Statins and Atherosclerosis

A recent study (JUPITER) on the statin Crestor was ended prematurely when the drug was shown to dramatically reduce vascular events. The statin was tested on patients with chronic inflammation as judged by elevated C-reactive protein, but with low LDL. These patients would not normally be treated with statins and therefore represent an immense new market for statins.

Statins are supposed to act by interfering with the synthesis of cholesterol and thereby lowering the serum concentration of the lipid carrier LDL. Lowered LDL is supposed to decrease vascular disease that is aggravated by accumulation of cholesterol at sites of inflammation on the surface of blood vessels.

Unfortunately the data linking cholesterol production, LDL levels and vascular disease is weak. Thus, it is possible to lower LDL and have no impact on cardiovacular disease statistics. The recent study on Crestor was interpreted as being support for the link between LDL levels and vascular disease, but I think it shows something very different.

There is increasing evidence that vascular disease is based on diet-based chronic inflammation and that statins have a mild impact on reducing inflammation. It follows then that statins will reduce inflammation enough to have an impact on vascular disease, independent of effects on LDL levels. The Crestor study actually showed that patients with low levels of LDL but chronic inflammation benefited from lowering of inflammation. The LDL levels were unimportant. Reducing inflammation was the point and using statins to reduce inflammation is unnecessarily expensive and ineffective. Adjusting diet makes a lot more sense.

Drug companies are already pushing for increased use of statins on larger segments of the US population to provide prevention from atherosclerosis, stroke and heart disease. This would be immensely expensive with marginal returns. It is also just treating the symptoms without addressing the cause.

The solution to cardiovascular disease is dietary. Omega-6 oils and low availability of omega-3 fish oils is the major cause of the chronic inflammation that is the major risk factor for cardiovascular disease. The major US vegetable oils, corn, soybean, cottonseed, safflower, need to be drastically restricted and olive oil needs to be encouraged. We need to recognize that saturated fats are safer than the omega-6 polyunsaturated fats that have replaced them. Elimination of omega-6 vegetable oils and use of fish oil supplements are cheap and effective ways of lowering chronic inflammation.

Cardiovascular disease is also based on decreasing muscle mass, sarcopenia, which is also the basis for increasing chronic inflammation inappropriately attributed to aging. People get less physical exercise as couch potatoes or with decreasing activity as they age. The result is replacement of muscle by fat, and fat is inflammatory. Obesity is an extreme of this trend that leads to high chronic inflammation identified as metabolic syndrome, the prelude to a suite of nasty degenerative diseases: diabetes, atherosclerosis, allergies, cancer, Alzheimer’s, etc.

The obvious bottom line is to avoid all of these problems with an anti-inflammatory diet and lifestyle.

Dr. Oz Five Food Felons

---the other 200 posts---

Biofilms on intestine microvilli

The medical industry is slowly pulling away from diet advice that has contributed significantly to disease in America.  It promoted or at least tolerated, the shift from butter to margarine and polyunsaturated vegetable oils, and from saturated fats in meats to starches and grains.  The medical emissary, Dr. Oz, still supports medical advice that is not based on medical research.

Dr. Oz's Five Food Felons and Why His Choices Are Unhealthy:

"1) Trans fats raise lousy LDL cholesterol and triglyceride levels, lower your healthy HDL cholesterol level and fuel disease-triggering inflammation."  Trans fats are inflammatory and should not be eaten.  New labeling has permitted substantial amounts of trans fats to be added to processed foods and still be labelled "No trans fats."  LDL blood levels reflect inflammation, but artificially lowering the LDL with statins has no impact on heart disease.  Lowering LDL, by lowering inflammation with fish oil and/or repair of gut flora, diet and exercise is effective.

"2) Saturated fat in red meats, poultry skin, full-fat dairy products and palm and coconut oils fuels cancer risk, coronary artery disease, dementia, obesity and diabetes."  Linking saturated fats with heart disease, etc. was never supported by medical research.  Elimination of red meat, removing skin from chicken, avoiding egg yolks, etc. and replacing them with omega-6 polyunsatured vegetable oils has been a major contributor to inflammation and disease.  Full fat milk is the healthful choice, especially for children.  The change was dangerous and is being reversed with new emphasis placed on omega-3 fish oils.

"3) Added sugars and 4) sugar syrups cause the proteins in your body to be less functional and age your immune and cardiovascular systems and your joints. Plus, they disrupt your metabolism and contribute to almost every lifestyle-related malady, including some cancers."  Oz got this right even though they initially promoted high fructose corn syrup (half glucose/oligos) and its evil and even higher fructose sister agave nectar (all fructose/oligos.)  Equally bad, however, are the hyperglycemic starch in breads (including whole grain!) and over cooked pasta.

Gut flora

"5) Refined and processed grains don't contain the fiber or nutrients (contained in 100 percent whole grains) that you need to keep the bacteria in your guts happy, glucose levels regulated, immune system strong and digestion running smoothly."  Dr. Oz and company fail to understand the basics of vitamins, soluble fiber and gut flora.  Grains are not healthy for most people, because of the toxicity of gluten and hyperglycemic starch.  Ultra fine milling and fast commercial bread making eliminate the resistant starch.  "Whole grain" processed foods just add back the insoluble fiber that is considered toxic, because of its phytic acid content.  Grains should just be replaced with whole foods, such as vegetables that contain the soluble fiber that feeds the gut flora that provide all of the needed vitamins and are required for immune system development.

Why Does Dr. Oz Make Health Mistakes?

Dr. Oz has been criticized for promoting foods, supplements, medical treatments, etc. that are not supported by medical research.  While that is true, I think that he is just following the general views of the medical industry and simply doesn't know any better.  Sadly, most doctors don't have the background to read scientific research papers, let alone their own biomedical literature that is rife with scandals of nonreproducibility and inappropriate industry influence.  Doctors find it hard to give valid dietary advice, because nutritionists have false information and celebrity doctors, and their research teams, don't do their homework.  The result is the mix of ancient orthodoxy, industry promotion, alternative medicine and unscientific fads that appears in the media.  Doctors need a scientific background sufficient to answer the essential question posed to health claims, "Does it make sense?"

American Heart Association OKs Linoleic Acid and Arachidonic Acid

Can the AHA be correct in promoting omega-6 PUFAs? Doesn't this conflict with the broad therapeutic action of omega-3 PUFAs, EPA/DHA, against inflammatory diseases?

The dietary shift from saturated animal fats to polyunsaturated fatty acids (PUFAs) from vegetable oils paralleled the shift from infectious diseases to inflammatory/degenerative diseases as predominant killers in the Western world. Treatments for degenerative diseases associated with aging have improved, but these diseases have become more prevalent and the age of onset has decreased. And medical costs have skyrocketed. Omega-6 vegetable oils seem to be the problem, but the American Heart Association (AHA) has recently given these PUFAs a clean bill of health.

