- Lactation/breastfeeding lowers risk of breast cancer (improves path of normal mammary duct micro biome from nipple.)
- Tubal ligation lowers risk of ovarian cancer (eliminates path for bacteria from vagina.)
- Aspirin reduces pancreatic cancer (by reducing inflammation involved in the transition from bacterial infection to cancer.)
- Pancreatic and breast cancer risks are both dramatically increased by BRCA (tumor suppressor genes involved in 5% of breast cancer.)
- Bacteria are transported from gut to blood to breast to milk to infants. (Google entero-mammary bacterial circulation involving intestinal M cells and dendrocytes.)
Friday, July 18, 2014
—-The other 200 posts—-
The readers of this blog are probably aware of my interest in the causes and related cures of diseases. Juxtaposition of recent research findings has made me reconsider the role of bacteria in breast cancer.
Bacteria Have Access to Organs with Common Cancers
Serum or fluid flows from organs outward; liver to gall bladder to intestines, pancreas to intestines, prostate to urethra, ovary to fallopian tube to uterus to vagina. In each case there is also an related infection and inflammation associated with the backward path to the organ. Urinary tract infections can lead to prostatitis. Vaginitis can lead to pelvic inflammation, gastritis to stomach cancer, and intestinal infection/inflammation can result in pancreatitis. The theme seems to be that bacterial infections can cause inflammation that leads to cancer.
Bacterial Path to the Breast
Lactating women occasionally have bacteria that migrate back up milk ducts to cause mastitis, but this is not quite parallel to my other examples of bacterial movement, because women are not continually producing milk. There is, however, another path of bacteria to mammary tissue. Prior to birth, bacteria move from the maternal gut, through the blood (presumably in lymphocytes) and into mammary tissue. Subsequent nursing transports the bacteria to the infant to initiate the milk controlled gut flora unique to exclusively breastfed infants.
Monthly Transport of Bacteria to Breast
The menstrual cycle is an abbreviated ovulation, conception, gestation and birth, which suggests that just as in the normal prelude to lactation, there may also be monthly transport of gut bacteria to mammary tissue. These bacteria may also cause infection and inflammation, though they may not be sufficient to cause more than transient breast tenderness.
Healthy Gut Flora Means Healthy Breasts
I expect that many diseases in infants may be associated with the wrong bacteria being transported from maternal gut to breast to infant. Clearly, if the mother suffers from dysbiosis, which is very common, it may be difficult for the correct Lactobacilli and Bifidobacteria to be transported to mammary tissue. Transport of other bacteria may cause problems. Those problems may be severe as a consequence of menstrual cycles that don’t end in pregnancy, but rather end in infection, inflammation and breast cancer. It may all come down to gut flora. The difference between women who develop breast cancer and those that remain healthy may be the health of their gut flora. Breastfeeding, of course, reduces the risk of breast cancer, as well as improving infant gut flora. Formula is always a risk factor for infant health, because it attacks normal infant gut flora and promotes inflammation. Since many breast cancers naturally resolve, it may also be the case that a healthy immune system can reverse breast cancer and the health of the immune system is determined by the gut flora.
Tuesday, July 15, 2014
The health of your gut flora (the interacting trillions of bacteria of a couple of hundred different species that make up the pound of bacteria that you carry primarily in your large intestines) is more important than your genetics to your overall health. Thus, your health is a result of diet, gut flora adapted to your diet and exercise. Everything else, your genetic risks, environmental toxins, etc. are of only minor impact.
I am trying to paint the big picture of how the food that you eat and your gut flora interact to determine your health, by which I mean whether you get sick, become obese and/or bloat with gas.
Health Depends on Gut Flora
If you are healthy, you have a couple of hundred different species of bacteria that help you to digest the protein, fats and carbs that you eat in meat and vegetables. Your body easily digests protein and fats in meat, fish, eggs and dairy, because enzymes to digest them are present in your stomach and small intestines. The only carbs that your body can digest are some simple sugars and starch. The rest of the polysaccharides present in plants cannot be digested without the help of bacteria. The polysaccharides that your gut flora can digest are fermentable, soluble fiber, e.g. resistant starch, pectin, inulin, arabinogalactan, xylans, beta-glucan, etc. If you can’t digest soluble fiber, because you have damaged gut flora, dysbiosis, and are missing essential bacterial species normally found in a healthy gut, then the soluble fiber just passes through as insoluble fiber and readily dehydrates into hard, constipated stools. Partial digestion due to just a few missing bacterial species produces the symptoms of food intolerances.
Constipation Results from Dysbiosis
The bottom line is that the volume of healthy, soft, firm stools is made up of gut flora that digested dietary soluble fiber and converted it into more bacteria. If you eat more soluble fiber, this food for your gut flora, will produce proportionately more bowel movements.
Gut Flora Guide Immune System Development
Most of cells of your immune system are in the lining of your gut and there are particular species of gut bacteria directly involved in the development of immune cells that have different functions as they spread throughout your body. Some of these cells are aggressive and attack pathogens, while others make sure that the aggression doesn’t get out of control and cause autoimmune diseases or allergies.
Gut Flora Divided into Groups to Show Involvement in Disease
Recent studies have demonstrated the role of gut bacteria in producing nutrients, vitamins and neurotransmitters. To highlight the essential role of gut flora in disease, I have divided the hundreds of species of gut bacteria into groups to illustrate their direct involvement in development of the immune system and regulation of the flow of dietary nutrients involved in obesity. A recent study shows that an infection can produce a change in gut flora associated with marshaling additional fatty acid nutrients for the host instead of just producing more gut flora. Chronic change of gut flora in this way leads to obesity. Other types of dysbiosis contribute to infections, cancer, autoimmune disease, allergies, food intolerances, gas and bloating.
Group A Bacteria Provide Aggressive Immunity
There are several dozen species of bacteria in healthy gut flora, including the filamentous bacteria, that trigger the development of the aggressive part of your immune system that attacks pathogens, and kills cells of your body that are infected with viruses or are cancerous. Most antibiotics don’t permanently damage this group of bacteria, so after a course of antibiotics you can usually still stop infections. Excessive suppression of aggressive immunity contributes to cancer.
Group B Bacteria Provide Suppressive Immunity
There are dozens of other species of bacteria, including Clostridia, that control the development of the suppressive half of your immune system that produces immune cells, such as regulatory T cells, Tregs, that stop the aggressive cells of your immune system from attacking your own cells and innocuous things such as food and pollen. Many common antibiotics damage these species of bacteria and are thought to contribute to the development of autoimmune diseases and allergies. Inflammatory bowel disease is characterized by a simplified gut flora with only half the healthy number of bacterial species. Resistant starch preferentially feeds these bacteria to enhance suppressive immunity and in some individuals cure autoimmune disease.
