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).
39 comments:
All very interesting Prof Ayers.
Question: Skin microbiome is different than in the gut, and those with skin problems particularly atopic sufferers have a deficient skin barrier that makes the skin more subject to insult.
how does this tie in to the gut, if at all?
Seems airborne allergies may be unrelated to gut as microbiome of skin and skin integrity itself may allow for these allergies and may be unrelated to the gut and diet?
Your view of skin allergy testing?
What about those who are negative for food allergies via the skin; think the gut still involved in some way?
Dr Ayers, am I understanding this correctly, heparin contributes to Alzheimer's and dementia? Is the drug heparin helpful or harmful? I have gone back in your archives and can't seem to distinguish between heparan and heparin, as well as natural or synthetic. Is low dose aspirin on a daily basis with ample water, helpful or not, in reducing inflammation? Is thinner blood helpful in controlling inflammation? I'd appreciate any info or resources. Thanks for all of the info you provide here!
Steve,
Skin based allergies result from circulating antibodies that bind to cells in the skin that have receptors that display the antibodies for binding to antigen. Antigen triggers mast cells for example to release histamine and other factors that produce the symptoms of allergy. The skin microbiome is less important in allergies than the gut microbiome that is regulating antibody production.
The Tregs produced by the gut in response to the gut microbiome control suppression of inappropriate antibodies and hence skin allergies result from damaged gut flora that hampers Treg production.
Most food "allergies" are actually food intolerance due to missing gut flora to digest the trigger foods. Add back the right species of gut bacteria and the "allergies" are gone.
Allergy skin testing is meaningless. Skin integrity is unimportant in skin allergies. Most skin integrity issues are due to excessive use of skin care products, especially antimicrobial products. Washing skin causes more problems than dirty skin.
All allergies can be fixed by fixing gut flora.
Thanks for the questions.
Jan,
All members of the heparin/heparin family are synthesized as proteins with polysaccharides (heparan) that are sulfated by several different enzymes as the heparan sulfate proteoglycans (HSPGs) pass through the Golgi on the way to secretion. During the transit, the heparan sulfate can be digested into fragments, heparin.
Proteins, such as cytokines, bind to cells, by initially binding to the HSPGs that are sweeping over the surface of all cells. Prior to recycling of the HSPGs, bound cytokines are thrust against receptors clustered on the cell surface by also binding to HSPGs. Thus, pairs of cytokines and receptors are brought together as buns with the heparan sulfate as the hot dog.
The heparan sulfate is needed in dozens of different receptor/ligand interactions. Similarly, when proteins are stacked in a repeated orientation in amyloid fibers, the basic amino acids line up to make heparin binding regions. Heparan sulfate then becomes the rope used to line up school children for outings. Amyloid plaques in Alzheimer's, atherosclerosis and diabetes contain heparan sulfate. In fact, part of the toxicity of amyloids may be binding of HSPGs and blocking normal recycling.
There is no synthetic heparin. All is derived from animals and if it comes in contact with cells it is recycled along with the HSPGs on the cell surface. So heparin is innocuous, unless there is so much that it competes for the normal function of the HSPGs, as in the case of heparin administered to block clotting.
Inflammation blocks normal HSPG production and interferes with dozens of different cellular processes. It may also dampen inflammatory signaling, so that inflammation is localized and doesn't spread. So heparin is generally anti-inflammatory.
Aspirin is very potent. It can stop inflammation in several ways, but inflammation is required for many processes required for health, and also for cancer. Thus, swallowed aspirin blocks colon cancer, but also damages the lining of the gut. I don't take low dose aspirin, but I do occasionally take a normal strength aspirin with the thought of killing any colon cancer before it gets a foot hold.
Inhibiting clotting should be a temporary therapy and the source of the clotting tendency, e.g. inflammation, should be fixed. Fixing diet and gut flora would be sensible.
Taking drugs, whether pharmaceutical or prepharmaceutical, i.e. plant, does not make sense because the side effects are always more numerous that the intended consequence. It is much wiser to understand the cause and cure it. Therapy should always be temporary. Supplements should always be temporary. Superfoods are myths.
Thanks for the questions.
Dr Ayers-I appreciate your answer and I could really understand it...thanks! I've been on the fence about aspirin and have not been taking it. When you say understand the cause and then cure it, it sounds so simple, but how to do that is the challenge. With Hashimoto's and food sensitivities, I have gone down many natural, herbal and nutritional paths. I get some improvements but feel like I'm chasing inflammation without finding a cause. Your information always adds a new view and is very helpful. Thanks again!
