Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Tuesday, May 27, 2014

Metformin, Antibiotic with Autoimmune Side Effects

----The other 200 posts are here----
Metformin
Major points linked in this article:
  • Metformin is commonly used in the treatment of diabetes.
  • Metformin is structurally and chemically related to arginine, guanine and Canavanine.
  • Side effects of Metformin include GI upset and autoimmune lupus (same with Canavanine.)
  • Metformin also kills bacteria, i.e. it is an antibiotic.
  • Many pharmaceuticals, e.g. statins, were first identified as antibiotics produced by fungi.
  • Antibiotics select for antibiotic resistance genes, i.e. essential bacterial genes that have mutated to no longer be inactivated by antibiotics.
  • New antibiotic resistance genes are combined with other resistance genes on multiple resistance plasmids that are transferred as a group.
  • Because of its wide use, resistance to Metformin (and statins) as an antibiotic probably already exists and has been incorporated into multiple drug resistance plasmids.
  • Many common pharmaceuticals are also antibiotics and probably select for multiple drug resistance.
  • A major contributor to multiple drug resistance, “super bugs”, and the rapid loss of efficacy of antibiotics is the over use of pharmaceuticals in general, in addition to the specific abuse of antibiotics designed to kill pathogens.
Metformin is a Good Anti-Diabetic, but...
Arginine
Metformin is the treatment of choice for type 2 diabetes and yet, like many other common drugs, the full extent of its impact on the body (and the body’s essential microbiome of bacteria and fungi) has not been studied.  This article should not be seen as a criticism of the pharmacological efficacy of Metformin in lowering blood sugar.  The point here is that Metformin alters gut flora and its major pharmacological impact may result from alteration of the gut flora and not direct action on cells of body organs.  Metformin, because of its structure and size would be expected to act relatively indiscriminately in numerous cell functions, but I don't think that these interactions are as important as the impact on gut flora.  Metformin has all of the properties of an antibiotic selected to lower blood sugar and have limited side effects.  It would not be expected to cause a dramatic increase in autoimmunity, because diabetics already have elevated autoimmunity and associated deficiencies in gut flora.

Metformin is a Diguanide
 I previously explored the interesting properties of Metformin in my laboratory and through computer modeling experiments, and found it would react with many cellular enzymes and receptors similarly to the amino acid arginine.  This was no surprise, since the working end of arginine is a guanide and Metformin is a Siamese twin of guanides, i.e. a biguanide.  I might as well also say that another guanide, Canavanine, a toxic, antimicrobial phytoalexin in bean sprouts, has similar properties.
Canavanine