Group C Bacteria Convert Soluble Fiber to Short Chain Fatty Acids (SCFA)
The fermentable soluble fiber in your diet is typically from vegetables and it is converted by the largest and most diverse group of bacterial species into short chain fatty acids. Each different plant polysaccharide, and there are hundreds, requires many enzymes for complete digestion to the simple molecules used by the bacteria to make its own proteins, fats and polysaccharides. Absence of bacteria that are specialized for the digestion of particular polysaccharides or other dietary components can disrupt gut flora and cause digestive disturbances that are experienced as food intolerances (also confused with food allergies that are rare.) Some of the bacterial species convert polysaccharides into butyric acid and other short chain fatty acids that are the major source of energy for cells that form the lining of the intestines. These SCFAs are also a major food source for other gut bacteria.
Group D Bacteria Convert SCFAs to Fecal Bacteria to Produce Bulk of Bowel Movements
In healthy people, the SCFAs produced by gut flora feed the intestines and the remainder produced in the large bowel is converted into more gut bacteria, which forms soft stools. Antibiotics typically damage these bacteria and result in constipation. These bacteria are typically more sensitive to antibiotics than those that digest the soluble fiber and produce SCFAs, so the excess SCFAs pass into the blood stream and contribute to obesity instead of stools. Lean mice with gut flora exchanged from obese mice, become obese. Cattle are fed antibiotics to enhance the conversion of corn polysaccharides into SCFAs and body fat prior to slaughter.
Group E Bacteria convert Soluble Fiber to Methane and Hydrogen, Bloat
Increased volume of the intestines, bloating, results from conversion of soluble fiber into methane, hydrogen and carbon dioxide gases. Some of this gas is absorbed into the blood and can pass from the large intestines, through the blood, and back to the stomach and small intestines. Helicobacter pylori, the cause of stomach ulcers and gastric cancer, can utilize hydrogen from the blood as an energy source.
A+B+C+D = healthy, normal weight
A+C+D = normal weight, autoimmunity and allergies
B+C+D = normal weight, susceptibility to cancer, chronic Lyme disease, food poisoning
A+B = normal weight, constipated
A+B+C = obese, constipated
A+B+D = normal weight, food intolerances
A+B+C+E = obese, constipated, bloated
Cure for Dysbiosis and Associated Diseases is Repair of Gut Flora
The excitement about the use of resistant starch (RS) and probiotics with Clostridia and other soil bacteria to reverse the symptoms of autoimmune diseases is based on the ability to repair gut flora damaged by poor nutrition and antibiotics. Low carbohydrate diets that do not provide soluble fiber to feed gut flora lead to dysbiosis and chronic diseases. Resistant starch, as the name suggests, passes on to the colon by avoiding digestion with amylases in the small intestines and acts as a soluble fiber to feed gut flora in the colon. Clostridia convert the RS to sugars and SCFAs usable by other gut flora. Note that some species of Clostridia produce toxins and it is these pathogens that take over in hospitals after the healthy species are killed off with antibiotics. Fecal transplants are the best treatment for these hospital acquired infections.
I have discussed the role of hygiene, muddy veggies, fermented foods, etc. in several other posts on repair of gut flora.
Complete repair of gut dysbiosis is possible, but it requires more than just changes in diet and dairy probiotics, as typically recommended erroneously by the medical industry.
Health is dependent on:
- an Anti-Inflammatory Diet,
- gut flora adapted to your diet
- exercise and
- adequate sleep
The rest (genetics, vegan vs. paleo, environmental toxins, organic veggies, GMOs, etc.) are minor contributors, less than 10% in aggregate, to overall health.
Friday, July 4, 2014
More healthcare begets more health costs and less health. Tests detect symptoms that trigger treatment, but more often than not fail to contribute to health. Apple’s newly announced HealthKit promises to facilitate increased surveillance of personal health statistics and to integrate the data with the health industry. If recent history is a guide, more data will simply mean more inappropriate interventions, greater expense and further deterioration of public health. More public interaction and scrutiny is needed to keep the public safe from the health industry and to hold doctors to their pledge to do no harm.
Breast, Prostate and Pelvic Exams Lead to Costly, Harmful, Unnecessary Interventions
In the last two years, major studies have found that frequent breast exams, prostate tests and pelvic exams cause more harm than good. The surgery, followup procedures and treatments that the screening tests trigger are worse than the cancers that went unnoticed under more relaxed scrutiny. The bottom line is that the information gathered from screening was not sufficient to produce appropriate, measured treatment. Patients were harmed without benefit and the health industry was compromised by increased profits from inappropriate tests and treatments. Doctors routinely convinced themselves of the value of routine exams that they performed to yield excessive false positives that resulted in unnecessary biopsies or disfiguring surgery. Those flawed exams, tests and procedures also contributed substantially to the profitability of their practices. Patients may have inadvertently been harmed, but the doctors knew that they benefited.
The Health Industry Pursues Profitable Tests and Treatment, not Causes and Cures
I was astounded a few years ago to read an article in the biomedical literature by a researcher who bemoaned the lack of interest in understanding the causes of diseases and the pursuit of cures. Public and private funds were only spent on patent-protected tests and treatments. I watched as the development and testing of fecal transplants demonstrated a safe and effective treatment for numerous diseases, and yet this approach was tracked down and caged by the health industry. I think broad use of this approach could save billions of health dollars, but there is no patent protection and minimal profit, so the approach was stiffled. The efficacy of fecal transplants also points directly at damaged gut flora (and antibiotics) as the cause of many diseases. Where is the public forum to discuss the use of public funds to promote approaches that are safe, effective, cheap, but without potential for proprietary exploitation? What will happen to simple cures, such as resistant starch and probiotics with Clostridium butyricum?
Is HealthKit Personal Data for Personal or Corporate Gain?
Will there be mechanisms for individuals to contribute their HealthKit data to large scale public health experiments to determine simple lifestyle, dietary and exercise approaches that can replace expensive and destructive pharmaceutical-based health industry approaches? HealthKit provides the potential to wrest health from the health industry. We will see if there is an app for that.
Wednesday, June 25, 2014
Antibiotic resistance results, because spontaneous mutations occur so frequently that all bacteria are different. It is just a matter of exposing enough bacteria to an antibiotic to find one that is insensitive to a particular antibiotic. More bacteria mean a greater chance of mutations to antibiotic resistance. The gut contains a lot of bacteria and sewage treatment plants are loaded with gut flora.
Antibiotics are Ubiquitous
All organisms, plants, fungi and animals/humans produce chemicals that kill bacteria, i.e. antibiotics. I have written many articles about the natural antibiotics of plants, a.k.a. phytoalexins or “antioxidant” polyphenolics, and the human defensins that are peptides with heparin binding domains. Bacteria also produce viruses, called bacteriophages, that kill other bacteria. All of these natural antibiotics are small molecules that interact with many different human proteins, and it is these side effects that permit their exploitation as pharmaceuticals. Thus, statins were selected from fungal antibiotics that inhibited an enzyme needed for human synthesis of cholesterol, metformin was a phytoalexin found to reduce blood sugar and resveratrol is a grape phytoalexin.
Plant Antibiotics are Natural
The flavoring chemicals in herbs and spices have a far more important use in food preparation than titillation of taste buds, since those chemicals kill common food pathogens. More profoundly, it is important to realize that the selective advantage of phytochemicals/polyphenols/alkaloids/essential oils to the plants that make them, is as natural antibiotics. Plants kill bacteria, as well as fungi and insects, for a living.
