Essential Oils, Phytoalexins, Drugs Are All Antibiotics

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Superbug multidrug resistant plasmid

A recent, informative article by Tori Rodriguez for The Atlantic suggests that,

Essential Oils Might Be the New Antibiotics.

I want to discuss other ramifications of using essential oils as antibiotics to avoid multiple antibiotic resistant superbugs.

The logic for using essential oils in place of medical antibiotics is compelling: 

• Essential oils are extracts of plants, which have myriad traditional uses, including food.
• Most antibiotic use is to increase livestock production. 
• Antibiotics selectively kill gut bacteria in livestock and make them obese.
• Antibiotic resistance occurs within a week of use in livestock (or people.)
• Medical antibiotics are quickly losing efficacy.
• Antibiotic resistance genes quickly move from agriculture to superbugs to people.
• Plants/essential oils contain natural antibiotics that kill gut flora and increase livestock productivity.
• Resistance to essential oil antibiotic activity is slower, because of simultaneous use of multiple antibiotics.

Obesity is a Symptom of Antibiotic Damage to Gut Microbiome

Antibiotics make meat fatter

We may enjoy a fat marbled steak, but the corn and antibiotics used to produce that mouth-watering plate of satiety, is not so healthy.  Corn and antibiotics make that meat on the hoof fit for human consumption, but the cattle are quickly dying and the fat marbling is a symptom of cattle metabolic syndrome.  The corn and antibiotics disrupt the bovine gut microbiota and alter energy flow.  The result is prime beef. 

As It Is with Cattle, so It Is with Middle Americans

General descriptions of Americans with metabolic syndrome and steers ready for the abattoir are similar.  That should not be surprising, because both are caused by damaged gut microbiota and consequences of metabolic syndrome.  Americans routinely damage their gut microbiota with antibiotics (processed food, etc.) and the major symptoms of the resulting gut dysbiosis are chronic inflammation, depression, autoimmune diseases, obesity and metabolic syndrome.  Repairing gut microbiota reverses all of these symptoms. 

But Essential Oils Are Just Natural Antibiotics

Essential oils are natural antibiotics

Is it better to use essential oils than medical antibiotics to fatten cattle or treat Lyme disease or hospital infections such as C. diff.?  Most pharmaceuticals were derived from plants or fungi and were originally used to kill microorganisms, i.e. they were natural antibiotics.  We call these phytochemicals by a variety of names, e.g. antioxidants or essential oils, but they are more appropriately called phytoalexins, all natural, all plant, all toxic antibiotics.  It is entertaining that essential oils have had so many different traditional and pharmaceutical uses, and yet they have always been experienced by microorganisms (and our livers) as simply toxic.  Essential oils do have the significant advantage of being a mixture of antibiotics and might be very useful where pharmaceutical antibiotics have problems.  The toxicity of essential oils, especially toward gut bacteria, should not be ignored.

Resistance to Essential Oils as Antibiotics

Antibiotic resistance develops in sewage

I previously kept track of laboratory strains of bacteria by simply exposing large numbers of the bacteria to an antibiotic and selecting for the rare individual that had already spontaneous mutated (DNA replication error of one in a million).  We could then use the new drug resistant strain in experiments and identify it by its resistance.  The same thing happens to your gut bacteria with an overnight exposure to an antibiotic.  And of course it also occurs immediately in livestock exposed to antibiotics or in sewage plants where tons of antibiotics and gut bacteria are mixed.  Resistance to each of the chemicals in an essential oil also would rapidly occur, if bacteria were exposed to each alone and in a  toxic concentration.  This is repeatedly observed, since commonly used drugs are just individual components of essential oils that have been produced in large amounts in pills and marketed based on their predominant physiological activity, rather than just another antibiotic.  Thus, resistance to a statin or Metformin, as antibiotics, could be easily observed (even on multiple drug resistance plasmids), but is just ignored.

Essential Oils Are just Mixtures of Natural Antibiotics

Statins from fungal antibiotics

The impact of essential oils on gut microbiota is unpredictable, because the composition of essential oils is highly dynamic and so are gut microbiota.  Each component of an essential oil has a different spectrum of toxicities to hundreds of different target proteins to each of the hundreds of different species of bacteria in the human gut.  Ingested essential oils are modified by the detox enzymes of the intestine and liver.  The modified phytochemicals have different toxicities and act as additional antibiotics.  Mixtures of antibiotics, as in essential oils, less likely to select for resistance than individual antibiotics, but an antibiotic is still just an antibiotic, regardless of whether it is straight from the plant or via a pharmaceutical salesman. 

Common Medicines Are the Source of Superbugs

Common meds are antibiotics

Doctors with prescription pads and steers eating antibiotics are blamed, I think unjustly, for the crisis of antibiotic resistance.  The real culprit is you taking NSAIDs, statins, proton pump inhibitors, antidepressants and other common medicines.  Since they are all developed from plant antibiotics, they are still antibiotics, and they still select for antibiotic resistance.  It is important to remember that pharmaceuticals are repurposed natural antibiotics from plants.  The answer to the superbugs that are resistant to all of the common antibiotics is to dramatically reduce the use of all pharmaceuticals.  The initial goal should be a 90% reduction.  Costly pharmaceutical chemicals could be replaced with preventive diets and less disruptive manipulations of gut microbiota, e.g. ingestion of capsules containing freeze-dried gut flora.  This more gentle approach to health care would also provide huge cost savings, as well as vastly improving health.

