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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Apr
23
2016

Healing Powers Of Green Tea

Powerful catechins that are a special form of bioflavonoids provide the healing powers of green tea. Research teams have proven that these catechins are only contained in green tea, not so much in black tea. The most effective of several catechins contained in green tea is EGCG, which stands for EpiGalloCatechin-3-Gallate. It crosses the blood/brain barrier and is very important for the protection of the brain from Alzheimer’s disease. But green tea or green tea extract has a diversified pharmacological action. It is said to protect you from cardiovascular disease, from obesity, from diabetes, from autoimmune disorders, from cancer and from Alzheimer’s and dementia.

In the following I like to comment on how green tea or its extract can protect from all of these diseases.

Alzheimer’s disease

Although there are 5 or 6 approved anti-Alzheimer’s drugs, none of them work for very long. They may at best postpone the deteriorating memory for 6 months, but then the effect of the drug wears off. The reason is that the drugs do not stop the production of the deadly beta-amyloid. It is the beta-amyloid that damages nerve cells that you want to preserve so you can think and memorize. In contrast a simple phytochemical, the catechin EGCG has been shown in animal experiments and in human trials to stop beta-amyloid production and increase solubility of beta-amyloid fragments in the brain. The end result is better memory and no further deterioration.

In a study of 13,988 elderly Japanese observed over 3 years the group that consumed 3 to 4 cups of green tea daily had 33% less strokes, cognitive impairment and osteoporosis.

Researchers at the University of Basel, Switzerland enrolled 12 healthy volunteers aged 21 to 28 and fed them extracts of green tea or placebo fluid via feeding tubes. This was done to rule out taste as a factor. Functional MRI scans were applied as the subjects were given memory-stimulating tasks. Only the green tea extract was boosting activity in the frontal brain of the subjects. This was located in a specific area, called dorsolateral prefrontal cortex. This area is known to be involved with language comprehension, reasoning and learning. It also switches short-term memory into long-term memory, called working memory processing.

Studies in animals have shown that nerve cells are protected from the toxic effect of beta-amyloid and at the same time the production of new brain nerve cells (neurons) is triggered by green tea extract. This is really good news for Alzheimer’s disease patients and their families: green tea extract delays further memory deterioration and stimulates the development of new nerve cells in the brain!

Cardiovascular disease

In a 2006 Japanese study 40,530 Japanese adults aged 40 to 79 years without history of stroke, coronary heart disease, or cancer at baseline were observed for 7 years. Diaries were kept about how many cups of green tea each person was drinking per day. The biggest effect was seen with regard to prevention of heart attacks and strokes.

Men had a mortality reduction of 12% for heart attacks when they drank 5 cups or more of green tea; in women the corresponding mortality reduction for heart attack was 31%, a bigger effect. Overall mortality from strokes was lower than from heart attacks making the effect of green tea consumption even more beneficial with respect to stroke prevention. In this study no cancer preventing effect was observed for green tea.

Obesity

It appears that green tea increases heat production and burns fat in the process. There was a small effect in terms of weight loss and a beneficial effect increasing the protective HDL cholesterol in this 2012 Polish study on obese patients. The authors compared either 379 mg of green tea extract, or a placebo, daily for 3 months. They concluded: “The results of this study confirm the beneficial effects of green tea extract supplementation on body mass index, lipid profile, and total antioxidant status in patients with obesity.”

Diabetes

Although there are claims in some studies that green tea would prevent diabetes, this question was thoroughly investigated in this Chinese 2014 study.

No effects were noted on fasting blood sugars or on hemoglobin A1C values, a very sensitive indicator for the presence or absence of diabetes. All these lab tests were unchanged following consumption of green tea or green tea extract. Forget using green tea for diabetes prevention; cut out sugar and starchy foods instead.

Autoimmune disorders

Sjogren’s syndrome and lupus are both autoimmune diseases. Green tea extract has shown in humans that symptom severity can improve; green tea polyphenols (GTPs) possess anti-inflammatory properties that benefit patients with autoimmune diseases.

In an animal model arthritis researchers determined that T helper cells are weakened and bone resorption is inhibited by EGCG from green tea extract.

Researchers at Harvard Medical School, Boston, MA have noted that green tea extract is useful in calming down the immune response in autoimmune diseases. They concluded: “Altogether, these studies identify and support the use of EGCG as a potential therapeutic agent in preventing and ameliorating T cell-mediated autoimmune diseases.”

Cancer

Many research papers have found that EGCG from green tea extract has immune modulatory effects that are useful in combination with chemotherapy. A combination of cisplatin therapy with green tea extract has been found to have more effects on colorectal cancer and ovarian cancer than each one on its own. Similarly chemotherapy of breast cancer had better results in humans when EGCG from green tea extract was added as an immune modulation. More research, particularly in humans is needed to fully understand the mechanism of action of EGCG.