Plant Chemicals Attack all Aspects of Bacteria
Most of the thousand genes that are present in a bacterium code for proteins/enzymes and most antibiotics target those enzymes. Penicillin binds to an enzyme needed to make bacterial cell walls, streptomycin target protein synthesis, rifampicin blocks RNA synthesis, actinomycin D inhibits DNA synthesis, etc.
Mutation to Antibiotic Resistance is Automatic in Bacteria
Each time a cell replicates, mistakes are made and the new DNA molecule of each chromosome is slightly different than the original. There are about a thousand genes on the single chromosome of a bacterium and about the same number on each of the 23 human chromosomes. About a dozen mistakes, mutations, are made each time bacteria replicate. The mutations that alter the gene target of an antibiotic and produce a bacterial enzyme that is unaffected by the antibiotic, yield an antibiotic resistant bacterium. The mutant gene now codes for antibiotic resistance and the presence of several resistance genes in the same bacterium produces multiple antibiotic resistant "superbugs."
Mutations are Random, but Antibiotics Select for Resistance
Each cellular replication produces random mutations throughout the bacterial DNA, but of the billion sites along the DNA that can mutate, only a few will produce a modified enzyme that will no longer interact with a particular antibiotic and thus be resistant. Antibiotic resistance mutants are rare, less than one in a million, but a million bacteria can grow from a single cell in a day and occupy a volume less than a crystal of salt. Ten hours later, after ten more doublings of the million bacteria, there will be a billion, and there will be a good chance that among those will be a mutant that is resistant to a particular antibiotic. In the pound of bacteria in the human gut, there are mutants that are resistant to most antibiotics, including the antibiotics that have not yet been developed. Of course, most of those antibiotic resistant bacteria are just flushed down the toilet. Treatment with antibiotics kills all of the sensitive bacteria and leaves only the resistant. Thus, antibiotic treatments select for antibiotic resistant bacteria.
Common Use of Antibiotics Selects for Resistance on Plasmids
Genes are transferred between bacteria by bacteriophages, conjugation (a kind of bacterial sex) and transformation, which is the release of DNA from one bacterium with subsequent uptake by another. Biofilms, which are communities of many different species of bacteria, stimulate transformation and exploit bacterial DNA as a matrix material to hold the communities together. The human gut is lined with biofilms and the biofilm bacteria secrete vitamins as the quorum sensing signals that coordinate community activity. Thus, some vitamins must stimulate transformation, the exchange of DNA among members of the different species of bacteria in the biofilms with evolution of new and novel species. Rapid change in the gut environment selects for a shift in genes that provide for adaptation to the new environment to small DNA fragments, plasmids, that move most readily between bacteria. Antibiotic treatment results in antibiotic resistance genes on plasmids.
Use of Multiple Antibiotics Selects for Multiple Antibiotic Resistance Plasmids
Persistent use of an antibiotic will spread resistance to a particular antibiotic through the gut flora, facilitated by antibiotic resistant plasmids. Replacement of a second antibiotic will result in a new plasmid with both antibiotic resistance genes. Hospitalization and exposure to a plethora of bacteria with multiple antibiotic resistance plasmids will result in rapid conversion of gut flora to multiple antibiotic resistance upon exposure to any antibiotics. Hospital staff would be expected to be natural repositories for multiple resistance genes, especially if they are exposed to any antibiotic (or pharmaceutical.)
Most Pharmaceuticals Select for Multiple Antibiotic Resistance Plasmids and Superbugs
The frightening rise of superbugs resistant to all known antibiotics has been attributed to the accelerated use of antibiotics in medicine and agriculture. Mixing megatons of bacteria in the guts of billions of people with tons of antibiotics, and still more in sewage treatment plants and agriculture, is bound to produce bacteria with every type of multiple antibiotic resistance plasmid imaginable. But that is not the biggest problem, since fingering the commercial use and misuse of antibiotics ignores biggest exposure of bacteria to antibiotics. It ignores the fact that most popular pharmaceuticals, NSAIDs, statins, anti-depressants, anti-diabetics, etc., also have substantial antibiotic activity. Most of these pharmaceuticals started out as phytoalexins and then were found to also have pharmaceutical activity. Pharmaceuticals are just repurposed natural antibiotics. When you take an aspirin or Metformin or a statin, you are taking an antibiotic. When you take a pharmaceutical, you are selecting for multiple antibiotic resistance plasmids in your gut flora and you may be making the next superbug.
Friday, June 13, 2014
Arthritis, Alzheimer’s, diabetes, cardiovascular disease, osteoporosis, cancer, etc. are all diseases of cellular metabolism and secretion. What goes on inside cells and on their surfaces explains a lot about health and why we get sick. Cells feed off of what’s around them, use some of those materials to replicate and package up cell-made materials for export. Eat, replicate and secrete. Symptoms of disease result if those processes are compromised.
The connective tissue that makes up the cartilage of tendons and the non-mineral parts of bones, as well as a layers of skin, is made up of proteins (collagen) and polysaccharides (glycosaminoglycans, GAGs), e.g. heparan sulfate, hyaluronan and chondroitin sulfate, produced by chondrocytes or fibroblasts. These proteins and polysaccharides are synthesized and then secreted by cells. This process goes on continuously, since the connective tissue is alive and literally crawling with cells that make the cartilage. To keep the connective tissue healthy, the old tissue has to be digested, so that new material can replace it. Thus, the cells that live in cartilage also eat cartilage. These cells get all of their nutrients, e.g. protein and carbs, from eating cartilage. They don’t get glucose and amino acids, or even oxygen (they ferment), from the blood, because there are no blood vessels in cartilage. The photomicrograph at left shows the red chondrocytes surrounded by a light capsule of heparan sulfate as they burrow through the purple cartilage. The next micrograph shows the cytoskeleton of actin filaments (stained with a red fluorescent dye, that lies under the cytoplasm of a chondrocyte. Motor proteins move other proteins, such as syndecans, the proteins to which the heparan sulfate chains are attached, through the cell membrane (see the animations below.) The last micrograph shows the green stained microtubule network on which vesicles move to carry heparan sulfate products from one end of the cell to the other (under the actin and past the orange-dyed nucleus) during synthesis and digestion.
Chondrocytes are the cells that eat and make cartilage, but all of this eating and making goes on at the same time that the cartilage is also holding everything together, i.e. it is still strong. If cartilage is cut and the cut ends are held tightly together, the chondrocytes will knit the cartilage together and it will become as strong as it was.
