Chronic inflammatory diseases are becoming increasingly important, especially in the western world:

• Doubling of allergy sufferers in the last 20 years (Schlaud M et al. 2008, Bundesgesundheitsblatt 50: 701-710)
• Incidence of Crohn's disease more than doubled in 24 years (Jacobsen BA et al. Eur J Gastroenterol Hepatol. 2006; 18:601-6)
• Multiple sclerosis today almost 3x more common than in 1970 (Alonso A, Hernan MA. Neurology 2008, 8;71:129-35)
• Autoimmune diabetes mellitus increased by 70% in 12 years (Mayer-Davis ENE Engl. J Med. 2017; 13:1419-29)
• Increase in the prevalence of periodontitis since 1997 by 26.9% (35-44 year old adults) and by 23.7% (senior citizens > 65 years) (Schiffner U et al. Community Dent Health 2009;26:18-22 Oral health in German children, adolescents, adults and senior citizens in 2005)

What do chronic inflammatory diseases have in common?

Inflammatory diseases are based on loss of immune tolerance: A good immune system controls both attack (i.e. the ability to eliminate pathogens or tumor cells effectively and quickly) and tolerance (i.e. the ability not to attack endogenous cells, commensal pathogens or trivial allergens).
They are therefore all based on immunological "overreactions" against:

• Allergens: hay fever, drug allergies etc
• Autoantigens: Type I diabetes, Hashimoto's, multiple sclerosis, celiac disease, ulcerative colitis etc
• (commensal) infectious agents: periodontitis, Crohn's disease, candidiasis etc

Loss of immune tolerance can have various causes - such as: stress, biocides, electromagnetic fields, plasticizers, unhealthy diet, titanium, plastics, industrial toxins, metals etc. (Source: Pall, Dr. (PhD) ML: Explaining 'Unexplained Illnesses')

How can I diagnose systemic inflammation?

Increased immune activation, measurable by:

• TNF-alpha
• IP-10
• Histamine --> Evidence of a mast cell-associated inflammation

mitochondriopathy, measurable by:

• ATP (adenosine triphosphate = the "cell energy" produced in the mitochondria)  low intracellular ATP can be an indication of a disturbed mitochondrial function of the leukocytes

Oxidative stress, measurable by:

• MDA-LDL: increased MDA-modified LDL as an indication of significant lipid peroxidation as a result of oxidative stress

Nitrosative stress, measurable by:

• Nitrotyrosine: increased nitrotyrosine indicates increased formation of nitrogen monoxide (NO)

The immune activation is at the center of the inflammation:

3 types of inflammation related to the immune system:

1. Inflammation by mast cell activation

• Mast cells are part of the innate immune system
• Immediate defense against infection at the interface between the body and its environment
• Have messenger substances like histamine stored
• Histamine is a messenger substance in the inflammatory reaction to cause tissue swelling (blood vessels become more permeable so that the immune cells can get into the affected tissue more easily; since more liquid gets into the tissue, it swells)

2. Inflammation by macrophage activation

• Scavenger cells belong to the leukocytes
• Kill antigens
• The tumour necrosis factor (TNF) is a signaling substance that is mainly released by macrophages

3.Inflammation by T helper cell activation (lymphocytic inflammation)

• T cells are part of the acquired ("adaptive") immune system
• A distinction is made between T killer cells (“kill off”), T helper cells (“sound the alarm”) and regulatory T cells (prevent excessive attacks on intact body cells)
• T helper cells produce inflammatory cytokines such as TNF-alpha, interferon (IFN)-gamma and interleukin 2 (IL2) and thus activate macrophages, NK (natural killer cells / part of the innate immune system) and T- Killer cells (part of the adaptive immune system / recognize foreign cells via antigens)

Possible effects of chronic inflammation on

immune system

• Inflammation symptoms
• Oxidative/nitrosative stress through induction of oxygen and NO radicals

nervous system

• Depression: inflammation-mediated tryptophan degradation reduces serotonin
• Sleep disorders (melatonin is formed from serotonin)

hormonal system

• Inflammation increases ACTH production and thus cortisol levels
• Chronically high cortisol levels reduce testosterone and estrogen production
• Infertility and loss of libido can thus be indirectly attributed to chronic inflammation

muscles

• Inflammation increases protein catabolism, decreases transmembrane potential and increases pain perception
• Muscle pain (myalgia) can thus be the result of chronic inflammation

bones (osteoporosis, periodontitis etc)

• Proinflammatory cytokines play an important role in destroying inflamed joints
• In rheumatoid arthritis, TNF, IL-1, IL-6 and IL-17 increase the activation of osteoclasts and thus induce bone destruction

In the event of an existing inflammation, the immune system draws on all energy and vital substance reserves

Therefore, therapy for chronic inflammation starts on two levels:

1. Search and elimination of the individually relevant triggers of the inflammation
2. Diagnosis and therapy of cellular functional deficiency: supplementation of trace elements, vitamins, antioxidants etc

Specific therapy approaches for chronic inflammation

1. Suppression of Toll-like receptors by adaptogens (immunomodulators)

What are toll-like receptors (TLR)?

