Disease Genes in the Gut Microbiota

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Species of Gut Microbiota

 

Summary:  Doctors take medical histories and enquire about family diseases.  It seems like they think there are human genes behind human diseases, but when we say, “It runs in the family,” what we actually mean is our gut bacteria, microbiota, are shared with relatives along with our eating habits.  Diseases result from problems with gut bacteria and not from problems with our genes.

Genetic Diseases are Rare

Not too many years ago, the technology for massive projects to thoroughly identify the genes behind the most prevalent human diseases became available.  The results were clear and shocking.  Genes were not a major contributor (less than 10%) to disease.  And yet, the families studied clearly had a major predisposition to each of the diseases studied.  Something was causing the disease in those families, but it just wasn’t any of the 23,000 genes identified in the human genome project.  People all have essentially the same physiology determined by very similar genes.  Health differences are predominantly due to gut bacteria.

A Decade Later, Genetic Map Yields Few New Cures

Genes are not Destiny

Commercial analysis of personal gene sequences was recently prohibited as a method of determining risk of disease, because the link between gene sequences and risk could not be substantiated.  The reality is that, aside from a few obvious molecular diseases, most genetic variations in gene sequences do not matter in an otherwise healthy person.  There aren’t  Alzheimer’s or obesity or heart disease genes.  Diet, gut microbiota, sleep and exercise are far more (>90%) important.  Most genetic risk factors can be overcome by an Anti-Inflammatory Diet with fermented vegetables, and a robust gut microbiota protected from medicine/antibiotics.

Gut Bacteria are Family

So if it is not human genes that run in families to make relatives share similar diseases, what is making them sick?  Relatives share their eating habits and gut bacteria.  This makes sense.  Diet and gut microbiota are the major determinants of disease and relatives pass their bacteria around the table with their food.  There are eating habits and particular patterns of gut microbiota that lead to common diseases.  Unbeknownst to us, most of the diseases of modern life, e.g. heart disease, obesity, diabetes, cancer, autoimmune disease, mental illness, are transmissible by gut bacteria.

The Hygiene Hypothesis is Right and Wrong

For decades it has been obvious that early exposure to a farm environment, meaning an abundance of microbes, a diverse microbiota, eliminates allergies and many autoimmunities.  The Hygiene Hypothesis explained how early exposure to abundant microorganisms could eliminate allergies, as an early exposure to antigens that trained the immune system.  Early training of the immune system was later discounted, but the Hygiene Hypothesis then morphed into the current explanation, that early development of a diverse gut microbiota is needed to produce a healthy immune system.

Fix Your Diet, Fix Your Gut Microbiota and Fix Your Diseases

The good news is that all of the chronic diseases that threaten your future can be cured by just fixing your diet and repairing the complex bacterial communities in your gut.  Your immune system is critical to your health and damage to your immune system is the typical beginning to most diseases.  Damage to the immune system starts in the gut, where the aggressive and suppressive halves of the immune system develop in response to particular species of bacteria.  Those essential bacteria grow on the food in your diet that is not digested in the stomach and absorbed as nutrients in the small intestines, i.e. prebiotic fiber.  Thus, you eat to feed yourself and your gut bacteria.  Without the gut bacteria, you would be deficient in vitamins, your immune system would cease to function and you would be constipated.  Fixing your diet and gut microbiota will cure your diseases.

Posts that discuss repair of gut microbiota 

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.

Health Diagrams II — Curing Autoimmunity and Allergies

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In this second in a series of posts explaining the concepts that I think are central, but misunderstood, about health, I am focusing on how diet and gut flora impact the immune system and cause autoimmunity and allergies.  This cause also suggests a simple cure.

Health in Diagrams I -- Gut Flora and Diet
Health in Diagrams III -- Inflammation from Cell to Tissue

Gut Flora to Tregs to Suppression of Autoimmunity

It is important to understand at the outset that autoimmunity and allergies are caused by a damaged immune system, and repairing the damage cures the diseases.  Damage to the immune system typically represents a break in the continual development of immune cells in the lining of the intestines.  Immune cell development in the gut is dependent on bacteria, the gut flora.  Damage to the gut flora, e.g. by antibiotics, processed foods that lack flora feeding fiber or extreme diets, disrupts development of immune cells.  Typically, loss of the immune cells that keep the aggressiveness of the immune system in check, regulatory T cells or Tregs, results in autoimmunity.  Fix the gut flora and autoimmunity recedes.  

Health Requires Suppression of the Aggressive Immune System

For simplicity, I am focusing on the T cells of the immune system that develop in the intestines and either kill other human cells that are dangerous, e.g. virus-infected or cancer cells, or provide protection by regulating the aggression, Tregs.  Normal functioning of the immune cells permits elimination of damaged or dangerous human cells, while at the same time avoiding rampages of lethally armed T killers.  Examples of untamed T killers in action are degenerative autoimmune diseases, such as arthritis, asthma, prostatitis, celiac, Hashimoto’s thyroiditis, type I diabetes, inflammatory bowel diseases and atherosclerosis. 