Heparan Sulfate Circulates over the Surface of Cells
Chondrocytes are not actually rigidly embedded in the cartilage, but rather maintain a capsule of heparan sulfate around themselves. Thus, they continue to secrete a mixture of heparan sulfate, chondroitin sulfate and collagen, but the heparan sulfate is recycled through the capsule and the other molecules merge into the existing cartilage. Thus, the heparan sulfate is a kind of carrier that keeps the cartilage from “setting up” while it is being made and transported. Other cells of the body, such as neurons, don’t make cartilage, but they still have heparan sulfate (HS) circulation that is intimately involved in many other processes, such as the action of hormones. Disruption of HS circulation causes the symptoms of Alzheimer’s or type 1 diabetes, for example, since amyloids assemble as filaments on threads of HS, and the amyloid filaments jam essential HS circulation. Plaque in atherosclerotic vessels is high in HS content. HS is also a major component surrounding vessels to form the blood brain barrier and the barrier to protein loss from kidneys into urine or loss into the gut lumin. Heparin (fragments of HS) is continually released from mast cells in the lining of the gut to prevent pathogens from binding to cell HSPGs.
HS Sweep the Cell Surface
There is a constant flow of heparan sulfate proteoglycans (HSPGs) through the cell membrane from the rear of the chondrocyte to the front where the HS is digested again and the protein that was embedded in the membrane, syndecan, is recycled to the Golgi for another trip. HSPGs (animation to left with blue protein and yellow HS) are attached to motor proteins that propel them through the membrane along microfilaments of actin that form the cyctoskeleton just under the membrane in the cortical region of the cell. Thus, the heparan sulfate of the HSPGs stick out like hair from the cell surface and sweep continuously from the back to the front of the cell. At the front of the cell, the HS sweeps through the intact cartilage and reverses the process of cartilage assembly. The chondroitin sulfate, collagen and HSPGs are dragged into the cell and digested. The protein parts of the HSPGs are transported to the Golgi and the HS is synthesized along with other cartilage components and moved in vesicles along microtubules before it is secreted.
HS is Secreted at One End and Eaten at the Other
The animation left shows 1) the initial digestion of the cartilage proteins and polysaccharides on the left. These cartilage components of amino acids and sugars, are used by the chondrocytes as their sole nutrients 2), and to produce new proteoglycans 3) HS and chondroitin sulfate proteoglycans, in the Golgi, are 4) packaged into secretory vesicles and are 5) secreted on the right. The HS chains, attached to proteins, are 6) swept through the membrane (see the first animation above) toward the front of the cell, leaving the collagen and chondroitin sulfate for form cartilage behind. In the process, the heparan sulfate proteoglycans 7) disrupt and solublilize old cartilage ahead as the chondrocytes 8) move through the connective tissue like moles digging through soil.
Other Cell Processes Involving Heparan Sulfate:
- Amyloids of Alzheimer’s and type I diabetes assemble bound to HS.
- Hormones bind to receptors wrapped around HS.
- Blood clotting is controlled by HS.
- Complement is controlled by HS.
- Blood brain barrier is composed of HS.
- Kidney protein barrier is composed of HS.
- Inflammation blocks HS synthesis and promotes heparanase synthesis.
- GAGs are animal soluble fiber when eaten and feed gut flora.
- Pathogens bind to HS.
- HIV-TAT is transported between cells by HS circulation.
- Heparin is made by heparanase fragmentation of HSPG in mast cells and is secreted along with histamine.
- NFkB activation inhibits HSPG production and stimulates heparanase production.
- Heparan sulfate proteoglycans organize nerve synapses and acetylcholine esterase binds to HS.
- Gastric proteases cleave around heparin binding domains of proteins, e.g. milk, consist of clusters of basic amino acids. Peptides with heparin binding domain are antimicrobial; all of the heparin binding peptides are subsequently degraded by pancreatic proteases.
- Heparanase is initially secreted inactive and bound to HSPGs, but it remains bound and is internalized again along with the recycling HSPGs, and is activated before being secreted again.
- Allergens and autoantigens are unusual proteins with sequences of three adjacent basic amino acids (arginine or lysine) that require HSPG circulation for presentation of the immune system. Nuclear proteins that interact with nucleic acids have sequences of four basic amino acids, the nuclear translocation signal, and are therefore common antinuclear auto antigens.
Tuesday, May 27, 2014
----The other 200 posts are here----
Metformin is the treatment of choice for type 2 diabetes and yet, like many other common drugs, the full extent of its impact on the body (and the body’s essential microbiome of bacteria and fungi) has not been studied. This article should not be seen as a criticism of the pharmacological efficacy of Metformin in lowering blood sugar. The point here is that Metformin alters gut flora and its major pharmacological impact may result from alteration of the gut flora and not direct action on cells of body organs. Metformin, because of its structure and size would be expected to act relatively indiscriminately in numerous cell functions, but I don't think that these interactions are as important as the impact on gut flora. Metformin has all of the properties of an antibiotic selected to lower blood sugar and have limited side effects. It would not be expected to cause a dramatic increase in autoimmunity, because diabetics already have elevated autoimmunity and associated deficiencies in gut flora.
Metformin is a Diguanide
I previously explored the interesting properties of Metformin in my laboratory and through computer modeling experiments, and found it would react with many cellular enzymes and receptors similarly to the amino acid arginine. This was no surprise, since the working end of arginine is a guanide and Metformin is a Siamese twin of guanides, i.e. a biguanide. I might as well also say that another guanide, Canavanine, a toxic, antimicrobial phytoalexin in bean sprouts, has similar properties.
Phytochemicals as Antibiotics
- Metformin is commonly used in the treatment of diabetes.
- Metformin is structurally and chemically related to arginine, guanine and Canavanine.
- Side effects of Metformin include GI upset and autoimmune lupus (same with Canavanine.)
- Metformin also kills bacteria, i.e. it is an antibiotic.
- Many pharmaceuticals, e.g. statins, were first identified as antibiotics produced by fungi.
- Antibiotics select for antibiotic resistance genes, i.e. essential bacterial genes that have mutated to no longer be inactivated by antibiotics.
- New antibiotic resistance genes are combined with other resistance genes on multiple resistance plasmids that are transferred as a group.
- Because of its wide use, resistance to Metformin (and statins) as an antibiotic probably already exists and has been incorporated into multiple drug resistance plasmids.
- Many common pharmaceuticals are also antibiotics and probably select for multiple drug resistance.
- A major contributor to multiple drug resistance, “super bugs”, and the rapid loss of efficacy of antibiotics is the over use of pharmaceuticals in general, in addition to the specific abuse of antibiotics designed to kill pathogens.
Metformin is a Good Anti-Diabetic, but...
Metformin is a Diguanide
I previously explored the interesting properties of Metformin in my laboratory and through computer modeling experiments, and found it would react with many cellular enzymes and receptors similarly to the amino acid arginine. This was no surprise, since the working end of arginine is a guanide and Metformin is a Siamese twin of guanides, i.e. a biguanide. I might as well also say that another guanide, Canavanine, a toxic, antimicrobial phytoalexin in bean sprouts, has similar properties.
