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).