Why the AHA Conclusions Seem Just Wrong

The rise of inflammatory/degenerative diseases follows the shift to processed foods rich in omega-6 PUFAs (corn, soy, cottonseed, safflower oils) and simple carbohydrates (grain starch, sugar, high fructose corn syrup), but the AHA presents scientific data to exonerate omega-6 PUFAs. The central problem is that the AHA’s conclusions are not based on a conceptual framework to explain cardiovascular disease. Instead, conclusions are derived from experiments in which various diets are fed to people and consequences are analyzed. With some diseases, in which there is a simpler cause and effect relationship, this approach might lead to useful answers, unfortunately, the inflammatory component central to cardiovascular disease can have multiple, alternative origins and simple experiments yield misleading conclusions.

Experimental Basis for AHA Support for Omega-6 PUFAs

• Conversion of short PUFAs found in the diet, e.g. LA, to the long PUFAs that serve as the precursors of cellular hormones. But conversion is thought to be inefficient, so that less than 1% conversion occurs and short PUFAs have little impact on cellular long PUFA concentrations. Moreover, the brain does not perform the conversion and the high brain content of DHA is supplied on demand from DHA circulating in the blood.
• There don’t appear to be any direct, inflammatory derivatives of LA (C-18), but after it is converted to AA (C-20), the arachidonic acid is the starting point for the conversion to most of the inflammatory and anti-inflammatory cellular hormones, e.g. prostaglandins, leukotrienes and lipoxins. Thus inflammation is initiated by AA-derived products, but resolution and return to normal physiology is also based on other AA-derived products.
• Increases in blood plasma AA are associated with anti-inflammation, not inflammation.
• Increases in dietary AA and/or LA result in a decrease in cardiovascular disease. Replacing dietary saturated fat with PUFA leads to a reduction of disease by 25-50%. Higher serum LA translates into less disease.
• Increases in dietary LA result in lower serum cholesterol and LDL, but paradoxically they also lead to a narrowing of arteries.
• The relative amounts of dietary PUFAs (USA) are LA 15grams/day, AA 0.15g/d, ALA (omega-3, C-18, linolenic acid) 1g/d, EPA/DHA <>

Statins Lower Cardiovascular Disease by Lowering Inflammation (LDL Not Important)

The JUPITER study showed that the statin Crestor was effective in lowering heart disease, because it lowered inflammation. Individuals with chronic inflammation responded to Crestor by lowering inflammation. Lowering of LDL levels, however, was not related to decreasing disease. Elevated LDL levels may reflect inflammation.

Relating the JUPITER results to the AHA conclusions suggests that LA and AA may reduce inflammation and as a consequence also reduce serum LDL.

Inflammation Is the Cellular and Tissue Response to Many Stresses

The list of pathogens that trigger inflammation is long and includes specific signals from viruses, bacteria, fungi and protozoa. Pathogen-caused damage, as well as physical trauma, cause inflammation. Disruption of cellular metabolism and energy flow by vitamin, mineral, amino acid, or fatty acid deficiencies or excesses all produce inflammation. One of the difficulties of diagnosis is the overlapping of symptoms originating from numerous sources of underlying inflammation. Herniation of vertebral disks, for example, can be triggered by physical trauma, but it also may be initiated by the intestinal inflammation of gluten-based celiac. Acne and depression are common symptoms of chronic inflammation that may result from dietary deficiencies, gum disease, gluten sensitivity, etc. All of these examples respond to anti-inflammatory diets.

It is difficult to identify the sources of inflammation in experimental studies. In cardiovascular disease, the sources of inflammation are commonly not known in individual cases and the cardiac symptoms are treated. In reality, these are actually many different diseases, all with different sources of inflammation, pigeon-holed under the same symptom, a cardiac event. The most effective long term treatment for the dispart group is general suppression of inflammation. Any specific treatment of a root cause only works on a small subset of the group and would be considered ineffective. Thus, statins are considered effective against heart disease, because they reduce inflammation that is common to the whole group. Reduction of LDL is inadvertently used as a measure of control of inflammation and has become inappropriately designated as a risk factor. Directly lowering LDL has no impact on heart disease, but it is easy to measure. Inflammation is hard to measure and finding the source of inflammation is harder still.

Omega-6 Vs. Omega-3 Is Another False Dichotomy

Just as there is no opposite to inflammation, omega-6 and omega-3 fatty acids are not in opposition. The action of aspirin is the big clue. Aspirin changes the structures of the enzymes involved in converting AA into inflammatory prostaglandins and leukotrienes, with the result that anti-inflammatory lipoxins are produced instead. Aspirin is a biochemical switch that mimics the natural transition of the cellular machinery from producing enzymes that accentuate inflammation, to enzymes and signals that are the next step in the cycle, repair and restoration of normalcy.

Omega-6 PUFAs are needed for both inflammation and restoration of normal cellular functions. Some of the enzymes produced during inflammation are needed for the reset to normalcy. The difficulty comes when inflammation is sustained, components are depleted and the cycle cannot be completed. The result then is chronic inflammation, the symptoms of metabolic syndrome and degenerative diseases.

Why Did Demonizing LA and AA Seem Right?

It seems wise not to trust medicine, dietitians and the food industry, because they have made so many lamentable mistakes making dietary suggestions that have shortened so many lives. Professional societies like the AHA also frequently give silly advice, because the advice doesn’t reflect the best information from the biomedical literature. So it makes sense to be skeptical.

In this case the AHA appears to be right, only because established views were supported by straightforward experiments. What determines if an excess of dietary LA and AA is going to be a problem with inflammation is the absolute amount of AA and EPA available on the surface of immune cells. PUFAs are attached as part of the phospholipids of the lipid rafts on the membrane surface of immune cells that have received a inflammatory signal, e.g. bacterial lipopolysaccharide. There is usually adequate AA to be converted by enzymes on the cell surface to produce further inflammatory signals. The problem comes if there is so much AA that the EPA never made it to the lipid rafts. The result would be inadequate EPA conversion to anti-inflammatory prostaglandins and failure to return to normalcy. This would be a particular weakness in the presence of a large depletion of the EPA pools during sustained inflammation and chronic inflammation would result.

Thus, the AHA promotion of omega-6 PUFAs is half right. They should have said that omega-6 fatty acids are not a problem, if there is adequate EPA/DHA and no sustained inflammation. Unfortunately, the Western diet provides inadequate EPA/DHA and deficiencies that constantly produce inflammation. Of course, those enjoying an anti-inflammatory diet and lifestyle have biochemical tolerance for the AHA’s suggestions. Others eat vegetable oils at their peril.

reference:

Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM, Engler MB, Sacks F. 2009. Omega-6 Fatty Acids and Risk for Cardiovascular Disease. A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009 Jan 26. [Epub ahead of print]

Aricept: dementia treatment

Aromatic Binding to Enzymes -- 

Aricept, an acetylcholine esterase inhibitor used to treat Alzheimer’s disease and other conditions that benefit from enhanced accumulation of acetylcholine, is an example of a molecule with multiple hydrophobic rings that binds to an enzyme.

