The clinical significance of larval, cellular inflammation in our chronic, progressive diseases

Dr. Tamás Nagy - 17/07/2018

The association between adiposity, inflammation, and insulin resistance has become increasingly known since it was first described by Hotamisligil et al. In 1993 (30).

A number of inflammatory mediators are produced in adipose tissue that  contributes significantly  for chronic inflammatory conditions and metabolic complications associated with obesity. This is a  strongly researched and well-described with evidence  a process that can link seemingly separate diseases. These include insulin resistance, hypothyroidism, depression, arthritis, varicose veins, or PCOS (polycystic ovary syndrome).
These problems are usually treated separately by those skilled in the art, although if the deep-seated disease process continues without intervention, there is a straight path to atherosclerosis through the same pathomechanism.
Thus, it is no coincidence that every second of our compatriots loses their life in a cardiovascular disease. Given that in Hungary
  a WHO European Mortality Database  based only in 2016  62,846  man died of this disease, it is by no means an exaggeration to see a more detailed mapping of this disease process. It should be emphasized that the 45-59 age group is the most vulnerable.




THE  balance of cells, tissues, homeostasis  is modern today  due to environmental impacts and nutrition.  Researcher  they claim that persistent mild, latent inflammation at the level of our cells is numerous  cardiovascular (cardiovascular), neurological  (nervous system) and cancer  plays a role in its development.
Cell damage caused by inflammatory cytokines circulating in the blood increases the amount of superoxides (free radicals) in the cell.
  also starts. The resulting "oxidative stress" further damages the  cells and new inflammatory substances are released. This completes the "vicious circle" and triggers the  premature aging and the development of chronic diseases. Inflammation also contributes to the development of diabetes, obesity and insulin resistance. Indirectly, inflammation may be associated with effects on the immune system, depression, and other neurological disorders. 

Among the influencing factors, inflammatory cytokines,  primarily TNF (tumor necrosis factor system), the  IL-6 (interleukin-6), as well as white blood cells (monocyte / macrophag chemo-attractans protein-1) and adipose tissue regulatory peptides, the so-called the role of adipokines, whose effects are predominantly auto- and paracrine, and to a lesser extent endocrine. The role of these factors in obesity is increasing: an increase in adipogenesis (fat formation) results in an increase in their production, and macrophage infiltration and low-grade chronic inflammation develop in adipose and liver tissue. 

Several studies suggest that nuclear kappa light chain enhancer (NF-κB), a protein complex in activated macrophage cells, controls DNA activation. NF-κB is involved in the regulation of numerous genes, including cytokines, cell adhesion molecules, and genes that regulate apoptosis.  



Importance of intestinal-brain axis


It is a well-known feeling when you are going through a heavier, tense period, feeling tight or trembling in your stomach. Old sayings, folk wisdoms also evoke the connection between the stomach and feelings, for example, “the path leads to a man’s heart through his belly”, “butterflies fly in his belly”, “he is egg-clean”, “he behaves stomach-turning”.

These effects have long been known to occur through the planetary alien (nervus vagus) and are independent of our determination.  The mechanism of action of the so-called efferent (regulatory) branch is known: its effect extends to the intestinal tract, where the system with the second largest number of neurons, the intestinal nervous system, is located. The cells of the intestinal nervous system are located in the wall of the gut, the number of neurons exceeds the number of cells in the spinal cord, so it is no wonder that in many publications it is referred to as a “second brain”. (1)


The relationship between the brain and the intestinal tract is two-way, and more and more reports are appearing about the exact details of this reciprocal relationship. Experts in the field can regularly read about the latest advances in this relatively new discipline, neurogastroenterology, in one of the best-known professional publications, Neurogastroenterology & Motility (2). Three key facts about the operation of the gut-brain axis are worth mentioning.


  • One is that a significant, 80–90%, of the stimuli that travel through the planetary alien run from the gastrointestinal tract, the ascending branch, and reach the brain (3). The network, also called the gut brain, thus actively communicates with the brain, and signals from the gut run into different areas of the brain.  These brain areas (the  insula, limbic system, prefrontal cortex, amygdala, hippocampus)  and they are also decisive for the spiritual and emotional world of people: self-image, morality, anxiety, memory, motivation. Of course, this does not mean that we, as our second brain, control our experiences of morality, our anxieties, but it  in any case, it means that their condition affects them. 

  • The other fact is that the vast majority of serotonin, a neurotransmitter that plays an important role in brain function, is produced in the gut. Serotonin is responsible for  among other things - for the development of a sense of happiness. (4.5)

  • The third, and perhaps most surprising, fact is probably less well known, even among professionals. Researchers at the University of Ohio have shown in mouse experiments (6) that cytokine production in experimental animals increased as a result of social stress, resulting in a very rapid and radical change in the intestinal flora of the animals. The intestinal flora of normal animals is characterized by the fact that they can contain hundreds or even thousands of strains of bacteria. In contrast, the researchers found that stress reduced the diversity of the intestinal flora and the number of bacterial strains. The decrease typically occurred among bacteria belonging to the Bacteriodes strain. Simultaneously with the decrease of beneficial bacterial strains, the proportion of pathogenic bacteria, mainly Gram-negative Clostridium, increased.



