Did you know?
Metformin, today’s leading diabetes drug, was originally derived from Galega officinalis, a medieval herb once used in folk medicine to treat symptoms of diabetes.

Metformin

Researched by:

Karen Pendergrass ID

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.

April 28, 2025

Metformin is a synthetic derivative of guanidine derived from the guanidine alkaloid of the plant Galega officinalis L. with significant hypoglycemic effects. It is a first-line antihyperglycemic agent due to its efficacy, low cost, and favorable safety profile.

Research feed

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.

Researched by:

Karen Pendergrass ID

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.

Last Updated: April 28, 2025

Overview

Metformin is a synthetic derivative of guanidine derived from the guanidine alkaloid of the plant Galega officinalis L. with significant hypoglycemic effects. It is a first-line antihyperglycemic agent due to its efficacy, low cost, and favorable safety profile. Beyond glucose control, metformin exhibits anti-inflammatory, anti-tumor, and anti-aging effects. Notably, a substantial portion of metformin remains in the gut unmetabolized, where it interacts with the intestinal environment. Growing evidence indicates that metformin’s benefits are partly mediated through modulation of the gut microbiome. This microbiome-targeted activity has sparked interest in repurposing metformin for conditions like metabolic syndrome, polycystic ovary syndrome, and even aging-related diseases where dysbiosis and metabolic inflammation are contributors. ^[1]

Mechanisms of Action

Metformin’s mechanisms of action involves direct action on host cells and indirect modulation via gut microbes. Metformin is transported into intestinal cells (via PMAT/OCT transporters) to activate AMPK signaling, reducing hepatic glucose output. Concurrently, metformin alters gut bacteria, leading to the production of short-chain fatty acids (SCFAs) that activate receptors (e.g. GPR43) on L-cells to increase GLP-1 secretion, and it influences microbial components that interact with immune receptors (TLR2/TLR4) to reduce inflammation. ^[2]

What is the mechanism of action of Metformin?

Mechanism	Details
Host Cell-Mediated Effects	Metformin is transported into intestinal cells via PMAT/OCT transporters where it activates AMP-activated protein kinase (AMPK), leading to reduced hepatic gluconeogenesis and increased peripheral glucose uptake. This improves insulin sensitivity, stabilizes body weight, enhances lipid metabolism, and confers cardiovascular benefits. Metformin also stimulates GLP-1 secretion from intestinal L-cells, contributing further to glycemic control. ^[3]
Microbiome-Mediated Effects	Metformin alters the gut microbiota composition by increasing luminal glucose, which microbes ferment into short-chain fatty acids (SCFAs) like acetate and propionate. SCFAs activate receptors such as GPR43 on L-cells and immune cells, enhancing GLP-1 secretion and reducing inflammation. Metformin additionally modulates bile acid metabolism, promoting TGR5 activation and favoring bile-tolerant bacteria. ^[4]^[5]
Biofilm Disruption and Antimicrobial Activity	At higher concentrations, metformin exhibits direct antimicrobial properties. It reduces bacterial virulence by inhibiting quorum sensing and biofilm formation in pathogens like Pseudomonas aeruginosa, potentially limiting gut colonization by opportunistic organisms and supporting a healthier microbiota. ^[6]
Immune Modulation via Microbial Changes	Metformin-induced enrichment of SCFA-producing bacteria enhances binding to immune cell receptors (e.g., GPR43), promoting anti-inflammatory effects. It also increases beneficial species like Akkermansia, which modulate Toll-like receptor pathways (upregulating TLR2, downregulating TLR4), ultimately suppressing NF-κB-mediated inflammation and reducing circulating endotoxin levels. ^[7][8]

Microbial Implications

Metformin therapy induces significant shifts in gut microbiome composition and function that contribute to its metabolic effects and side-effect profile. Key alterations include the enrichment of beneficial taxa such as Akkermansia muciniphila and various short-chain fatty acid (SCFA)-producing genera, enhancing SCFA production and improving host metabolic parameters like insulin sensitivity and gut barrier integrity.^[8] Simultaneously, metformin suppresses opportunistic and pro-inflammatory bacteria, such as Intestinibacter and members of the Enterobacteriaceae family, reducing systemic inflammatory triggers like lipopolysaccharides (LPS). While its impact on overall microbial diversity varies by patient population, metformin consistently induces functional remodeling of the microbiome, notably increasing fermentation and carbohydrate metabolism pathways.^[9] These microbial shifts not only underlie clinical benefits, including improved glycemic control and weight stabilization, but also contribute to gastrointestinal side effects observed in some patients, such as bloating and diarrhea, emphasizing the importance of dose titration to promote microbial and host adaptation.