Gut Microbiome 2014: Diet, Inflammation, Disease, and Repair

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The year 2014 began with my posts on damage to the gut microbiota caused by antibiotics, processed foods and excess hygiene.  I lamented the inadequacy of information from the media on damage/repair of the gut bacteria and highlighted medical myths with a post on some of Dr. Oz’s own ills that are self-inflicted by his diet and hygiene recommendations.  I also started to discuss how to cure autoimmune diseases by repairing damaged gut flora and by avoiding the antibiotic activity present in many common drugs.

With my 200th post in March, I summarized my thoughts on the causes and cures of common diseases in a series of diagrams on:

Health Diagram I    — Gut Flora and Diet, 

Health Diagram II   — Curing Autoimmunity and Allergies,

Health Diagram III  — Inflammation from Cell to Tissue  

I illustrated the relationships among diet, inflammation and diseases mediated by gut flora that I have discussed, since I started my blog in 2008.  Now after a couple of hundred articles and more than two million visits to my blog, I think that I am starting to grasp some of the major issues that cause inflammatory diseases.  The cures also now seem obvious.

Antibiotics Contribute to Autoimmune Diseases

Some species of gut bacteria are needed for the development of the aggressive half of the immune system and other species are needed for the suppressive half.  Thus, starving or poisoning gut flora leads to immune system problems and diseases.  Antibiotics are a quick way of crippling the immune system.  It seems that the aggressive part of the immune system is less fragile, because in most cases antibiotic treatments produce autoimmune disease due to loss of bacteria that are needed for development of immune cells that block the aggressive half of the immune system from attacking innocuous cells of the body or environment, i.e. antibiotics usually trigger deficient tolerance, and autoimmunity.

Feed the Gut Microbiome for a Healthy Immune System

Diet provides food for the body and flora.  Protein and fat are the macronutrients needed for the body, while the gut microbiota lives off of plant polysaccharides (except starch) that pass through the small intestines undigested into the colon.  The hundreds of plant polysaccharides are hydrolyzed by hundreds of enzymes made by gut flora and produce short chain fatty acids, e.g. acetate and butyrate, that feed colon cells.  Food processing systematically removes polysaccharides that feed gut flora and compromises the components of the immune system dependent on those bacteria.

Repairing the Gut Microbiome by Eating the Missing Bacteria

It is easier to see that eating a diet that lacks food for the gut microbiota will be a problem, than it is to figure out where to find replacements for lost species of gut bacteria.  The only way that bacteria get into the gut is down the throat.  To repair a damaged gut microbiota requires both changing diet and introducing the missing types of bacteria by eating them.  Eating dairy probiotics and fermented vegetables can provide a quick, but only temporary fix.  Most of the needed bacteria are more common in soil than in food.

Phytochemicals Are First and Foremost Antibiotics

I was shocked that my background in phytochemicals didn’t lead more directly to a major culprit causing modern diseases.  The gut microbiota is clearly a major factor in health and sickness.  Antibiotics that kill bacteria, damage the gut microbiota.  It is also unsurprising that processing food to reduce soluble fiber, damages gut flora, by systematically depriving gut bacteria of their major source of food.  The proliferation of antimicrobial products also damages the gut flora.  What I missed in this onslaught of modern lifestyles on the gut microbiota, was the major player in antibiotic resistance — phytochemicals are natural antibiotics. 

I Missed the Antibiotic Activity of Common Medicines

I studied phytochemicals and wrote research articles on their toxic, antibiotic activities, but everyone else was merchandizing phytochemicals as antioxidants, essential oils and superfoods.  This is a major conceptual problem.  Our bodies expend a significant fraction of our energy resources to detoxicify phytochemicals and human cultures have elaborate rituals to avoid phytochemicals and domesticate plants by breeding for the least toxic.  What I missed was the implication that the pharmaceutical industry was repurposing toxic, antibiotic phytochemicals as medicines and then skipping the "antibiotic" label.

Unlabelled Antibiotic Drugs Cause the Rise of Superbugs

Overuse of antibiotics is a problem, because it damages the gut microbiome and contributes to the modern increase in autoimmunity.  Food processing is another culprit and so is the mania for hyperhygiene and the demonization of bacteria.  Unfortunately, the major culprit in the development of multiple antibiotic resistant superbugs is the tons of commonly used pharmaceuticals that systematically attack gut bacteria, but are not labelled as antibiotics.  Most modern drugs were developed from phytochemicals and were initially used in plants to kill bacteria and fungi, i.e. phytoalexins.  Pharmaceutical companies acknowledge the antibiotic activities of common drugs, by sponsoring research conferences to develop existing drugs as new classes of antibiotics for treatment of superbugs.

Frankincense and Myrrh, Terpenoids

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Frankencense Resin

 'Tis the season to discuss phytochemicals.  Plants produce a vast array of organic chemicals starting from molecules produced by all organisms, including humans.  Essentially all of these phytochemicals are potent adaptations to kill.  Phytochemicals kill plant pathogens, bacteria and fungi, as well as insects.  Thus, the natural, plant extracts that humans use for flavor enhancers (herbs, spices, and teas), fragrances, recreational/medicinal mind and attitude modifiers (alkaloids, psychopharmaceuticals, etc.), herbal medicines, etc. are present in plants, first and foremost, as antibiotics and insecticides.  Humans have evolved to taste (bitter) and smell phytochemicals to avoid their toxicity, and have adapted culturally to exploit the impact of phytochemicals on body and mind.  In this seasonal post, I focus on the terpenoids in Frankincense and Myrrh, to explore how plant biochemistry contributed to the gifts of the Magi.

