Jan
21
2017

Effects Of Metformin On The Gut Microbiome

Matthew Andry, MD talked about the effects of metformin on the gut microbiome. He delivered his talk at the 24th Annual World Congress on Anti-Aging Medicine. The congress took place from Dec. 9 to Dec. 11, 2016 in Las Vegas. A lot of the sessions that I attended dealt with the gut flora and how it affects our health. This talk belongs to the theme of what a healthy gut microbiome can do for us.

History of metformin

Dr. Andry is a clinical associate professor of the Indiana School of Medicine. He pointed out that metformin is in use for a long time for type 2 diabetes, particularly, if fasting insulin levels are high. Metformin is a biguanide. It seems like it was isolated from French lilac (also known as Goats Rue). As a matter of fact in the middle ages physicians used this herb to treat “thirst and urination”. In retrospect we probably recognize these as symptoms of diabetes. Chemists were able to synthesize the active ingredient in this herb in the 1920’s.

Metformin reduces blood sugar without raising insulin levels

At that time it got the name metformin. Dr. Jean Stern was able to show in the 1950’s in clinical studies that Glucophage, the brand name of metformin was able to reduce blood sugar without raising insulin levels. Between 1977 and 1997 metformin enjoyed wide spread acceptance for treating diabetics. Most noteworthy, several clinical investigators demonstrated that diabetic patients on metformin lived longer and had less heart attacks than patients who receive other treatments.

Metformin is the first-line drug in the treatment of type 2 diabetes in children and adults. It is very popular with physicians who prescribe this drug throughout the world with 120 million prescriptions per year.

Off-label use of metformin

Metformin is beneficial for many other clinical conditions. Polycystic ovary syndrome (PCOS), obesity, prediabetes, metabolic syndrome and nonalcoholic steatohepatitis are a few examples of off-label use of metformin. In addition, metformin is also in use as an anti-aging agent as it elongates telomeres, which helps people to live longer. Equally important, researchers also found that metformin is a possible cancer prevention agent. In prostate cancer it was found to have an effect against prostate cancer stem cells. Not to mention that without these cells prostate cancer does not recur after surgical removal.

Action of metformin

For the reason that metformin increases the action of an enzyme, AMPK, this leads to lipid oxidation and breakdown of fatty tissue (catabolism). Furthermore, in the liver metformin inhibits the metabolic pathway of making sugar from fatty acids, called gluconeogenesis. Also, metformin causes increased uptake of sugar into skeletal muscle tissue. This is the reason for the stabilization of blood sugar. Then, metformin has two beneficial effects on the liver. First it stabilizes insulin sensitivity. This means that a given amount of insulin has a larger effect on the liver. Secondly metformin decreases the toxic effect of fatty acids on the liver tissue. In other words metformin has a healing effect on non-alcoholic steatohepatitis, a precursor to fatty liver and liver cirrhosis.

Metformin suppresses appetite

Metformin also has an effect on the appetite center in the brain. It helps many obese and overweight people, but not all to lose weight. The mechanism for that effect is in the hypothalamus, where the appetite center is located. Metformin inhibits the neuropeptide Y gene expression in the hypothalamus leading to reduced appetite.

Finally, metformin also normalizes the gut flora. This last point was the main focus of Dr. Andry’s talk.

Metformin and the gut

An animal experiment on mice showed in a study published in 2014 that metformin was stimulating the growth of a beneficial gut bacterium, Akkermansia. This is a mucin-degrading bacterium. But it also affects the metabolism of the host. The authors found that metformin increased the mucin-producing goblet cells.

Akkermansia muciniphila bacteria were fed to one group of mice. This group was on a high fat diet, but not on metformin. The mice showed control of their blood sugars, as did the metformin group. In other words manipulation of the gut flora composition could achieve control of the diabetic metabolism. The authors concluded that pharmacological manipulation of the gut microbiota using metformin in favor of Akkermansia might be a potential treatment for type 2 diabetes.

Effect of metformin on the gut flora

Akkermansia muciniphila bacteria comprise 3%-5% of the gut flora. It does not form spores and is strictly anaerobe, in other words oxygen destroys it. This is the reason why it is difficult to take it as a supplement. It is mostly growing in the mucous of the epithelium layer of the gut. The colon and to a lesser degree the small intestine of all mammalian species including the human race contain the highest number of Akkermansia bacteria.

Here are the effects of metformin on Akkermansia:

  • Metformin increases the Akkermansia bacteria count both in a Petri dish as well as in the gut of experimental mice. This suggests that metformin acts like a growth factor for Akkermansia.
  • Metformin increased the count of Akkermansia bacteria by 18-fold up to a maximum of 12.44% (up from the normal 3-5%) of all of the gut bacteria.
  • Researchers observed that the mucin layer of the lining of the gut in metformin treated mice was thicker. This suggests that the thickness of the mucin layer plays a role in increasing the Akkermansia count.