Significance of microbial alteration in the development of subclinical inflammation


Recent published research suggests that inflammation can be triggered by intestinal bacteria - through the activity of lipopolysaccharides (LPS). LPSs are components of the cell wall of Gram-negative bacteria (endotoxin) and their entry into the bloodstream can be blamed for an inflammatory condition leading to obesity (obesity) and IR (insulin resistance).

Chronic inflammation induced by low grade endotoxinemia (7).  In their experiment, Cani et al. Demonstrated that mice fed a high-fat diet for four weeks developed an obesian phenotype associated with a change in the composition of intestinal bacteria (a decrease in the proportion of Bifidobacteria and Eubacteria) while a 2-3-fold increase in circulating LPS. levels  (8).  This is called “metabolic endotoxinemia” because it is distinguished from septic shock, where LPS  plasma concentrations are much higher. 

Other observations suggest that changes in intestinal bacterial composition caused by antibiotic treatment reduce metabolic endotoxinemia and LPS levels in the coecum (colon), closely related to the improvement in obesity phenotype. 

Subsequently, the role of LPS in inducing systemic inflammation was investigated in human settings. Anderson et al. Found that with a similar degree of endotoxinemia, the so-called amount of cytokines  (tumor necrosis factor-TNF alpha and interleukin-IL6) which promotes the development of IR (9). In addition, a diet rich in fat and carbohydrates results in a significant increase in postprandial (postprandial) LPS in the blood plasma. The above changes are not at all noticeable with the fiber and fruit-rich diet recommended by the American Heart Association (AHA). 

Taken together, the above data confirm that endotoxinemia may play a key role in the pathogenesis of the inflammatory condition associated with obesity and that food intake may affect plasma endotoxin levels.



Phenotyping of adipocytes


Obesity has now become the fifth leading cause of death worldwide, as being overweight can be a progressive cause and / or aggravating factor for many diseases, such as cardiovascular disease, liver disease and type 2 diabetes. According to the data, not only is obesity itself a cause, but fat cells also undergo a so-called phenotypic change.

This is due to the fact that the increased adipose tissue during obesity not only serves to store excess fat, but also its cells, adipocytes, function as secretory cells that secrete many bioactive substances.  An increase in fat cell mass during obesity leads to an abnormal response. Reactive oxygen radicals accumulate in large amounts in fat cells, inhibiting the action of insulin and increasing the production of proinflammatory cytokines. Increased oxidative stress increases the levels of nuclear factor kB (NFkB), an activator protein-1 (AP-1) that promotes the production of interleukin (IL) -6 and tumor necrosis factor-α (TNF-α), which resulting in impaired phosphorylation of insulin receptor proteins. These processes lead to the development of insulin resistance. Due to the insulin resistance of fat cells, the hydrolysis (breakdown) of triglycerides in fat cells increases, so a large amount of free fatty acid flows out. Hyperglycaemia (high blood sugar) increases the production of insulin by the b cells in the pancreas (pancreas), which in turn leads to hyperinsulinemia. Hyperinsulinemia, hyperglycemia, and large accumulation of free fatty acids together increase the production of very low-density lipoprotein (VLDL) in the liver. The best known adipokines are chemerin, leptin, resistin, vaspin, adiponectin, visfatin, omentin, perilipine.


With overweight, obesity, metabolic syndrome, and type 2 diabetes, the amount of adipose tissue increases and macrophage infiltration is observed.  Such macrophage proliferation is also observed in liver tissue. As a result of adipose tissue and macrophage activity, the production of partially specific adipose tissue cytokines that cause inflammation begins. (10,11,12,13)


Cytokines that cause inflammation  mechanism of action


The mechanism of cytokines involved in inflammatory reactions produced by white blood cells (macrophages) is supported by a number of observations and experiments. Cytokines, e.g. TNF-alpha, IL-6, binds to the cytokine receptors on target cells to activate the enzyme NAD (P) H, which causes the cell to overproduce superoxide.  (superoxide is a very aggressive cell damaging free radical). Superoxide overproduction is intracellular  leads to oxidative stress, which induces inflammation in the cell. (16)

Attila Bácsi and Petra Diószegi from the University of Debrecen examined tumor necrosis factor α (TNF α), interleukin 6 and 1β (IL-6, IL-1β), tryptase and nerve growth factor β in obese and control rats. β NGF). Obese animals are IL-6  plasma concentrations were found to be significantly higher compared to control animals. In their experiment, they provided further evidence that inflammatory processes leading to higher plasma concentrations of proinflammatory adipokines (IL-1β and IL-6) are enhanced in obese patients. Furthermore, in addition to their role in inflammation, these adipokines may contribute to the development and / or exacerbation of obesity-related diseases through their putative metabolic effects.