Phytochemicals as Antibiotics
I have studied (and written about) the natural plant antibiotics, phytoalexins, in legumes, and particularly in soy beans, so I would expect all of the chemicals, (a.k.a. phytochemicals or “antioxidants”) extracted from plants, e.g. alkaloids, polyphenols and essential oils, to kill bacteria and be toxic to human cells. The selective advantage to plants in producing phytochemicals is the antibiotic activity of those chemicals. Pathogens that have adapted for growth on one species of plant have resistance genes to that plant’s phytoalexins. Thus, bacterial genes for resistance to the antibiotic activity of drugs derived from phytochemicals are common in nature and broad use of these drugs merely selects for the transfer of these genes to gut flora.
|Canavanine and Lupus|
What put together more pieces of the gut flora/antibiotic/autoimmune disease puzzle for me, was coming across Dr. Loren Cordain's recent reiteration of the toxicity of legumes and his singular example of Canavanine from alfalfa sprouts as a contributor to the autoimmune disease, lupus. When I looked up the structure of Canavanine and found it to be a guanide, I immediately started making comparisons to Metformin and was amazed to see that these chemicals share the same list of side effects focused on the gut. Moreover, lupus is also a side effect of both Metformin and Canavanine. It was initially surprising, that a recent study suggests that the anti-diabetic action of Metformin may result indirectly from its antibiotic effects on gut flora. I now expect that Canavanine causes lupus by killing or altering the metabolism of particular species of bacterial gut flora involved in the normal functions of the immune system, e.g. Tregs required for immune tolerance. It is now a common observation that many pharmaceuticals act indirectly via their impact on gut flora, i.e. many pharmaceuticals are fundamentally antibiotics, and particular antibiotics can duplicate the activity of pharmaceuticals.
Thursday, May 1, 2014
--- Here are the other 200 blog posts ---
I was just reading announcements of new synthetic chemicals (SweetMyx) to enhance the taste and help reduce sugar and salt in "health foods". The new taste enhancers have already been approved by industry organizations that designate the chemicals as GRAS, generally recognized as safe. I, of course, was curious about how the SweetMyx chemicals made food taste sweeter with less added sugar. Notice how convenient it is that the food industry has found a way to charge more for less sugar, just as labels have been changed to specifically designate "sugar added:".
Alapyridains are Taste Enhancers
I searched the chemical literature for new taste enhancers, since the chemical ingredients in SweetMyx are trade secrets and will not be disclosed on food labels. It didn't take long to find that the likely suspects are called alapyridains. This group of related chemicals are synthesized with a central pyridine ring familiar from the related cytosine and thymidine of nucleic acids, the plant alkaloid nicotine and the vitamin niacin. A guanide group (half of the diabetes drug metformin, which is a biguanide) is added to make a salt enhancer, and a benzene ring is added to make a sugar enhancer. Without these additions, the central structure inhibits the ability to taste the bitterness associated with "healthy plant antioxidants," phytochemicals and essential oils.
Will SweetMyx Just Tickle your Taste Buds?
The alapyridains that I expect to be in SweetMyx seem to be similar to common plant alkaloids, which are natural pesticides and antibiotics, i.e. phytoalexins. So I would expect these compounds to also be antibiotics with unknown impact on our gut flora, nervous and immune systems, just like all of the medical antibiotics. Based on the general putative structure of the taste enhancers and similarity to other molecules with known reactivities I would also expect these molecules to react with enzymes that bind sugars, e.g. glycosidases, or with hundreds of other proteins that bind to heparin, e.g. embryological growth factors, clotting factors, cytokines, amyloids, etc., etc., etc. It would also be expected that these enhancers will encourage consumption without satiety and therefore, just as artificial sweeteners, contribute to further obesity. In other words, these taste enhancers can be expected to have numerous, unpredictable medical and ecological side effects that will not be understood for decades.
Tuesday, April 29, 2014
Milk is a baby's first prebiotic and a major function of mother's milk is to prevent adult gut bacteria from inflaming a newborn's gut, before the gut is sealed up and a new immune system is developed. Formula companies scurry to get parents hooked on their expensive substitutes that promise ease of use and nutritional equivalence, but the sad truth is that these artificial milk substitutes undermine baby gut flora with tragic results. Even in the rare cases where mothers are not able to breastfeed their babies, there is a safe alternative, donor milk banks. This post is a plea for new parents to wise up and smell the poop. You may need to tell hospital staff that you will be checking diapers and taking names to make sure that your baby only gets your breast milk.
Background: Up Close and Personal Birth and BreastfeedingI have been personally and professionally concerned about the care and nurturing of babies for the past three decades. I was introduced to breastfeeding, milk and babies by my wife. My first faculty position was teaching premed students at Harvard and my wife was a nurse at the Harvard Medical School affiliate, Brigham and Women's Hospital. We honeymooned near a well baby clinic in Malawi. My three daughters were all born at home and never used formula -- they started to eat some mashed up food at about six months and continued to nurse for more than two years. My wife worked evening shifts, she provided some pumped milk and I drove the girls back and forth, so she could nurse during her break. She was also a La Leche League leader for more than 25 years, was co-founder of the Singapore branch of LLL and has been an International Board Certified Lactation Consultant for 20 years. Because of our applied discussions of lactation, I also spent several years studying passive immunity and tolerance of the mucosal immune system of the gut.
Breast milk is nutritive for the newborn, but it also establishes the baby's gut flora. It is the quality of the gut flora, which species of bacteria, that determines if a newborn will thrive or die. If the baby is delivered by Caesarian, then her first gut flora will resemble the nursery staff. If she forces her way out the old fashioned way, her first flora will resemble her mother's vaginal flora. Interestingly, as birth approaches, the mother's vaginal flora shifts toward that found in fermented dairy products, i.e. dairy probiotics. As soon as milk starts to reach the mother's nipples prior to birth, it is colonized by lactic acid bacteria, the only bacteria that can survive in the harsh milk environment. Thus, breast milk is the source of both food and flora, and it is not surprising that breastfed baby poop looks and smells like curds and whey.
Breast Milk Kills Adult Gut Flora
I used to enjoy watching the student perplexity when E. coli in lab experiments progressively died in contact with raw milk. All of the ingredients in milk conspire against normal adult gut bacteria to withhold essential vitamins, minerals and macronutrients. The baby' stomach enzymes also convert milk proteins into antimicrobial peptides, e.g. lactoferrin into lactoferricin (FKCRRWQWRMKKLGAPSITCVRRAF, note the heparin-binding domains consisting of basic amino acids, K & R.) Human milk oligosaccharides (HMOs, bifidus factor) are abundant in breast milk and block the attachment of pathogens to the lining of the gut to prevent infection. At the same time, milk hormones seal the intestines to prevent leakiness.
Formula Kills Pathogens with Inflammation
Formula provides macronutrients for rapid weight gain (obesity risk), but lacks the protective components of breast milk. The result is a rapid and irreversible shift to dominant adult gut flora and the fecal smell of E. coli. It is not surprising that the use of formula in under developed countries results in a high rate of infant mortality. It is, however, surprising that the gut inflammation caused by formula provides enough protection to permit its use in countries with high hygiene and good water quality.