Effect of the gut on the body’s metabolism

Other researchers have investigated how a high fat diet can change the composition of the gut bacteria, which in turn are altering the body’s metabolism. Essentially a shift in the bowel flora can increase the gut’s permeability. The medical term for this is “leaky gut syndrome”. It leads to absorption of lipopolysaccharides (LPS) from bad bacteria in the gut. The end result is endotoxemia in the blood. This causes systemic inflammation in the body. Insulin resistance and obesity develop and often at a later date type 2 diabetes develops. It is interesting to note that often a high fat diet leads to these changes. But increasing Akkermansia bacteria in the gut or treating the patient with metformin can reverse this process.

An interesting mouse experiment showed that the changes that take place in the gut bacteria with cold exposure could be transferred to germ-free mice with no gut flora. This changed their metabolism proving that gut bacteria have profound influences on the metabolism. The fact that the gut bacteria have a profound influence on the metabolism is not only true for animals, but also for humans.

Akkermansia Facts

Here are a few facts about the Akkermansia bacteria.

  • The amounts of Akkermansia bacteria in the gut are inversely related to how fat we are. This is measured by the body mass index (BMI). Fat people have less Akkermansia in their guts.
  • A high fat diet lowers the amount of Akkermansia in the gut
  • Systemic inflammation is present with low Akkermansia counts
  • A high fat diet causes gut permeability (leaky gut syndrome).
  • Appendicitis and inflammatory bowel disease can be caused by low levels of Akkermansia.
  • Fat storage (both in subcutaneous fat and visceral fat) can be caused by low levels of Akkermansia.
  • Low levels of Akkermansia cause insulin resistance (associated with diabetes) and high blood sugars.
  • Brown fat’s ability to burn calories increased when Akkermansia was increased , which leads to weight loss.
  • Decreased Akkermansia counts lead to fat storage (weight gain).
  • Gut-barrier integrity improves when Akkermansia increased
  • Increased Akkermansia reduces visceral and total body fat
  • Synthesis of sugar in the liver (gluconeogenesis) reduces when Akkermansia is increased

We have 10 times more bacteria in the gut than we have cells in our body. The Akkermansia percentage of the gut flora can be decreased from antibiotics or food that contains traces of antibiotics. If there is a lack of Akkermansia species, there is more gut permeability, causing LPS increase and causing increase of inflammation in the body. This translates into high blood pressure, heart attacks, strokes, and degenerative neurological diseases like Parkinson’s disease, Alzheimer’s disease or MS. But it can also cause inflammatory bowel disease and autoimmune diseases.

What increases Akkermansia?

We can increase Akkermansia bacteria in the gut by eating Oligofructose-enriched prebiotics. Oligofructose belongs into the inulin type soluble fibers. It is found in a variety of vegetables and plants. This includes onions, garlic, chicory, bananas, Jerusalem artichokes, navy beans and wheat. But wheat can be problematic. Clearfield wheat is the modern wheat variety which is now grown worldwide. It is much richer in gluten and can cause problems with gut permeability.

Eating lots of vegetables and fruit will give you enough of oligofructose to maintain a healthy percentage of Akkermansia in your gut bacteria.

Metformin as pointed out earlier can is in use as pharmacotherapy. But I must emphasize that the use of metformin for dysmetabolic syndrome is off-label. There are real side effects of metformin. Lactic acidosis with an unusual tiredness, dizziness and severe drowsiness can develop. Also chills, muscle pain, blue/cold skin and fast/difficult breathing can occur. Slow/irregular heartbeat, vomiting, or diarrhea, stomach pains with nausea are other side effects.

Effects Of Metformin On The Gut Microbiome

Effects Of Metformin On The Gut Microbiome

Conclusion

Our gut bacteria are important for us, more so than you may be aware of. An anaerobe bacterium, Akkermansia makes up 3%-5% of the gut flora. This bacterium lives in the mucous layer of the lining of the gut and ensures that the gut wall is tight. When these bacteria are lacking (due to consumption of junk foods) the gut wall becomes leaky, which is why this condition has the name “leaky gut syndrome”. Irritating toxic substances can now leak into the blood stream and lipopolysaccharides are among them. This causes inflammation in the gut wall, but can go over into the blood vessels and the rest of the body including the brain. High blood pressure, obesity, diabetes, heart attacks, strokes, and degenerative neurological diseases like Parkinson’s disease, Alzheimer’s disease or MS can develop from the inflammation. But it may also cause inflammatory bowel disease and autoimmune diseases.

Eating lots of vegetables and fruit will give you enough of oligofructose to maintain a healthy percentage of Akkermansia in your gut bacteria. In particular, onions, garlic, chicory, bananas, Jerusalem artichokes and navy beans provide lots of oligofructose to support Akkermansia in your gut bacteria.

As pointed out earlier metformin as a drug is in use to treat dysmetabolic syndrome. I need to emphasize that the use of metformin is off-label. It is also important to remember, that with effects there are side effects of metformin.

It may be news to you, how our overall health depends so much on the health of the gut. With the knowledge that food can be your medicine, choose your foods wisely. Add some or all of the above named foods that help you support beneficial gut bacteria, and take care of your health!

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About Ray Schilling

Dr. Ray Schilling born in Tübingen, Germany and Graduated from Eberhard-Karls-University Medical School, Tuebingen in 1971. Once Post-doctoral cancer research position holder at the Ontario Cancer Institute in Toronto, is now a member of the American Academy of Anti-Aging Medicine (A4M).