What are the microbial implications of Metformin?

Microbial Implications	Details
Enrichment of Beneficial Genera	Metformin increases abundance of Akkermansia muciniphila, a mucin-degrading bacterium associated with improved metabolic health. It also promotes expansion of SCFA-producing bacteria, including butyrate-producing Clostridia, Bifidobacterium, Butyricimonas, and Prevotella. These shifts enhance SCFA production (butyrate, propionate), improving insulin sensitivity, glucose homeostasis, gut barrier function, and reducing inflammation.^[9]
Reduction of Pathogenic or Opportunistic Bacteria	Metformin consistently reduces Intestinibacter (formerly Clostridium XI), a genus associated with bile acid deconjugation and insulin resistance. It also limits endotoxin-producing Enterobacteriaceae overgrowth, lowering plasma LPS levels, and restrains Proteobacteria expansion in disease models, helping preserve a healthier, balanced microbiota. ^[10][10]
Microbial Diversity and Functional Changes	Metformin’s effect on alpha-diversity is variable: it may slightly decrease in non-diabetics but remains stable or modestly increases in diabetics. Regardless, metformin consistently enriches functional pathways related to carbohydrate metabolism, fermentation, and SCFA production (acetate, propionate, butyrate). These functional shifts correlate with clinical improvements such as increased GLP-1 secretion and SCFA levels. ^[11]^[12][13]
Clinical Relevance of Microbiome Changes	Microbial shifts toward Akkermansia and SCFA-producers contribute to weight loss, better glycemic control, and reduced systemic inflammation. Conversely, microbiome alterations underlie gastrointestinal side effects; expansions of gas-producing bacteria (e.g., Escherichia, Streptococcus) and increased fecal SCFAs may cause bloating or diarrhea. Gradual dose titration is recommended to allow host and microbiome adaptation. ^[14]^[15]

Conditions

Metformin’s established and investigational uses span a range of conditions, often leveraging its microbiome-modulating properties. Below is a summary of conditions where metformin is either validated or showing promise, with relevance to the microbiome.

Conditions	Status
Polycystic Ovary Syndrome (PCOS)	Validated as a Microbiome-targeted intervention (MBTI) for p olycystic ovarian syndrome (PCOS). Metformin is widely used off-label to improve insulin resistance and menstrual regularity. In PCOS, metformin increases beneficial gut bacteria (e.g. lactobacilli) and reduces inflammatory microbes, contributing to lower androgens and weight loss.^[16]
Endometriosis	Validated as a Microbiome-targeted intervention (MBTI) for endometriosis. However, metformin is not widely used off-label for the condition.^[17]
Non-alcoholic Fatty Liver Disease (NAFLD/NASH)	Promising Intervention. Shows modest improvements in liver fat and enzymes in diabetics.^[18] In mice, metformin protected gut barrier function and prevented endotoxin influx, attenuating liver inflammation. ^[19]
Obesity / Weight Management	Promising Intervention. Off-label use in obesity, especially if insulin resistance is present. Metformin-linked microbiome changes (e.g. increased Akkermansia) are associated with weight loss and improved adiposity measures in some studies.^[20] Ongoing research (e.g. in adolescents) is evaluating its microbiome-related benefits for obesity.
Cancer (Adjuvant Therapy)	Epidemiologic studies show that diabetics on metformin have lower incidence and better outcomes in some cancers.^[21] Trials in breast cancer are exploring metformin as an adjunct therapy. ^[22] Mechanistically, a healthy microbiome promoted by metformin (increased SCFAs, reduced pro-carcinogenic bile acids) might improve immune surveillance and response to therapy.
Aging	Being studied in trials (e.g. TAME) for extending healthspan. Metformin may combat age-related microbiome changes (loss of diversity, pro-inflammatory flora).^[23] It has been shown to preserve a “youthful” microbiome profile and reduce chronic inflammation (“inflammaging”) in animal models. Metformin also reduces aging-related leaky gut and improves cognitive function by modulating the gut microbiome/goblet cell/mucin axis.^[24] Metformin is not yet indicated for general anti-aging, pending clinical trial outcomes.