I want to discuss aricept as an arbitrary example that I just looked up to illustrate the lack of specificity of statins that I will characterize in another article as little more than molecular skeleton keys that work on many different enzymes.

I have presented two diagrams of the structure of Aricept. It has two isolated rings on the left and then a fused pair of rings on the right. The major chemical feature here is the inability of the rings to hydrogen bond with water. The result is that water next to the faces of the rings is highly structured in a high energy configuration. Two rings will be at a much lower energy if they are stacked together, because two of the surfaces will no longer be exposed to water.

Typical low energy, noncovalent bonds in water, such as ionic bonds are readily broken by the thermal, kinetic energy of water -- they get knocked apart. The energy of these bonds is only 1-2 kcal/mol. In contrast, the stacked hydrophobic rings are quite stable, because it takes ten times the energy to separate them, 20 kcal/mol.

Aricept binds to acetylcholine esterase, the enzyme that degrades the neurotransmitter acetylcholine by at least three stacked rings. These ring structures are shown in the close up of the tunnel leading to the enzymes active site near the yellow tryptophan on the left. Part of the enzyme shown by the white, ribbon-like twists of the amino acid backbone have been removed over the tope of the grey-red and blue aricept molecule, to make it easier to see.

I also showed the aricept in the tunnel with the surface of the protein shown to indicate how the aricept slips and sticks in the enzyme and blocks its activity.

The aricept is bound to yellow tryptophans at both ends and the middle ring is bound to the hydrophobic ring of orange tyrosine. The geometry of the interaction is important, but many other molecules with fewer rings would also bind to the same hydrophobic, aromatic ring amino acids. Acetylcholine, which can form hydrogen bonds with the paired electons of the acetyl oxygens, will just slip across the surface of the hydrophobic rings on its way into the enzymatic tunnel.

Statins were found by testing fungal extracts for molecules that would inhibit an enzyme (HMG-CoA reductase) in lipid metabolism. The normal lipid substrates for that enzyme would also be expected to bind to the surface of rings in the acetylcholine esterase enzyme. In fact, I would expect to find molecules from fungal extracts that would inhibit acetylcholine esterase.

I demonstrated the nonspecificity of all of these binding events with the aromatic rings in the active sites of enzymes by having one of my students check for the binding of a flat hydrophobic molecule, metformin, one of the common drugs for treating type II diabetes, to a common bacterial enzyme, beta galactosidase. Kinetic studies demonstrated competitive inhibition of typical beta galactosidase substrates, which indicates that the metformin binds the aromatic amino acids that are known to be involved in binding of the sugar substrates, e.g. lactose, of the enzyme. I would not be surprised if the statins are transported into cells by the same organic cationic transporter that transports metformin.

I am setting the stage for a discussion in a future article of what kind of activities would be expected from fungal molecules that were identified by the statin screening. It is not surprising that the statins have many activities other than reducing LDL. The only statins that are effective in treating cardiovascular disease are those that also lower inflammation. It is also not surprising that statins have many side-effects.

Medical Advice Is Just Wrong

Medical advise says to avoid sun, fats and red meat, but to drink lots of water, eat polyunsaturated vegetable oils and focus on the grain-rich bottom of the food pyramid. The medical advice is simply wrong and is not supported by the biomedical literature. A recent article in a major medical journal claims that about 90% of medical advice is not based on clinical research studies, but rather represents the opinions of experts who are supported by the health industry. Most research is conducted to support products. Unfortunately the advice that comes from medical societies is not healthy.

Here I will provide a few examples to illustrate that medical advice is frequently, if not usually, wrong about diet, nutrition, cause of disease, appropriate drug use and whether to spend a few unprotected moments basking in sunshine.

The Sun Is Not the Enemy, but Sun Blockers Can Increase Skin Cancer

Medicine is supposed to provide instructions on how to handle dangerous chemicals and procedures safely and to enhance health. Solar radiation is dangerous and will cause skin cancer if used inappropriately, but solar radiation is also needed to produce vitamin D in skin. The public response to the medical mandate to limit solar exposure to reduce radiation-based skin cancer resulted in increased use of solar-blocking lotions. Unfortunately, the result was that some people spent more time in the sun, assuming that avoiding sun burns meant that they were avoiding skin cancer. Unknowingly they had shifted their skin exposure down from doses sufficient to kill cells and cause inflammation, to levels sufficient to just cause solar mutagenesis -- the lower exposures were optimal for skin cancer production.

Spare the Sun and Spoil the Child

Babies and children are the most sensitive to solar radiation induced skin cancer and need protection from over exposure, but the public response to medical advice has been to avoid prudent exposure to the sun. Now kids in the U.S. are showing symptoms of rickets, a vitamin D deficiency disease common during early industrialization, in which air pollution, urban poverty and factory work limited solar exposure. Babies in strollers are completely covered. One frightening consequence of this over-reaction could be a resurgence of poor bone growth that in the 1920’s resulted in the development of the now-trendy Cesarean section procedure to accommodate women with malformed pelvises due to rickets.

Rickets Is Rampant

Ubiquitous vitamin D deficiencies due to inadequate sun exposure is compounded by inadequate sources of dietary vitamin D and inappropriate medical interventions. Most vitamin D deficiencies go unnoticed, because the typical symptoms of deficiency mimic other forms of inflammation. When serum levels of vitamin D are actually measured and found to be inadequate, supplements of 600-1000 iu/day of vitamin D3 are prescribed. Unfortunately, there is seldom followup testing and a recent study indicates that most treatment for vitamin D deficiencies is inadequate -- much higher doses, ca. 2-5000 iu/day are required to reach optimum levels. Most people are and remain vitamin D deficient.

Scourge of Scurvy

Vitamin C deficiencies are also a problem. Most people get enough vitamin C to avoid losing their teeth (vitamin C is needed for collagen production), but subclinical deficiencies still produce chronic inflammation. The major cellular anti-oxidant is glutathione, but vitamin C is another major defense against reactive oxygen species (ROS). An increase in ROS triggers oxygen stress and inflammation. Deficiency of vitamin C indicates that more vitamin C is being used up than is being replenished in the diet. Numerous metabolic disturbances associated with other deficiencies or infections can result in vitamin C depletion and chronic inflammation. Most people are vitamin C deficient.

Vegetable Oils Are the Problem, Not the Cure

Medical advice to avoid saturated fats in meats and shift to omega-6-rich vegetable oils is a major contributor to chronic inflammation and modern degenerative diseases. The original claimed association between saturated fat consumption and cardiovascular disease was tenuous, but produced a glacial shift in diet toward consumption of omega-6 fatty acids, e.g. corn and soy oils. The medical dependence on measurements and treatments of LDL, has outweighed the actual data in the biomedical literature -- LDL levels are not important in cardiovascular disease. Drugs that lower LDL, serum cholesterol, are only effective in reducing heart disease, if they lower LDL by lowering inflammation. The risk factor is the inflammation, not the LDL level. Agricultural practices that use grain over grass further reduce the omega-3 fatty acid content of meat and increase the inflammatory omega-6 fatty acid level.

