Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Thursday, July 16, 2009

Chronic Disease, Cryptic Infections, Hibernation

Suppression of Inflammation and Surviving Cytokine Storms

There are numerous unanswered questions in modern medicine. What is aging, for example? Why do people become more inflamed as they age? What’s with all of the chronic, degenerative diseases? Why is lipid metabolism (LDL, HDL, triglycerides) linked to degenerative diseases, along with immune system function and inflammation? I am only going to start the answers here.

I might as well continue to be cryptic and give you the string of words/concepts I am trying to connect to answer the other questions:
Hydrogen sulfide (H2S), endorphins, hibernation, nuclear receptors (PPARs), antibiotics, chronic inflammatory diseases (fibromyalgia, arthritis, chronic fatigue, Lyme, Morgellon’s, Alzheimer’s, prostatitis, pancreatitis, cancers, etc.), autoimmunity, leaky gut/kidney/brain barrier, autism and H1N1.

First a word of advice: Beware of assuming that molecules are specific, i.e. with unique interactions, and that a small molecule will bind to one and only one protein target. [There are lots of bizarre exceptions to the assumption: Aldolase acts as a structural protein for Toxoplasma motility. Fluorescein is added to make protein fluorescent, but the fluorescein is also transported into cells on its own, i.e. fluorescein and rhodamine labeling can give different results. Heparin binds to most extracellular proteins and it is mostly a hydrophobic interaction -- heparin is not just for clotting anymore.]

Observations from the literature:
  • Maternal autoimmunity is linked to autism.
  • Autism is linked to leaky gut and chronic inflammation.
  • Gut/kidney/brain barriers are based on integrity of extracellular matrix (heparan sulfate) that is compromised by inflammation.
  • Chronic diseases require inflammation and circulating inflammatory cytokines (TNF, IL-1, IL-6) are elevated..
  • NSAIDs induce leaky gut and release of bacteria toward liver.
  • Phagocytosis of bacteria leads to transport of some bacteria, e.g. Chlamydia pneumoniae to other sites of inflammation, e.g. gut to joints.
  • Opiods can induce hibernation in rodents.
  • Sulfides can induce hibernation in rodents.
  • H1N1 my cause lethal pneumonia by lung cytokine storm.
  • Inflammatory cytokines and inflammation result from activation of NFkB.
  • Hibernation involves PPARs (another nuclear receptor transcription factor).
  • Omega-3 fatty acids reduce inflammation via COX-2 prostaglandins, but also by binding to PPARs.
  • For most of the diseases under consideration, suppression of inflammation will eliminate symptoms.
  • Antibiotics can impact all of these diseases in unpredictable ways. In some cases complete remission can be achieved and in other cases antibiotics can produce lethal cytokine storms.
  • Bacterial cell wall components, e.g. lipopolysaccharide, lipid A, are intensely pyrogenic, i.e. inflammatory.

Cryptic Bacteria in our Tissues

The role of bacteria in numerous diseases, including cancers, has been proposed since the early isolation of bacteria from human tissues. Many of these bacteria are difficult to culture and have variable forms viewed by microscope. Because these bacteria are difficult for microbiologists to handle with conventional approaches, their existence and significance has always been questioned. Use of antibiotics to treat chronic, inflammatory conditions has seemed inconsistent with the unproven existence of a bacterial cause. Thus, there is surprise when the inappropriate use of antibiotics leads to a cure.

Cryptic Bacteria Suppress Local Inflammation and Promote Chronic Inflammation

I think that the fundamental problem is the assumption that human tissue is sterile, i.e. free from microorganisms, such as bacteria, unless there is overt infection. Part of the sterile assumption derives from the intense inflammatory response to bacteria. In order for bacteria to survive in tissue, the bacteria must suppress inflammation and the tissue must tolerate the slow leaching of inflammatory bacterial materials.

Chronic Disease Hypothesis

Based on the cryptic bacterial infection hypothesis, many, if not all chronic diseases are initiated by inflammatory events that release bacteria into the blood stream carried in phagocytic cells. The cells migrate and take up residence at a region of inflammation. The bacteria produce molecules that produce tissue hibernation and quell local inflammation in response to the bacteria. The bacteria are, however, a source of ongoing irritation to the tissue and a chronic inflammatory disease results.