Jan,
My first impression for someone who says they have Hashimoto's and food sensitivities, is that they have a typical presentation for antibiotic dysbiosis. Antibiotics have damaged the gut flora and specifically the bacteria that stimulate the Tregs that would normally block autoimmune disease. In your case, you also have gluten sensitivity and combined with a lack of Tregs, you have autoimmune celiac that spreads to your thyroid.
The cure is to fix your gut flora and avoid wheat. The simplest approach would be to read my previous posts on diet, gut flora and autoimmunity (Health in Diagrams -- I & II) and my blogs on resistant starch. If you stop eating wheat, start eating resistant starch and take a probiotic containing Clostridium, you will probably be fixed in a couple of months. It takes a while for your Tregs to build up and start suppressing.
I think that your food sensitivities will be fixed if you start making and eating your own fermented veggies. You may need to adjust your preference for less crisp fermented veggies, because if you use less salt, you will encourage additional bacterial species that are more likely to include those you are missing.
I think that it is that simple, but will require a little work. The natural and herbal solutions didn't have much science behind them. Please read my post on phytochemicals.
Thanks for your questions.
Hi Raj,
I think that you may be right and that may also explain how vitamin D produces hair loss and is reversed by either supplemental vitamin D sufficient to block inflammation or just fixing the inflammation.
It is interesting that all of the steroids, sex hormones and vitamin D, influence inflammation and vice versa.
Thanks for the questions/comments.
Thanks Dr Ayers for your response
I hear what you say about skin integrity, but family members who have atopic eczema have no issues when the there is humidity,but lots of issues when there is none. The skin goes from smooth and moist to dry when the weather becomes cold and dry.
You saying that get the Tregs up by right probiotic, anti inflam diet and fermented veggies will work magic for them?
Should RS be started at same time as probiotic with Clostridium?
What about one with only L Plantarum?
I get fermented veggies that are raw, unpasturized and lacto fermented from a local co-op
Steve,
The skin symptoms are re-exposure to the antigen, but don't reflect the initial exposure that required inflammation, lack of Tregs and an appropriate antigen. The initial exposure didn't happen in the skin, but resulted in antibodies that circulated to the skin.
Not all probiotics are the same. Most of the bacteria in commercial probiotics are present just to increase the list on the bottle. Some of the dairy probiotics are useful temporarily. Clostridium is useful only with RS and is usually eaten with fermented veggies, but may be missing from commercial products, such as those found at your local co-op.
Thanks for the questions.
Hi,
What i buy is from Real Pickles Co and is naturally fermented and raw.
no vinegar or heating.
That is not good?
Thanks,
Steve,
My impression is that the companies are concerned about the quality/crispness of the pickles and limit the bacteria present to a few pure fermenting strains. For gut flora repair, I am interested in the other types of bacteria that are present as wild contaminants in homemade fermented veggies. These are the bacteria that would digest the plant polysaccharides, soluble fiber, of the veggies and make them soft. These are normally inhibited at higher salt, and grow better and make the veggies mushy and would add the off flavor of butyric acid at a little lower saltiness.
Thanks for persisting and asking questions.
I have an intolerance to a lot of different foods. I'm alright avoiding most of them for the time being but read here, as well as mark'sDA and perfecthealthdiet.com, that I would really benefit from adding more starch to my diet. I just can't reach any where near 90 grams/ day without waking in pain afterwards. Is there any starch you would recommend that would be easier to tolerate whilst repairing my gut flora. I eat home made fermented veg, I've ordered pro-3 and potato starch. I am hlab27 with AS and have been following MDA's exercise routine and as close to his diet as possible for quite some time now.
Thank you again.
Hi Dr Ayers:
Only way to learn is to ask questions! Thank you for your patience and responding!
I will look for some sources on how to ferment various veggies until the book you recommend is available in
Sept. Until then are there any other sources you might recommend?
I think you mentioned that you may post some recipes
As to the Probiotic 3, the package says to take three per day. That make sense; was thinking to just take one?