It All Starts with Central Metabolism

Phytochemicals are complicated plant chemicals that are produced by a series of enzyme-controlled reactions (Central Metabolism) from the array of chemicals used by plants to convert photosynthetic carbohydrates (fructose and glucose) into the molecules (sugars, amino acids, fatty acids, nucleic acids) used to make the macromolecules of cells (polysaccharides, proteins, fats, DNA/RNA).  Alkaloids and phenolics, e.g. phytoalexins, are made from amino acids (phenylalanine) and terpenoids are made from fatty acids (acetyl CoA/Mevalonate) or other intermediates in glycolysis.  Thus, central metabolism that converts glucose/fructose into pyruvate and the acetyl CoA (see mevalonate pathway left) of mitochondrial fatty acid metabolism, is further converted into amino acids and plant secondary compounds, phytochemicals.  I am going to talk mainly about terpenoids in Frankincense (triterpenoid Boswellic acids) and Myrrh, and many related molecules (steroids) also produced by humans.  

The major thesis here is that carbon dioxide is converted by photosynthesis into either sugars used to build the cell wall polysaccharides (soluble fiber) or larger toxic defensive chemicals, e.g. phytoalexins, resins, essential oils or lignin.  Phytoalexins, e.g. the natural antibiotic resveratrol in wine, are made from phenylalanine along the same biochemical pathway used to produce lignin.  Glyphosate, the herbicide, kills by blocking this unique plant pathway.  Essential oils and resins are another group of natural antibiotics produced by converting acetyl CoA into a five carbon unit, IPP, which is then linked into larger and larger (10, 15, 20 carbons) molecules, terpenoids, that can rearrange into multiple ring structures.  Only the smallest chemicals in the series evaporate to provide identifiable smells, e.g. Frankincense and Myrrh, while larger forms, e.g. cholesterol or testosterone in animals, are odorless solids.

Acetyl CoA to IPP

IPP

For those who enjoy the beauty of biochemistry:  The most abundant enzyme on earth is RibisCo (ribulose bisphosphate carboxylase), the plant enzyme that combines carbon dioxide from air with a five-carbon phosphorylated sugar, ribulose bisphosphate, to produce two, three-carbon intermediates of glycolysis that can be converted into glucose or into acetyl CoA, the starting chemical for fatty acids, the mitochondrial TCA cycle, or via mevalonic acid to isopentanyl pyrophosphate (IPP), the building block for terpenoid synthesis.

In brief:  Photosynthesis uses the energy from sunlight to convert carbon dioxide into sugars (glucose and fructose).  Those sugars can be converted into a five-carbon, molecular building block for terpenoids, IPP.  IPP molecules can then be linked together to make increasingly longer chains and those chains can be ultimately twisted into rings to make resins in plants and steroids in humans.

Five, Ten, Fifteen, Thirty; IPP (5), GPP (10), Sesquiterpenoids (15), Triterpenoids (30)

Terpenoid Polymerization

Terpenoid synthesis begins with IPP, which has five carbons in a branched chain and has a pair of phosphates, pyrophosphate that provide the energy to form chains of 5, 10, 15, etc.  In plants, molecules of each of the incremental lengths are produced together and additional enzymes in different species of plants result in mixtures of molecules with different rings and functional groups.  The smaller molecules evaporate more readily, so that mixtures are extruded from damaged trees as oils and gradually form resins as the remaining larger molecules predominate and solidify.

Shark Livers and the Horn of Africa

IPP with five carbons, an isoprene, is used to make GPP with ten, a monoterpene.  Common monoterpenes are geranol and limonene that make the characteristic odors of geraniums and lemons. Sesquiterpenoids (15 carbons made from three IPPs) include the fragrance of patchouli. Diterpenes, such as sweet steviol, have twenty carbons, which can be chemically twisted into the chemicals that predominate in Myrrh resin, the Balm of Gileade.  The triterpenes with 30 carbons can be rearranged with five rings to form steroids, such as cholesterol in animals or Frankincense.  Linear squalene, is the major component in shark liver oil and provides the same function as a swim bladder in a boney fish.

Essential Oils Are Mixtures of Distilled Terpenoid and Phenylpropanoid Phytoalexins

Boswellic Acid

Phytoalexins and terpenoids have evolved as plant defenses against bacteria, fungi and insects, and they are toxic, because they interact aggressively with proteins through their chemical ring structures that are hydrophobic.  These ring structures make the smaller versions volatile and soluble in organic solvents.  Many of these chemicals have properties similar to petroleum products and may be used as solvents themselves, e.g. paint strippers or thinner.  Steam distillation of plants produces mixtures of phytoalexins and terpenoids commonly called essential oils, which contain the volatile components “essential” for the odor identity of a plant.

Statins Block Cholesterol Synthesis

Statins were identified among a group of fungal antibiotics for their ability to block an early enzyme (marked in the mevalonate pathway above) in the production of cholesterol.  The toxic side effects of statins derive from wholesale disruption of all of the essential pathways (everything below the inhibited enzyme) that are related to cholesterol, such as blood heme A found in hemoglobin, and ubiquinone (CoQ) found in mitochondrial electron transport and needed to reduce oxidative stress and glucose intolerance.  Thus, for these examples, statins would contribute to anemia and type II diabetes/metabolic syndrome.  The side effects are not surprising, since statins are fungal antibiotics that target pathways common to bacteria and human mitochondria.  It is also not surprising that statins have unpredictable impacts on gut flora and the immune system.

