Essential Oils, Phytoalexins, Drugs Are All Antibiotics

---  the other 200 posts  ---

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

---  My other 200 posts here  ---

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

 --- the other 200 posts ---

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.

Antibiotic Resistance, Superbugs and Drugs

--- All 200 posts here ---

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

----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.]

Health in Diagrams I — Gut Flora and Diet

---All 200 posts here---

This is the first of three posts to summarize my thoughts on diet, inflammation and disease mediated by gut flora.  I decided that I needed to make my points as explicit as possible by putting them down in diagrams and making references to my other posts.  By the time I finish, I will reach my 200th blog post at Cooling Inflammation.

Health in Diagrams II -- Curing Autoimmunity and Allergies

Health in Diagrams III -- Inflammation from Cell to Tissue

Everyone Leaves Out Gut Flora

I want to first explain and diagram my current understanding of the relationship between gut flora (the complex community of hundreds of different types of bacteria and fungi in the intestines) and diet.  My impression is that many people have health problems based on diet, but when they try to heal their health, they fix their diet and see only limited benefits.  Medicine provides only a temporary treatment using dairy probiotics.  The problem is that they failed to fix their gut flora, which was also damaged by their unhealthy diet.  

Health Requires a Match between Diet and Gut Flora

It is a myth that gut flora will just adjust to diet and a healthy diet leads to a healthy gut flora.  

A damaged gut flora lacks necessary species of bacteria.  Antibiotics, for example, can permanently delete dozens of particular bacterial species of gut flora that can only be replaced by reintroducing the missing bacteria by eating those bacteria again.  The missing bacteria may be needed to digest particular foods and the result is food intolerances, commonly mistaken for food allergies.  Antibiotic use frequently leads to autoimmune diseases, that are caused by deficient regulatory T cells of the immune system that develop in the lining of the intestines in response to particular gut bacteria.  The natural source of gut bacteria is eating the bacteria clinging to raw or fermented vegetables.

Antibiotics and Autoimmunity

Diagram Showing the Interaction of Food, Gut Flora and the Immune System

Food is just Protein, Fat and Soluble Fiber

The human body produces enzymes to fully digest proteins, fats and one polysaccharide, starch.  All other parts of plants and animals are edible (fermented by gut flora) soluble fiber polysaccharides or insoluble, undigestible fiber consisting of cellulose or lignin, which together also make up the undigested organic matter, humus, of soil.  Grains are problematical for health, because their starch is readily converted to sugar, i.e. high glycemic, and their fiber is insoluble (not fermented by gut flora) and high in phytate.  Phytochemicals, plant polyphenolics, are of questionable value as antioxidants and are of unexplored importance for their antimicrobial impact on gut flora.

Phytochemicals, Natural Antibiotics and Antioxidants

Polymers (Protein, Starch) are Hydrolyzed by Enzymes to Oligomers and then Monomers (Amino Acids, Glucose)

The stomach mixes protein digesting enzymes, proteases, and starch digesting amylase, with food protein and starch.  Proteases convert the long chains polypeptides, polymers of protein amino acids, into shorter fragments, oligopeptides.  The specific nature of the stomach proteases leaves groups of basic amino acids (lysine, arginine), heparin-binding domains, intact.  These peptides, similar to the defensins of the microvilli crypts, are anti-microbial and work with residual acidity to reduce bacterial growth in the first part of the small intestines.  Pancreatic enzymes then digest the peptides further and the small peptides are ultimately digested by enzymes on the surface of intestinal epithelial cells just prior to absorption.  Similarly, starch is degraded to oligosaccharide amylodextrins, which are then hydrolyzed to glucose at the intestinal surface prior to absorption.  Amino acids and glucose are not normally available to bacteria in the intestines.

Antimicrobial Heparin-binding Domains

Fats are Dissolved by Bile, Digested by Lipase and Absorbed

Fats are triglycerides, i.e. three fatty acids attached to the three hydroxyl groups of glycerol.  Fats are hard to digest, because they form oily droplets.  The droplets are dissolved in the intestines with bile, which is an acidic form of cholesterol, that is produced in the liver and stored in the gall bladder.  Fat in a meal triggers bile release from the gall bladder into the small intestines.  The bile represents a huge reservoir of the cholesterol that is synthesized by the body and dwarfs the cholesterol content of any meal.  Statins decrease body production of cholesterol, interfere with bile/fat digestion and lower lipid cholesterol levels.  (Unfortunately, lowering lipid cholesterol levels has minimal impact on heart disease and the only impact of statins on cardiovascular disease is through weak anti-inflammatory side effects.)  Pancreatic lipase removes two of the fatty acids from each triglyceride.  The fatty acids (a.k.a. soap) and monoglyceride are absorbed by the intestinal cells and reformed into triglycerides that make their way to lymphatic lacteals and are dumped into the blood, where they circulate as chylomicrons surrounded in lipoprotein.  Lipoprotein lipase binds to heparan sulfate on the surface of blood vessels and gradually removes fatty acids, until the diminished chylomicron is absorbed by the liver and exits as a VLDL.  (Note that this is another connection between lipid metabolism and inflammation, since inflammation decreases heparan sulfate on cell surfaces.  Heparan sulfate also mediates LDL binding to cells and amyloid stacking.)