Eradication of Cryptic Bacteria

Antibiotics would be a typical choice for killing infecting bacteria. In the case of cryptic, chronic infections, however, application of therapeutic antibiotics may be problematic. The established infections may have produced privileged locations isolated from the vascular system and protected by a bacterial community, e.g. a biofilm. Alternatively, the death of the bacteria and release of pyrogenic factors my produce life-threatening inflammation, that requires careful support.

Hibernation in Rodents Provides Treatment Clues

The compromise of tissue inflammation in response to cryptic bacteria is similar to the physiology of rodent hibernation. In both cases, systemic inflammation is suppressed. At the cellular level, this means that other signaling pathways silence the inflammatory NFkB expression pattern. One of the major nuclear receptors that is activated in hibernation is PPAR. PPAR is activated by opiods and H2S, which also induce hibernation in rodents. There are numerous analogs, inhibitors and H2S donors that could be used to disrupt hibernation (free local suppression of inflammation) or reduce symptoms by suppressing systemic inflammation.

Inflammation Compromises Tissue/Blood Barriers

Inflammation causes a disruption of the integrity of the endothelial extracellular matrix at sites of local inflammation. NFkB activation shuts down the expression of genes involved in heparan sulfate proteoglycan (HSPG) synthesis makes the tissue/blood barrier leaky. Locally this facilitates the recruitment of lymphocytes and neutrophils for defense, but systemically it leads to leaky gut/kidney/brain barriers that permit bacteria to cross.

Convergence of Therapies to Attack Cryptic Infections

The central approaches to attack cryptic infections are a combination of antibiotics and suppression of cytokine storms. These approaches are used in Marshall’s Protocol [ ], which also exploits a vitamin D receptor antagonist, Olmesartan, that also inhibits NFkB and inflammation.

A similar protocol has been developed by Dr. Michael Powell to inhibit hibernation and attack cryptic infections:

These approaches are similar to the lengthy use of antibiotics for the treatment of chronic Lyme disease.

It is very interesting to note that some of the most effective treatments for a long list of degenerative chronic diseases, autoimmune diseases and cancers, use essentially the same protocol that should attack cryptic bacteria and provide support for ensuing inflammation.


Anonymous said...

Dear Dr. Ayres,

I am just a layperson whose son has been recently diagnosed with PDD-NOS, so I am reading all I can about inflammation and ways of controlling it.

The protocol suggested by Dr. Marshall seems to have one big disagreement with you. Whereas you actively promote high dose Vitamin D with Omega 3 fish oils, the Marshall protocol suggests that almost any intake of Vitamin D be avoided at all costs, including obsessive avoidance of sunlight.

Which view towards Vitamin D intake and sun exposure is the correct one?

Dr. Art Ayers said...

I don't think that the vitamin D component is a strong point of the Marshall Protocol. It is not clear if the drug used to turn on the vitamin D receptor, Benicar or Olmesartan, is effective, since the only data presented are protein modeling/docking.

It must be kept in mind that the most important aspect of the protocols is to make the financial model of the treatment secure. This is difficult if the treatment is simply to attack the cryptic, perhaps biofilm-entrenched, bacteria with antibiotics and protect the body from subsequent, potentially lethal inflammation.

I believe that most people suffering from chronic diseases have a large resident population of diverse bacteria. If those bacteria suddenly die, then conditions analogous to toxic shock will ensue. It is difficult to kill a complex population of bacteria with antibiotics and it is difficult to treat cytokine storms resulting from massive presentation of bacterial pyrogens.

Marshal's use of benicar may be just to suppress inflammation through its effects on NFkB, the inflammation transcription factor. This effect makes sense and the action on the vitamin D receptor and the rationale for vitamin D avoidance is to me unsupported. Marshal is not a medical doctor, nor is his spokesperson Amy Proal.

Returning to your son's condition. The symptoms of the chronic infections treated with Marshal's Protocol are related to inflammation. My anti-inflammatory diet and lifestyle recommendations will reduce the symptoms. Vitamin D acts as both an anti-inflammatory, as well as an activator of innate immunity.

For minimizing symptoms in a safe manner, I would personally pursue the general anti-inflammatory approach. For treatment using long term antibiotics, I would seek medical advice from a rheumatologist.

Good luck.

Anonymous said...

Thanks Dr. Ayres.

