Metformin Reduces Diabetic Risk by Improving Gut Health

The gut microbiome consists of trillions of microorganisms that inhabit the human gastrointestinal tract.

Having an imbalanced gut microbiome is associated with cancer, vascular disease, allergies, neurodegenerative disorders, and depression.^1-3

In 2017, researchers at Johns Hopkins Bloomberg School of Public Health announced a series of discoveries linking disturbances in the microbiome to diabetes.⁴

Fortunately, they also found a solution.

Metformin is the most widely prescribed drug to treat type II diabetes.

Since 1995, Life Extension® has recommended metformin to nondiabetics as a possible way to slow biological aging.

Metformin’s primary beneficial mechanism is to increase cellular AMPK.

As people age, AMPK activity declines and sets the stage for a host of degenerative illnesses.

New studies have uncovered another benefit to metformin: It boosts a beneficial intestinal bacterium called Akkermansia muciniphila.⁴

Studies show that this bacterium has specific actions that combat diabetes and obesity.

This study from Johns Hopkins sheds new light on metformin’s role as a microbiome-modifying, anti-diabetic drug.

Akkermansia Improves Metabolic Health

Gut health hinges on having a healthy balance of the right kinds of bacteria.

Akkermansia muciniphila is one of the good guys, and its specialty seems to lie in beneficially affecting metabolic health.⁵

Until 2016, little was known about the organism’s role in human metabolism.^5-9 That changed with publication of a French study.⁵

In a 12-week dietary intervention, the Sorbonne’s researchers studied 49 overweight and obese adults. Subjects undertook six weeks of a calorie-restricted diet followed by six weeks of a diet aimed at weight stabilization.

The study showed that subjects with the highest baseline abundance of Akkermansia muciniphila in their stool had the best parameters associated with metabolic health, including:

• The lowest fasting glucose,
• The lowest waist-to-hip ratios (a measure of central obesity),
• The lowest mean diameter of fat cells, and
• The best metabolic status, as indicated by lower plasma-triglyceride levels and better body-fat distribution.⁵

Having an abundance of Akkermansia also predicted greater improvements following the calorie-restriction phase of the study. For example, the subjects with higher baseline Akkermansia levels had greater improvements in markers of insulin resistance, blood lipids, and body fat composition after the intervention, compared with those having lower abundance of the organism.⁵ They also showed less liver-cell damage, a common outcome of excessive liver fat associated with non-alcoholic fatty liver disease (NAFLD).

As an added benefit, having plenty of Akkermansia muciniphila was associated with having an abundance of other microbial species with known benefits to metabolic health.⁵

In addition to confirming Akkermansia muciniphila’s role in metabolic health, this study also suggests that interventions that boost Akkermansia are likely to be useful in counteracting obesity, diabetes, and their deadly cardiovascular consequences.

And it turns out that an unanticipated yet potent way to boost Akkermansia is a drug that’s already well-known for its glucose-lowering, anti-diabetic benefits: metformin.

Metformin’s Akkermansia-Boosting Effects

Metformin is a derivative of the French lilac (Galega officinalis) with an ever-expanding list of benefits and an excellent safety record.^10-12

It has been used for more than 50 years to treat type II diabetes.¹³

More recently, reports have indicated that metformin’s metabolic benefits might involve alterations to the gut microbiome. Intrigued, researchers at the Johns Hopkins Bloomberg School of Public Health teamed up with colleagues in Colombia to develop a deeper understanding of metformin’s impact on the microbiome.⁴

The study involved 28 individuals with diabetes and 84 others without diabetes that were matched to the diabetic subjects by sex, age, and body mass index (BMI). Half of the diabetic subjects were taking metformin, while the other half were not.⁴

What the researchers found was remarkable. Compared with subjects who did not have diabetes, the diabetic subjects taking metformin had higher abundance of Akkermansia muciniphila, while diabetics not taking metformin lacked this increase.⁴

There may be no citizen of the gut microbiome community better suited to protecting us against diabesity—the combination of diabetes and obesity—than Akkermansia because of its ability to improve insulin resistance, blood lipids, and body-fat composition.

As an added benefit, the diabetics given metformin also had higher levels of bacteria known for their ability to produce essential short-chain fatty acids (such as butyrate).⁴ Short chain fatty acids are increasingly being recognized for their anti-inflammatory properties in the intestine and elsewhere in the body.^14,15

In sharp contrast, diabetics not taking metformin showed a higher abundance of bacteria in the Clostridiaceae family, which have been associated with higher levels of gut and system-wide inflammation.^4,16,17

These beneficial shifts in the diabetic gut microbiome are precisely what one would desire in an antidiabetic therapy: reduction in bacteria associated with inflammation (which promotes insulin resistance and therefore diabetes), and increases in bacteria known to protect gut integrity and soothe inflammation.

Metformin’s Metabolic Effects

Another study out in late 2016 vividly demonstrates the important health benefits of metformin as a gut microbiome-modulating drug.¹⁸

It found that metformin’s ability to improve the gut microbiome can reverse a condition known to cause everything from digestive issues and hormone imbalances, to skin issues and food allergies, to autoimmune diseases and depression.