TLR are part of the innate immune system, are usually located on the cell surface of macrophages (but also on mast cells, B lymphocytes, on the intestinal epithelium, etc.) and serve to recognize pathogens by recognizing structures that only occur on pathogens. In this way, the immune system can differentiate between endogenous and exogenous substances. If such a pathogenic structure is recognized, the TLR initiate the immune reaction (including via cytokines such as TNF-alpha, IL-1, IL-6) and modulate it.

According to the current state of knowledge, there are 13 different TLRs that react to different pathogens.

The anti-inflammatory effect of many naturopathic preparations can be explained by the suppression of toll-like receptors (TLRs) on macrophages:

• Curcuma extract: "Inhibition of homodimerization of Toll-like receptor 4 by curcumin." (Biochem Pharmacol. 2006;72:62-9)
• Cinnamon (e.g. contained in the liver and detoxification complex CLEAN): "Cinnamaldehyde suppresses toll-like receptor 4 activation mediated by through the inhibition of receptor oligomerization" (Biochem Pharmacol.2008; 75:494-502)
• Vitamin D3/K2: “Vitamin D3 down-regulates intracellular Toll-like receptor 9 expression and Toll-like receptor 9-induced IL-6 production in human monocytes” (Rheumatology 2010; 49:1466-71)
• Resveratrol: "Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol" (J Immunol. 2005; 175:3339-46)

What potent adaptogens are there in Ayurveda and Traditional Chinese Medicine?

• Ayurveda: Brahmi, Ashwagandha, Shatavari
• TCM: Medicinal mushrooms (due to their beta-glucans) such as Agaricus blazei (almond mushroom), Hericium or Reishi

2. Reduce Advanced Glycation Endproducts (AGE): Nutrition and Antioxidants

What are AGEs?

Advanced Glycation Endproducts are cross-linked structural proteins and can be considered as “fuels” of systemic inflammation. They are formed by the irreversible “gluing” (glycation) of proteins, lipids and nucleic acids with sugars (fructose, glucose and galactose).

AGEs bind to the RAGE receptor of monocytes, macrophages and endothelial cells. By activating transcription factors such as NFkB, this leads to the formation of pro-inflammatory messenger substances such as TNF-alpha, IL-1 and -6, IGF-1 (insulin-like growth factor).

How do AGEs arise?

AGEs can either be supplied directly through certain foods (exogenous) or form in the body over several weeks (endogenous):

Exogenous:

• Foods with a lot of saturated fatty acids are usually rich in AGE, such as meat, cheese or sausage. But also the way food is prepared, such as grilling, roasting, deep-frying or cooking for a long time can increase the AGE percentage many times over.

Endogenous:

• Sugar from food, e.g. in cereals (wheat), cake, chocolate, etc., reacts irreversibly with endogenous proteins, lipids, nucleic acids to form so-called early glucation products, which become AGEs over the course of several weeks
• Endogenous AGE formation is induced by high blood sugar levels. Therefore, all foods that greatly increase blood sugar levels should be avoided if AGEs are to be reduced. Wheat, for example, is digested very quickly by amylase, causing blood sugar to rise sharply and is therefore a strong AGE-former.
• Independent of the blood sugar level, however, oxidative stress also promotes AGE formation. Therefore, factors that trigger oxidative stress (e.g. cigarette consumption) must be identified and prevented. In addition, the body's own enzymatic antioxidant system should be supported by supply of antioxidants through food or through supplements.

3. Intestines as a potential source of inflammation: treat leaky gut and candida with medicinal mushrooms

Since inflammation stimulation with antigens takes place primarily via the intestine, the intestine should always be examined in the case of chronic inflammation.

"Leaky Gut": These are microscopic holes in the gut. Small intestine cells only have a mean lifespan of about five days as they are always exposed to toxins, pathogens etc, so they need to regenerate quite frequently. Some substances even reduce the service life to only about two days. If, for example, the micronutrients required for the regeneration of the small intestine cells are missing and substances such as gluten loosen the connection between the cells, then undigested food proteins or toxins can get into the body through these microscopic holes, which promotes various chronic diseases such as Autoimmune diseases, diabetes, allergic diseases, high blood pressure.Autoimmune diseases in particular are very often associated with leaky gut

The vital mushroom Hericium can accelerate the regeneration processes in leaky gut by stimulating the intestinal epithelium to grow. However, with leaky gut, it takes about 6-8 months much longer than in the stomach for the mucous membrane to be "patched up" and regenerated.