My wife and I are currently pursuing the anti-inflammatory diet and lifestyle for our son. We've done the following:

1 -- Glutein free / Casein free / Soy free / Corn free diet -- can't kick the rice and potatoes for snacks for a 2 year old

2 -- 1 tsp of Omega 3 fish oil

3 -- multivitamin supplement with lots of Vitamin A and B complex

4 -- 300 mg of Vitamin C

5 -- strong probiotics (20 billion units)

6 -- digestive enzymes

7 -- lots of sunshine for vitamin D production

The Vitamin D is what I was worried about given the "Th1 Infection" theory about underlying infections from Amy Proal and Dr. Marshall.

Dr. Art Ayers said...

I think that you have a good anti-inflammatory diet. I assume that your 2 yr old is getting plenty of different meats, fish and vegetables.

[Since my wife is a lactation consultant and I previously did research on passive immunity, I feel compelled to mention that a healthy approach would be to continue breastfeeding until at least 2 yrs of age. Longer is better. Breastfeeding during the transition to solid food is best and formula is best avoided altogether, since it promotes inflammatory gut flora.]

My impression from the literature is that being in a low inflammatory state should optimize solar vitamin D production and eliminate the need for supplements. Most people use vitamin D supplements to lower their inflammation to a manageable level.

For my kids, I would eliminate the use of typical vegetable oils (corn, soy, safflower, etc.) since these are highly inflammatory due to their high omega-6 oil composition. Switch to olive oil and butter for cooking.

I don't worry much about dairy. Cheese and fermented products are great by me. Eggs are great, especially from free-range and omega-3 supplemented chickens. Bacon is much safer than margarine. High fructose corn syrup will be forced from commercial use as dangerous to health. Minimize fruit juices (just high fructose, minimal benefit).

All that I am advocating is returning to whole foods and avoiding cooking oils, starch and sugars.

If your son has signs of chronic inflammation damage (or food allergies), then treating the symptoms is the safest approach. Vitamin D supplements would only be suggested if his blood work showed a deficiency. If he is getting plenty of brief exposures to sun (no sunburn and control length of exposure instead of sun block) and still has a vitamin D deficiency, then that is another indication to me of chronic inflammation.

I think that the fear of heavy metal exposure from eating fish is overblown, but oily fish in the diet and omega-3 supplements may need to be increased to see if behavior improves. It is important to get a handle on any symptoms indicative of rising chronic inflammation, because ASDs appear to be based on gut/brain/blood barrier disruption due to systemic inflammation. Omega-3 fish oils can reduce this risk.

I hope this helps. Thanks for your comments.

Anonymous said...

It definitely helps.

One extra note: The Marshall Protocol has to be absurd in avoiding vitamin D (even the sunlight variety) because it fails to consider evolutionary pressures. If it were so easy for L-shaped bacteria to leach on to us, then our ancient ancestors (the hunter gatherer ones) would have shown a lot of evidence for chronic illness. The fossil and bone record shows the opposite (no arthritis and teeth in tact even for 40-50 year olds). That's not the case for those who diet after the advent of ancient agriculture. The hunter gatherer ancestors were out in the sun all day, so the idea of vitamin D promoting stealth bacteria would have been selected out.

One more comment: my son only eats turkey, chicken, and eggs (the organic +Omega 3 variety you talk about). I can't get him to eat fish anyway, so we supplement with fish oil.

Dr. Art Ayers said...

I felt I was secure in the knowledge of my oldest daughter's ( then 3 yrs old) eating preferences, until we went to visit grandma's friends at a dress-up cocktail party. All of the ladies were seated with napkins, plates and tiny forks in their laps and the hostess was providing each with a delicate smoked oyster. My daughter, who "never ate fish", walked up next to her grandma, smiled and quickly popped three oysters in her mouth with her dextrous little pudgy hand, and said "mmmm."

shel said...

what a find.

you're going in my favorites.

Bill said...

Dr. Ayers,
I have read recently from a number of sources, that it can take up to 48 hours to absorb the full benefits of exposure to strong sunlight. The guideline seems to be to avoid washing the exposed skin areas for up to 2 days.
What is your take on this? Seems logical to me.

Bill said...
This comment has been removed by the author.
Bill said...

Another interesting view, regarding full spectrum sunlight and inner health.

I have not worn sunglasses this year, and I don't seem to squint as I used to in sunlight.
Dr. Ayers, as a spectacle wearer, have you looked into this?

