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 3 times more common than in 1970 (Alonso A, Hernan MA. Neurology 2008, 8;71:129-35)
• autoimmune-related diabetes mellitus increased by 70% in 12 years (Mayer-Davis E. N 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% (seniors > 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 loss of immune tolerance A good immune system controls both attack (ie the ability to effectively and rapidly eliminate pathogens or tumor cells) as well as tolerance (ie the ability not to attack the body's own cells, commensal pathogens or irrelevant allergens).
They are therefore all based on immunological "overreactions" against:

• allergens: hay fever, drug allergies, etc.
• autoantigens: Diabetes type I, Hashimoto, multiple sclerosis, celiac disease, ulcerative colitis etc.
• (commensal) infectious agents: Periodontitis, Crohn's disease, candidiasis etc

A 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 mast cell-associated inflammation

mitochondrial disease, measurable by:

• ATP (Adenosine triphosphate = the "cell energy" produced in the mitochondria)  low intracellular ATP can be an indication of impaired 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 nitric oxide (NO)

Immune activation is at the heart of inflammation:

3 types of inflammation related to the immune system:

1stInflammation caused by mast cell activation

• Mast cells are part of the innate immune system
• Immediate defense against infections at the interfaces between the body and its environment
• Do messenger substances such as histamine saved
• Histamine is a messenger in the inflammatory reaction to cause tissue swelling (blood vessels become more permeable so that defense cells can more easily reach the affected tissue; as more fluid also enters the tissue, it swells)

2. Inflammation caused by macrophage activation

• phagocytes belong to the leukocytes
• Killing antigens
• The tumor necrosis factor (TNF) is a signaling substance that is mainly secreted by macrophages

3. Inflammation caused 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”), T-helper cells (“raise 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

• inflammatory 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 therefore be indirectly attributed to chronic inflammation

muscles

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

Bone (Osteoporosis, periodontitis etc)

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

When inflammation occurs, the immune system draws on all its energy and vital substance reserves.

Therefore, the therapy for chronic inflammation on two levels:

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

Specific therapeutic approaches for chronic inflammation

1stSuppression of Toll-Like Receptors by Adaptogens (Immunomodulators)

What are Toll-Like Receptors (TLRs)?

TLRs are part of the innate immune system, are usually found on the cell surface of macrophages (but also on mast cells, B lymphocytes, on the intestinal epithelium, etc.) and are used to detect pathogens by recognizing structures that only occur on pathogens. This enables the immune system to distinguish between endogenous and foreign substances. If such a pathogenic structure is recognized, the TLRs initiate the immune reaction (including via cytokines such as TNF-alpha, IL-1, IL-6) and modulate it.

According to current knowledge, there are 13 different TLRs that respond to different pathogens.

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

• turmeric 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 the “fuels” of systemic inflammation. They are formed by the irreversible “bonding” (glycation) of proteins, lipids and nucleic acids with sugar (fructose, glucose and galactose).

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

How do AGEs arise?

AGEs can either be supplied directly via 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 AGEs, such as meat, cheese or sausage. But the way in which food is prepared, such as grilling, roasting, deep-frying or long cooking, can also increase the AGE content many times over.

Endogenous:

• Sugar ingested through food, e.g. in cereals (wheat), cakes, chocolate, etc., reacts irreversibly with the body's own 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 significantly 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.
• Irrespective of blood sugar levels, oxidative stress also promotes AGE formationTherefore, factors that trigger oxidative stress (e.g. cigarette consumption) must be identified and prevented. In addition, the body's own enzymatic antioxidant system is supply of antioxidants through food or supplementation.

3. Intestine as a potential source of inflammation: Treating Leaky Gut and Candida with medicinal mushrooms

Since inflammation stimulation with antigens occurs primarily via the intestine, the intestine should always be considered in cases of chronic inflammation.

"Leaky Gut": These are microscopic holes in the intestine. Small intestinal cells only have an average lifespan of about five days, as they are constantly exposed to toxins, pathogens, etc., so they have to regenerate quite frequently. Some substances even reduce the lifespan to just about two days. If, for example, the micronutrients required for the regeneration of small intestinal cells are missing and substances such as gluten break the connection between the cells, then undigested food proteins or toxins can enter 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 medicinal mushroom Hericium can accelerate the regeneration processes in Leaky Gutby stimulating the intestinal epithelium to grow. However, with Leaky Gut it takes significantly longer than in the stomach, about 6-8 months, until the mucous membrane is "patched" and regenerated.

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

Candida: Another typical small intestine disease is fungal infection 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, ie an imbalance in the intestinal flora, or with hypoacidity in the stomach, so that pathogens reach the small intestine via the stomach.

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

For 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 discuss the topic of antioxidants in more detail 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 body's own enzymatic antioxidant system is overwhelmed by strong oxidative stress, supplementing with antioxidants can help.

You should always take an antioxidant complex in which the individual components work synergistically, for example by regenerating each other. Such a synergistic relationship exists, for example, between vitamins C and E. This is because by reducing a free radical, the vitamin itself is oxidized (= into a free radical) and can then be reduced again (= "defused") by the other vitamin. Alpha-lipoic acid is not only a strong antioxidant in itself, but is just as potent in the regeneration of other antioxidants and should therefore not be missing from 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 functions: 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 of which contribute to acute inflammation!

The Omega 3 fatty acid EPA on the other hand is metabolized into

• Prostaglandins 3 series
• Leukotriene 5 series
• E-Resolvins (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 inflammation!

DHA is also metabolized into anti-inflammatory lipid mediators, especially in protectins and D-resolvins: Resolvin D2 causes endothelial cells to produce nitric oxide, which prevents the adhesion of leukocytes and thus their migration into the inflamed tissue.

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

Omega 3 fatty acids…

• provide only the “good” eicosanoids and inhibit the formation of “bad” eicosanoids from arachidonic acid
• works anti-inflammatory, antirheumatic, cardioprotective and promote the mental development of the embryo

Omega 6 fatty acids

Omega 6 fatty acids can have both anti-inflammatory (linoleic and linolenic acid) and pro-inflammatory (arachidonic acid / so) and even form 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) are present, more inflammation-promoting 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. These two enzymes are also needed to convert the omega-6 fatty acid linoleic acid into other omega-6 fatty acids. By reducing the proportion of omega-6 fatty acids in the diet, 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  at 4:1. Due to livestock farming, fattening and agriculture, the ratio has continued to deteriorate to the detriment of omega 3 fatty acids and is now at ~20:1 in western societies (the DGE recommends a ratio of 5:1)!