Phytochemicals as Antibiotics


  
I have studied (and written about) the natural plant antibiotics, phytoalexins, in legumes, and particularly in soy beans, so I would expect all of the chemicals, (a.k.a. phytochemicals or “antioxidants”) extracted from plants, e.g. alkaloids, polyphenols and essential oils, to kill bacteria and be toxic to human cells.  The selective advantage to plants in producing phytochemicals is the antibiotic activity of those chemicals.  Pathogens that have adapted for growth on one species of plant have resistance genes to that plant’s phytoalexins.  Thus, bacterial genes for resistance to the antibiotic activity of drugs derived from phytochemicals are common in nature and broad use of these drugs merely selects for the transfer of these genes to gut flora.
Canavanine and Lupus
What put together more pieces of the gut flora/antibiotic/autoimmune disease puzzle for me, was coming across Dr. Loren Cordain's recent reiteration of the toxicity of legumes and his singular example of Canavanine from alfalfa sprouts as a contributor to the autoimmune disease, lupus.  When I looked up the structure of Canavanine and found it to be a guanide, I immediately started making comparisons to Metformin and was amazed to see that these chemicals share the same list of side effects focused on the gut.  Moreover, lupus is also a side effect of both Metformin and Canavanine.  It was initially surprising, that a recent study suggests that the anti-diabetic action of Metformin may result indirectly from its antibiotic effects on gut flora.  I now expect that Canavanine causes lupus by killing or altering the metabolism of particular species of bacterial gut flora involved in the normal functions of the immune system, e.g. Tregs required for immune tolerance.  It is now a common observation that many pharmaceuticals act indirectly via their impact on gut flora, i.e. many pharmaceuticals are fundamentally antibiotics, and particular antibiotics can duplicate the activity of pharmaceuticals.
Pharmaceuticals Select for Multiple Antibiotic Resistance
I have one other concern about the wide use of drugs derived from phytoalexins.  Metformin can be considered one of those drugs, and just like phytoalexins, it is a potent antibiotic.  There is no difference between purified natural plant antibiotics/ phytoalexins/ polyphenols/ antioxidants and commercially synthesized antibiotics with respect to selecting for resistance.  I would expect that resistance to Metformin, as an antibiotic, has already developed in common gut flora and consequently, that multiple drug resistance plasmids from hospital pathogens now contain Metformin resistance.  Thus, I would also expect Metformin and many other pharmaceuticals to select for multiple antibiotic resistance. [An additional example is the antibiotic activity of NSAIDs on Helicobacter pylori.  I think that prevalent use of NSAIDs in many countries is responsible for the decline in H. pylori.]



29 comments:

Charles Grashow said...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117136/

"Metformin is an anti-oxidant that is routinely used to treat diabetic patients. Metformin exerts its potent anti-oxidant effect by inhibiting mitochondrial complex I, thereby preventing mitochondrial ROS production and mitochondrial oxidative phosphorylation. Thus, metformin functions as a “weak” mitochondrial poison."

David said...

Just want to say I really enjoy this blog and please keep the posts coming.
I was wondering if your opinions had changed regarding lectins/wga/ legumes and autoimmunity? Previously (2008/9) your posts indicate that these are safe to eat and don't have the potential to leave the gut.
Has your opinion changed? (Given the link to Dr. Cordains) blog?
Thanks in advance!

Lisa said...

May I suggest that you also look into the effects of Metformin on mitochondria? Here is an article on that topic - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1133963/

Here is another interesting article about Metformin - http://www.hormonesmatter.com/pcos-pregnancy-metformin-and-vitamin-b12-deficiency/

Gretchen said...

Art. I enjoy your blog and noticed you got your PhD at U Colorado, working with plants. I was wondering if you know Peter Albersheim. I was his first grad student and visited him recently.

I can't find contact information for you. If you reply, you can find my contact info at http://wildlyfluctuating.blogspot.com/

steve said...

As a diabetologist, metformin is one of the only oral medications that I still have any faith in. Maybe, I’m wrong, but its hard to argue against the improvements in blood sugars that we see with it, not to mention other peripheral benefits such as improved lipid profiles and weight loss. One would speculate that if it did have a clinically significant antibiotic effect, we would see the opposite resulting from dysbiosis. New onset autoimmune conditions associated with metformin are extremely rare and if anything, the evidence might suggest that it may be beneficial. A pubmed search for “metformin and autoimmune” provides a good sampling of studies to review showing potential benefits. I respect your opinion, so would love to explore this issue more….thanks for your insight!

Dr. Art Ayers said...

Charles,
I addressed the promiscuous interaction of Metformin with many enzymes and would expect activity in many different in vitro assays. The statement quoted is just a summary of thoughts not represented by data presented in the paper.

Even if the in vitro concepts were relevant, the fact remains that Metformin and most other drugs also act as antibiotics and will impact drug resistance.

Thanks for the comment.

Dr. Art Ayers said...

David,
I am familiar with lectins and how they work, since I am a glycobiologist, but I think that our gut is adapted to minimize the impact of eaten (especially cooked) lectins. I still don't think that plants were adapted to be eaten and therefore should be eaten with care. I still don't understand why gluten is so dangerous, but I think that we haven't evaluated the impact of its polyglutamines.