Hospital Use of Formula and Bovine Products Increases Infant Mortality
Full term babies are pretty tough and have been known to survive major calamities in addition to formula-induced inflammation. Tiny preterm newborns are a different story and their immature GI tracts are fragile. Unfortunately, the first line of defense for the newborn gut, newborn gut flora, is frequently ignored in neonatal intensive care nurseries, and a major killer of preterm newborns is necrotising enterocolitis (NEC), in which bacteria common to adults overruns the immature gut. NEC is dramatically reduced by using only breast milk, but hospital nurseries change slowly and doctors, staff and parents are unaware that formula and cow's milk products put newborns at increased risk.
Night Nurses Would Rather Feed Formula
Recent studies show that newborns designated as "breast milk only" are still given bottles of formula, because night nurses don't understand the risks of formula and enjoy feeding the babies. The mothers are not usually told that their baby received formula and inexperienced mothers fail to recognize why their baby never had normal bowel movements. Some hospitals continue to use bovine, cow milk, products simply because they always have and they are unaware of the damage to newborn gut flora and the cause of NEC.
Donor Milk Banks
Some mothers produce more milk than their baby needs and so they arrange to donate the extra to milk banks. The milk banks pasteurize and distribute the milk. Many hospitals are unfamiliar with milk banks and donations have not been energetically encouraged, so both the supply and demand for donor milk are developing. It is important to realize that newborn and premature babies have very small stomachs of only a few ounces, and some mothers can easily produce a cup of milk at each feeding. Thus, the cost of using only breast milk by all babies for their first few days after birth is negligible compared to the risk of disease caused by formula use.
Demand at Least Second Best
The bottom line is that parents must demand that only breast milk be used in hospitals, even if it must be from milk banks, and all parents must be able to check diapers for the yogurty smell typical of exclusively breastfed babies.
For more information see the Human Milk Banking Association of North America
For more information see the Human Milk Banking Association of North America
Monday, March 24, 2014
— all 200 Posts —
I started posting to Cooling Inflammation on 21 Aug, 2008 with How Your Diet Makes You Sick or Healthy. My impetus for writing was my growing awareness that diet was the major reason why people were sick, and that health myths were preventing people from being healthy. Inflammation originated by diet-inflicted injury and people attributed their sickness to genetics, environmental toxins and pervasive pathogens.
My Path to the Obvious
My research background started with plant biochemistry, including carbohydrate structural analysis and polyphenol chemistry. At that stage I was interested in understanding how plants protected (phytoalexins) themselves from pathogens, and I expected to use this perspective to explore human innate immunity. From there, I went on to enzymology and protein characterization, biofilm structure, plant genetic engineering and breeding, monoclonal antibody production, mycotoxin detection, stem cell analysis, passive immunity in neonates, computational modeling of collagen and heparin binding, and heparan sulfate proteoglycan inhibition by inflammation. These were temporary foci and the research imperatives, in retrospect, prevented me from seeing the bigger pictures, although they did leave me with a broad skill set.
Perspective: Water and Surface Tension
When I finally decided to slow down, smell the flowers and start having kids, I switched from research to teaching, from university to small liberal arts college. For the first time, I actually thought about what I was teaching and my first revelation was that after teaching biochemistry for twenty years, I didn’t understand water and surface tension. I could provide the platitudes from the Molecular Biology of the Cell, but I couldn’t do it mechanistically with colliding, sticky, energetic water molecules in my mind or at the blackboard. I had to develop functional explanations of hydrogen bonds, entropy and thermal energy, that translated into the structuring of a layer of water molecules responsible for hydrophobic interactions and surface tension. I extended that to include an explanation of the two layers of water holding together cytoplasmic membranes, the tube of structured water that holds together the cylinder of stacked bases in DNA or the shrink wrapping water layer surrounding proteins.
Perspective: Heparin Binding and Amphipathy of Sugars and Basic Amino Acids
As the kids got older, I started to dabble in research again and my expertise in carbohydrate chemistry led me into cartilage (mostly the glycosaminoglycan, GAG, chondroitin sulfate) synthesis and ultimately another GAG, heparan sulfate proteoglycans (HSPGs). I was attracted to the dynamic HSPGs, that recycled with a half-life of six hours and formed layers around chondrocytes that secreted cartilage as they burrowed/ate through living cartilage. I learned that the heparin filled granules of mast cells could be stained with berberine, which similarly stained the heparin in basement membranes of tissues and amyloids of Alzheimer’s, atherosclerosis and diabetes. I was led by protein modeling of collagens to the binding of heparin to proteins and the revelation that basic amino acids (heparin binding domains) and sugars (heparin) are amphipathic, i.e. they have both hydrophobic and hydrophilic regions. This is also true of plant polyphenolics. Thus, polyphenolics, “basic” amino acids, “hydrophobic” amino acids, and sugars will all stack together.
- DNA bases stack.
- Heparin binding sites of proteins are basic amino acids (Arg, Lys).
- Sugar binding sites in enzymes and lectins are hydrophobic amino acids (Trp, Tyr, Phe).
- Nuclear translocation signals, quartets of basic amino acids, bind to receptors with tryptophans.
- Tryptophans are the most highly conserved amino acids in the same proteins across great evolutionary distances.
- Hydrophobic bonding between tryptophan and a sugar or basic amino acid is ten times greater than hydrogen or ionic bonds.
- Tryptophan/Arginine ladders zip regions of proteins together.
- Polyphenols can disrupt cellular protein interactions by binding to receptors for carbohydrates/heparin, steroid hormones, amyloids, etc.
- Heparin holds dozens of hormones to receptors and changes the shapes of proteins, e.g. clotting and complement.
- Most nucleic acid binding proteins will also bind to the more negatively charged heparin.
- Bacteria use a pair of lysines to mark proteins for export.
- Peptides containing the basic amino acids of heparin binding domains (also produced by the specificity of gastric proteases) are antimicrobial, e.g. defensins, and so are plant polyphenols.
- Many drugs are active because they are domesticated plant polyphenols.
From Heparin Binding to Antigen Presentation
As soon as I realized that basic amino acids were involved in heparin binding, I started to look for the basic amino acids (R for arginine and K for lysine in amino acid sequences) in proteins known to bind heparin. After study of hundreds of structures, it became obvious that heparin binding domains were simply a pair of basic amino acids (RR or KK or RK) with another within a distance of six amino acids. No particular structure was necessary, as I later deduced, since binding to the heparin provided the structure. In fact, in many X-ray crystallographic structures, the heparin binding regions on the surface of the protein are missing, because they are not in a defined shape. I suspected that protein antigens involved in autoimmunity and allergy might be brought into cells for presentation to the immune system by interacting with HSPGs on the surface and so started to check them out for heparin binding domains. I was very skillful at picking out pairs of Ks or Rs within sequences of hundreds of amino acids by that time, so I was shocked to see that the first dozen antigens that I checked, all had a triplet of basic amino acids. I had discovered that autoantigens and allergens utilize a basic triplet analogous to the basic quartet used in nuclear translocation! This also explained why proteins that interact with nucleic acids and are transported into the nucleus with a basic quartet are also prominent autoantigens.