Thanks
Dr Ayers, I have been wheat free for almost 3 years and have been eating Paleo/PHD for that time. I was LC for a while but added in safe starches and recently RS in various forms. I have tried AORProbiotic 3 once a day to get the Clostridium strain and it makes my hand itch intensely and I sneeze.? Not sure why, but when I stop taking it, it stops. I do take Prescript Assist and my fermented foods are raw small batch sauerkraut and coconut water kefir. I will try making my own soon and will read up on your other posts. I can say that it is hard to take some of these steps while the gut is irritated and not able to handle different foods and supplements, like probiotics and RS. I can add or try one thing and pay for it all day. I just go slow and keep good notes. Thanks!
Okay, I just received my bottle of Probiotic 3 and started it with my RS today. Hopefully the Clostridium Butyricum work their magic. I've been on PS now for a couple of months with a different soil based probiotic that didn't contain CB so hopefully this will help more. I've maintained my scalp psoriasis and general inflammation to manageable levels but would be happy to see it all disappear. I tolerate zero amounts of fructose, dairy or gluten. I'd also love to see my chronically cold hands and feet warm up and maybe just maybe be able to eat a piece of cheese without my scalp peeling off and my brain fogging over. I'll update.
Dr. Art,
Regarding the use of aspirin to help control nf-kappa b in the gut, do you think it would be helpful to fully dissolve the aspirin in a full glass of water before taking it to help alleviate the potential negative effects on the lining?
I tried it to see if the taste was tolerable, and it was, at least for me.
Thank you.
Art
Hi Dr. Art;
I am going to start a batch of sauerkraut, and had a thought - are the innoculant critters floating around my home likely to be of reasonable diversity ? We have been below -10C outside for about 5 months now, so what's in the house is what we got!
Are you worried about by low-level chronic inflammation resulting from mycotoxin exposure? If so - what sources of food do you suggest we be weary about in this regard?
Thanks
You keep saying Omega6 from veg-oils are inflammatory - they provide inflammatory eicosanoids, e.g. Leukotriens, that switch on nfKB
-
But Omega6 from veg-oils are Linoleic Acid, and LA is too short and not enough unsaturated to makes eicosanoids. It must be elongated/desaturated in GLA-DGLA and then in Arachidonic Acid, the big precursor of inflammatory eicosanoids.
This pathway needs several enzymes: elongase, desaturase…
-
Do you think that in adult humans the conversion rate AA/LA is high?
And what about AA already present in animal food, e.g. egg yolks, organ meet, sausages?
And what about DGLA, precursor of anti-inflammatory eicosanoids, derived from LA?
-
The main point is: do you agree with Barry Sears eicosanoids theory or not?
Thanks Prof Ayers
I thought I would leave a post here in case 1 tidbit of my story can help even 1 person. A colonoscopy several years ago left me with chronic diaherra. Tried to self fix with probiotics and gave myself massive upper gut fermentation/sibo. Begged a GI for refaximin because an SI now acting like a colon is very painful. That refaximin is the bomb. Cleaned out that SI quite nicely. At least that's what the yeast /fungas thought. Party Time. I just was clueless still at this time as to what was inside me.
OK now bedridden. My body was no longer mine. Only time felt OK was not eating otherwise I was feeding the monster inside me(love that show) It especially loved lactose, starch and sugar. My sweet mummy called me one day and said "could it be candida" Called my gp and begged to get in. She did not want to give me the nystatin at first without tests but I told her I would not even have the strength to come back. I had mustered every ounce of strength to make it that day. She agreed. I was out of bed and shopping in 3
days.
N
The SI was now a inflamed, broken organ though. The next couple of years had been full of set backs. Most self inflicted in my quest to feel better faster . The last 6 months I have turned a major corner. Mostly using Dr. Ayers classic. Protein, fat, a variety of vege fibers, moderation is my friend. Eat 2 twice a day and the rest of the time let my SI rest. I c, lay on my side now. Couldn't for 2 years. My SI was so tender. I burned the poor thing with herbs I thought would help too. I do not believe an increase in pain is a part of healing. It's your body saying STOP. I don't believe in the herx effect. Nystatin really gave me a fighting
chance and there were no herx symptoms. If PS or probiotics cause bad symptoms..stop. Thank you Dr. Ayers for your sensible advice. Oh and apples have also done great things for digestion. I think my animals are a little freaked out by all the hugs and kisses they get now:-)
In response to Bea,
I think the candida/yeast element is a very important topic for individuals with dysbiosis. I myself am a sufferer of the yeast syndrome. 3 months of broad spectrum anti-biotics left me with the dozens of digestive/immune/skin conditions.
I think having a yeast overgrowth makes it that much harder to re-inoculate the intestines with the proper flora. Even with diet, omega 3, ferments, vit d, etc.