Celiac, Gluten and Trypsin Inhibitor

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Wheat

Summary

Forget the gluten.  Celiac is caused by trypsin inhibitors (ATI) that were increased in wheat fifty years ago to combat pests.  Immune response to ATI spreads to include gluten and transglutaminase that perpetuates the disease.  Celiac is an unexpected consequence of traditional plant breeding that could be fixed with GMO approaches.

Plants Protect Themselves with Antibiotics, Pesticides and Trypsin Inhibitors.

Plants respond to pathogens and pests by making themselves toxic.  Thus, plants produce natural antibiotics, phytoalexins, a.k.a. phytochemicals, polyphenolics or antioxidants, to kill bacteria and fungi.  They also produce chemical pesticides and proteins, e.g. trypsin inhibitor, that block the digestion and utilization of plant proteins by insects.  One of these trypsin inhibitors makes ground soybeans inedible until it is removed in water rinses during the production of tofu.  Another of these trypsin inhibitors, in wheat, is the cause of celiac.

Plants Target the Nerves, Immune Cells and Intestines

Plants have evolved chemicals and proteins that attack and punish plant-eating animals.  A single molecule of caster bean toxin protein, for example, can kill a human cell.  Plants produce some of the most toxic molecules on earth.  The nervous system of insects and other herbivores is typically targeted by plants.  Many recreational drugs, e.g. opioids, THC, nicotine, caffeine, etc., for example, are made by plants in self defense.  Human nerves respond to these natural pesticides and the bitter taste and the vomit reflex help us to detect and avoid toxic phytochemicals.  Gluten proteins contain polyglutamine stretches of amino acids that resist digestion and bind to intestinal cells.  Seed lectins bind to the glycoproteins on the surface of the intestines and inhibit digestion.  Wheat seeds also contain an inhibitor of starch and protein digestion, the amylase/trypsin inhibitor, ATI.  ATI binds to the receptors on immune cells that trigger general inflammatory responses to pathogens, e.g. TLR4.  It is the ATI in wheat that starts an immune response to gluten and celiac.

Wheat trypsin inhibitor causes celiac and autoimmunity

ATI Increased to Make Wheat Resistant to Pests

More than fifty years ago, plant breeders began to screen wheat varieties for resistance to pests.  Breeding ultimately resulted in enhanced pest resistance that resulted from increased production of ATI in wheat kernels.  Modern wheat flour contains modest changes in gluten and other components over the last century with the singular exception of ATI, which has increased about 50 fold.  It is also interesting that ATI is a major wheat allergen.  This suggests that celiac starts as an allergy to ATI present in wheat flour.

Celiac Results from Superfine Milling of High-ATI Wheat

Wheat has been milled more and more finely to improve the shelf-life of bread flour.  The inedible bran and the germ are first removed from the wheat kernels and then the endosperm is ground so finely that the starch granules are broken.  Even "whole wheat flour" is ground in the same way and the bran and germ are simply added back to make it “whole.”  The important point here is that superfine milling results in starch that is readily digested by amylase in the small intestines, instead of acting as soluble fiber to feed gut flora.  The result of eating bread from superfine flour is that gut flora are starved for soluble fiber and the immune system is depleted of Tregs that would otherwise suppress allergy and autoimmunity.  Superfine milling of high-ATI wheat presents ATI to an immune system that is primed for allergy.

ATI is a Good Immunogen

Allergy development requires 1) inflammation, 2) an appropriate immunogen and 3) lack of Tregs (immune system cells that develop in the lining of the intestines and block allergies and autoimmunity.)  The modern milling of wheat flour eliminates a major source of soluble fiber, starves gut flora and reduces Tregs, but allergy development still requires inflammation and an appropriate immunogen.  An immunogen is a protein that will interact with cells of the immune system to produce antibodies and activate aggressive attacks.  I have found that all proteins of food or the environment, i.e. allergens, or of the body, i.e. autoantigens, that act as immunogens to initiate allergies or autoimmunity have the same sequence of three amino acids, a "basic triplet."  ATI has a characteristic basic triplet in its protein amino acid sequence and that is why it is a good immunogen to initiate allergies.

Allergy to ATI is Aggrevated by TLR Recognition of ATI

ATI enriched, superfine flour Is a powerful initiator of allergies, because it starves gut flora to block Treg production and is a good immunogen, but the immune system will still ignore ATI in the gut, unless inflammation is also activated.  Unfortunately, ATI actively stimulates inflammation of the intestines by specifically binding to TLR4, which is the receptor that also binds/recognizes the LPS of bacteria.  Thus, ATI is a way for the wheat plant to defend its seeds by triggering excessive Intestinal inflammation.  Inflammation, immunogen and Treg insufficiency is the ATI allergy trifecta.

Wheat ATI Allergy Leads to Celiac

First exposure to ATI and development of an allergy will make subsequent expose to wheat proteins more immunologically intense.  I discussed the response of the intestinal lining to gluten in previous posts.  Wheat gluten proteins are adapted to provide nutrients for growing wheat embryos and to provide defense against pathogens and herbivores.  Gluten proteins contain long stretches of amino acid glutamine, which is poorly digested by gut enzymes.  The glutamine is also converted into glutamate by the gut enzyme, transglutaminase, tTG.  Unfortunately, during the process, the enzyme is covalently connected to the undigested gluten fragments.  The allergic ATI reaction combined with gluten/tTG conjugates, leads to presentation of the gluten/tTG to the immune system and antibody production agains both gluten and tTG.  Subsequent exposure to gluten results in the autoimmune disease of celiac.