Clinical Evidence

The evolving understanding of metformin’s microbiome-mediated effects has expanded its clinical significance beyond glycemic control. Decades of research established metformin as a cornerstone therapy for type 2 diabetes,^[25] yet emerging studies now reveal that modulation of gut microbial composition and function is integral to its metabolic efficacy.^[26] Increasingly, clinical and mechanistic evidence implicates the gut microbiota in mediating metformin’s benefits across diverse conditions, including diabetes, metabolic disease, polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD), oncology, aging, and even infectious diseases such as COVID-19. ^[27]

What is the clinical evidence supporting the use of Metformin?

This section outlines key findings that connect microbiome alterations to metformin’s therapeutic outcomes and highlights the translational potential of these insights.

Diabetes and Metabolic Disease

Metformin’s clinical efficacy in type 2 diabetes was established in landmark trials decades ago. For example, the UKPDS trial in the 1990s showed metformin significantly reduced diabetic complications in overweight patients.^[28] Beyond glycemic control, recent studies have illuminated the microbiome’s role in this efficacy. A 2015 study in Nature disentangled diabetes vs. drug effects on the microbiome, finding that metformin treatment itself drives distinct gut microbial changes (such as increases in Escherichia and decreases in Intestinibacter) that improve metabolism. ^[29] In 2017, de la Cuesta-Zuluaga et al. showed that metformin-treated individuals had a higher relative abundance of Akkermansia muciniphila and SCFA-producing taxa; these microbiota features correlated with better glucose tolerance and insulin levels.^[30] Such findings suggest that part of metformin’s anti-hyperglycemic effect is mediated by restoring gut microbial balance. In new-onset diabetes, metformin rapidly alters the microbiome within days to weeks – one trial noted increased Prevotella and Oscillibacter along with functional shifts after only 3 months of therapy.^[31] Notably, antibiotic co-administration can blunt metformin’s metabolic benefits: in a mouse experiment, metformin failed to raise GLP-1 or improve glycemia when broad-spectrum antibiotics had wiped out the gut bacteria, whereas adding back SCFAs restored the GLP-1 response, providing direct evidence that the drug’s full effect depends on an intact microbiome.^[32]

Microbiome Signatures and Mechanistic Studies

Mechanistic evidence from preclinical studies reinforces these clinical observations. In diet-induced obese mice, metformin dramatically shifted the gut microbiota and improved metabolic parameters. For instance, Shin et al. (2014) reported that metformin treatment increased Akkermansia in obese mice and improved their glucose tolerance, linking this bacterial change to metabolic benefit (coadministration of Akkermansia itself reproduced some of metformin’s effects.^[33] Other rodent studies demonstrate that metformin enriches butyrate-producing bacteria and mucin-degraders, which in turn augment gut hormone release of hormones involved in the neuroregulation of appetite and satiety signaling (GLP-1, PYY) and reduced systemic inflammation.^[34] A pivotal study by Brandt et al. (2019) showed that metformin prevented the development of fatty liver in mice on a high-calorie diet by preserving the gut barrier and microbiome: treated mice had near-normal intestinal tight junctions and significantly lower portal endotoxin levels than controls.^[35] Their gut microbiota composition under metformin remained closer to healthy chow-fed mice, indicating the drug opposed the NAFLD-associated dysbiosis. This mechanistic link between microbiome, gut permeability, and metabolic inflammation is a key piece of evidence for microbiome-targeted therapy in NAFLD.

Repurposing and Translational Research

Clinicians have leveraged metformin’s pleiotropic actions in other conditions, and emerging clinical studies are evaluating these uses. In PCOS, multiple RCTs have shown that metformin improves menstrual cyclicity, ovulation, and weight, with some of these benefits now attributed to changes in gut microbes and their metabolites (such as reductions in inflammatory Proteobacteria).^[36] Small trials in women with PCOS found that metformin and probiotic supplements independently improved metabolic and hormonal profiles, suggesting a common pathway via the gut ecosystem.^[37] In oncology, retrospective analyses in colorectal and breast cancer patients with diabetes noted better survival in those on metformin, spurring prospective cancer trials. While large trials (e.g. in breast cancer) have had mixed results, subgroup analyses hint that patients with certain favorable gut microbiome profiles derive more benefit, aligning with the idea that metformin’s anti-cancer immune effects may be microbiome-dependent. Additionally, the TAME (Targeting Aging with Metformin) study was designed to test if metformin can delay multiple age-related diseases; although results are pending, it is hypothesized that metformin’s promotion of a “younger” gut microbiota (higher diversity, more SCFAs) could be a mechanism for reduced chronic inflammation in aging. ^[38] Finally, during the COVID-19 pandemic, observational studies suggested metformin use was associated with lower mortality in diabetic patients. While confounders exist, one proposed mechanism is that metformin’s microbiome/immune modulation (e.g. increasing gut production of antiviral metabolites like butyrate and lowering inflammatory cytokines) helped ameliorate the hyperinflammatory response.^[39] This remains an active area of research, exemplifying how an old drug’s new applications often circle back to the gut microbiome.