Statins Are a Problem, Not the Cure

Statins are broad spectrum disrupters of the function of many different enzymes and proteins. They were originally isolated from fungi based on their ability to poison bacteria, i.e. they are antibiotics. They disrupt fat metabolism and thereby lower LDL levels, but they also cause many undesirable and potentially dangerous side-effects. One of these actions is to block inflammation triggered by activation of the inflammation transcription factor, NFkB. By blocking NFkB activation, some statins lower inflammation and thereby decrease cardiovascular disease. This activity is similar to aspirin, which acts on COX-2 as well as directly on NFkB. Both statins and aspirin (NSAIDs) have multiple activities on numerous areas of cellular metabolism. The activities of both include reduction in inflammation, but they also produce other undesirable side effects. Chronic inflammation is better treated by diet, exercise and traditional herbs and spices, rather than more dangerous statins.

Water Is Miraculous, but just Satisfy Your Thirst

If you are thirsty drink tap water. There is no improvement in health by drinking some extra amount of water each day. Drinking water in plastic bottles from magical sources provides no improvement in health. Much of the “spring water” with designer labels is only locally bottled tap water. The plastic bottles are an ecological disaster and the “purified” water in the bottles is contaminated with compounds leaching from the bottles. If you want a constant source of water, bottle your own tap water. If you want to avoid the minor contaminants added to avoid bacterial contamination of municipal water supplies, use a simple point-of-use filter.

Starch Is the Problem

Starch is rapidly converted into blood glucose and that spike in blood sugar causes major problems. The foundation of the old food pyramid, grains, is no different than table sugar in being hyperglycemic, i.e. rapidly raising blood sugar. A large muscle mass and high physical activity can minimize the rise in blood sugar, by using up the sugar for muscle energy as it enters the blood. Unfortunately, most people do not have enough muscle and are not physically active enough to be protected from the starch and sugars in their diets. The result is chronic inflammation in the form of metabolic syndrome and degenerative diseases, e.g. diabetes, allergies, depression, acne, infertility, cardiovascular disease, autoimmune diseases and cancers.

One slice of white bread with a meal may be too much starch for some people. The maximum for most people is: one half of a ripe banana or one half cup of a starchy entree such as pasta, potato, rice, or one of the two buns on a burger. The starch needs to be spread over several meals. Eating too much starch with a meal produces intense hunger, as the blood sugar rapidly rises, triggers insulin release and a subsequent crash in blood sugar. Don’t believe any of the diets that recommend starches to replace fats. Many “lite” diet foods are more unhealthy than the higher fat originals that they replace. Replacing saturated fats with saturated starch is dangerous. The temporary high blood sugar level produces the increased health risks routinely associated with diabetes.

Insufficient Food Is the Problem -- Insufficient Minerals

It takes only 2-3000 Calories per day to energize most people. That means that most people can eat their day’s worth of calories with the sandwich plate at a fast food restaurant. That meal will provide an overdose of starch and sugar, but will be deficient in vitamins and minerals. A major dilemma is that it takes so little food to provide adequate energy for a low activity lifestyle, that the choice must be made between obesity and vitamin/mineral deficiencies. Eating just enough to satisfy energy needs results in deficiencies, but eating more to avoid vitamin/mineral deficiencies, results in obesity. The only solutions are to eat supplements to supply needed vitamins, minerals, antioxidants, etc. or increase physical activity and body muscle mass, so that more can be eaten without producing obesity. For most people the solution is a combination of increased physical activity and supplements. That combination is also found to reduce inflammation and the associated risk of degenerative diseases.

It’s the Stupid Diet

The obsession of medicine with drugs and invasive procedures provides additional health risks for patients. Many researchers complain in the biomedical literature that there is insufficient focus on the cause of disease and too much emphasis on the study of the impact of specific drugs on disease symptoms. The result is that in most cases the symptoms are treated and the disease becomes chronic. Of course this also means that the patient is a permanent consumer of health care.

The foundation of all healthcare should be to improve the lifestyle of the patient. Diseases don’t just happen. The biggest contributions of immediate family to disease of an individual are not defective genes, but rather defective diet and lifestyle habits. Our healthcare system is too no fault. People are sick because there is something wrong with how they live. They eat too much or they eat the wrong foods. They don’t get enough exercise to develop a healthy muscle system to support their joints. Most importantly, bad diet and lifestyle choices produce chronic inflammation. Drugs can reduce chronic inflammation, but will also produce additional side effects that will also require interventions. It makes more sense to attack the original causes of inflammation.

Every treatment program should address the pervasive contribution of chronic inflammation by including a diet and lifestyle inventory and an assessment of the cause of the disease that is being treated. An appropriate anti-inflammatory diet and a path toward a more active lifestyle should be the foundation of every treatment plan.

I Don’t Believe It ...

There are too many myths in biomedical science. I think that our fears are misplaced and if we just address the real threats, e.g. inflammatory vegetable oils, we can enter the New Year with realistic hopes for good health.

Don’t Worry about Genetic Predispositions to Disease

Mendel was wrong in asserting that there is one gene for each phenotype. Modern clearinghouses of genes reveal the relationships between gene sequences and numerous protein functions. In the Human Protein Reference Database (HPRD), for example, each human gene is listed with all of its synonyms. The synonyms frequently reveal that genes lead multiple, unrelated lives and have sundry tangled relationships with dozens of other proteins. So the idea that there is one gene for each physical trait, phenotype, is a misleading simplification.

The good news is that the complexity would only be a problem, if our individual genetic composition was important to our health. In most cases, I think that our individual genetic predispositions to disease would only be important, if we stress our bodies (usually with an inflammatory diet) to the point of failure. With a healthy diet and lifestyle, I don’t think that most genetic predispositions to disease would ever affect health. To be specific, most people should be able to live until 80 with few physical compromises. This is very hopeful.

Don’t Worry about Drug Side-Effects (avoid the need for drugs)

Drugs have many side effects, simply because we don’t know enough about the interactions of small drug molecules with all of the possible protein targets. Take heparin, for example. Heparin is one of the most commonly used drugs to inhibit blood clotting. There is a clotting assay to measure how well heparin blocks clotting and injecting more heparin makes clotting slower. It appears that heparin binds to a protein involved in clotting. Heparin does bind to anti-thrombin, which in turn inhibits thrombin that is needed for clotting. Heparin also binds to several other proteins required for clotting and also binds to a dozen proteins involved in the complement system needed to kill pathogens or infected cells. Heparin binds to hormones, growth factors and their cell surface receptors. There are hundreds of proteins that use heparin to facilitate attachment to other proteins, to change shape and activity or to enter or leave cells. The point here is that heparin is a vivid example of a drug used to treat blood clotting, while at the same time dozens of other major interactions are ignored.