Celiac is Self-Perpetuating

The aggressive immune attack on the intestines in response to eating gluten-containing grains, is bad in itself, but it also causes a series of related autoimmune diseases.  Attack on the intestines also disrupts the development of the lining of the intestines, which in turn disrupts the community of bacteria and fungi, gut flora, that are essential for digestion of plant polysaccharides, soluble fiber, and the development of the immune system.  Gut flora dysfunction results in vitamin deficiencies, food intolerances and autoimmunity.  Thus, celiac is self-perpetuating, because it causes inflammation, immunogen presentation and Treg deficiency.

Celiac Causes Numerous Autoimmune Diseases

Celiac is often associated with other autoimmune diseases, because it causes them.  Antibodies to tTG are diagnostic for celiac and the autoimmune attack on the intestines is mediated by anti-tTG antibodies.  But anti-tTG antibodies of celiac don’t just attack the intestines, they attack any other tissues that have tTG, such as the thyroid gland and hair follicles.  Thus, it should not be a surprise that celiacs are at high risk for autoimmune disease, e.g. Hashimoto’s thyroiditis, of the thyroid gland, including both hypothyroid and hyperthyroid diseases, depending on which region of the thyroid is attacked.  Some forms of hair loss, alopecia, are also initiated by autoimmune attack on the tTG in hair follicles.  Persistent exposure of celiacs to gluten will result in a cascade of autoimmune diseases as other body antigens are presented to the immune system and tissues with those antigens are targeted and attacked to produce arthritis, vitiligo, etc.

Pest Resistance, Plant Breeding and GMO Solutions

Genetic modification of plants occurs every time seeds are planted.  Traditional plant breeding by selecting desirable individual plants grown from crosses of selected parents is one form of genetic modification.  Specifically introducing desired genes using recombinant DNA techniques is another, more controlled method.  Traditional plant breeding has systematically destroyed the diversity of crop plants by loss of genes that are not selected, but even the traits, such as pest resistance, that provide benefit, have also brought unintended consequences.  We now have grains with many desirable features of high yield and disease resistance, but they also provide increased risk of celiac, gluten intolerance and associated autoimmune diseases.  Maybe it is time to consider GM techniques as a safer alternative to fix modern wheat and to examine milling approaches to save our gut flora.

Health Diagrams II — Curing Autoimmunity and Allergies

Cure for Celiac and Autoimmunity

Celiac and other autoimmune diseases are perpetuated by the presence of the corresponding autoantigen/allergen, in this case tTG and gluten proteins, and a deficiency of Tregs.  Oddly enough, some pathogens (Helicobacter pylori) and parasites (Helminth worms) stimulate Treg development in the lining of the intestines, in addition to normal gut flora, Clostridium spp.  It may be the relative absence of pathogens and parasites in affluent societies that reduces Tregs and enhances the incidence of allergies and autoimmunity.  Antibiotics and the antibiotic activity of pharmaceuticals in general may also contribute to Treg deficiencies by damage to gut flora.  Clearly, the repair of gut flora and reestablishment of the associated immune system will go a long way toward curing autoimmune diseases such as celiac.  Celiac, however, provides the added complexity that it damages the ability of the intestines to maintain a functional gut flora.  Thus, the cure for celiac would require simultaneous repair of both the gut and its flora, e.g. by a  fecal transplant and supportive diet containing numerous soluble fibers to which the donor flora have been previously adapted, i.e. lacking antigenic triggers.

Antibiotic Resistance, Superbugs and Drugs

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Antibiotic resistance results, because spontaneous mutations occur so frequently that all bacteria are different.  It is just a matter of exposing enough bacteria to an antibiotic to find one that is insensitive to a particular antibiotic.  More bacteria mean a greater chance of mutations to antibiotic resistance.  The gut contains a lot of bacteria and sewage treatment plants are loaded with gut flora.

Health in Diagrams

Antibiotics are Ubiquitous

All organisms, plants, fungi and animals/humans produce chemicals that kill bacteria, i.e. antibiotics.  I have written many articles about the natural antibiotics of plants, a.k.a. phytoalexins or “antioxidant” polyphenolics, and the human defensins that are peptides with heparin binding domains.  Bacteria also produce viruses, called bacteriophages, that kill other bacteria.  All of these natural antibiotics are small molecules that interact with many different human proteins, and it is these side effects that permit their exploitation as pharmaceuticals.  Thus, statins were selected from fungal antibiotics that inhibited an enzyme needed for human synthesis of cholesterol, metformin was a phytoalexin found to reduce blood sugar and resveratrol is a grape phytoalexin.

Plant Antibiotics are Natural

The flavoring chemicals in herbs and spices have a far more important use in food preparation than titillation of taste buds, since those chemicals kill common food pathogens.  More profoundly, it is important to realize that the selective advantage of phytochemicals/polyphenols/alkaloids/essential oils to the plants that make them, is as natural antibiotics.  Plants kill bacteria, as well as fungi and insects, for a living.