Thanks for the comments.

Dr. Art Ayers said...

Steve,
I have altered my text to make it clear that I am not maligning Metformin, but merely pointing out that it acts in the gut as an antibiotic. One would expect in diabetics who already have damaged gut flora that are adapted to other pharmaceuticals and are already displaying autoimmune symptoms, that only moderate gut disturbance would be observed taking Metformin. That is what is observed and as resistance increases, disturbance abates.

I am not trying to change or criticize the use of Metformin in clinical settings. I merely want to point out that pharmaceuticals alter gut flora and could be responsible for accumulation of multiple drug resistance due to their prevalent, studied antibiotic activities.

Are you claiming that diabetics don't have an increased risk of autoimmune disease or that some antibiotics don't reduce symptoms of autoimmune disease?

Thanks for your comments.

David said...

Thanks for the response. I was wondering if you would mind commenting on nightshades as Dr. Cordain also feels they are damaging.
Finally, whats your thoughts on eggs and the proteases the whites contain.
Apologies for the multiple questions!

Ingrid Spielman said...

Are statins really antibiotics? Was wondering if you had any resources for more information on that. Thanks!

Dr. Art Ayers said...

Ingrid,
Yes, the first statin was purified from a mixture of chemicals produced by a fungus, which tested positive for inhibition of an enzyme involved in cholesterol synthesis. The selective advantage for the fungus to produce the compound in the first place was to kill bacteria. Subsequent testing for antibiotic activity confirmed that.
Numerous studies can be found via a Google search for:
"antibiotic activity of statins"

Once again. It is widely known in the pharmaceutical industry that most drugs have significant antibiotic activity on gut flora. Moreover, it is problematical that most pharmaceutically relevant activity results from the differential antibiotic effects on gut flora. This is true for anti-diabetics and statins.

Thanks for your questions.

Raj said...

Hi Dr. Art,

L-Arginine increases porcine β-defensins

http://www.livestockscience.com/article/S1871-1413(12)00181-3/abstract?cc=y?cc=y

You have talked about how gut converts protein to defensins, cathelicidins in another article using Vitamin - D.

Looking at the similarity between Metformin and Arginine hopefully body doesn't create an unstable version of either defensins or cathelicidins, just a random thought.


Raj

Anonymous said...

Statins are antibiotics, see here:
http://en.wikipedia.org/wiki/Statin#Available_forms

Some reading on statin discovery here:
http://www.zoeharcombe.com/2013/10/how-statin-drugs-really-lower-cholesterol-and-kill-you-one-cell-at-a-time/

Now there must be a difference between permanent treatment by taking for instance Lovastating pills (killing bugs and blocking the cholesterol production pathway) and occasional eating of oyster mushrooms (killing some bugs, feeding others with beneficial glukans).

Natasha T. said...

Dear Dr. Ayers,

Hi! I am really enjoying your blog. Excellent research!

I have just finished reading Blaser's "Missing Microbes" and Velasquez-Manoff's "Epidemic of Absence". And, I monitor FTA and AnimalPharm.

I am a little overwhelmed about where to start and how to apply all of this information to myself and my husband.

Regarding myself, age 40, born naturally but *not* breastfed (soy formula). I am not aware of an antibiotics until I was 11 - my Mom was trying to do things healthy. So, antibiotics at age 11, age 17 and then again age 39. Each time period - I now realize - coincided with major weight gains. Age 11 (40 pounds), age 17 (105 pounds over two years), age 39 (15 pounds). Age 17 was a simple surgery but I was given intravenous anti-biotics - it took me 10 years to recover my health from this surgery, another couple of years to lose the 100 pounds. I was diagnosed CFS/ME/chemical sensitivity. I currently have food and pollen allergies (terrible this year). As you can imagine, I also had terrible periods and starting at 11 and only normalized a few years ago after lots of alternative treament.