Dosage

In adults with type 2 diabetes, metformin is typically initiated at 500 mg once or twice daily with meals and titrated to an effective dose of 1500–2000 mg per day (in divided doses) to minimize GI side effects. Clinical trials and practice have shown that doses around 1500 mg daily are needed for substantial glycemic effect. [2] The maximum recommended dose is generally 2000–2550 mg/day (depending on the formulation), beyond which little additional benefit is seen. Metformin is available in immediate-release (IR) form (taken 2–3 times daily) and extended-release (XR) form (once daily dosing). The XR formulation, often 1000–2000 mg QD, can improve gastrointestinal tolerability by slowing delivery to the colon. ^[40]

What is the microbiome-targeted dosing for Metformin?

Interestingly, research into metformin’s gut-focused actions has led to exploration of lower-dose or modified-release regimens. A delayed-release metformin (Metformin DR) that largely bypasses absorption in the upper intestine has been tested to concentrate the drug’s action in the gut lumen. In a study of type 2 diabetics, this gut-restricted formulation at ~800 mg achieved glycemic improvement comparable to higher doses of absorbed metformin.^[41] This suggests that even subclinical doses can exert metabolic benefits via the microbiome and local pathways. However, such formulations are not yet commercially available. For conditions like prediabetes or for anti-aging trials, lower doses (e.g. 750–1000 mg/day) are sometimes used to test efficacy with fewer side effects. When repurposed for conditions like cancer or NAFLD in research settings, metformin’s dose typically mirrors the diabetes regimen (1500–2000 mg/day), since that level is known to engage relevant mechanisms (e.g. AMPK activation, microbiome changes). Clinicians should always start low and titrate as tolerated; many patients acclimate to full doses over 2–4 weeks, during which the gut microbiota and host adapt to the drug.

Safety

Metformin is generally well-tolerated and has a strong safety record established through decades of clinical use. However, specific adverse effects and precautions must be considered to optimize therapy and minimize risks. Key safety considerations associated with metformin include common gastrointestinal effects, rare but serious complications, microbiome-mediated impacts, and important clinical cautions.

What safety aspects should be considered?

Safety Aspect	Details

Gastrointestinal Effects

Gastrointestinal symptoms, including nausea, abdominal cramping, flatulence, and diarrhea, occur in up to 20–30% of patients, especially during initiation. These effects are dose-dependent and usually transient. Metformin-induced fermentation by gut bacteria can lead to bloating and osmotic diarrhea due to excess SCFAs. Gradual dose titration and use of extended-release formulations significantly improve tolerability. Persistent symptoms may reflect gut dysbiosis; probiotics or temporary dose reduction can aid adaptation.^[42]

Lactic Acidosis (Rare)

Metformin-associated lactic acidosis is extremely rare (~3–9 cases per 100,000 patient-years) and occurs primarily in the context of tissue hypoperfusion or renal failure. Metformin inhibits hepatic gluconeogenesis via AMPK activation, which can impair lactate clearance under critical conditions. In the absence of contraindications, the risk remains comparable to non-metformin users. ^[43][44]

Vitamin B₁₂ Deficiency

Long-term metformin use reduces vitamin B₁₂ absorption, affecting 10–30% of patients, occasionally leading to anemia or neuropathy. Mechanistically, metformin promotes the expansion of B₁₂-utilizing bacteria in the gut and impairs small intestinal motility. Periodic monitoring of B₁₂ levels is recommended, especially after 4–5 years of therapy, with supplementation as needed. Symptoms such as fatigue, neuropathy, or cognitive decline warrant evaluation.^[45]

Immune and Microbiota Considerations

Metformin generally exerts beneficial immune-modulating effects without causing clinical immunosuppression. It may enhance certain immune responses, correlating with lower cancer and infection rates in observational studies. Broad-spectrum antibiotic use can temporarily blunt metformin’s efficacy by disrupting gut microbiota, leading to transient loss of glycemic control. Normalization occurs as microbial communities recover. Very high fiber intake may initially exacerbate GI symptoms; balanced diet and hydration are advisable.^[46]

Other Contraindications and Cautions

Metformin is contraindicated in patients with acute or unstable heart failure, severe liver failure, a history of lactic acidosis, or hypersensitivity to biguanides. It is renally excreted; thus, renal function must be assessed before initiation and monitored periodically, particularly in the elderly. Metformin is considered safe during pregnancy (Category B) and does not independently cause hypoglycemia but should be used cautiously with insulin or sulfonylureas to prevent additive hypoglycemic risk.