Plant Chemicals Attack all Aspects of Bacteria

Most of the thousand genes that are present in a bacterium code for proteins/enzymes and most antibiotics target those enzymes.  Penicillin binds to an enzyme needed to make bacterial cell walls, streptomycin target protein synthesis, rifampicin blocks RNA synthesis, actinomycin D inhibits DNA synthesis, etc.

Mutation to Antibiotic Resistance is Automatic in Bacteria

Each time a cell replicates, mistakes are made and the new DNA molecule of each chromosome is slightly different than the original.  There are about a thousand genes on the single chromosome of a bacterium and about the same number on each of the 23 human chromosomes.  About a dozen mistakes, mutations, are made each time bacteria replicate.  The mutations that alter the gene target of an antibiotic and produce a bacterial enzyme that is unaffected by the antibiotic, yield an antibiotic resistant bacterium.  The mutant gene now codes for antibiotic resistance and the presence of several resistance genes in the same bacterium produces multiple antibiotic resistant "superbugs."

Mutations are Random, but Antibiotics Select for Resistance

Each cellular replication produces random mutations throughout the bacterial DNA, but of the billion sites along the DNA that can mutate, only a few will produce a modified enzyme that will no longer interact with a particular antibiotic and thus be resistant.  Antibiotic resistance mutants are rare, less than one in a million, but a million bacteria can grow from a single cell in a day and occupy a volume less than a crystal of salt.  Ten hours later, after ten more doublings of the million bacteria, there will be a billion, and there will be a good chance that among those will be a mutant that is resistant to a particular antibiotic.  In the pound of bacteria in the human gut, there are mutants that are resistant to most antibiotics, including the antibiotics that have not yet been developed.  Of course, most of those antibiotic resistant bacteria are just flushed down the toilet.  Treatment with antibiotics kills all of the sensitive bacteria and leaves only the resistant.  Thus, antibiotic treatments select for antibiotic resistant bacteria.

Common Use of Antibiotics Selects for Resistance on Plasmids

Genes are transferred between bacteria by bacteriophages, conjugation (a kind of bacterial sex) and transformation, which is the release of DNA from one bacterium with subsequent uptake by another.  Biofilms, which are communities of many different species of bacteria, stimulate transformation and exploit bacterial DNA as a matrix material to hold the communities together.  The human gut is lined with biofilms and the biofilm bacteria secrete vitamins as the quorum sensing signals that coordinate community activity.  Thus, some vitamins must stimulate transformation, the exchange of DNA among members of the different species of bacteria in the biofilms with evolution of new and novel species.  Rapid change in the gut environment selects for a shift in genes that provide for adaptation to the new environment to small DNA fragments, plasmids, that move most readily between bacteria.  Antibiotic treatment results in antibiotic resistance genes on plasmids.

Use of Multiple Antibiotics Selects for Multiple Antibiotic Resistance Plasmids

Persistent use of an antibiotic will spread resistance to a particular antibiotic through the gut flora, facilitated by antibiotic resistant plasmids.  Replacement of a second antibiotic will result in a new plasmid with both antibiotic resistance genes.  Hospitalization and exposure to a plethora of bacteria with multiple antibiotic resistance plasmids will result in rapid conversion of gut flora to multiple antibiotic resistance upon exposure to any antibiotics.  Hospital staff would be expected to be natural repositories for multiple resistance genes, especially if they are exposed to any antibiotic (or pharmaceutical.)

Most Pharmaceuticals Select for Multiple Antibiotic Resistance Plasmids and Superbugs

The frightening rise of superbugs resistant to all known antibiotics has been attributed to the accelerated use of antibiotics in medicine and agriculture.  Mixing megatons of bacteria in the guts of billions of people with tons of antibiotics, and still more in sewage treatment plants and agriculture, is bound to produce bacteria with every type of multiple antibiotic resistance plasmid imaginable.  But that is not the biggest problem, since fingering the commercial use and misuse of antibiotics ignores biggest exposure of bacteria to antibiotics.  It ignores the fact that most popular pharmaceuticals, NSAIDs, statins, anti-depressants, anti-diabetics, etc., also have substantial antibiotic activity.  Most of these pharmaceuticals started out as phytoalexins and then were found to also have pharmaceutical activity.  Pharmaceuticals are just repurposed natural antibiotics.  When you take an aspirin or Metformin or a statin, you are taking an antibiotic.  When you take a pharmaceutical, you are selecting for multiple antibiotic resistance plasmids in your gut flora and you may be making the next superbug.

Metformin, Antibiotic with Autoimmune Side Effects

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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.]

SweetMyx Taste Enhancers, Alapyridains?

---  Here are the other 200 blog posts ---
I was just reading announcements of new synthetic chemicals (SweetMyx) to enhance the taste and help reduce sugar and salt in "health foods".  The new taste enhancers have already been approved by industry organizations that designate the chemicals as GRAS, generally recognized as safe.  I, of course, was curious about how the SweetMyx chemicals made food taste sweeter with less added sugar.  Notice how convenient it is that the food industry has found a way to charge more for less sugar, just as labels have been changed to specifically designate "sugar added:".

Alapyridains are Taste Enhancers

I searched the chemical literature for new taste enhancers, since the chemical ingredients in SweetMyx are trade secrets and will not be disclosed on food labels.  It didn't take long to find that the likely suspects are called alapyridains.  This group of related chemicals are synthesized with a central pyridine ring familiar from the related cytosine and thymidine of nucleic acids, the plant alkaloid nicotine and the vitamin niacin.  A guanide group (half of the diabetes drug metformin, which is a biguanide) is added to make a salt enhancer, and a benzene ring is added to make a sugar enhancer.  Without these additions, the central structure inhibits the ability to taste the bitterness associated with "healthy plant antioxidants," phytochemicals and essential oils.