It is always important not just to rely on the fungi, but always to keep an eye on all the micronutrients: If, for example, the intestinal cells lack building substances and growth factors due to a vitamin D deficiency, the diet or lifestyle should be changed or in this case vitamin D supplemented and e.g. gluten removed from the diet.

Candida: Another typical small intestine disease is fungal infestation by Candida albicans, which can cause flatulence, abdominal pain or diarrhea. Colonization of the small intestine by bacteria or candida is usually associated with colon dysbiosis, i.e. an imbalance in the intestinal flora, or with hypoacidity in the stomach, so that pathogens can get into the small intestine via the stomach.

In these cases, the Shiitake is the first choice, as it is a natural antibiotic and can thus effectively remove pathogens from the small intestine. Incidentally, many people show a detoxification reaction when taking shiitake in larger quantities or concentrated as an extract, which is often misinterpreted as intolerance.

On the antimicrobial effect of Shiitake see also https://pubmed.ncbi.nlm.nih.gov/15773410/ "The juice of this mushroom at a concentration of 5% from the volume of the nutrient medium was found to produce a Pronounced antimicrobial effect with respect to C. albicans, S. aureus, E. faecalis, E. coli O-114 and to stimulate the growth of E. coli M-17. Bifidobacteria and lactobacteria exhibited resistance to the action of L. edodes juice."

4. Reduce oxidative stress through antioxidants

We will go into more detail on the topic of antioxidants in a separate article.

At this point it should only be mentioned that the body has an enzymatic antioxidant system that has the task of defusing free radicals. Free radicals are highly reactive and can damage tissue and trigger inflammatory reactions. If this endogenous, enzymatic antioxidant system is overwhelmed by strong oxidative stress, supplementing with antioxidants can help.

An antioxidant complex should always be used in which the individual components have a synergistic effect, e.g. by regenerating each other. Such a synergistic relationship exists, for example, between vitamins C and E. Because by reducing a free radical, the vitamin itself is oxidized (= to become a free radical) and can then in turn be reduced again (= "defused") by the other vitamin. Alpha-lipoic acid is not only a strong antioxidant itself, but is also potent in the regeneration of other antioxidants and should therefore not be missing in any good preparation.

5. Influence of unsaturated fatty acids on inflammatory processes

Unsaturated fatty acids are starting materials for eicosanoids ("tissue hormones"), which have important control tasks: in addition to cell division and platelet aggregation (blood clotting), they are primarily involved in inflammatory processes.

Important eicosanoids are

• prostaglandins
• Prostacyclins
• thromboxanes
• leukotrienes

Arachidonic acid (the "bad" omega 6 fatty acid) is metabolized into

• Prostaglandins 2 series
• thromboxanes
• leukotrienes 4 series,
• ...all contributing to acute inflammation!

The omega 3 fatty acid EPA on the other hand is metabolized in

• Prostaglandins 3 series
• Leukotrienes 5 series
• E-Resolvine (E1 inhibits the migration of inflammatory cells into the inflamed tissue and the formation of the messenger substance interleukin 12),
• ..which contribute to the active resolution of the inflammation!

DHA is also metabolized into inflammation-dissolving lipid mediators, especially into protectins and D-resolvins: Resolvin D2 causes endothelial cells to produce nitrogen monoxide, which causes the adhesion of leukocytes and thus their Immigration into the inflamed tissue is prevented.

Despite strong similarities in molecular structure, the biological functions of omega 3 and omega 6 fatty acids are very different:

Omega 3 fatty acids...

• supply only the "good" eicosanoids and inhibit the formation of "bad" eicosanoids from arachidonic acid
• have anti-inflammatory, antirheumatic, cardioprotective and promote the intellectual development of the embryo

Omega 6 fatty acids

Omega 6 fatty acids can form anti-inflammatory (linoleic and linolenic acid), as well as pro-inflammatory (arachidonic acid / see above) and even carcinogenic eicosanoids (Omega 3, on the other hand, only forms the "good", anti-inflammatory eicosanoids (+/-))

If large amounts of "good" omega 6 fatty acids (linoleic/linolenic acid) accumulate, more pro-inflammatory arachidonic acid can be formed! Therefore, the ratio of omega 6 to omega 3 is important.

The body needs the enzymes delta-6 and delta-5 desaturase to convert plant-based ALA into EPA/DHA. However, these two enzymes are also required to convert the omega 6 fatty acid linoleic acid into other omega 6 fatty acids. By reducing the omega 6 fatty acid content in food, the body has more enzymes available to convert ALA into EPA/DHA.

Interesting: In the Stone Age, the ratio of omega 6 to omega 3 was 4:1. Due to cattle breeding, fattening and farming, the ratio of omega 3 fatty acids has continued to deteriorate and is now ~20:1 in western societies (the DGE recommends a ratio of 5:1)!

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