How does metformin’s effect on the gut microbiome impact diabetic patients?

Metformin beneficially alters the gut microbiome in ways that improve metabolism. It increases bacteria that produce short-chain fatty acids and mucin-degraders like Akkermansia, which enhance GLP-1 release and reduce intestinal inflammation.^[47] ^[48]This microbiome shift is thought to contribute to better blood sugar control and weight stabilization. Practically, this means metformin’s glucose-lowering effect may partly depend on a healthy gut microbiota. If a patient has recently been on antibiotics or has gut dysbiosis, metformin might be slightly less effective until their microbiome recovers. ^[49]

Overall, the microbiome impact is beneficial – it’s one reason metformin improves insulin sensitivity beyond what its direct cellular effects would predict. As a clinician, you don’t usually need to intervene on this specifically, but it helps explain why metformin can take a few weeks to reach full effect (as the microbiome adapts) and why GI side effects occur (due to microbial fermentation).

Research Feed

June 27, 2014

•

What was reviewed?

This review examines the role of metformin in managing polycystic ovary syndrome (PCOS), specifically focusing on its effectiveness in treating PCOS-related infertility. The paper reviews evidence from randomized controlled trials (RCTs) and other studies, discussing the use of metformin as an insulin-sensitizing agent for women with PCOS who experience anovulatory infertility. It also explores metformin’s impact on metabolic dysfunctions, hyperandrogenism, and its potential use alongside other treatments like clomiphene for improving fertility outcomes in women with PCOS.

Who was reviewed?

The review considers various studies and clinical trials on the use of metformin in women with PCOS. These studies involve women with varying degrees of obesity and insulin resistance, who are experiencing anovulatory infertility, hyperandrogenism, or both. The review synthesizes results from RCTs that examined the effectiveness of metformin alone or in combination with other treatments like clomiphene citrate and aromatase inhibitors in improving ovulation, fertility, and reducing the metabolic disturbances associated with PCOS.

What were the most important findings?

The review highlights several key findings regarding the use of metformin in treating PCOS-related infertility. Metformin has shown efficacy in improving ovulation rates in women with anovulatory infertility, particularly in non-obese women. A Cochrane review of seven RCTs revealed that metformin significantly increased clinical pregnancy rates compared to placebo. However, while metformin showed promise, it did not outperform clomiphene citrate as a first-line treatment for ovulation induction in women with PCOS, particularly in obese patients. The review also found that metformin, when used in combination with clomiphene, can be effective for women who are resistant to clomiphene alone.

Additionally, the review emphasized that metformin has benefits beyond fertility induction. It helps reduce hyperinsulinemia and insulin resistance, which are common in women with PCOS, and can improve associated metabolic conditions such as dyslipidemia and obesity. Furthermore, metformin was found to reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing in vitro fertilization (IVF). Although metformin’s role in improving long-term health outcomes, such as the prevention of type 2 diabetes, cardiovascular disease, and endometrial cancer, remains inconclusive, it offers significant short-term reproductive benefits.

What are the greatest implications of this review?

The review suggests that metformin should be considered a suitable first-line treatment for non-obese women with anovulatory infertility due to PCOS. For women who are resistant to clomiphene or prefer an alternative to the oral contraceptive pill (OCP) for managing hyperandrogenic symptoms, metformin can be an effective option. Additionally, metformin’s role in reducing the risk of OHSS during IVF procedures underscores its importance in assisted reproductive treatments. The review also raises the need for further research to better define metformin’s long-term benefits in preventing the metabolic and reproductive complications associated with PCOS, as well as its potential to improve long-term health outcomes like diabetes prevention.

March 9, 2023

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.

December 5, 2023

•

What was studied?

This study focused on identifying new drug candidates for the treatment of Polycystic Ovary Syndrome (PCOS), with an emphasis on evaluating the effects of various compounds on PCOS pathophysiology. The study investigated the use of Irosustat (STX64), STX140, and compound 1G as potential alternatives to metformin in managing symptoms related to hormonal imbalance, metabolic dysfunction, and oxidative stress commonly seen in PCOS.

Who was studied?