I have started FTA's protocol with resistant starch and SBO's. What else can I do? Is there any specific gut bug that I should focus on, considering I never had breast milk and thus had a limited microbiome to start with?

My husband is T1-diabetic (auto immune). Last year he was struck by another auto immune illness (Sarcoidosis). Fortunately, it only attacked his lungs and not his heart. However, he is still doing poorly (extremely fatigued). No allergies. No gluten issues.

What do you think of the parasite solution? Would he benefit? He has *not* taken SBO (yet).

My general health is OK, but I am so tired of being fat. Especially because I managed to lose that 100+ weight gain (low cal, paleo type diet). In the past year I have done low calorie, low carb, low carb high fat, Dr. Eades diet too, and now switching to anti-inflammatory diets. No matter what, my recently higher weight (195 pounds at 5/6") won't shift at all. Sorry to be shallow, but I have worked so hard and "know" what to do to lose...and its not working.

Advice? Thank you! Natasha

Dr. Art Ayers said...

Natasha,
It seems that all members of your family have damaged gut flora. The Anti-Inflammatory Diet that I outline should be all of the diet recommendations that you need. The remainder is to add the bacterial species that you are missing.

Health requires 1) diet, 2) exercise and 3) gut flora

Diet changes will have no impact without adding back missing bacteria.

I have a hundred articles on this general subject.

I agree for you to start resistant starch plus a probiotic with Clostridium butyricum.

I think that everyone should learn to ferment their own vegetables with just salt and natural bacteria (not commercial cultures, because I think most are missing the right bacteria to supplement gut flora.)

With your autoimmune symptoms, you are probably also vitamin D deficient. Supplement (10K D3) and check your serum levels. Check Mark's Daily Apple for carb levels with a paleo diet, and Animal Pharm for parasite info.

Remember that fat cells cause inflammation, so you may have to add additional omega-3 to further suppress inflammation.

I think that inflammation causes obesity and obesity produces inflammation. In both cases, the gut flora are mediated the action. I think that the whey shakes in the Drs. Eades diet that I have discussed, can impact gut flora and change the eating behavior associated with obesity.

Thanks for your questions. Keep me updated.

Tim Steele said...

Hi, Art - Still trying to wrap my head around antibiotic resistance. Does having a large population of gut bugs that are resistant to the effects of Metformin, or any antibiotic for that matter, effect the function of the biome?

Or is your concern mainly that Metformin will kill off a large group of microbes that will never return to pre-Metformin levels?

Dr. Art Ayers said...

Tim,
The importance of the antibiotic activity of common drugs is that activity selects for corresponding bacterial mutants that are resistant. Any bacterium that picks up the new resistance gene will be at a selective advantage if the selective drug is present. That selective advantage will also result in the new drug resistance gene being added to preexisting multiple drug resistance plasmids.

Thus, taking Metformin will now select for multiple drug resistance that will be transferred to any pathogens. Common drugs indirectly select for and result in the construction of multiple antibiotic resistant super bugs.

Development of antibiotic super bugs has been blamed on abusive overuse of antibiotics in agriculture and medicine, but I think that the culprit is the natural antibiotic activity of common drugs. Drug use in general leads to super bugs. World use of pharmaceuticals needs to be reduced dramatically, e.g. a target of 1% of the current level! for antibiotics to remain useful.

Thanks for persisting in your questions.

Gretchen said...

What's your opinion of this comment?

"Recent animal studies have also found that metformin may actually play a role in shaping the gut microbiome. Metformin is a first-line drug for treating type 2 diabetes, but it is also sometimes prescribed for overweight and obese individuals seeking to lose weight. Although metformin has been used for decades, new research suggests it could hold the key to new treatments that target the intestinal flora. Preliminary studies reveal the positive effects of metformin – changes in the metabolic pathways of bacteria and growth of helpful bacteria, to name a few. While the exact details remain unknown, it’s fascinating to find that the medications we take can actually affect the microbes we host."