I believe Art has touched on the subject briefly if remember correctly. Suggesting possible benefits of complete bowel irrigation with PEG (striping bio-films). While I have had some relief with PEG in the past, I've yet to do this in tandem with Nystatin.
-Dan
Hi Dr. Ayers,
If butyrate is important for tight junctions in the gut, is it important for tight junctions elsewhere, for example, in the urinary tract? I am trying to relate how urinary tract infections (brought on by intercourse) might be a result of low butyrate and hence loose junctions in the urinary tract?
Sally,
As you may note from some of my diagrams, my research has suggested that inflammation blocks heparan sulfate production and encourages heparin digestion. Heparin is synthesized by gut and bladder mast cells and secreted to inhibit adherence of pathogens to surface heparan sulfate. Thus, bladder inflammation or chronic systemic inflammation can make the urinary tract more easily infected. One treatment is to empty the bladder and then refill it with heparin. The heparin will be taken up by the lining of the urinary tract and heparin will be produced and wash out pathogen for a while.
Of course, the cure would be to eliminate sources of inflammation and protect from UTIs by adequate heparin.
Chronic inflammation typically produced vitamin D deficiency, which also causes problems. I would expect that you are vitamin D deficient and need to have it tested before you supplement. Dental problems are another source of chronic inflammation.
Keep in touch.
Raphi,
I was a founder of a company that developed commercial mycotoxin detection kits.
I don't worry about mycotoxins. For most people sugar, wheat, vegetable oils, processed foods lacking soluble fiber, antibiotics and antimicrobial soaps are much, much bigger problems than environmental toxins, GMOs, etc. that are the focus of public attention.
Thanks for your questions.
Kay Dee,
I am a skeptic of modern research on very controversial and lucrative products such as vegetable oils. In the 1990s, studies showed that linoleic acid was readily converted to arachidonic acid, but more recent studies, which seem to be carefully constructed to dilute newly made and premade phospholipids, find no conversion.
I believe the earlier studies and avoid vegetable oils.
Thanks for your questions.
The problem I have, is, that probiotic LPS equivalents also activate NF-kappaB. So what's the difference?
How can a probiotic and a pathogen exert such differential effects using the same receptors?
George,
As I see it, the probiotics only come into casual contact with the intestinal surface, whereas pathogens adhere and alter the epithelium to the extent that micro colonies form and bacteria enter and release their LPS. Thus, with pathogens, the LPS can reach cells that respond with inflammation, probiotics don't, since their LPS stays on the bacteria in the lumin of the gut.
I also think that the permeability of the gut can be altered to permit probiotic bacteria to release their LPS inside and trigger inflammation and diarrhea. This is a defense mechanism to sweep away problems,like pathogens or toxins.
Thanks for the questions.
@George Henderson
Think of it this way: there are many ways for pathogens to adhere, invade, survive/replicate in/out of a cell, exit/proliferate etc., - in fact, there seems to be a nearly infinite number of “pathways” pathogens can use to accomplish these things, addition to an equally impressive number of host cells requiring further ‘card-shuffling’ (i.e., new combination of pathways used). So there is a substantial number of ways for host cells/immune systems to RESPOND to LPSs, teichoic acids, extracellular matrix material & so on. Also, different cells take up pathogens through a multiplicity of mechanisms (pinocytosis, endocytosis, zipper mechanisms etc…). It’s more about “how the host responds” to a material (e.g. LPS) rather than “what is prompting a response”.
Maybe a useful extract from “Candida albicans interactions with epithelial cells and mucosal immunity” - How do ECs discriminate between the yeast and hyphal form of C. albicans?
“Given the apparent importance of hypha formation in pathogenicity and epithelial activation, determining how ECs are activated by the yeast and hyphal form of C. albicans is of fundamental importance. To this end, recently a novel mechanism was identified that enables oral ECs to discriminate between C. albicans yeast and hyphae. Oral ECs orchestrate responses to C. albicans via NF-κB and a bi-phasic MAPK signaling response. Activation of NF-κB and an initial, transient MAPK response, resulting in activation of the c-Jun transcription factor, is independent of morphology and thus activated by both yeast and hyphae. However, activation of a second, stronger MAPK response, resulting in activation of the c-Fos transcription factor and production and stabilisation of the MAPK phosphatase MKP1, is specifically associated with hypha formation and correlates with proinflammatory responses and cell damage. A key finding was that the hypha-mediated response was strongly dose-dependent, indicating that this MAPK/MKP1/c- Fos activation system may constitute a ‘danger response’ mechanism that permits epithelial tissues to remain quiescent in the presence of low fungal burdens whilst responding specifically and strongly to damage-inducing hyphae when burdens increase. If so, this mechanism may be critical to the host’s ability to identify when this normally benign fungus has become pathogenic.”