All drugs have multiple interactions with myriad proteins, but during screening, a drug is identified as having a significant desired affect. All drugs have side effects, because they are not completely specific. The side effects are often exploited as off-label uses for the drugs. Statins, for example, can impact lipid metabolism and change LDL blood levels. Unfortunately, research shows that lowering LDL does not affect heart disease. Fortunately, statins also lower inflammation and inflammation causes heart disease, so statins can be used as very expensive anti-inflammatory drugs.

The hopeful side is that most drugs are not necessary and there are other approaches that are more effective and cheaper to prevent and treat disease.

Don’t Worry about Your Gut Flora

There is a major NIH initiative to identify all of the bacterial species that live in or on the human body. That sounds potentially very useful in the context of all of the hype about pre- and probiotics. Your gut flora are important and people are doing very dumb things by killing off the bacteria that protect their skin from pathogens. The problem is that the concept of species of bacteria is wrong. In your gut, there is so much transfer of DNA between all of the different types of bacteria, that the idea of bacterial species doesn’t work.

Consider the pathogenic, toxin-producing E. coli strain. E. coli gets a bum rap, because we have created a new bacterium by treating cattle with antibiotics. The antibiotics increase fat accumulating in the beef, by altering the gut flora. The antibiotics eliminate some bacteria that normally live by adhering to the rectal areas of the cattle. E. coli can colonize the vacancies, but only if the gut lining releases nutrients and the E. coli is resistant to the antibiotics. The solution comes in the form of a plasmid from another bacterium. The plasmid is a small segment of DNA that carries genes for resistance to several different antibiotics and a toxin that causes intestinal cells to leak. The cattle don’t care much about the new Frankenstein E. coli, but if that plasmid-toting E. coli goes from cowpie to hamburger, and replaces your natural E. coli, it can be deadly.

The point is that the bacteria needed to fill all of the niches in your gut environment are created by approximation from the myriad genes of your whole gut flora community. You are constantly creating new “species” of bacteria. The problem is that you produce your own gut flora based on what you eat and by interactions with your gut. Those interactions can make you healthy or keep you sick. A single bottle of formula, for example, can permanently compromise the gut flora of a breastfed baby. We are learning how to control the development of healthy gut flora, probiotics, by supplements containing particular polysaccharides and oligosaccharides, i.e. prebiotics.

The hopeful side is that diets that have been shown to be healthy also produce healthy gut flora. That isn’t much of a surprise.

Don’t Worry about Toxins

The world is a dangerous place, but people have been there and done that. Plants have been standing around synthesizing a witch’s brew of natural toxins for millions of years. They are so good at it that even the most highly evolved species, bacteria, can’t eat them and survive. You can find a plant toxin that will interact with every human protein. That is why most human drugs are derived from plant toxins.

We know not to eat green potatoes, but pregnant women who make the mistake of eating rotten potatoes will regret the birth defects in their babies. There are so many toxins in plants that we have to be careful to watch what toddlers put in their mouths and every poison control center has to be able to identify plants over the phone to recommend emergency treatment. Pregnant women have a built in system to avoid plant toxins during the embryo’s most vulnerable first trimester. It is called morning sickness. A healthy diet during this time is to avoid vegetables and stick to meat and starch. Women build up baby fat to get through this sensitive time without exposure to plant toxins that their bodies may not be able to detoxify.

The happy thought here is that environmental toxins of human origin are not what make us sick, any more than eating plants generally is not a problem. With a healthy diet, even one modestly contaminated, we will not get sick. With a diet that compromises our health, even natural toxins become a threat.

Don’t Worry about Environmental Estrogens (except to save the rest of the animals)

There is an abundance of synthetic molecules that mimic human sex hormones, but once again, plants have been producing estrogen mimetics for millions of years. The second most abundant biological polymer (macromolecule), after cellulose, is lignin. Lignin is what makes up a large part of plant tissue and is what permits plants to be stiff. Lignin is also the “organic” material in fertile soil. This polymer is black in soil, because it is so complex that it has molecular structural components that can absorb all wavelengths of light. Lignin has no defined structure, but rather it is essentially a combination of thousands of structures.

Now imagine the mucky, black, lignin-laden banks of a forest stream. Tons of complex organic molecules leach into the stream and many of those molecules can mimic the shape of estrogens and bind to human molecules, receptors, that would normally bind to estrogen. It is possible to have excess estrogen leach from a sewage treatment plant, because it is not specifically targeted for removal, and the estrogens could temporarily reach a level to affect sensitive aquatic species, but there are already so many natural sources of estrogenic compounds, that the impact on humans would be expected to be unmeasurably small.

It is certainly possible for humans to pollute streams with other molecules, antimicrobial toothpaste ingredients, for example, that have unusually high environmental stability and bind with unnatural strength to estrogen receptors. Those would be problems like DDT. It would make sense to avoid exotic compounds and use natural plant products where possible, just because biological systems can digest them more readily.

The hopeful perspective here is that we already have ways of avoiding most of the problems with manmade estrogens and although these may be environmental hazards, they probably won’t affect human fertility.

An Anti-Inflammatory Diet and Lifestyle Is the Simple Solution

Prevention is the easiest way to stay healthy and since chronic inflammation is the foundation of degenerative, autoimmune and cancer diseases, an anti-inflammatory diet and lifestyle avoids most of the diseases. These same diseases also provide a modern description of aging, i.e. the consequences of mismanaged chronic inflammation. A healthy body is also the best protection from environmental threats, genetic weaknesses and the dangers of modern medicine.

The hopeful perspective for the New Year is eating and living well can keep you healthy and physically fit into your eighth decade.

Diabetic Hypertension, Browning of the Arteries

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I decorated a flan with a drizzle of honey, and my torch produced a toasted spiral.  That was just fructose plus proteins, with a little heat, to produce advanced glycation end products (AGE) that are brown.  If you prefer, you can do the same reaction with egg whites and sugar in meringues, or by grilling brined pork chops basted with honey and anchovy paste.  Fructose is 10X better than other sugars at producing glycation, AGE and browning.

AGE and Arteries

Why do we care about the Maillard reaction and advanced glycation end products (AGEs)?  Of course, understanding the biochemistry of cooking is inherently satisfying and it helps to explain why Dr. House used vinegar to stop meatballs from browning too fast in his cooking class, but it also explains what’s cooking in atherosclerosis, cardiovascular disease.  It turns out that AGEs are highly inflammatory and inflammation of arteries leads to plaque formation.  [LDL is less important, because it only aggravates the primary event, inflammation, and that is why fish oil is more helpful for cardiovascular disease than statins.]  So increasing blood sugar is a problem, because it increases the rate of the Maillard reaction in binding blood sugar to the amino acids of proteins, such as hemoglobin to produce HgA1C, and causing vessel inflammation.  AGE in small capillaries also kills the capillaries and causes a rise in blood pressure by making harder for the heart to force blood from arteries to veins.  AGE causes hypertension and that is why salt consumption is not as important.   High blood sugar also increases the level of another powerful glycation agent, methylglyoxal, the active antibacterial agent in Manuka honey.  Honey is effective as a wound dressing, because it AGEs microbes to death!