From http://www.diatribe.org/issues/64/what-were-reading

This suggests that yes, it affects bacteria, but it may select for helpful bacteria. I haven't read the article they cite as it's behind a paywall.

Dr. Art Ayers said...

Gretchen,
This is completely consistent with my perspectives of Metformin, which has beneficial effects on blood sugar levels by acting on gut flora. The action on gut flora is clearly selective and other studies show that it is an antibiotic. I just point out that the antibiotic activity of purified drugs always results in selection for corresponding resistance that ultimately leads to adding of that resistance to multiple antibiotic resistance plasmids. Subsequent use of Metformin or any of the antibiotic resistance genes on the plasmid, selects for all of the others simultaneously and the basis for super bugs is established.

It is easy to test if resistance genes for anti-diabetics, statins and NSAIDs already exist in hospitals on multiple antibiotic resistance plasmids.

Thanks for your comments.

Gretchen said...

I understand what you're saying. But I think we should try to reduce the massive use of regular antibiotics before we try to limit use of drugs that have beneficial effects on various diseases.

What we really need is new types of antibiotics that the bacteria can't build up defences against. If they ever figure out how to live in the presence of chlorine, we'll be in real trouble.

My grad school thesis was on enzymes that break down the polysaccharide coat on certain types of pneumococcus (now streptococcus pneumoniae). When the bacteria had no coats, they were not pathogenic. And you could, indeed, protect mice from pneumonia by injecting these enzymes.

But shortly after this was discovered (one of the discoverers was Avery, of Avery, McCloud, and McCarty fame), penicillin came around and the research on this was abandoned except for theoretical interest.

Of course, bacteria might develop ways of breaking down these enzymes. We need to find antibiotics of various different types to increase the probability that bacteria wouldn't be able to deal with at least some of them.

Dr. Art Ayers said...

Gretchen,
I agree that antibiotics are used excessively and the vast majority can be eliminated without major economic consequences except to pharmacy profits. Unfortunately, I think that the assumption that antibiotic use is the source of the rise of antibiotic resistance seems obvious, but is wrong.

Natural plant antibiotics, phytoalexins, have been isolated from plants, assessed for their pharmacological utility and repackaged as "beneficial drugs." They are just as active as antibiotics as their sister phytoalexins that are openly marketed as antibiotics and they represent the new classes of antibiotics that you would seek. However, all forms of antibiotics, including all natural phytoalexins, target bacterial gene products that are ever changing by rapid mutation.

Natural antibiotics that target bacterial cell wall components have been well studied and are readily produced as components of bacteriophages. They also readily produce resistant mutants. The same is true for phytoalexins and plant pathogens. Resistance is always produced.

Antimicrobial peptides (peptides with heparin binding domains), e.g. defensins, would be good candidates for antibiotics without well known resistance, and all of the possible sequences have been patented. Unfortunately, they are rather hard on gut flora.

Also note that most drugs act indirectly by using their inherent antibiotic activity to alter gut flora. It is the altered gut flora that provide the pharmaceutical benefit. That is what happens with the growth enhancing drugs, a.k.a. antibiotics, used in the cattle industry.

We use multiple antibiotics every time we eat veggies. That is the actual impact of phytochemical "antioxidants." These toxic phytochemicals continually alter our gut flora and are rapidly cleared, detoxified from our system.

I think the answer is to make people healthier rather than relying on drugs/antibiotics to fix the symptoms of disease. This means that the problem is predatory food and medical industries that make people sick and keep them sick. Prevention and cures are much cheaper than perpetual treatment.

Thanks for your comments. They help to clarify my points.

Raj said...

Great explanation Dr.Art cleared lot of doubts in my head. Tim brought this topic in previous post about how resistance gene or bio film get activated at industrial strength but not at low level plant phytoalexins.
Looks like it still gets activated for low doses too.