Gut Flora and Immunity
Twenty years ago I read a curious description of leprosy that said that the course of infection could be either innocuous or devastating depending on whether the aggressive or the suppressive part of the immune system dominated. I remained perplexed until I realized that diet and gut flora were the major determinants. I was aware of the importance of diet at the outset of this blog, because it was clear that diet trumped genetics. I was also aware thirty years ago in my studies of passive immunity, that milk contained bifidus factor, now known to be milk oligosaccharides, that controlled the growth of Lactobacilli that in turn controlled the development of the neonate immune system. It was also known that bacteria-free mice had impaired immune systems. It still took me several years for the relationship between diet, gut flora and immunity to make sense. I began searching the literature for connections between gut flora and development of the immune system and soon noted experiments that linked filamentous bacteria with aggressive components and Clostridium spp. with Tregs. A further refinement was linking resistant starch, a soluble fiber, with Clostridium.
My Current Views are Summarized in Three Health Diagrams
Diet, Gut Flora, Inflammation, Antigen Presentation, Tregs and Autoimmunity
Protein from the body and from food don’t normally stimulate the immune system, because there in no inflammation, the proteins lack basic triplets that enhance presentation, and antibody production and aggressive T cells are suppressed by Tregs. Diet can throw the balance toward autoimmunity and allergy, by producing inflammation, e.g. hyperglycemia/AGE or high omega-6 fatty acids/prostaglandins, and starving gut flora needed for Treg production by eating processed food lacking soluble fiber. The combination of inflammation and Treg deficiency causes proteins, either self or potential allergens, which have basic triplets to be presented to the immune system and stimulates attack by the immune system.
The Cure is to Cool Inflammation and Stimulate Tregs with Diet and Bacteria
I have provided an outline with The Anti-Inflammatory Diet to avoid inflammation, to stimulate existing gut flora with soluble fiber and encourage Treg production. Mark Sisson, on Mark’s Daily Apple has provided an excellent dietary guide that also provides starch guidelines. If you already have symptoms of autoimmune disease or allergies, then Richard Nikoley provides gut flora repair advice on Free the Animal, and Dr. B G provides more details on Animal Pharm.
Autoimmunity and allergies are not genetic destiny and they can be cured with diet and bacteria.
Wednesday, March 19, 2014
I have explained my perspective in diagrams of the relationship between diet, gut flora and disease:
and of the interaction between gut flora, the immune system and autoimmunity:
Now I am discussing how inflammation, the foundation of most chronic diseases, begins at the cellular level and results in the classic symptoms of tissue inflammation: redness, heat, swelling and pain.
NF-kB is the Transcription Factor that Controls Inflammation Genes
Of the 23,000 human genes, about 1,000 on each of 23 chromosomes, five dozen, e.g. enzymes involved in nitric oxide (vasodilation and erection hormone), synthesis of heparin sulfate and prostaglandin synthesis from omega-6 fatty acids or cytokines (IL-1, IL-6, TNFa), are associated with inflammation. These inflammatory genes are turned on or expressed in individual cells, when the inflammation transcription factor, NF-kB, is activated by any of numerous external signals, including inflammatory cytokines, bacterial or fungal cell wall materials (LPS or beta-glucan), advanced glycation end products (AGE, e.g. HgA1C, resulting from high blood sugar) or reactive oxygen species (ROS, e.g. super oxide, from insulin resistance).
Inflammation is the Foundation of Growth, Birth, Cancer and Pain
We think of inflammation as the sum of physical symptoms, and our purpose in responding to inflammation is typically to limit its impact. We try to stop swelling by applying cold or hot, and we take aspirin to lower fevers and stop pain. We fail to realize that inflammation is essential to the growth and development of many different tissues, and that inflammation is a cycle that leads back to normal function.
Body tissues, such as the lining of the intestines or the uterus, continually produce new cells to replace the old that are sloughed off. NF-kB must be turned on for these growth and attrition cycles. Taking aspirin blocks NF-kB in the gut and stops local development of the lining, resulting in weak areas that bleed. That is why doctors encourage patients to drink a half glass of water before and after swallowing aspirin tablets.
Another more dramatic example of control of inflammation is conception, gestation and birth. Conception and gestation require inhibition of inflammation, to permit growth of a foreign organism (a fetus is half sperm genes) in the uterus. Chronic inflammation limits the ability of the uterus to suppress immune attack and can produce infertility, which is treated by aspirin and heparin, which suppress chronic inflammation. The return of inflammation at the end of gestation precipitates labor and birth. Excess Inflammation produces high levels of circulating inflammatory cytokines, which causes postpartum depression. Depression and chronic inflammation have the same cytokine profiles, i.e. depression is a symptom of chronic inflammation.
Proliferation, or enhanced cell division, is another aspect of inflammation and is also the foundation for cancer. That is the reason that some doctors recommend low dose aspirin to reduce colon cancer. Similarly, since inflammation is the basis for coronary artery disease, doctors sometimes recommend low dose aspirin, although this is controversial. Doctors also use aspirin as a so called blood thinner, since it blocks inflammatory signaling in platelets and discourages clotting. Inflammation of nerve cells is experienced by the brain as pain.
When it is understood that inflammation is an essential feature of many normal, healthy cell and tissue functions, then “inflammation," with its negative connotations, becomes a misnomer.
NSAIDs Inhibit Inflammatory Prostaglandin Production
Aspirin directly inhibits NF-kB activation inside the cell, but it also chemically modifies COX, the enzyme that converts omega-6 polyunsaturated fatty acids (common in polyunsaturated vegetable oils) into inflammatory prostaglandins. Other NSAIDS (Non-Steroidal Anti-Inflammatory Drugs) just inhibit COX, but Aspirin transfers its acetyl group to make acetyl-COX, which has a new activity that converts omega-6 fatty acids into anti-inflammatory prostaglandins. The high omega-6 fatty acid content of vegetable/seed oils, such as corn, soy, canola, etc. is why these oils, in contrast to olive oil or butter, are inflammatory. Omega-3 fish oil is anti-inflammatory, because it is converted to anti-inflammatory prostaglandins. Plant omega-3 fatty acids are shorter and are not converted to prostaglandins, but inhibit omega-6 conversion.
Nitric Oxide, Vasodilation and Viagra
Swelling is caused by vasodilation, the relaxation of blood vessels, and accumulation of serum in the tissue. This vasodilation also makes the tissue red and warm from the increased amount of warm blood in the capillaries. Vasodilation is caused by nitric oxide, NO, that is produced by an enzyme under the control of NF-kB, which takes the nitrogen from arginine (or nitroglycerine). The NO diffuses easily and binds to receptors that produce an amplified signal, cyclic GMP, that relaxes the muscle cells surrounding blood vessels. [Viagra is potentially dangerous, because it just exaggerates the amplified signal and obscures the underlying vascular damage, e.g. hypertension, that causes erectile dysfunction by blocking normal vasodilation.]