Heparin-binding Domains

Plant Polysaccharides are Soluble Fiber and Food for Gut Flora

All that remains of food after the protein, fat and glycemic starch (glycogen) have been removed in the small intestines are plant cell wall polysaccharides, resistant starch, storage polysaccharides, e.g. inulin, plant beta-glucan, animal glycans, e.g. chondroitin sulfate and heparan sulfate, and insoluble fiber.  The insoluble fiber passes on to be a minor contributor to the bulk of stools and the rest of the polysaccharide is potentially fermentable by gut flora into short chain fatty acids (formic, acetic, propionic, butyric acids).  Some of the polysaccharides are simple repeating units of one or two sugars in long chains, but others are made of five to ten different sugars in complex branched structures.  Simple repeating polysaccharides require just a few different enzymes for their initial synthesis and a few for their digestion.  Thus, resistant starch can be digested by a couple of enzymes into glucose that can be used by most gut flora.  Arabinogalactan, on the other hand, requires a dozen enzymes for plant synthesis and an equal number of hydrolytic enzymes to produce arabinose and galactose, which require further enzymes for metabolism in a select few of species of gut flora bacteria.  

Resistant Starch as a Panacea

Food Intolerance/“Allergy” Indicates Missing Bacteria

Gut flora in general can produce several hundred different enzymes for digestion of diverse soluble fiber,  but most soluble fiber polysaccharides can only be digested by certain bacteria and those bacteria increase, if the complementary fiber is present in the diet.  If a fiber is absent from the diet, bacteria that specialize in digesting that polysaccharide will be eliminated.  People living on diets limited to just a few types of soluble fiber can only digest those fibers and a shift in diet to other types of soluble fiber will lead to symptoms of dietary upset, such as bloating, gas production and food intolerance.  Food intolerances reflect inadequate diversity in gut flora and a mismatch between bacteria and food.  Food intolerances can be eliminated by repairing gut flora and the typical repair solution is eating homegrown fermented vegetables that provide the missing species of bacteria.

Paleo Gut Flora Repair

Immune Cells Develop in Response to Gut Bacteria

Most of the body’s immune cells are in the intestines.  Cells of the immune system are constantly dividing in bones and the thymus gland, developing in the lining of the intestines and migrating to other tissues.  Filamentous bacteria of the gut flora stimulate the development of aggressive immune cells that kill other cells that are infected with pathogens or viruses or are cancerous.  Furrows perpendicular to the flow of food cultivate the growth of Clostridium species that ferment soluble fiber, e.g. resistant starch, and release butyric acid that stimulates the development of regulatory T cells, Tregs.  It is the Tregs that control the aggressive immune cells and prevent attack on self (autoimmunity) or innocuous antigens (allergy).  It appears that merely eating resistant starch, e.g. potato starch, with probiotics that contain butyric acid producing Clostridium bacteria may provide a cure for many autoimmune diseases.

Free the Animal: A Resistant Starch Primer for Newbies

Gut Biofilms Release Vitamins as Quorum Sensing Signals

 The gut flora lines the intestines in numerous biofilm communities, which form from dozens of different species of bacteria that communicate by exchanging molecules called quorum sensing signals.  These signals from the biofilms intimately attached to the lining of the intestines are vitamins.  Thus, healthy gut flora are the major source of vitamins and other sources, such as fruits and vegetables are only needed, if the gut flora is damaged, e.g. by antibiotics.

Dr. Oz, Vitamins, Biofilms

Volume of Stools Reflects Gut Flora Fermenting Soluble Fiber

The bulk of bowel movements, stools, is bacteria, the compressed gut flora that accumulated in the colon while fermenting soluble fiber.  We always hear that we need to eat fiber for regularity, but since insoluble fiber is only a minor contributor to stool volume and it is associated with anti-nutritive attributes, such as the binding and removal of zinc and iron by phytate, the fiber that counts for regularity is soluble fiber.  Regularity results from the fermentation of soluble fiber polysaccharides producing short chain fatty acids, such as butyrate, that are the major source of energy for colon cells.  And the growing bacteria in the colon provide most of the bulk of the hydrated stools.  Inadequate dietary soluble fiber or damaged gut flora, dysbiosis, leave only dehydrated insoluble fiber and compact stools of constipation.  Constipation can result from dehydration or excessive retention, but chronic constipation, even in the presence of adequate dietary soluble fiber, is an indication of damaged gut flora and an increased risk for diseases resulting from deficiencies of Treg production:  autoimmune diseases and allergies.  Constipation and associated autoimmune diseases can be cured by repairing gut flora and supplying adequate dietary soluble fiber.

Milk, Kefir and Gut Flora

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.