@Dr. Art Ayers
I ask because I haven’t had the time to delve into mycotoxin research and trying to distinguish if European safety levels in coffee are adequate and those in the US are inadequate (according to Dave Asprey, in terms of avoiding chronic low-dose exposure). I’m guessing you don’t worry about such an effect then?
https://www.bulletproofexec.com/one-ugly-mug-the-science-bwehind-just-one-mold-toxin-in-your-coffee/
https://www.bulletproofexec.com/100-coffee-titan-dan-cox-on-caffeine-coffee-and-mycotoxins-podcast/
My other reason for asking is because a lot of focus is being placed on ‘classical’ microbial gut bugs but mycotoxins/spores/virions are being somewhat ignored in terms of inclusion into this ‘working framework’ that is being built for understanding the nature of our microbiota.
Thanks
Dr Ayers,
I would just like to add my thanks to you for making your knowledge and ideas available on the web.
Inflammatory conditions are tricky. I was told I had Prostatitis, then non-bacterial prostatis, and now "Pelvic pain syndrome". This appears to be a way for Doctors to say, "yes , there is something wrong with you but we don't know what it is or how to treat it". One of my sypmtons is ED. Both you and Dr BG on Animal Pharm address this issue and point to the "usual suspects"...high blood pressure, overweight, lack of excersize. I can assure you both that the world isn't that straight forward: I have 13% body fat, optimal blood pressure, and get plenty of excersize. Anyway....not looking for advice just simply pointing out that the eteology of inflammatory conditions is not a one size fits all....
I really think you should consider getting your ideas and theories out in a book. I'm sure it would be very well recieved.
Isn't it HbA1c instead of HgA1c? I don't think it has anything to do with mercury.
Greetings, Dr. Ayers!
I've followed your blog for some time now and am very happy to see you start posting again. I was dismayed when you stopped last year and hadn't returned since just this last month. It was a lot to catch up on!
First, I think you're an excellent teacher in that you provide excellent carrots on sticks for us inquisitors to follow down into deep rabbit holes of knowledge.
Second, a few questions with a prefaced explanation.
You speak of "adult flora" with respect and in contrast to the "infant flora" induced by maternal milk. This flora seems to involve sufficient levels of (commensal?)e. coli, which I believe contributes to a healthy flora due to its biofilm production. I.E. sufficient e. coli creates a biofilm that holds together other commensal flora. Further, my second assumption involves the suspicion that adequate levels of LPS-binding in the gut are necessary for the regulation of inflammation through some form of instantiated, close-looped process that does not result in overt inflammation.
My first question is, am I correct in the assumption that healthy adult flora is dependent on e. coli biofilm production? If so, what strains of e. coli are commensal and where can they be reliably found?
My second question involves the possibility of low levels of LPS binding yielding a positive response on immune regulation. How plausible is this?
Thank you again. I look forward to your insight.
This just in from the American College of Cardiology 2014 Scientific Sessions: A retrospective study presented on March 29 at the sessions associates celiac with a nearly double risk for CAD. The ACC released findings through heartwire, Medscape etc. I haven't found a published paper, though. Principal is R.D. Gajulapalli from Cleveland Clinic.
Hi Prof Ayers,
Extremely informative blog! Our son had severe expression of genetic condition when he was given antibiotics 12 years ago. Restoring his gut with Body Ecology type diet and sulfur eliminated his symptoms.
Both of us had symptoms after mold exposure and had to restore again. Four years ago, my older daughter and I started a Fermentation Festival in Santa Barbara. Many people are desperate for this info. Would love to have you be a participant this year. Can't find other contact info for you. Could you contact me at lynn@cultivateevents.com?
Wow. What a gold mind I found in here!So much information!
I would be very interested in your opinion about iodine, e.g supplementing with it, and by much higher doses than the RDI (150mcg). (I did not find any iodine related articles here.)
Have you any experience on this subject, since iodine seems to have very profound influence on our immune system, starting from gastric lining up to the glandular health (breasts, thyroid, ovaries, prostate etc.)?
Thank you!
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