The study utilized female Wistar rats to investigate the therapeutic effects of these drug candidates. PCOS was induced in the rats by administering letrozole (1 mg/kg/day) for 35 days, with the onset of abnormal estrous cycles confirming the induction of the condition. Rats were then divided into treatment groups, with one group receiving metformin (500 mg/kg/day) as a reference drug, while the others received STX64, STX140, or 1G for 30 days. The effects were analyzed through biochemical measurements, oxidative stress markers, and histological studies.

What were the most important findings?

The study found that the drug candidates Irosustat, STX140, and compound 1G all demonstrated promising effects on PCOS-related features. Treatment with these compounds resulted in significant improvements in various biochemical parameters, including lipid profiles, blood glucose levels, and hormone levels (testosterone, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol). These treatments also showed beneficial effects on oxidative stress and inflammation pathways, with improvements in Akt, mTOR, and AMPK-α signaling pathways. Histological studies revealed a reduction in the weight of ovaries and the disappearance of fluid-filled cysts in the treatment groups, suggesting potential for reversing ovarian morphology associated with PCOS. The drug candidates also demonstrated less adverse effect on metabolic parameters compared to untreated PCOS rats, thus highlighting their therapeutic potential as alternatives to metformin.

From a microbiome perspective, these improvements could be linked to the modulation of gut microbiota and reduced systemic inflammation. For example, Irosustat and STX140, by regulating androgen levels and improving metabolic health, may impact the gut's microbial balance, favoring beneficial bacteria that support metabolic functions and reduce inflammation. Additionally, these compounds' effects on oxidative stress markers could influence the gut-brain axis, which is crucial in the pathophysiology of PCOS.

What are the greatest implications of this study?

The greatest implication of this study lies in the identification of promising drug candidates, particularly Irosustat, STX140, and compound 1G, as potential treatments for PCOS, especially for patients who do not tolerate metformin. These drug candidates work by targeting oxidative stress, inflammatory pathways, and hormonal imbalances, which are central to PCOS pathophysiology. The findings suggest that these drugs could offer a more comprehensive treatment approach compared to current options, potentially improving not only the metabolic and hormonal aspects of PCOS but also the quality of life for affected women. The study also opens the door for further exploration into the use of these compounds in human trials, highlighting the need for personalized treatment options for women with PCOS

August 21, 2023

•

What was reviewed?

This review explores the role of metformin in treating polycystic ovary syndrome (PCOS)-related infertility. PCOS is a common endocrinological disorder that can lead to infertility, characterized by insulin resistance, hyperandrogenism, and anovulation. The review discusses metformin’s mechanisms, its impact on insulin sensitivity, its role in improving ovulation, and its effectiveness in managing metabolic and hormonal imbalances in women with PCOS. The review also emphasizes the drug's benefits in improving menstrual cyclicity and reducing hyperandrogenism, ultimately aiding in fertility restoration.

Who was reviewed?

The review synthesizes findings from various clinical studies and trials examining the effects of metformin on women with PCOS. It draws on observational studies and randomized controlled trials to evaluate the efficacy of metformin in addressing infertility associated with PCOS. The women studied in these trials typically had anovulatory infertility, hyperandrogenism, and varying degrees of insulin resistance, and they were treated with metformin to assess its impact on ovulation and fertility.

What were the most important findings?

The review found that metformin has significant therapeutic benefits for women with PCOS, particularly in restoring menstrual regularity and improving ovulation rates. Metformin works primarily by improving insulin sensitivity, which reduces hyperinsulinemia—a key factor in the pathogenesis of PCOS. This insulin-sensitizing effect contributes to lower circulating androgen levels, which is crucial in managing symptoms like hirsutism and acne. In several studies, metformin, either alone or in combination with other treatments like clomifene citrate, successfully induced ovulation in women who were resistant to standard treatments.

Furthermore, metformin appears to improve metabolic dysfunctions common in PCOS, including insulin resistance, dyslipidemia, and obesity, all of which contribute to the infertility and long-term health risks associated with the condition. However, the review also noted that while metformin improves metabolic and reproductive outcomes, its efficacy in women with significant obesity is less pronounced. The review also highlights that metformin is generally well-tolerated, although some women may experience gastrointestinal side effects.

What are the greatest implications of this review?

