Jan
21
2017

Effects Of Metformin On The Gut Microbiome

Matthew Andry, MD talked about the effects of metformin on the gut microbiome. This talk was delivered 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 has been used for a long time for type 2 diabetes, particularly, if fasting insulin levels are high. Metformin is a biguanide, which was isolated from French lilac (also known as Goats Rue). In the middle ages this herb was used to treat “thirst and urination”. In retrospect we recognize these as symptoms of diabetes. Chemists were able to synthesize the active ingredient in this herb in the 1920’s. Since then it is known as 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. Several clinical investigators demonstrated that diabetic patients on metformin lived longer and had less heart attacks than patients who were treated otherwise.

Metformin is the first-line drug in the treatment of type 2 diabetes in children and adults. It is one of the most widely prescribed drugs throughout the world with 120 million prescriptions per year.

Off-label use of metformin

There are many other clinical conditions for which metformin have been found to be beneficial. Polycystic ovary syndrome (PCOS), obesity, prediabetes, metabolic syndrome and nonalcoholic steatohepatitis are a few examples of off-label use of metformin. Metformin is also used as an anti-aging agent as it was found to elongate telomeres, which helps people to live longer. Metformin has been identified as a possible cancer prevention agent. In prostate cancer it was found to have an effect against prostate cancer stem cells. Without these cells prostate cancer does not recur after surgical removal.

Action of metformin

Metformin increases the action of an enzyme, AMPK, which leads to lipid oxidation and breakdown of fatty tissue (catabolism). In the liver the metabolic pathway of making sugar from fatty acids, called gluconeogenesis is inhibited. Metformin causes increased uptake of sugar into skeletal muscle tissue. This is the reason for the previously mentioned stabilization of blood sugar. 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 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. The neuropeptide Y gene expression in the hypothalamus is inhibited by metformin 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 highest number of Akkermansia bacteria is found in the colon, lesser amounts in the small intestine of all mammalian species including the human race.

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. This is called 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 this can be followed by type 2 diabetes. It is interesting to note that the effects of a high fat diet that led to these changes can be reversed by increasing Akkermansia bacteria in the gut or by treating with metformin.

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).
  • Low levels of Akkermansia causes worsened severity of appendicitis and inflammatory bowel disease.
  • Low levels of Akkermansia causes fat storage (both in subcutaneous fat and visceral fat).
  • Low levels of Akkermansia cause insulin resistance (associated with diabetes) and high blood sugars.
  • Increased Akkermansia counts increase brown fat’s ability to burn calories, which leads to weight loss. Decreased Akkermansia counts lead to fat storage (weight gain).
  • Increased Akkermansia improves gut-barrier integrity
  • Increased Akkermansia reduces visceral and total body fat
  • Increased Akkermansia reduces synthesis of sugar in the liver (gluconeogenesis)

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 be used as pharmacotherapy. But it must be stressed 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 has been described. Slow/irregular heartbeat, vomiting, or diarrhea, stomach pains with nausea are also listed under 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 is called “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 can be used as pharmacotherapy of dysmetabolic syndrome. But it must be stressed 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 close the health of the gut is connected to our overall health. 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).