The Trouble with AGE-ing is Inflammation

Cells detect the presence of AGEs with a surface Receptor for AGE (RAGE).  Binding of AGE to RAGE turns on the inflammation transcription factor, NFkB, with the release of inflammatory cytokines and the symptoms of inflammation.  One of my students did some computational protein modeling of the RAGE, because I was interested to see if RAGE would also bind Metformin.  Sure enough, our hunch was confirmed, indicating that Metformin might also reduce some forms of inflammation and be a treatment for diabetic high blood pressure.

Fructose vs. Inulin; AGE vs. Soluble Fiber

Fructose and the storage polymer of fructose, inulin, are similar to glucose and the storage polymer of glucose, starch.  The polysaccharides, inulin and starch can be converted to the sugars, fructose or glucose by industrial heating or enzymes.  Thus, agave inulin is converted into nectar, and corn starch is converted into syrup.  The polysaccharides are not sweet, but the sugars are.  The polysaccharides don't form AGEs with amino acids (unless they are broken up by high heat into sugars first) and fructose is 10X more chemically aggressive in forming AGEs than glucose.  Agave nectar (fructose) is a better browner than honey or high fructose corn syrup (corn syrup treated with a commercial enzyme to convert some of the glucose into sweeter fructose.)  Both inulin and some forms of starch (resistant starch), reach the colon and are digested by gut flora, i.e. they are soluble (fermentable) fiber.  The gut flora convert the resistant starch into short chain fatty acids that are anti-inflammatory.  Typical starch, e.g. corn starch or wheat flour, is digested by gut enzymes and goes directly into the blood as glucose, it is high glycemic and never reaches the gut flora.

AGE in Food

Should we fear browned foods as inflammatory.  I don't think that AGE in foods is any more of a hazard than all of the toxic phytochemicals that are touted as plant antioxidants.  I think that the gut and liver provide protection.  I brown the sugar on my flans and sear my steaks, even as I relish eating my veggies.  The body can detox these natural products in the gut better than it can handle the AGE made by high blood sugars.

Take Home Messages:

• Sugars in baked goods or blood, react with amino acids or proteins to make inflammatory AGEs.
• Blood sugar tests only measure glucose and ignore fructose, which is even more unhealthy.  So, foods laced with fructose can be low glycemic, but very unhealthy.
• The major AGE in blood is HgA1C.
• Diabetics have more stable, lower blood sugar on low carb diets, e.g. my Anti-Inflammatory Diet.  The liver produces needed blood sugar from protein.
• Diabetic use of fructose or agave nectar or honey encourages AGE, inflammation and diseases of diabetes.
• Starch (not RS) is the only polysaccharide digested by gut enzymes and is high glycemic.
• AGE is inflammatory leading to artery plaque and hypertension.
• AGE as browned foods are probably tolerated by the body.

Rosacea, Brain Cooling and Niacin Flush

Other players include:  Cathelicidins, Prostaglandins, Cryptic Bacteria, Nerves, Gut

What does it take to make your face red?  Excessive solar exposure can lead to apoptosis of skin cells overloaded with DNA damage and trigger inflammation: vasodilation, recruitment of neutrophils, swelling, etc.  Similarly, a local infection can cause inflammation and the accumulation of neutrophils (see The Inner Life/Extravasation for slide show), lymphocytes, etc., that is observed as pus.  These are general responses that occur in skin anywhere, but the face also blushes in response to emotional cues and flushes with exercise.  Rosacea seems to involve all of these reactions to produce a variety of symptoms of wide severity.  Here I try to provide an overview of the complex physiological interactions involved in rosacea.

Rosacea is Persistent Vasodilation of the Face with Accumulation of Neutrophils

The nervous and circulatory systems of the face are unique and provide numerous triggers for inflammation.  Emotional blushing is a common trait among those who progress to rosacea, even though this type of vasodilation is not easily observed with some facial characteristics.  Thus, many rosaceans claim to have never flushed before their first outbreak, but tests of skin circulation indicate that these individuals had skin types that prohibited display of the blushing.  The face is also adapted to control brain temperature, so changes in body temperature, physical activity, etc. can also trigger flushing.

Facial Blood Circulation to Cool the Brain

The cooling of the blood as it traverses the facial skin is used to cool the brain during extensive exercise or in warm environments.  This unique adaptation also means that control of facial vasodilation can potentially be disrupted in disease and cause symptoms of pathology.  In rosacea,  the brain cooling response is disturbed (see reference below), resulting in persistent vasodilation and suggesting that the unique control of inflammation in the face is why rosacea is limited to the face.  The pattern of blood circulation in the face, however, only roughly approximates the inflammation pattern in rosacea.

Nerves to the Face

The face receives sensory branching from the trigeminal nerve.  The enervation pattern of the branches matches emotional blushing, but they also appear to approximate the pattern of reddening in rosacea.  It makes sense that rosacea involves nerve-triggered dilation of the blood vessels of the face.  One contrast between emotional blushing and rosacea is that emotional blushing does not lead to the offloading of lymphocytes, whereas rosacea produces localization of neutrophils that exacerbate and prolong inflammation.

Cathelicidin, Vitamin D Receptor, DNA Complexes, Autoinflammation

A major component of the innate immune system is the group of basic antimicrobial peptides, cathelicidins.  Cathelicidins are effective against bacteria and they are produced during inflammation and are partially controlled by the vitamin D receptor acting as a transcription factor.  Thus, part of the action of vitamin D in providing protection against disease is by enhancing cathelicidin production.  Cathelicidin action in the skin parallels the control of intestinal villi development by defensins, that are also basic antimicrobial peptides under the control of vitamin D.  Cathelicidins also form complexes with host DNA from damaged cells.  These cathelicin/DNA complexes bind to toll-like receptors (TLRs) and trigger inflammation.  This reaction has been associated with psoriasis and may explain how neutrophil damage can perpetuate inflammation in rosacea.

Niacin Flushing Implicates Arrestins

The unique circulatory system of the face also makes it susceptible to flushing with niacin, a.k.a. nicotinic acid or vitamin B3.  Niacin is cheaper and much more effective at raising HDL and lowering triglycerides and LDL than statins, but is not fully utilized because it also produces intense facial flushes.  A recent article (below) has demonstrated that the lipid benefits can be separated from the flushing and implicated beta-arrestin 1 activation by niacin binding to GPR109A (G-protein-coupled receptor) as the triggering event.  Arrestin, which is involved in clathrin-mediated endocytosis, activates phospholipase A2 that in turn releases arachidonic acid (ARA) from phospholipids.  The ARA (that got into the phospholipids as the omega-6 fatty acid in vegetable oils) is converted by COX-2 into the inflammatory prostaglandin D2.  This prostaglandin is what stimulates vasodilation.  It is possible to produce chemicals that will stimulate the lipid metabolism alterations of niacin, without producing the arrestin activation and inflammation.  Aspirin can be used to inhibit COX-2 and other parts of NFkB-mediated inflammation and eliminate the niacin flush.  It is also interesting that the modified lipid metabolism of schizophrenics also eliminates niacin flushing.  Salicylic acid, the same as the acetylsalicylic acid of Aspirin without the acetate, is also used in some topical applications to quiet the symptoms of rosacea.  Arrestin activation may be involved in rosacea.