Will SweetMyx Just Tickle your Taste Buds?

The alapyridains that I expect to be in SweetMyx seem to be similar to common plant alkaloids, which are natural pesticides and antibiotics, i.e. phytoalexins.  So I would expect these compounds to also be antibiotics with unknown impact on our gut flora, nervous and immune systems, just like all of the medical antibiotics.  Based on the general putative structure of the taste enhancers and similarity to other molecules with known reactivities I would also expect these molecules to react with enzymes that bind sugars, e.g. glycosidases, or with hundreds of other proteins that bind to heparin, e.g. embryological growth factors, clotting factors, cytokines, amyloids, etc., etc., etc.  It would also be expected that these enhancers will encourage consumption without satiety and therefore, just as artificial sweeteners, contribute to further obesity.  In other words, these taste enhancers can be expected to have numerous, unpredictable medical and ecological side effects that will not be understood for decades.

Phytochemicals, Natural Antibiotics and Antioxidants

Plants are mean and sneaky.  They are natural organic chemists and make the nastiest toxins on earth.  Never trust a plant.  Eat them at your peril… or because they taste good.

Phytoalexins

Plants are Fast and Lethal

I was shocked when people started to laud the virtues of phytochemicals.  I thought that they must have alkaloid poisoning.  My PhD training involved separating and measuring the antifungal chemicals produced by soybean cotyledons exposed to the wall polysaccharides of a pathogenic fungus.  The plants would go crazy and produce a witch’s brew of toxins to provide protection from the fungus.  I eventually wrote a chapter on these toxic natural antibiotics, phytoalexins, for the Encyclopedia of Science and Engineering.  All plants produce these chemicals and as one might expect, seeds/nuts are provided with special protection to avoid being digested.

Lignin

Plants are Natural Chemical Killers

I developed a profound respect for the ability of plants to protect themselves.  Fungal spores germinate on the surface of leaves and their slender, threadlike hyphae attach and glue themselves to the waxy outer surface and then forcefully and enzymatically penetrate to the spongy cells below.  When the tip of the hypha touches the wall of the underlying cell, the plant nucleus lurches as its cytoskeleton reorients.  The surrounding plant cells respond in sympathy and all of these neighbors mobilize their biochemical processes to kill everything in their vicinity.  In a few hours, the plant chemicals kill the cells producing them along with the pathogen, and would continue to kill more and more of the leaf, but plant cell walls also contain enzymes that convert the phytoalexins to more wall material, lignin, and protect cells outside of the influence of the fungus.  As lignin in wood and plant litter is slowly degraded by microorganisms, it forms humus, the natural organic material in compost and soil, and also releases a potpourri of potent plant phenolics like BPA.  Compost is also a rich source of cell wall polysaccharides, a.k.a. soluble fiber, that feeds soil bacteria.

Phytochemicals are Natural Antibiotics

Most phytochemicals have evolved in plants as pathogen or herbivore defenses.  Since the nervous system is adapted to detect other organisms, it is not surprising that plants target the sensory system, brain and nerves of herbivores, and we detect the flavor and smell of plants/herbs/spices by their defensive molecules.  All of the flavor and taste components of herbs and spices are phytochemicals that kill bacteria, fungi and other pathogens.  Nicotine and caffeine are insecticides.  A detailed, worldwide study showed that spices are used in specific global areas, because of the local availability of the spices and their effectiveness against local food storage pathogens.  People develop a taste for the plant defensive chemicals that they must be exposed to for sustenance.  Cuisine represents a knife edge that separates attractive stimulation from death.  Natural or organic does not mean safe or healthy.  Plants are as dangerous to eat as pufferfish.

Phytoalexins are Useful, but Be Very Careful

Perfume Ingredients

If a grape notices a nearby fungal pathogen, it produces its phytoalexins, including resveritrol, which is a notable “antioxidant” that has been recognized as contributing to longevity.  People are encouraged to drink red wine for the health benefits of its phytoalexins.  Most of the pharmaceuticals derived from plants are phytoalexins in disguise.  Of course, the evolutionary origins of phytoalexins as natural broad spectrum antibiotics, makes it no surprise that phytoalexins are commonly toxic, carcinogenic and very dangerous to fetuses.  Morning sickness has been explained as nature’s way of telling a mother carrying a vulnerable fetus to not eat plants and potentially phytoalexins.  It is wise for women to avoid plants, perfumes and essential oils during their first trimester.  Essential oils are phytoalexin extracts from plants and many of these components are the essence of perfumes.  These same chemicals, e.g. limonene, serve dual purposes as fragrances and paint strippers, recreational drugs and insecticides.  We can smell these natural plant chemicals, because they are attacking our nervous system.  Multipurpose mixtures of essential oils, such as Vick’s Vaporub, contain menthol, camphor, eucalyptus oil and terpentine that kill bacteria and fungi (toe nail fungus) and also stimulate cold/hot sensing nerves in the skin, which triggers endorphin production and reduces underlying joint inflammation.

