PCOS Metabolism Gut Microbiome Metformin

Metabolism, the Microbiome, Berberine and Metformin

Many people don’t know that the most popular drug commonly used to treat Polycystic Ovary Syndrome (PCOS) and type 2 diabetes – Metformin- is a drug that profoundly affects the human microbiome(1). In this article, I want to tie together some interesting information on our GI microbiome – basically the “bugs” that live within our guts – with our metabolic health. I’ll use Metformin to highlight this connection, however I hope you’ll see that the connection holds true in a general way also. I am not promoting the use of Metformin, nor am I against its use – though as a naturopath I believe that there are treatments (like berberine for example) which are just as effective with far less side effects and risk. Overall however, I think each patient must make a personal health decision when it comes to medications – carefully considering risk vs. benefit. That being said, the effects of Metformin and Berberine do illustrate quite beautifully the connection between our microbiome and our metabolic health.

GI Side Effects from Insulin Sensitizing Agents

Many patients who take Metformin experience gastrointestinal symptoms – including nausea, bloating, cramping and loose stools. Interestingly, this is likely related to the medication’s effects on the organisms within the GI tract. In fact, it’s known that Metformin is an antibiotic, and can significantly alter our GI flora(1). Research has clearly highlighted that Metformin can alter the types of and quantities of different organisms that take up residence within in our guts(2).

We also know that Berberine (a natural product) has insulin sensitizing actions of similar magnitude to Metformin – and it also has clear antibiotic action. Coincidence? I certainly didn’t think so and was intrigued to learn more about the connection. Given that Metformin is such a widely used drug, there is some good research on its effects within the gut. On discussion of this article with Dr. Michael Murray,  he shared this new study comparing 

comparing the effects of berberine and metformin on the human microbiome – which suggests that their actions are remarkably similar.

Each of them were able to alter the microbiome, in favour of bacteria that produce beneficial short-chain fatty acids.This may contribute to the alleviation of inflammation, insulin resistance and obesity by reducing the release of intestinal endotoxins into the blood. Interestingly, berberine is less bioavailable than metformin, and as such it’s primary action on insulin resistance and inflammation may have its origins in the microbiome. This may be of benefit given that metformin also has significant action in the mitochondria, which is still controversial particularly among women of reproductive age. 

The Metabolism and the Microbiome

First, the connection between the GI microbiome and our metabolism is not new. It’s well-known that specific differences in the gastrointestinal flora are seen in obesity, and also when a high calorie diet is consumed. When mice are given fecal transplants from humans who were fed a Western style diet they quickly become overweight (3).

When it comes to the microbiome, we’ve known for some time that the bugs that live in our gut have an very real effect on human metabolism. There have been case reports of weight gain after fecal transplantation. A case comes to mind of a woman who was being treated for recurrent Clostridium difficile (aka C. Diff), an opportunistic bacteria that causes chronic diarrhea and that can be resistant to antibiotics. One of the most effective treatments for resistant C. difficile is fecal transplantation – transplanting a sample of fecal microbes from a healthy donor – these microbes inhibit the C. Diff in the patient with the infection. This patient received her transplant from a donor (who happened to be her daughter). Her daughter was healthy, but overweight. Subsequent to her transplant, the patient with C. difficile infection rapidly gained 34 pounds, despite having maintained a stable weight prior to the transplant(5).

We do know that at least in part, the effects of metformin on blood sugar and metabolism lie within the mitochondria. Metformin upregulates the energy production pathway in the mitochondria, known as cAMP and it affects how glucose is metabolized in the liver.

However it’s interesting to consider that the impact of metformin on the gut may also be one of the biggest players in it’s metabolic effects.

Sugar and Refined Carbohydrate on GI Microbiome

The most serious side effect of using Metformin is lactic acidosis -which is rare, but potentially fatal. This could be attributed to metformin-mediated inhibition of an enzyme known as glycerophosphate dehydrogenase(6). A contributing source of excess lactate in this issue may actually be derived from bacteria in the gut. Metformin may alter the way that carbohydrate is absorbed from the intestine. and unabsorbed glucose within the GI tract provides a substrate for d-lactate-producing bacteria. Accumulation of colonic lactic acid contributes to the significant GI side effects observed in metformin users, especially those consuming diets intensified with starch and sugars. This is likely why consuming carbs and sugar is so aggravating to patients taking Metformin(6).

Microbiome and GI Health for Optimal Metabolism

Interestingly, a recent study from March 2015 found that adding a gastrointestinal microbiome modulator to patients who were taking Metformin improved BOTH their gastrointestinal side effects as well as their glucose tolerance levels(7). It’s known that the microbiome in patients who have type 2 diabetes is composed of species of bacteria that harvest primarily sugars(7). In this study, patients were given what is known as a GIMM (gastrointestinal microbiome modulator) – basically food for bacteria and nutrients which benefit the intestinal environment.