Gut Flora, Biofilms and Cryptic Bacteria

The gut is probably involved in most cases of rosacea and bacteria are also implicated by the modification of rosacea symptoms by antibiotics.  This area has not been explored, but I suspect that gut flora controlled by diet, as well as pathogenic biofilms and cryptic bacteria, e.g. Clamydia pneumoneae, in facial tissue are involved in varying degrees in the panoply of pathologies called collectively, rosacea.  Since the bacteria in contact with the gut determine the development of the lymphocytes in the lining of the gut, e.g. Tregs vs. T cells that fight infections, pathogenic gut biofilms may disrupt the normal function of the immune system and support rosacea.  Die off and release of cell wall endotoxin from cryptic bacteria could explain the paradoxical inflammation in response to many treatments that are normally anti-inflammatory.  I have discussed in another article potential approaches to strip off biofilms.

Treatment with Anti-Inflammatory Diet

The Anti-Inflammatory Diet (AID) and Lifestyle that I advocate on this blog would seem to be a natural cure for rosacea.  It should eliminate the inflammatory background that supports rosacea and was probably essential for its development.  This diet also eliminates acne, which is directly related to the accumulation of lymphocytes to make pus.  Inflammation is also needed for the offloading of neutrophils that exacerbate inflammation in rosacea.  Vitamin D is instrumental in cathelicidin production to eliminate cryptic bacteria. 

In most cases of rosacea, the AID should be helpful.  Eliminating dietary sources of inflammation, especially vegetable oils (the source of omega-6 fatty acids that are converted into inflammatory prostaglandins), should reduce rosacea symptoms.

In advanced, severe cases, however, it appears that maintenance of the suppression of the response to cryptic bacteria is required to prevent endotoxin-based inflammation.  Thus, most treatments that decrease inflammation, e.g. omega-3 oils, vitamin D3, Vagal maneuvers, can paradoxically produce elevated inflammation.  These treatments may also inadvertantly contribute to inflammation by upsetting pathogenic interactions between bacteria and intestinal cells.  I have discussed these paradoxical ramifications in another article.

references:
Brinnel H, Friedel J, Caputa M, Cabanac M, Grosshans E.  1989.  Rosacea: disturbed defense against brain overheating.  Arch Dermatol Res. 281(1):66-72.
Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ.  2009.  Beta-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice.  J Clin Invest. 119(5):1312-21.

Anti-inflammatory, Gluten-Free Diet for Celiac

Low Grain Is Good for Everyone

I don’t think that I have an intolerance for grain, i.e. a gluten sensitivity, but it is so common and the biochemistry is so obvious, that it is only prudent to avoid wheat and related grain products. A low or gluten-free diet is also similar to the other common healthy diets, e.g. low carb and anti-inflammatory.

Gluten-free diets came to my attention recently in two ways. First, I saw Food, Inc., a documentary movie about abuses by multinational food processors. After that movie, I felt like I was a goose being readied for foie gras. Second, was a newspaper article on the expense of a gluten-free diet and the challenges of avoiding gluten.

I haven’t had to worry about wheat contaminating my diet, but I am sympathetic to the celiacs that I know who have to labor with a sloppy and exploitative food industry that uses the cheapest ingredients to compose the processed foods that are consumed in modern diets -- processed foods are complex blends of many different potential allergens from innumerable sources throughout the world.

A Celiac Diet Is Good for All
Fortunately, the answer to pervasive gluten is just a modest modification of the basic anti-inflammatory diet that I recommend on this blog. Unfortunately, people who have already developed gluten intolerance, have probably had the problem for years before diagnosis and that means that their intestines have already suffered major physiological alterations and they have problems absorbing nutrients and vitamins. Celiacs also, because of their chronic inflammation and autoimmunity, tend to readily develop food allergies and other autoimmune diseases. The recommended anti-inflammatory diet will help to avoid celiac, put celiacs into remission and avoid development of subsequent allergies and autoimmune diseases.

Vitamin D Is Usually Deficient (and a source of inflammation)
The basic anti-inflammatory diet starts with a return to optimal vitamin D with the use of an initial blood test, followed by high level supplements to reach a suitable level and then maintenance with D3 supplements of usually 2,000-5,000 IU per day. Depending on the D3 supplement, vitamin A will also need to be supplemented, because it interacts with vitamin D. Remember that sunshine is only effective in producing adequate vitamin D if you do not suffer from chronic inflammation. I would assume that all celiacs tend to be vitamin D deficient.

A Low Carb Diet Is Easier for Celiacs
The next component of the basic diet is low carbohydrates, that means a minimum of high glycemic foods, which means to avoid sugar and starch, do not cook vegetables more than necessary and don’t over-chew your veggies. This is good for celiacs, because it reduces the need for common grain foods that no one should eat: bread, cereal, pasta, etc. Everyone should lower their consumption of these wheat products in solidarity for celiacs and for general good health. Cereal is a very bad idea for children!

Most Vegetable Oils Are Unhealthy
Most vegetable oils contribute substantially to world-wide inflammation and celiacs don’t need the added burden of inflammatory omega-6 vegetable oils. Only olive oil and butter should be used. Saturated fats are safer than typical polyunsaturated vegetable oils.

Eat Wild Fish or Tons of Fresh Flax
Most people eat too little omega-3 long chain fatty acids, since these are most abundant in fatty fish, such as wild salmon (farmed fish are fed corn and have reduced omega-3 and increased omega-6 fats.) Few vegetable sources are available, since the omega-3 fatty acids are unstable and present in leaves rather than seeds. Flax seeds have short chain omega-3 fatty acids and must be freshly ground and consumed by the cupful, because the conversion to the long chains, in which they are useful, is very inefficient. Most celiacs will need to use fish oil (or krill oil, if fish is not tolerated) supplements (4-8 EPA/DHA capsule per day taken in a meal rich in fats for bile uptake) to balance the ubiquitous inflammatory omega-6 in their diets.

Grassfed Meat/Eggs Are Your Friends
Celiacs should seek out grass/pasture fed meats, eggs and wild caught fish. Corn-fed animals have higher levels of omega-6 fats and these contribute to dietary inflammation. Celiacs can usually eat meat and fish and these are very healthy foods. Red meat was not shown to contribute to degenerative diseases, it was the high carbs eaten with the meat that produced the inflammation that contributed to heart disease. (Remember that statins only decrease cardiovascular disease because they inadvertently lower inflammation, not because they lower serum lipids, LDL.)

No, No’s: HFCS and trans fats
High fructose corn syrup and trans fats are inflammatory and unhealthy for anyone, and should be avoided as much as wheat gluten. Fruits should be eaten as seasoning, since their fructose is not healthy and they also contain ample sucrose.