Dr. Art Ayers said...

I have occasionally run across experiments that implicate different parts of the UV spectrum for health. Much of the benefit is attributed to vitamin D production. I have not seen anything about slow development of vitamin D following solar exposure. I have no way of introducing a slow aspect to the relatively simple light/enzyme reactions involved.

I must admit that my goal is to provide a molecular explanation to explain disease and I dwell on traditional approaches as a rich source of time-tested contributing observation. The experiments and observations by John Ott, which you reference are provocative. As noted, there is limited possibility of making money off them and they displace billion dollar businesses.

From my perspective, someone needs to provide some thought into the molecular explanation of the Ott observations. I, of course, would look for an inflammatory angle related to heparan sulfate-mediated signaling.

My prejudices from working with UV make me fearful of short wavelength UV below 300nm, so I am still hesitant to get too much sun exposure without UV protection for my eyes, but I can be convinced by some data. Ott wasn't a research scientist and couldn't get data. That is a shame. The experiments needed to support his claims are probably already done, but used for other purposes. I will keep my eyes (and mind) open.

Dennis Mangan said...

Dr Ayres, what evidence or even suggestion is there that cryptic bacteria in tissues cause disease?

Dr. Art Ayers said...

Your question is at the core of the discussion of cryptic bacteria. If these difficult to isolate-identify-culture bacteria could be demonstrated to cause disease (Koch's Postulates), then there would be no discussion. Absent the obvious proofs of medical cause of infectious disease, then alternative evidence must be evaluated.

Diverse bacteria in abundance can be identified by molecular techniques in all human tissues, i.e. human tissue is not sterile or axenic.

The cause of most common diseases is embarrassingly lacking. What initiates cancer, cardiovascular disease, allergies, autoimmune diseases? Bacteria at least provide a potential answer, since they are present at the right time and the right place.

Antibiotics cure diverse diseases. This argument assumes the specificity of antibiotics to act on bacteria, but the fact remains that antibiotics can work were the rest of medicine cannot.

The molecular biology from bacterial infection through physiological response is starting to make sense. What causes cardiovascular disease? The literature is abundant on contributing factors, but the molecular biology is missing key steps. In the end, genetic predispositions are invoked. Cryptic bacteria connect all of the dots.

The biggest problem with cryptic bacteria causing disease is that it provides a simple, cheap solution to most diseases. The health care dilemma that is eating the public's wallet and glutting the medical and insurance industries would be decimated. Most expensive procedures and specialists would be unnecessary. Imagine going to a nurse and being told that you have pancreatic cancer and that you would die unless you took the pills that cost $100 and would cure you in a month.

Cryptic bacteria require a paradigm shift to be seen simply as pathogens that cause complex diseases, but they explain disease better than the current hypotheses.

Thanks for your comments.

Robert Andrew Brown said...

Dr Ayers

Fascinating material.

My mind goes numb thinking about the amount you must have rattling in your brain.

I need to find time to read it all. (-:

Anonymous said...

Dr. Ayers,

your comments on this please :

Dr. Art Ayers said...

The Mercola website has a lot of information on how to treat Lyme disease. Some of it is just the dietary and simple local remedies that I describe to reduce inflammation. Some of it is taken from general treatments to "stimulate the immune system" or reduce "toxins". I don't think that these components do anything. Unfortunately there are no data to show if the system actually works. I assume that some medical people in the Lyme disease community have had experience with the protocol and know if it is effective.

It is difficult to assess procedures outside of the established science. I don't understand many of the physiological concepts that are invoked so they may be either naive or progressive.

Thanks for bringing the material to my attention.

Cristian Stremiz said...

An interesting protocol for Lyme disease:

3 grams of salt and 3,000 mg of vitamin C, 4 times per day

And the theory behind it's even more interesting: the no salt diet craze.

Any comment?

Dr. Art Ayers said...

The salt + C procedure is fascinating. There seem to be so many changes in cultural practices that parallel the increase in inflammatory disease, e.g. increase in dietary omega-6 oils, starch and sugar. I had not considered the decline in salt consumption.

It is interesting that anionic polysaccharides hold together the extracellular matrix (chondroitin sulfate and heparan sulfate) of animals and plants (pectin). Magnesium, calcium and zinc are important in cross-linking animal anions, whereas boron is important in plant cell walls.

