathogen-specific reduction in pro-inflammatory cytokine secretion, which potentially increases vulnerability to infections.
What Are the Greatest Implications of This Study?
Hyperglycemia impairs placental immunity in GDM by weakening defenses against infections through reduced beta defensin synthesis and cytokine tolerization. While insulin limits bacterial invasion, metformin provides additional benefits by actively reducing bacterial counts of E. coli and S. agalactiae. These findings emphasize the need for optimizing therapeutic strategies to enhance placental defenses in GDM, particularly leveraging metformin's antimicrobial properties.
Endometriosis
Endometriosis involves ectopic endometrial tissue causing pain and infertility. Validated and Promising Interventions include Hyperbaric Oxygen Therapy (HBOT), Low Nickel Diet, and Metronidazole therapy.
Major Microbial Associations (MMAs)
Major Microbial Associations (MMAs) are fundamental in understanding disease-microbiome interactions and play a crucial role in advancing microbiome-targeted interventions aimed at treating or preventing diseases through microbial modulation.
Streptococcus agalactiae (GBS)
Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is a Gram-positive, facultative anaerobe commonly found as a commensal organism in the gastrointestinal and urogenital tracts of humans. While asymptomatic colonization is frequent, GBS is also a major pathogen, particularly in neonates, pregnant women, and immunocompromised individuals.
Microbiome-Targeted Interventions (MBTIs)
Microbiome Targeted Interventions (MBTIs) are cutting-edge treatments that utilize information from Microbiome Signatures to modulate the microbiome, revolutionizing medicine with unparalleled precision and impact.
References
- High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin.. Jiménez-Escutia R, Vargas-Alcantar D, Flores-Espinosa P, Helguera-Repetto AC, Villavicencio-Carrisoza O, Mancilla-Herrera I, Irles C, Torres-Ramos YD, Valdespino-Vazquez MY, Velázquez-Sánchez P, et al.. (International Journal of Molecular Sciences. 2023)
- Metformin as a Potential Treatment Option for Endometriosis. . Kimber-Trojnar Ż, Dłuski DF, Wierzchowska-Opoka M, Ruszała M, Leszczyńska-Gorzelak B.. (Cancers (Basel). 2022)
Jiménez-Escutia R, Vargas-Alcantar D, Flores-Espinosa P, Helguera-Repetto AC, Villavicencio-Carrisoza O, Mancilla-Herrera I, Irles C, Torres-Ramos YD, Valdespino-Vazquez MY, Velázquez-Sánchez P, et al.
High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin.International Journal of Molecular Sciences. 2023
Read ReviewKimber-Trojnar Ż, Dłuski DF, Wierzchowska-Opoka M, Ruszała M, Leszczyńska-Gorzelak B.
Metformin as a Potential Treatment Option for Endometriosis.Cancers (Basel). 2022