Toxicity of green tea extract

Animal experiments showed that higher doses of green tea extract could cause toxicity in the liver and in the nose of rats and mice. I was not able to find objective evidence for green tea toxicity in the PubMed system with respect to humans.

Healing Powers Of Green Tea

Healing Powers Of Green Tea

Conclusion

Perhaps the most important discovery regarding green tea extract is that it crosses easily through the blood/brain barrier into the brain. This can postpone Alzheimer’s disease and can even lead to new neuron formation. The beneficial cardiovascular effects are also useful and combine well with exercise and good nutrition for prevention. Particularly stroke prevention is a useful property of EGCG from green tea extract. The effect on obesity is marginal whereas there was no effect of green tea on prevention of diabetes. The immune modulatory effect of green tea extract is useful in the treatment of autoimmune diseases and of cancer. Existing treatments for these conditions are becoming more effective by adding green tea extract.

Jan
31
2016

The Gut and Brain Connection

At the 23rd Annual World Congress on Anti-Aging Medicine (Dec. 11-13, 2015) in Las Vegas there were several lectures pointing out the importance of the gut flora for proper brain function. If you have the wrong gut flora, you can get a number of diseases like diabetes, fibromyalgia, rheumatoid arthritis, multiple sclerosis, muscular dystrophy, some cancers and even obesity. Martin P. Gallagher, MD, DC talked about this in his talk “Gut on Fire, Brain on Fire!”

Function of the microbiome

The microbiome is the sum of all microbial organisms inhabiting the human body, which colonize mainly the colon, but also to a lesser degree the small intestine. Dr. Gallagher stated that the microbiome weighs only 7.1 oz., although in the past have some have estimated its weight to be as high as 3 pounds. The purpose of the microbiome is to help form a gut/blood barrier. It forms a 30-micron thick layer in the GI tract, protects the intestinal lining and metabolizes food remnants, especially from carbohydrates. It also communicates with the immune system. There is a cross talk between the lining of the gut and the and the body’s immune system. The gut bacteria help the body to create stability; they also decrease intestinal permeability.

When inflammation occurs in the gut, the thickness of the biofilm is less than 30 microns. Intestinal permeability increases, which is called “leaky gut syndrome”. This can be the cause of autoimmune diseases and possibly other diseases.

The enteric nervous system

The gut can produce as many neurotransmitters as the brain and spinal cord can synthetize. The enteric nervous system communicates with the brain through the vagal nerve. Serotonin is an important neurotransmitter that has been found to regulate motility of the gut. The control system of the gut can work on its own and override the concerns of the central nervous system.

Parkinson’s disease is a disorder of the enteric nervous system as well as the brain. With Alzheimer’s disease the characteristic lesions found in the brain are also found in the enteric nervous system!

In a mouse experiment a Lactobacillus strain known to be part of the microbiome was shown to heal anxiety and depression related changes in certain parts of the brains of these experimental animals. But when the vagal nerve of these animals was severed, none of these healing changes occurred. This suggests that the gut bacteria are able to communicate to the brain via the vagal nerve. Researchers have coined this connection the “gut-brain axis”. These protective gut bacteria have the ability to protect humans from gastric acidity, from bile acid toxicity, they adhere to the lining of the gut and they persist to reside within the gastrointestinal tract. Probiotics help the immune system to maintain the immunologic memory and to secrete antibodies, called immunoglobulins.

Two strains with benefit to humans are Lactobacillus rhamnosus GG and Saccharomyces boulardii. Probiotics often help against diarrhea. The natural food for gut bacteria in the colon comes from starches of chicory, asparagus, inulin and onions that are indigestible in the stomach and small intestine, but are fermented in the colon to provide food for the bacteria residing there.

Small Intestinal Bacterial Overgrowth (SIBO)

Overgrowth of the small intestine with bacteria that produce endotoxins appears to have significance in both animal models and human disease. Chlamydia species as well as Borrelia burgdorferi (Lyme) can produce toxins that cause hypersensitive of pain in soft tissues in fibromyalgia and animal models of fibromyalgia. SIBO-small intestinal bacterial overgrowth- in experimental animals caused the same hypersensitivity of the soft tissues and also leaky gut syndrome.

Risk factors for SIBO

What causes SIBO is too little stomach acid production, treatment with proton pump inhibitors (powerful anti acid medications) and antibiotics. According to Dr.Gallagher SIBO also occurs in postsurgical patients, in patients with diabetes, and is brought on by alcohol, nicotine, drugs and GMO foods.

Neurogenic inflammation

Normally the blood brain barrier keeps immune cells from the body out of the brain. Only glucose, proteins and lipids are allowed into the brain, but not lipophilic neurotoxins. Neurogenic triggers, when admitted to the brain, will compromise the function of the immune cells of the CNS, called microglia. This can result in memory loss, Alzheimer’s, dementia, seizures, migraines, Parkinson’s Disease, multiple sclerosis, cancer, weakness, numbness, etc.

What triggers inflammation?