Fruits are Fake Seduction

Fructose is fruit sugar.  That is very appropriate.  Fructose derivatives are the most central intermediates of central metabolism, glycolysis; glucose is immediately converted to fructose after it enters a cell as the fundamental source of energy and carbon building blocks.  Fructose is not normally transported in plants or animals, because it is too chemically reactive and toxic.  It rapidly bonds and crosslinks proteins and is ten times worse than glucose in forming AGE (advanced glycation end products) such as hemoglobin A1C.  If you feed fructose to cattle, it makes their meat tough by cross linking protein fibers and it does the same thing to human skin.  Fructose in fruit is a fake, because it is cheap and sweet.  Animals eat fruit hoping to find starch, which is the only polysaccharide that animals can convert to glucose with their own (not bacterial gut flora) enzymes.  Starch quickly becomes sweet, because amylase in saliva digests the long chains of glucose molecules of starch into shorter dextrins that trigger sweet sensors in the tongue.  Fructose masquerades as starch by binding to sweet sensors a hundred times more strongly than dextrins.  The evolutionary advantage to using fructose to make plants sweet is that it takes much less energy and carbon, and it also poisons insects and microorganisms.  That is why honey is made of equal amounts of fructose and glucose, rather than sucrose, for example.  Fructose in high concentrations is toxic to microorganisms and honey can be used to dress wounds.  I can’t understand why fruits, especially juices, are recommended as part of a nutritional diet.  At best, fruit should be converted into juice.  The juice should be discarded and the pulp eaten as a source of soluble fiber, pectin, to feed gut flora. 

Phytochemicals Must be Detoxified to be Edible

Bacterial and fungal pathogens must avoid detection by plants to avoid death by phytoalexins.  Insects, similarly must avoid preformed phytochemicals that would kill or poison them with their first bite.  Pathogens and pests that are effective on one species of plant cannot eat others with different chemical defenses; plants and their pests/pathogens are mutually adapted.  Primates browse on new shoots of many different types of plants, to avoid building up lethal doses of particular phytochemicals.  The same is true of humans, who also have intestines and livers that chemically treat and neutralize plant toxins.  These same human defenses determine the rate at which other related chemicals, i.e. pharmaceuticals, most of which are derived from phytoalexins, are transformed and excreted.  Turmeric contains curcumin, which is the most potent inhibitor of inflammation yet identified.  Unfortunately, curcumin is “detoxified” in the intestine and large amounts must be eaten to suppress inflammation.  Fortunately, pepper contains another phytoalexin, piperine, which inhibits the detox system, so that most cuisines that use turmeric combine it with black pepper.

Trade Your Liver for Vegetables

The liver is the only organ that can be continually regenerated and that is because humans have evolved to eat plants, and phytoalexins take their toll on the liver.  As plants are digested and absorbed in the small intestines and transported to the liver, phytoalexins accompany the nutrients.  Most of the phytochemicals are chemically detoxified by liver enzymes, but the phytoalexins kill some liver cells with each meal and some of the phytoalexins circulate in the blood and reach other tissues.  The phytoalexins are evolutionarily adapted to bind to proteins to disrupt essential enzymes of microorganisms and herbivores, and like pharmaceuticals to which they are chemically and functionally related, they have numerous side effects.  The chemical reactivity is what is detected as the “antioxidant” property of phytoalexins.  Antioxidant is nutritionally meaningless and basically reflects the chemical toxicity of phytochemicals.  After all, you can’t easily sell chemicals that are inherently toxic.  Meat and humans are made of the same easily digestible stuff, i.e. protein, fat, plus indigestible polysaccharides in connective tissue, i.e. chondroitin sulfate and heparan sulfate.  Plants are essentially anti-human and are made of protein, vegetable oils (omega-6), digestible starch, undigestible cell wall polysaccharides, undigestible lignin and toxic phytoalexins.  Humans have adapted to eating plants with liver enzymes, liver regeneration, gut flora (to eat otherwise indigestible polysaccharides, soluble fiber to produce short chain fatty acids) and elaborate cultural habits.  We avoid most plants as too toxic and have domesticated some to produce reduced and tolerable levels of phytochemicals.  Of course this also means that the domesticated, defanged crop plants have a hard time defending themselves and we have to continually worry about blights and pestilences, and end up applying our own witch’s brew of fungicides, pesticides, and herbicides.

Polyphenols and Hormesis
I am going to add a few comments on the benefits of phytochemical "antioxidants", a.k.a. polyphenols, to clarify what I think is a misuse of the term "hormesis", which I thought meant the dilution of a toxin until it reached a magic lower concentration which was beneficial.  The trade offs of phytochemicals are nicely discussed by the Whole Health Source blogger, Dr. Stephan Guyenet.  I just don't think that the benefit of toxic chemicals stimulating the body's own antioxidant arsenal is an example of hormesis.  The point is that phytochemicals always act as toxins and stimulate toxin defenses.  Phytochemicals don't act as anti-oxidants in the body, even though they stimulate antioxidant defenses at all concentrations.  They provide a dubious benefit of unnecessarily heightening defenses with concomitant energy expenditure at low amounts and net damage at higher amounts.

Hakuna Matata and Sip the Tea

Tea Fanatic

I seem to have painted a compromising picture of plants as less than the perfect food.  They are tough and potentially toxic.  Plants clearly don’t like to be eaten and the best that can come of eaten plants is a full belly and a damaged liver.  But if you cook or ferment the plants first and bacteria start to digest and dull the chemical arsenal, plants can be safely and perhaps even enjoyably eaten.  We need not eat just safe meat.  We can also kick back and sip the tea.