The modulator contained ingredients to stimulate blooms of competing friendly microbiota that generate beneficial short chain fatty acids (SCFA) instead of lactic acid. It also contained ingredients that reduced the absorption of small molecules by thickening the contents of the intestine and strengthening the mucosal barrier, and included a potent antioxidant to combat oxidative stress and damage to the GI tract. Not only were patients better able to tolerate metformin, but their glucose control actually improved with this intervention.

The Bottom Line

  • In insulin resistance, as a general rule – eating sugar and excessive carbohydrate causes a shift in the gut organisms that is not optimal for metabolic health and promotes obesity(9). If you must take Metformin – avoid eating refined carbs and try to avoid sugar entirely. This will greatly reduce the negative effects on the GI tract.
  • Metformin may be best combined with probiotic strains that do not predominantly produce D-lactate. This doesn’t mean you must choose a only probiotics that are non-D lactate producing, however it means that choosing strains that predominantly produce other compounds may reduce some of the side effects. These strains include Lactobacillus rhamnosus (GG), Bifidobacterium longum, and Bifidobacterium infantis, among others.

    It’s important to know that the most important factor to whether or not a probiotic produces D-lactate is not just the strain of bacteria, but rather, it is the diet you consume (what the bacteria eat) that matters most. Sugar and refined carbohydrates are a major substrate when it comes to bacterial D-Lactate production. 

    We can clearly see this in patients using Metformin who ingest larger amounts of refined carbs and sugar at a meal – they often run directly to the washroom after eating.
  • In addition to specific strains of probiotics and following a diet that is reduced in carbohydrates, using a microbiome modulator including prebiotics may be helpful for some people. One of the best ways to get prebiotics is through the diet. However – in some sensitive individuals, particularly those who have chronic IBS, chronic fatigue, certain types of autoimmune disease or small intestinal bacterial overgrowth, the use of prebiotics may in fact be very aggravating.

    Though prebiotics can definitely feed friendly bacteria, they can also potentially “feed” the wrong bacteria – so proceed with caution and consult with a practitioner to determine the best course of action for your case. Food sources of prebiotics include chicory root, asparagus, onions, garlic and artichoke.
  • Adjunctive treatments that may help are: L-Glutamine to reduce intestinal permeability and fuel the cells of the intestine, thickening prebiotic fibre such as glucomannan or PGX for those who tolerate it, and antioxidants to minimize oxidative stress. Some examples of antioxidants include N-Acetyl Cysteine or polyphenols such as grapeseed or green tea (polyphenols are also “food” for the gut microbiome).

Have you experienced GI side effects while taking Metformin or have you had improvements in your GI symptoms when following a carbohydrate reduced diet? Please share your story below in the comments!

References

  1. Dash, A., Pattanaik, B., Behera, S., & Palo, A. (2011). Study of antimicrobial property of some hypoglycemic drugs. Chronicles of Young Scientists, 2(4), 219. http://doi.org/10.4103/2229-5186.93029
  2. Lee, H., & Ko, G. (2014). Effect of metformin on metabolic improvement and gut microbiota. Applied and Environmental Microbiology, 80(19), 5935–43. http://doi.org/10.1128/AEM.01357-14
  3. Ridaura, V. K., Faith, J. J., Rey, F. E., Cheng, J., Duncan, A. E., Kau, A. L., … Gordon, J. I. (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science (New York, N.Y.), 341(6150), 1241214. http://doi.org/10.1126/science.1241214
  4. http://coolinginflammation.blogspot.ca/2014/05/metformin-antibiotic-with-autoimmune.html
  5. Alang, N., & Kelly, C. R. (2015). Weight Gain After Fecal Microbiota Transplantation. Open Forum Infectious Diseases, 2(1), ofv004–ofv004. http://doi.org/10.1093/ofid/ofv004
  6. Madiraju, A. K., Erion, D. M., Rahimi, Y., Zhang, X.-M., Braddock, D. T., Albright, R. A., … Shulman, G. I. (2014). Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature, 510(7506), 542–6. http://doi.org/10.1038/nature13270
  7. Burton, J. H., Johnson, M., Johnson, J., Hsia, D. S., Greenway, F. L., & Heiman, M. L. (2015). Addition of a Gastrointestinal Microbiome Modulator to Metformin Improves Metformin Tolerance and Fasting Glucose Levels. Journal of Diabetes Science and Technology, 9(4), 808–14. http://doi.org/10.1177/1932296815577425
  8. Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., … Wang, J. (2012). A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature, 490(7418), 55–60. http://doi.org/10.1038/nature11450
  9. Walker A.W., Ince J., Duncan S.H., Webster L.M., Holtrop G., Ze X., Brown D., Stares M.D., Scott P., Bergerat A., et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 2011;5:220–230.

Live in Ontario and want to make an appointment with one of our NDs?  Click here to get started!