The condition is called leaky gut, and it occurs when the otherwise-tight intestinal wall becomes permeable, allowing things like toxins, bacteria, and undigested food to “leak” out of the intestines and travel throughout the body through the bloodstream. The immune system targets them as imposters and attacks them. This leads not only to the effects listed above, but to a body-wide state of low-grade inflammation.^18,19

Two primary underlying causes of a leaky gut include a high-fat diet and an unbalanced (dysbiotic) gut microbiome, and it can lead to a cascade of events that have a harmful impact on blood sugar and insulin resistance.²⁰

The chief culprit in this scenario is a ubiquitous, highly-toxic family of compounds called lipopolysaccharides, or endotoxins. When lipopolysaccharides are released into the circulation, they cause a profound inflammatory response, even when present in amounts as miniscule as one-trillionth of a gram.²¹

One of the most devastating results of lipopolysaccharide-induced chronic inflammation is the development of insulin resistance. This occurs when damaged cells lose the ability to respond to insulin signaling, leading to high blood-sugar levels that damage tissues.¹⁹

While it is virtually impossible to avoid these dangerous endotoxins, studies have shown that modulating the composition of the gut microbiome can limit how much of them are absorbed into the circulation—which has beneficial effects on metabolic health.

Metformin Reverses Leaky Gut

Another 2016 study found that metformin’s ability to modulate a dysbiotic gut microbiome has a profound impact on leaky gut and its consequences.

For this study, scientists fed mice a high-fat diet for 18 weeks to induce insulin resistance.¹⁸ They then treated the mice with either metformin alone, or metformin following injections of lipopolysaccharides to produce high-grade inflammation.

The results showed that metformin treatment:

• Reversed gut leakiness induced by a high-fat diet,
• Lowered the resulting elevated circulating lipopolysaccharide levels, and
• Increased the abundance of beneficial Lactobacillus and Akkermansia in the gut microbiome.

This study shows that metformin exerts favorable changes on a dysbiotic gut microbiome—a benefit that results in a sharp decrease in pro-inflammatory compounds associated with diabetes and obesity. It also offers additional insights into why metformin is such a potent actor in fighting these disorders.

This study highlights the importance of microbiome composition in metabolic health and strengthens the case for Akkermansia muciniphila as a chief guardian of gut balance.

Summary

Metformin is a multitargeted drug with broad-spectrum metabolic benefits in diabesity, the deadly combination of diabetes and obesity.

New studies show that some of metformin’s metabolic benefits stem from its impact on the gut microbiome.

These studies show that metformin boosts the amount of Akkermansia muciniphila. People with higher levels of Akkermansia have better metabolic health, lower blood sugar, and healthier body-fat distributions than those with lower levels.

By inducing these beneficial gut microbiome changes, metformin reduces gut leakiness and lowers levels of circulating toxins that induce inflammation throughout the body—effects that help to reduce inflammation-related insulin resistance and elevated blood-sugar levels.

Probiotics are one important means of supporting good gut microbiome balance and overall health. Metformin may be considered along with probiotics as a beneficial, gut microbiome-modulating intervention that can promote intestinal as well as metabolic health.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

1. Carding S, Verbeke K, Vipond DT, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis. 2015;26:26191.
2. Daulatzai MA. Role of stress, depression, and aging in cognitive decline and Alzheimer’s disease. Curr Top Behav Neurosci. 2014;18:265-96.
3. Sun J, Chang EB. Exploring gut microbes in human health and disease: Pushing the envelope. Genes Dis. 2014;1(2):132-9.
4. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, et al. Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. Diabetes Care. 2017;40(1):54-62.
5. Dao MC, Everard A, Aron-Wisnewsky J, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426-36.
6. Li J, Lin S, Vanhoutte PM, et al. Akkermansia Muciniphila Protects Against Atherosclerosis by Preventing Metabolic Endotoxemia-Induced Inflammation in Apoe-/- Mice. Circulation. 2016;133(24):2434-46.
7. Reunanen J, Kainulainen V, Huuskonen L, et al. Akkermansia muciniphila Adheres to Enterocytes and Strengthens the Integrity of the Epithelial Cell Layer. Appl Environ Microbiol. 2015;81(11):3655-62.
8. Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63(5):727-35.
9. Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut. 2014;63(9):1513-21.
10. Goodwin PJ, Thompson AM, Stambolic V. Diabetes, metformin, and breast cancer: lilac time? J Clin Oncol. 2012;30(23): 2812-4.
11. Perla V, Jayanty SS. Biguanide related compounds in traditional antidiabetic functional foods. Food Chem. 2013;138 (2-3):1574-80.
12. Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes. 2017;18(1):10-6.
13. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566-76.
14. Hansen CH, Frokiaer H, Christensen AG, et al. Dietary xylooligosaccharide downregulates IFN-gamma and the low-grade inflammatory cytokine IL-1beta systemically in mice. J Nutr. 2013;143(4):533-40.
15. Wang F, Liu J, Weng T, et al. The Inflammation Induced by Lipopolysaccharide can be Mitigated by Short-chain Fatty Acid, Butyrate, through Upregulation of IL-10 in Septic Shock. Scand J Immunol. 2017;85(4):258-63.
16. Scarpa M, Grillo A, Faggian D, et al. Relationship between mucosa-associated microbiota and inflammatory parameters in the ileal pouch after restorative proctocolectomy for ulcerative colitis. Surgery. 2011;150(1):56-67.
17. Villar-Garcia J, Guerri-Fernandez R, Moya A, et al. Impact of probiotic Saccharomyces boulardii on the gut microbiome composition in HIV-treated patients: A double-blind, randomised, placebo-controlled trial. PLoS One. 2017;12(4):e0173802.
18. Zhou ZY, Ren LW, Zhan P, et al. Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling. Acta Pharmacol Sin. 2016;37(8):1063-75.
19. Lee MS. Ed 05-2 Interaction of Gut Dysbiosis and Innate Immune Dysfunction in the Development of Metabolic Syndrome. J Hypertens. 2016;34 Suppl 1 2016:e187.
20. Bibbo S, Ianiro G, Giorgio V, et al. The role of diet on gut microbiota composition. Eur Rev Med Pharmacol Sci. 2016;20(22):4742-9.
21. Newton RC. The production of human interleukin-1 beta by blood monocytes. Prog Clin Biol Res. 1990;349:217-28.