Anionic polysaccharides and nucleic acids form the matrix of biofilms and in this case magnesium and calcium are cross-linkers.

In all of these cases, the polysaccharides act as a large matrix to which the divalent cations bind. It is very similar to the ion exchange resin used in water softener to exchange calcium in water for sodium initially bound to the resin. The divalent calcium binds more strongly and the sodium is displaced into the water. Sodium in water makes it softer. To recharge the exchange resin, a concentrated solution of sodium chloride is passed through the calcium saturated resin and the calcium is displaced.

This leads up to a possible reason why flushing the intestines with large doses of sodium chloride may destabilize biofilms and bacteria bound to the surface of intestinal epithelial cells. This would seem to be a variant on the biofilm stripping approaches that I discussed previously.

I enjoy seeing a cultural explanation for health issues. My father used to recommending "dosing with salt" as a general cure. Thanks for bringing this to my attention.

Cristian Stremiz said...

Interesting abstract on capsaicin

Intake of Capsaicin found in Red Pepper May Prevent Obesity-related Insulin Resistance, Hepatic Steatosis, and Diabetes
Kang JH, Tsuyoshi G, et al, Obesity, 2009 Oct 1;
Department of Food Science and Nutrition, University of Ulsan, Ulsan, South Korea).
Summary: In a study involving obese mice fed a high-fat diet for 10 weeks, supplementation with capsaicin (0.015% capsaicin) was found to reduce fasting glucose, insulin and leptin levels, in addition to reducing inflammation (decreases in levels of TNF-alpha, MCP-1, IL-6 mRNAs and proteins in adipose tissue and liver), and reducing macrophage infiltration, hepatic triglycerides, and TRPV-1 expression in adipose tissue as well.
Increases in mRNA/protein of adiponectin in the adipose tissue and PPARalpha/PGC-2alpha mRNA in the liver were found to be associated with capsaicin intake.
Furthermore, capsaicin was found to be capable of binding with PPARalpha.
Moreover, supplementation with capsaicin was found to reduce the impairment of glucose tolerance.
The authors conclude, “Our data suggest that dietary capsaicin may reduce obesity-induced glucose intolerance by not only suppressing inflammatory responses but also enhancing fatty acid oxidation in adipose tissue and/or
liver, both of which are important peripheral tissues affecting insulin resistance.”

Dr. Art Ayers said...

That is another great article combining the basics of the signaling processes in inflammation: hot/cold sensors, vagus stimulation/response, NFkB/PPAR transcription factors. The PPAR binding of capsaicin relates to castor oil and prostaglandins binding to the same sensors/transcription factors. Maybe ricinoleate binds to PPAR. Why is castor oil a cathartic?

Thanks for the provocative input.

Cristian Stremiz said...

A couple more provocative inputs:

Insulin has an anti-inflammatory effect that is independent of the reduction it causes in blood glucose.

Lifespan in obese rats extended 45% by Gastric Bypass

Dr. Art Ayers said...

You seem to be tweeking me with the controversial.

In the first paper they are claiming that they can isolate the anti-inflammatory effect of insulin by comparing inflammatory markers in two set of individuals using either insulin or metformin to lower blood glucose to the same level. Insulin showed lower IL-6, CRP and Hb1aC. To me this just says that their blood glucose levels were taken at a meaningless time after meals and didn't reflect maximum blood sugar levels, that were higher with metformin.

In the second paper, I am skeptical of the results of stomach surgery for weight loss, because an analysis attributed the weight loss to screen candidates for the ability to adhere to a low carb weight loss diet. So this would be news to me, as my impression is that the surgery failed to give lasting results, just as the diets do, because people go off the diet.

Anonymous said...

The marshal Protocol indicate against Vitamin D, not because Vitamin D is bad for you, but because in this particular protocol, Vitamin D will compete with the Drug Olmesartan (Benicar) at the VDR binding site.

It is extremely telling that from this article :
Category: cancer
Not so mysterious connection between insect bites and a cancer drug

And I quote : “Contrary to mainstream thinking, ticks and other insects are able to transmit many more bacterial species then simply Borellia. Thus, people who get tick bites are more likely to accumulate a variety of Th1 pathogens – bacteria that proceed to create ligands that block the Vitamin D Receptor and subsequently the activity of the innate immune system.”