Here is a long list of different items that cause inflammation: aging, hormone deficiencies, obesity, diabetes mellitus, cardiovascular disease, fungal infection, the Standard American diet (SAD), pain, trauma and mechanical stress, heavy metals, food allergies, toxins, gut dysbiosis, small intestinal bacterial overgrowth, mal-digestion/absorption, prescription drugs, over-the-counter drugs, recreational drugs and alcohol, lack of exercise and lack of sleep.

Neurotoxic insults start the chain of reactions (heavy metals, nutritional deficiencies, viruses/fungus/bacteria, inflammatory diet, MSG, solvents, pesticides, herbicides, etc.): one or more of these factors destabilize the tight junctions of the blood brain barrier, which leads to neurogenic inflammation. The result is Parkinson’s disease, MS, dementia, chronic pain, behavioral and personality changes, Alzheimer’s disease, ALS and Lyme disease.

What seems to be happening a lot is that there is overgrowth of abnormal bacteria in the small bowel, which produce toxins. These in turn lead to leaky gut syndrome, which allows neurogenic triggers to attack the blood brain barrier. From here it is a short step to neurotoxic insults of the brain overstimulating the microglia, which will produce the diseases listed above.

Healing of brain inflammation

Treatment starts with the Mediterranean diet, which has been shown to have anti-inflammatory properties. People who are gluten sensitive need to eliminate gluten entirely from their food; casein sensitive people need to eliminate dairy products. A triple strength, molecularly distilled fish oil product is taken as a supplement every day with 4 grams or more of DHA/EPA.

Glutathione: One of the most powerful antioxidants and anti-inflammatories is intravenous glutathione. This is given as intravenous chelation therapy, which removes heavy metals. Other chelation agents such as EDTA intravenously may be given alternatively. Dr.Gallagher said that glutathione serves as primary cellular defense against free radicals, is a powerful antioxidant and serves as detoxifying agent against xenobiotics. Xenobiotics are remnants of artificial fertilizers, pesticides and pollutants that are contained in crops we eat.

Dr. Gallagher gives 600mg of glutathione twice per day intravenously for 30 days. In Parkinson’s disease patients whose mid brain is often poisoned by mercury this leads to 42% decline of disabilities and the effect last for 2 to 4 months after this treatment has been stopped. This treatment also protects telomeres, the caps on the ends of cellular DNA as well as mitochondrial DNA. Glutathione is protective of neurons and nerves.

Curcumin: this common Indian spice, found in turmeric is a potent anti-inflammatory. It is a safe natural agent and has also anti-viral and anti-tumor activities. It binds to the vitamin D receptor and works synergistically together with vitamin D3. Solid lipid curcumin particle technology makes curcumin 65-fold more bioavailable; free curcumin is allowed to pass the blood brain barrier. Lower doses achieve the same effect than regular curcumin.

According to a publication using lipidated curcumin the following observations were made: improved vascular function, inflammatory markers reduced by 14%, triglycerides lowered by 14%, oxidative stress reduced, catalase increased and total antioxidant status improved.

Omega-3 fatty acids: omega-3 fatty acids are anti-inflammatory by countering the arachidonic acid pathway that leads to inflammation. It is best administered as triple strength, molecularly distilled fish oil. DHA/EPA are the active ingredients. Chronic inflammation requires 2 to 12 grams daily; irritable bowel syndrome 6 to 12 grams daily; depression, anxiety and insomnia require 2 to 4 grams per day; autoimmune disease, back pain and degenerative joint disease 4 to 12 grams per day.

Gut/brain dysbiosis: For gut/brain dysbiosis Dr. Gallagher recommended to start with a 10-day fruit/vegetable detox program. Milk thistle, glutathione and pancreatic enzymes are used in combination. Lipidated curcumin. Glutamine, prebiotics and probiotics are given for gut support. Molecularly distilled fish oil (DHA/EPA) and vitamin D3 are given as anti-inflammatories. Oral and intravenous glutathione is given to detoxify. Antifungals are given as a combination of glutathione, oregano, olive leaf and silver salts.

The Gut and Brain Connection

The Gut and Brain Connection

Conclusion

Inflammation can start in the gut, lead to leaky gut syndrome and break down the blood/brain barrier. The end result is that the brain also gets inflamed and Alzheimer’s disease and dementia can occur. The sooner treatment is begun, the faster the recovery will be. When the end stage is reached, it is difficult to turn the inflammatory process around. Fortunately there are effective ways to get the inflammation under control with intravenous glutathione in the beginning and subsequent treatment with lipidated curcumin, omega-3 fatty acid and vitamin D3. A permanent switch to a Mediterranean diet is important as well to keep inflammation under control.

A few years back this type of approach would have been considered as “quackery”; now it is the latest information from research into the brain/gut connection. A lot can be done on a preventative basis with lifestyle and nutrition choices. Treatment is possible, but once full-fledged disease is established, a full cure may not be possible.

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