Most People Would Be Healthier on a Celiac Diet
The anti-inflammatory diet proposed here for celiacs should be uniformly healthy, since it provides optimal vitamins (D, C, B12, etc.), low starch/sugar/carbs, an optimal omega-3 to -6 fatty acid ratio, increased meat and saturated fats, and avoids HFCS and trans fats. The only major adjustment for celiacs would be avoidance of individual food allergens, more attention to vitamin supplements to compensate for poor absorption and replacement of wheat by rice, potatoes, etc. The low carbohydrate nature of the diet makes it more approachable, since typical carbs, such as bread and cereal are avoided and replaced with meat and vegetables.

I look forward to advice and suggestions from readers who have experience with gluten-free diets.

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

More Inconvenient Truths

I am writing this shouting summary of bottom lines in response to recent good news and bad news. The good news is that Michael Pollan is speaking in Boise, near my home town. The bad news is the recent press coverage of the JUPITER study on statins.

Michael Pollan is one of my heros. He speaks simply and clearly about the role of national agriculture policy in promotion of hazardous foods that lead to profits in the healthcare industry, but death and disease for the US population. Pollan also provides wise advice to solve our problems.

A new statin, Crestor, was shown in the JUPITER study to significantly reduce the risk of cardiovascular events, e.g. heart attacks, stroke, death, in a study population with normal LDL and elevated C-reactive protein, an indicator of inflammation. The press supported the drug maker’s interpretation that the statin provided benefit by lowering LDL in a population with chronic inflammation. What is missing is the clarification that lowering LDL is unimportant in reducing cardiovascular risk. Lowering inflammation lowers cardiovascular risk and there are more appropriate ways of lowering inflammation than using very expensive drugs. It is much cheaper, healthier and effective to switch to an anti-inflammatory diet and lifestyle!

After reading thousands of articles in the biomedical research literature, here are a few of my obvious bottom lines. Diet affects your health and the most fragile stages of development and most fragile organs, are the most sensitive to abuse. Therefore, damaging diets are most harmful to fetuses, newborns, brains, the cardiovascular system and reproductive systems.

• Formula promotes inflammatory bacteria in newborn guts resulting in lower intelligence, disrupted immunity, infections, allergies, obesity, degenerative diseases and autoimmune diseases. Breastfeeding is the only anti-inflammatory answer for infants.
• The US diet (hyperglycemic starch/sugar, high omega-6 to omega-3 fatty acid ratio, HFCS, low vegetable anti-oxidants, low vitamin D/sun exposure, low vitamin C, grain-fed meat instead of fish) is inflammatory.
• The Mediterranean Diet (small portions of starch, low omega-6 oils, no HFCS, high vegetable anti-oxidants, routine sun exposure, adequate vitamin C, fish and grass-fed meat) is anti-inflammatory.
• Inflammatory diets lead to infertility (female and male), problems during pregnancy (e.g. preeclampsia is an omega-3 fatty acid deficiency) and prematurity/low birth weight.
• Mental illnesses of many different types benefit from anti-inflammatory diet and lifestyle. Diet-based brain inflammation may be a major predisposing factor.
• All of the prevailing drug therapies for cardiovascular disease benefit from anti-inflammatory diet and lifestyle. Most of the drugs that reduce cardiovascular events rely on anti-inflammatory activities. Inflammation is the primary cause of cardiovascular disease, not elevated blood lipids/cholesterol.
• Vegetable oils (corn, soy, cottonseed, safflower) are rich in omega-6 fatty acids and are dangerously inflammatory. These polyunsaturated oils are less healthy than saturated fats. Olive oil is the most healthy.
• Reasonable routine exposure to the sun could eliminate inflammatory vitamin D deficiencies.
• Obesity is inflammatory, but diet-based inflammation may also be a major contributor to obesity.
• Genetic predisposition to specific diseases is triggered by diet-based chronic inflammation.
• Diseases and disabilities associated with aging are symptoms of mismanaged chronic inflammation typically resulting from decreasing muscle mass and increasing fat.
• Sensible diet and lifestyles could dramatically improve quality of life and reduce healthcare expenditures in the US.

Prescription: eliminate vegetable oils, eliminate HFCS, eliminate trans fats, use olive oil, reduce starch, eat vegetables, eat more fish and less meat, get daily sun, use fish oil supplements, get frequent muscle-building exercise, and stay lean.

Common Medicines Make Superbugs, Not Prescription Antibiotics

--- The other 200 posts ---

Careless prescriptions and cattle fattening antibiotics are blamed for the rise of superbugs resistant to everything in the hospital arsenal, but that’s all wrong.  Antibiotics fail, because we are all abusing common medicines that also have powerful antibiotic activity.  All painkillers, anti-inflammatories, statins, antidepressants, and the whole list of common pharmaceuticals are the problem.  We simply use too many drugs.

Common drugs should also be labeled as antibiotics, because they kill the sensitive bacteria in your gut and leave behind just the resistant bacteria.  Unfortunately, the genetic mutations that make your gut bacteria resistant to drugs, also provide resistance to antibiotics needed to stop infections and that broad resistance to antibiotics can spread to pathogens that then become the dreaded superbugs.

Here are the simple facts that I have discussed at length in another post:

• Statins were antibiotics that were repurposed to lower LDL, “bad cholesterol.”

• Aspirin was an antibiotic that was shown to relieve pain and inflammation.

• Metformin was an antibiotic that later proved useful for treatment of diabetes.

• Many chemotherapy drugs are antibiotics developed for cancer treatment.

• Diuretics were antibiotics that indirectly reduce blood pressure.

• Antidepressants, such as Prozac, Zoloft, etc. are antibiotics.

Common Drugs Are Actually Antibiotics

Most pharmaceuticals are derived from phytochemicals, a.k.a antioxidants, adapted in plants to kill microorganisms, i.e. as natural antibiotics.  It is not surprising that drugs = antibiotics.  What is surprising is that people assume that if antibiotics are labeled with some other activity, that they cease to be antibiotics.  All drugs are also antibiotics and that is why a major side effect of most medicines is upset gut bacteria.

Overuse of Common Drugs Produces Superbugs

Simply put, common medicines you swallow, kill bacteria in your bowels.  Some bacteria survive and are called “drug resistant.”  Bacteria accumulate resistances to several different kinds of drugs and are called “multidrug resistant.”  As might be expected, hospitals are the breeding grounds for multidrug resistant, mutant bacteria of all different types.  Unfortunately, anyone who takes several types of medications is also a source for multidrug resistant bacteria, so nursing homes are the most frequent sources of superbugs that cause outbreaks of hospital infections.

The Only Way to Stop Superbugs is to Use Less Drugs

The bottom line is that even if doctors start to use antibiotics more rationally and antibiotic use in agriculture is eliminated, superbugs will still be a big problem, because they will be produced by excessive use of common drugs, i.e. those found on the shelves of drug stores and supermarkets, as well as prescribed by doctors.  

The only solution to the superbug problem is to reduce pharmaceutical use by 99%.