The review underscores metformin’s potential as a first-line treatment for women with PCOS-related infertility, especially for those who are insulin-resistant and non-obese. The findings suggest that metformin could be a safer and more accessible alternative to more invasive fertility treatments like in vitro fertilization (IVF). Moreover, metformin’s role in reducing the risk of ovarian hyperstimulation syndrome during assisted reproductive technology procedures makes it particularly valuable in IVF protocols. The review also emphasizes the need for further studies to determine the optimal dose and long-term benefits of metformin, particularly for women with more severe obesity or metabolic complications.

February 2, 2024

•

What was studied?

This study investigated the comparative effects of myo-inositol (MI) and metformin (MET) therapy on clinical and biochemical parameters in women with polycystic ovary syndrome (PCOS). The research focused on evaluating the impact of both therapies on insulin resistance (IR), hyperandrogenism, menstrual cycle regulation, and various metabolic markers in PCOS patients with normal BMI. The objective was to determine which therapy is more effective in improving these parameters.

Who was studied?

The study included 80 women diagnosed with PCOS who had insulin resistance but a normal body mass index (BMI). These participants were randomly assigned to two treatment groups: one group received myo-inositol, while the other group received metformin. The study was designed as a randomized controlled trial and aimed to assess the efficacy of these two insulin-sensitizing therapies.

What were the most important findings?

The results indicated that both myo-inositol and metformin significantly reduced insulin resistance, with a marked decrease in the area under the curve (AUC) of insulin during an oral glucose tolerance test (OGTT) for both groups. Both treatments led to improvements in the regulation of menstrual cycles, with more than 90% of patients experiencing regular cycles. The therapies also resulted in a statistically significant reduction in androgenic hormones (such as testosterone and SHBG), which are critical for managing symptoms like hirsutism. The findings suggest that both myo-inositol and metformin are effective in addressing insulin resistance, menstrual irregularities, and hyperandrogenism in women with PCOS, especially those with normal weight.

From a microbiome perspective, insulin resistance and hormonal imbalances are known to influence gut microbiota composition. Studies have shown that insulin resistance can contribute to an imbalance in the gut microbiome, potentially promoting pro-inflammatory taxa. Moreover, treatments like myo-inositol and metformin may have indirect effects on microbiota, such as modulating gut inflammation or affecting microbial populations associated with metabolic health.

What are the implications of this study?

The study highlights the potential of both myo-inositol and metformin as first-line treatments for managing PCOS in women with normal BMI, specifically targeting insulin resistance and hyperandrogenism. The results suggest that both therapies can be effective in improving metabolic and endocrine outcomes in PCOS, but myo-inositol may offer the advantage of fewer gastrointestinal side effects compared to metformin. This makes myo-inositol a promising alternative, particularly for women who experience adverse effects with metformin. The study also emphasizes the importance of considering personalized treatment options for women with PCOS, as different responses may be observed based on individual phenotypes.

Update History

2025-04-28 17:32:40

MBTI Validations major

Metformin identified as a validated microbiome-targeted intervention (MBTI) for Endometriosis and Polycystic Ovarian Syndrome (PCOS)