Milk Births Baby Immune System

It should not be surprising that the focus of immune system development is the gut.  We start as babies with explicit links between nourishment and immunological protection.  Milk connects the immune systems of mother to baby.  Immune cells from the mother are transferred in milk and colonize the respiratory and digestive system of the baby — the mother’s immune system coats and buffers the baby’s exposure to the world.  Milk hormones close the baby’s gut and milk bacteria are the first probiotics that exploit the milk prebiotics (bifidus factor, human milk oligosaccharides) to produce a gut flora.  [Also note that most commercial probiotics are adapted to grow on cow’s milk and hence these dairy probiotics do not survive in adults.]  The lymphatic system of the breast terminates at the nipple and samples antigens/pathogens from the baby’s mouth, resulting in baby-specific secretory antibodies that return in the milk.  Milk supports a starter set of gut flora, essentially dairy probiotics, that stimulates development of the baby immune system, but inhibits adult gut flora that would digest the protective components of milk.  Formula, on the other hand, is inflammatory to the baby gut, because it supports adult gut flora before the immune system is ready.  Inflammation and stimulation of innate immunity is sufficient, if supported with high levels of sanitation, to permit survival of babies fed formula.  Milk of any type is incompatible with adult gut flora, so breast milk will attack adult gut flora and adult gut flora will digest and inactivate the otherwise beneficial components of the milk.

Milk, Kefir and Gut Flora

Aggressive and Suppressive Cells of Immune System Develop in Intestines

Gut bacteria are required for the development of immune T cells in the lining of the intestines.  Mice grown without gut flora do not have functional immune systems.  In humans, extensive antibiotic treatment produces defective immune systems that are either overly aggressive, i.e. autoimmune, or susceptible to infection and cancer.  They can’t be both.  Aggressive T killers are stimulated to develop by filamentous bacteria and Tregs develop in response to members of the Clostridium family.  In a healthy body, there is a balance between aggression and suppression; there are functional defenses against infection and cancer, while also avoiding autoimmune disease and allergies.

Suppressive Tregs are Deficient in Autoimmunity

Immune cells result from replicative divisions of stem cells.  Antibody producing B cells are produced through a million random rearrangements of antibody genes and those B cells producing antibodies against common self proteins are killed (clonal deletion).  Similarly, T cells are produced by rearrangements of receptors and those that would recognize self are eliminated.  The T cells then migrate to the intestines where they can develop into killer T cells or Tregs, in response to gut flora.  The Tregs act to suppress killer T cells that mistakenly recognize healthy self cells.  Thus, the initial elimination of self-attacking T cells or for B cells that produce antibodies that bind to normal cells, is not perfect and the Tregs are needed to avoid the mistakes.  Tregs are necessary to avoid the immune attack on healthy cells that is the basis of autoimmunity.

Autoimmunity Starts with Inflammation, but Requires Deficient Tregs

Bacterial or viral infections, or physical damage causing inflammation is the first step in autoimmunity.  It is the inflammation that initiates the interactions between proteins, autoantigens, of normal cells and cells of the immune system that bind, internalize, fragment and present the antigen fragments/peptides to activate B or T cells with corresponding receptors.  The activated B cells make antibodies specific for the antigen and the T cells will kill cells displaying the antigen.  It is interesting that most proteins are not autoantigens and are never involved immune reactions.  Only proteins with an unusual triplet of basic amino acids, similar to the quartet of basic amino acids used to transport proteins into the cell nucleus, are candidates to be autoantigens or allergens.  In fact, since nuclear proteins already have a quartet, i.e. the nuclear localization signal, they are common autoantigens.  The last requirement for autoimmunity is a deficiency in Tregs, because if the Tregs are functioning, they will block attack on healthy cells.  Treg deficiency usually results from loss of the type of gut bacteria that stimulate Treg production in the lining of the intestines, i.e. species of Clostridium.

Hospitals are Notorious for Clostridium difficile Infections

Fecal transplants are now recommended as a safe and efficacious treatment for C. diff hospital infections.  That makes sense, because hospitals are where antibiotics are routinely used and C. diff can only infect people missing their healthy species of Clostridium.  Thus, the hospitals wipe out the gut flora with antibiotics and then recolonize them with their own antibiotic resistant C. diff.  More antibiotics can’t fix it, but providing healthy gut flora (transplant) can.

Autoimmune Diseases are Treated/Exacerbated with Antibiotics

Both the aggressive and the suppressive immune cells require gut flora, so after initial antibiotic treatment wipes out bacteria required for suppression and results in autoimmunity, the remaining aggressive half of the immune system can be eliminated by blasting the remaining gut flora with more antibiotics.  Of course this will leave a highly compromised, incompetent immune system that will ultimately yield more extreme symptoms.  This is the typical medical progression for Crohn’s disease, for example.  The alternative is just fixing the gut flora to begin with and curing autoimmunity.

Cure Autoimmunity by Feeding Clostridium Resistant Starch

Autoimmune diseases, by their symptoms, show that sufficient gut flora to stimulate the aggressive half of the immune system is still present.  What is missing are the Clostridium species that convert soluble fiber, such as resistant starch, into short chain fatty acids, e.g. butyrate.  Patients treated with antibiotics usually walk away from the hospital with a suggestion to eat some yogurt to repopulate their missing gut flora.  Unfortunately, dairy probiotics don’t survive in the gut and cannot repair the gut flora and immune system.  The result, after the gut fails to repair and the immune system crashes, is autoimmunity.  There is a more appropriate possibility to avoid or fix autoimmunity.  Some people suffering from autoimmunity (and with remnants of their gut flora intact) have simply fed their gut flora on resistant starch and achieved complete recoveries.  Others fail to respond, because their gut flora is too severely damaged and necessary bacterial species are gone.  Those individuals need to eat the missing species of bacteria and some probiotics (more common in Asia) contain Clostridium species.  Consistent with this use of soluble fiber to feed gut bacteria that produce butyrate and stimulate the suppressive immune system are reports of healing by combining potato starch (RS) and probiotics with Clostridium butyricum (Probiotic-3).  Repair of the suppressive immune system by repair of gut flora (including fecal transplants) and feeding gut flora with appropriate soluble fiber, may be a general approach to the cure of most autoimmune diseases and allergies.

Paleo Gut Flora Repair