I am always curious over herbal medicines so looks like constant herbal use should also lead to resistance. Here is a BBC documentary link to naturopath who gets 60% cancer cure using tree barks, very interesting. May be the 40% is the resistance/bio film that's making the difference.

https://www.youtube.com/watch?v=IGvDmyZBMtI

thanks
Raj

Gretchen said...

Making people healthier is a laudable goal. The problem is how.

Anna said...

Interesting blog! I am an MD and doing my PhD on effects of Metformin given to pregnant women. We have been giving pregnant women Metformin from first trimester until birth to see if it prevents pregnancy complications. It did not in our study. We are doing a follow up study, the oldest children are now 8. I am speculating how to best look for autoimmune disease in these children (and their mothers) resulting from Metformin use during pregnancy. Do you have any thoughts about that?

Natasha T. said...

Dear Dr. Ayers,

Thank you for the reply! I have ordered (!!!) a probiotic with Clostridium butyricum and will let you know how it goes.

Thanks to for this post about Metformin, just fascinating.

I am happy to tell you, I have half way through my small jar of my first home made fermented vegies. I took a workshop 3 weeks ago with the local . Organic green and red cabbage, ginger, garlic, hot green peppers and beets. I love the ginger part, don't care for the beets. I will attempt a bigger batch soon. :-) I have been eating lots of local kimchi, and have a "date" with my Korean friend's non-English speaking mom, to help make it the next time she does a batch.

I have learned so much on your blog, and I am reading and re-reading. My degree is arts, with only some science. Some things I will read and not understand until the very end, but the understanding is quite the reward!

I wanted to get your opinion on something else... My immune system reaction to potatoes includes - terribly painful and swollen joints (all, especially hip), crying, and anger. I have had to be careful with yams and sweet potatoes because I was having a similar problem. This past week, including today, I am having this reaction to plantain starch. :-( I think I triggered this by trying to eat potatoes last week after taking a series of SBO and BRM potato starch. Is this an immune system reaction as I suspect? It is so difficult to suddenly be in pain physically and not being able to control my emotions. The crying is sometimes accompanied by a sudden and extremely deep depression. It comes on one hour to exactly 24 hours after exposure, and lasts 24-36. When suffering, I wrack my brain for the things that upset me and I usually come up with a list of things my husband is deficient in.... I try to hold my tongue because I know my complaints against him are unfair... As you can imagine, I have avoided potatoes and starch religiously. I would love to be free of this....

Also, I have problems with scented laundry detergent. Yeah, really. It shuts down my brain. I can't think. I won't know what is wrong. I will just feel terrible. I used to have problems with all scents and all soaps. Now it is just scented laundry detergent - so I use unscented.

As you can imagine, none of this can be dealt with by my GP.

What do you think? Am I on the right track with all the changes I am making?

Thanks, Natasha

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Amy LaHait said...

Hi Anna, I was diagnosed with PCOS in my twenties and on metformin for seven years before having my two sons (had best diabetes for both). I did not take metformin during my first pregnancy and was hospitalized at 32,weeks with a partial placental abruption, low amniotic fluid, and breach presentation. I had him at 37 weeks via csection and he had many GI health issues and still does (,he is now six)., I went back on metformin during my second pregnancy and had no issues. My second son is much healthier. I now have sjogrens and possibly lupus and stopped metformin a couple of years ago due to B12,deficiency. Also my boys and I all have MTHFR defects and are positive for HLA B27.

Gretchen said...

Another recent article on metformin:

http://www.pnas.org/content/early/2014/05/29/1321776111

Anonymous said...

I am an MD....and had mother and grandfather die of pancreatic cancer and father developed diabetes type 2 and died of renal failure. I read in an MD Anderson study of diabetics treated with Metformin (5 years or so ago) drastically reduce their incidence of pancreatic CA. I decided then and there to take the plunge and go chronic Metformin. I think it was a decision with some merit.