Hot/Cold and Endorphins
The dilemma of whether to use hot or cold therapy to block inflammation is based on a misunderstanding of what the temperature changes are actually doing. Changing the temperature of the skin alters the structure of sensory proteins in nerves of the skin and triggers signals to the brain that register as hot or cold. Chemicals, e.g. capsaicin or menthol, can have the same effect without changing skin temperature. The important response for inflammation control, is return signals from the brain that release neurohormones, e.g. endorphins, from different nerves that reach not only some of the skin that was hot or cold, but also deeper tissue. The endorphins block inflammation and all of its symptoms. That is why chemically treated pads are more effective than icing or changing from hot to cold, because "hot" and "cold" signaling chemicals can be applied simultaneously. None of the treatments is more than skin deep. Actually chilling or heating tissue below the skin is damaging and causes more inflammation. Low dose Naltrexone may be effective in some cases of chronic inflammation, by stimulating systemic rebound endorphin production.
Lymphocyte Offloading, Mast Cells, Heparin
Rosacea is a group of diseases that involve inflammation of the face in an exaggerated blush. Any of the signals that would lead to blushing cause intense vasodilation. A blush is fleeting, but rosacea is made chronic by another aspect of inflammation, offloading of lymphocytes. Large numbers of lymphocytes accumulating in response to a local infection would produce pus. In the case of rosacea, the distributed leucocytes, including neutrophils, respond to the blushing signals by producing inflammatory signals, such as P protein. The result is cycles of inflammation, autoinflammation.
Mast cells can also be offloaded from blood vessels and provide a link between the immune system and inflammation. Mast cells display IgE receptors on their surfaces, which bind antigens and trigger release of histamine, heparin and protease. Histamine is a neurotransmitter that binds to receptors on blood vessels and nerve cells. In the gut, histamine mediates many digestive processes. Heparin released along with histamine, coats the gut and prevents attachment of pathogens by competing for binding to the heparan sulfate proteoglycans (HSPGs) that form the surface of cells that line the gut. [Heparin is the most common drug used in hospitals and is produced from intestines of cattle and hogs in the meat industry.] Heparin also binds and inactivates the proteases released from mast cells. Upon release, the now active proteases attack and activate receptors on nerves and immune cells.
Heparin is Anti-Inflammatory
Heparin is the most negatively charged polysaccharide, mediates most of the receptor/hormone interactions at cell surfaces; facilitates amyloid plaque formation, e.g. in Alzheimer's, atherosclerosis, diabetes, dementia; and controls numerous protease reactions in the complement system and clotting, etc. There are hundreds of heparin-binding proteins. Heparin is produced in secretory granules of mast cells by the action of heparanase on heparan sulfate proteoglycans. Heparin is a mixture of small fragments, oligosaccharides of heparan sulfate polysaccharides. Heparin is anti-inflammatory and is administered to facilitate conception and gestation. Inflammation also inhibits the genes involved in heparan sulfate proteoglycan production and since HSPGs are a major component of basement membranes of tissues and provide the barrier function of blood vessels in kidneys and brain, inflammation leads to proteinuria and loss of the blood brain barrier. Since HSPGs have a short half life of six hours and are rapidly recycled, heparin added to the blood is rapidly absorbed by vessels, and heparin taken orally is absorbed by intestinal cells, but does not reach the blood. HSPGs and heparin are central components of immunity and inflammation.
Inflammation Blocks Skin Synthesis of Vitamin D from Cholesterol
Inflammation blocks solar synthesis of vitamin D in the skin and is more important than skin pigmentation, use of sunblock or latitude in producing vitamin D deficiency. The vitamin D content of food is negligible compared to solar production in the skin. It is not surprising that rising chronic inflammation is also accompanied by rising vitamin D deficiency. Vitamin D supplementation is usually ineffective in curing vitamin D deficiency, because the supplements are too low and very high levels of supplemental vitamin D are required to reverse underlying chronic inflammation. Statins are very effective at blocking cholesterol synthesis and although reducing cholesterol has minimal impact on the target, cardiovascular disease, it dramatically reduces vitamin D causing muscle pain, etc.
Most vitamins are enzyme cofactors synthesized by gut bacteria and used as quorum sensing signals during formation of biofilms. Vitamin D, in contrast, is a steroid hormone and receptors for vitamin D are inside cells. The receptor/vitamin D complex is transported into the nucleus where it acts as a transcription factor to control the expression of genes. Vitamin D controls the expression of defensins in the crypts of the villi of the small intestines. The antimicrobial activity of defensins is based on the basic amino acids (arginine and lysine) of its heparin binding domains. Vitamin D also interacts with NF-kB in the nucleus and modulates inflammation.
Bacteria and LPS
Lipopolysaccharide is a wall component that is indicative of bacteria, just as beta-glucan is indicative of fungi, and both are intense activators of NF-kB and inflammation. LPS is released from damaged bacteria, e.g. by antibiotic treatment, binds to receptors on the surface of intestines and stimulates inflammation with release of NO, which produces diarrhea. Food intolerances, which are based on incomplete digestion of food components, because of an incomplete gut flora (immunological responses/food allergies are rare) are probably also the result of LPS release from gut flora and inflammation.
Innate Immunity is also Triggered by LPS
The basic defenses of humans against microorganisms are mediated at the cellular level by triggering molecules common to all microorganisms, e.g. LPS for bacteria. The responses are equally general: lysozyme to digest bacterial wall peptidylglycan, lactoferrin that binds iron and yields antibacterial peptides. LPS (and inflammatory cytokines) also stimulates the liver to produce CRP (C Reactive Protein) that binds to choline on bacteria as the first step in phagocytosis and DNAse I that digests NETs (neutrophil extracellular traps) that are the DNA and histones released by triggered neutrophil cells that enmesh bacteria for engulfment by phagocytic cells. [NETS plug peripheral catheters and can be cleared with probiotics that stimulate DNAse I release from the liver.] NETs are also present at sites of inflammation and the accompanying nuclear proteins have the basic triplets that stimulate immune presentation and act as autoantigens, i. e. produce anti-nuclear antibodies, in the absence of adequate Tregs.
Diet and Inflammation
The diagram outlines the interactions that produce the tissue symptoms of inflammation. Many components of modern diet can trigger inflammation:
Sugars and high glycemic starches raise blood sugar and enhance AGE/HgA1C.
Vegetable oils high in omega-6 oils are converted into inflammatory prostaglandins.
Wheat and other grains have high glycemic starch and insoluble fiber that is inflammatory. Gluten is inflammatory.
Antibiotics damage the gut flora and produce vitamin deficiencies, autoimmunity and allergies.
Food intolerances result from damaged gut flora and produce gut inflammation.
Fish high in omega-3 EPA and DHA are anti-inflammatory.
Health Results from a Balance of:
Diet (meat, fish, eggs, dairy, vegetables), containing macronutrients of protein, starch 30-100 g/d and fat (low omega 6/3 and saturated fat for most calories), and micronutrients
Soluble Fiber, e.g. resistant starch (consult Free the Animal), inulin, pectin, (plant polysaccharides, animal GAGs)
Gut Flora, diverse and adapted to dietary soluble fiber,
Mark’s Daily Apple provides an authoritative diet guide (except for the gut flora).