References

Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Synergistic Benefits: Exploring the Anti-Virulence Effects of Metformin/Vildagliptin Antidiabetic Combination against Pseudomonas aeruginosa via Controlling Quorum Sensing Systems. Khayat MT, Abbas HA, Ibrahim TS, Elbaramawi SS, Khayyat AN, Alharbi M, Hegazy WAH, Yehia FAA. (Biomedicines. 2023)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients.. Elbere I, Silamikelis I, Dindune II, Kalnina I, Briviba M, Zaharenko L, Silamikele L, Rovite V, Gudra D, Konrade I, Sokolovska J, Pirags V, Klovins J.. (PLoS One. 2020)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Gut Microbiota as a Potential Target for Treatment of Polycystic Ovary Syndrome.. Bingjie Zhang, Shanmei Shen, Yan Bi, Dalong Zhu.. (Diabetes. 2018.)
Metformin as a Potential Treatment Option for Endometriosis.. Kimber-Trojnar Ż, Dłuski DF, Wierzchowska-Opoka M, Ruszała M, Leszczyńska-Gorzelak B.. (Cancers (Basel). 2022)
Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels.. Pinyopornpanish K, Leerapun A, Pinyopornpanish K, Chattipakorn N.. (Gut Liver. 2021)
Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine.. Brandt, A., Hernández-Arriaga, A., Kehm, R. et al. . (Sci Rep 9, 6668 (2019))
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Metformin Reduces Aging-Related Leaky Gut and Improves Cognitive Function by Beneficially Modulating Gut Microbiome/Goblet Cell/Mucin Axis.. Ahmadi S, Razazan A, Nagpal R, Jain S, Wang B, Mishra SP, Wang S, Justice J, Ding J, McClain DA, Kritchevsky SB, Kitzman D, Yadav H.. (J Gerontol A Biol Sci Med Sci. 2020)
The Gut Microbiome, Metformin, and Aging.. Reddy N, Kansara P, Thomas SC, Xu F, Saxena D, Li X.. (The Annual Review of Pharmacology and Toxicology. 2021)
Metformin Reduces Aging-Related Leaky Gut and Improves Cognitive Function by Beneficially Modulating Gut Microbiome/Goblet Cell/Mucin Axis.. Ahmadi S, Razazan A, Nagpal R, Jain S, Wang B, Mishra SP, Wang S, Justice J, Ding J, McClain DA, Kritchevsky SB, Kitzman D, Yadav H.. (J Gerontol A Biol Sci Med Sci. 2020)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine.. Brandt, A., Hernández-Arriaga, A., Kehm, R. et al. . (Sci Rep 9, 6668 (2019))
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients.. Elbere I, Silamikelis I, Dindune II, Kalnina I, Briviba M, Zaharenko L, Silamikele L, Rovite V, Gudra D, Konrade I, Sokolovska J, Pirags V, Klovins J.. (PLoS One. 2020)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Effects of metformin on the gut microbiota: A systematic review.. Pavlo Petakh, Kamyshna I, Kamyshnyi A.. (Mol Metab. 2023)
Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine.. Brandt, A., Hernández-Arriaga, A., Kehm, R. et al. . (Sci Rep 9, 6668 (2019))
Gut Microbiota as a Potential Target for Treatment of Polycystic Ovary Syndrome.. Bingjie Zhang, Shanmei Shen, Yan Bi, Dalong Zhu.. (Diabetes. 2018.)
Gut Microbiota as a Potential Target for Treatment of Polycystic Ovary Syndrome.. Bingjie Zhang, Shanmei Shen, Yan Bi, Dalong Zhu.. (Diabetes. 2018.)
Gut Microbiota as a Potential Target for Treatment of Polycystic Ovary Syndrome.. Bingjie Zhang, Shanmei Shen, Yan Bi, Dalong Zhu.. (Diabetes. 2018.)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Review: metformin does not increase risk of lactic acidosis or increase lactate levels in type 2 diabetes.. Kruse, J. A.. (Evidence-Based Medicine, 9(4), 111–111.)
Metformin-related lactic acidosis: is it a myth or an underestimated reality?. Visconti L, Cernaro V, Ferrara D, Costantino G, Aloisi C, Amico L, Chirico V, Santoro D, Noto A, David A, Buemi M, Lacquaniti A.. (Ren Fail. 2016)
The antidiabetic drug metformin aids bacteria in hijacking vitamin B12 from the environment through RcdA.. Yao, L., Wang, Y., Qin, S. et al.. Yao, L., Wang, Y., Qin, S. et al. (Commun Biol 6, 96 (2023).)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)
Advances in the mechanism of metformin with wide-ranging effects on regulation of the intestinal microbiota.. Wang Y, Jia X, Cong B.. (Front Microbiol. 2024)
Gut microbiota is correlated with gastrointestinal adverse events of metformin in patients with type 2 diabetes.. Huang Y, Lou X, Jiang C, Ji X, Tao X, Sun J, Bao Z.. (Front Endocrinol (Lausanne). 2022)

Associated Conditions
- Endometriosis
- Polycystic ovary syndrome (PCOS)

Join the Roundtable

Contribute to published consensus reports, connect with top clinicians and researchers, and receive exclusive invitations to roundtable conferences.

Yes, I want to help shape the future of microbiome medicine.

Metformin

Welcome back! 👋

Create your account

Forgot Password

Overview

Mechanisms of Action

Microbial Implications

Conditions

Clinical Evidence

Microbiome Signatures and Mechanistic Studies

Repurposing and Translational Research

Dosage

Safety

Research Feed

What was reviewed?

Who was reviewed?

What were the most important findings?

What are the greatest implications of this review?

What Was Studied?

Who Was Studied?

What Were the Most Important Findings?

What Are the Greatest Implications of This Study?

What was studied?

Who was studied?

What were the most important findings?

What are the greatest implications of this study?

What was reviewed?

Who was reviewed?

What were the most important findings?

What are the greatest implications of this review?

What was studied?

Who was studied?

What were the most important findings?

What are the implications of this study?

Update History

References

What's on your mind?