Unfortunately, inflammation can develop without obesity

This is a less researched area, but according to data to date  one of the causes is a non-obesity-related hormone disease, hyperthyroidism, (in hyperthyroidism, the thyroid gland produces too much hormone, which speeds up metabolic processes and vital functions), where the same cytokines appear in the blood. (16)

Another cause is to be found in the adrenal gland, where another hormone, salt and aldosterone, which is responsible for water management, is overactive. This can also be caused by persistent stress. (16)

Finally, smoking has been clinically shown to increase cellular inflammation by a mechanism similar to that described above. (16)



Natural solutions to subclinical inflammation


Eating factors

There is also a wealth of clinically relevant and oral information on lifestyle factors. I do not want to reach into the professional competence of dietitians in this forum, so only from the point of view of inflammation  we would think through our basic foods.  


Foods that promote inflammation

  • Refined vegetable oils (such as corn and soybean oils, which are high in omega-6 fatty acids that increase inflammation).

  • Pasteurized dairy products (common allergens).

  • Refined carbohydrates and processed cereal products.

  • Caged, nutritious meat, poultry and eggs (high in omega-6s for feeding to animals and  due to cheap nutrients that have a negative effect on microbiomes).

  • Added sugars (packaged snacks, bread, spices, canned food, cereals, etc.).

  • Trans fats / hydrogenated fats (packaged, processed products).


Anti-inflammatory foods

  • Fresh vegetables (of all kinds), phytonutrients, at least four to five servings a day. The best include beets,  carrots, cruciferous vegetables (broccoli, cabbage, cauliflower and kale), dark green leaves (vegetables, kale, spinach),  onions, peas, lettuce greens.

  • Whole fruits (not juice): The fruit contains various antioxidants such as resveratrol and flavonoids. Three to four servings a day is enough  for most people, especially apples, blackberries, blueberries, cherries, nectarines, oranges, pears, pink grapefruit, plums, pomegranates, red grapefruit, or strawberries.

  • Herbs, spices and teas: turmeric, ginger, basil, oregano, thyme, etc., and green tea and organic coffee in moderation.

  • Probiotic foods, yogurt, kefir.

  • Wild-caught sea fish (fish get omega-3 fatty acids from the algae they eat).

  • Cage-free eggs and meat from grass-fed / grazed animals: richer in omega-3 fatty acids than farm-produced foods.

  • Zinc, selenium and B vitamins.

  • Healthy fats: spicy butter, coconut oil, extra virgin olive oil, nuts / seeds.

  • Ancient seeds and legumes: best germinated. Two to three servings a day, especially adzuki beans, black beans, black-eyed peas, chickpeas, lentils, black rice, buckwheat, quinoa.

  • Red wine and dark chocolate / cocoa in moderation: several times a week or a small amount daily.



How does omega-3 fatty acids affect subclinical inflammation?


One of the most studied omega-3 fatty acids of our time, Pubmed, is discussed in more than 27,000 articles. (17)  The omega-3 compound is used in many diseases because it is an important component of the cell membrane and also has an anti-inflammatory effect. Researchers at the University of San Diego in California have experimentally demonstrated the mechanism of the anti-inflammatory effect of omega-3. (18)


It essentially covers the receptors that allow the exchange of information between phenotyped fat cells and infiltrated macrophages, blocking them. In this way, it prevents the outflow of inflammatory cytokines.  



The problem of fish oil capsules  


If we don’t make the right choices, we can not only spend unnecessary money, but instead cause harm to our bodies. (19)

The most important: the source of fish oil, rancidity (oxidation)  issue, dose, and composition.


Production, rancidity

  • The fish oil industry produces its products in the largest quantities in South American factories, where non-fresh fish stored for an indefinite period is processed using chemical methods. The finished product in barrels  even stored for years.

  • Unsaturated fats are very decomposable and stand out for a short time. Rash is a huge problem because  this  chemically it means oxidative decomposition and what is oxidized produces oxygen free radical. Oxygen free radical is known to be an extremely aggressive cell damaging agent. Thus, omega-3 fatty acids are an anti-cellular substance, given virtually no error! The annoyance is that only a negligible number of antioxidants can be found in a number of formulations, e.g. polyphenols.

  • Fresh fish oil has a pleasant smell.  In the case of fish oils, the so-called A TOTOX value is used, but this also only determines the freshness at the time of extraction.


Dose, quantity

  • According to EU regulations, the minimum daily amount of omega-3 is 250 mg  necessary to be able to write a health effect on the box at all. Therefore, the manufacturers recommend 2-3 capsules a day and this 2-3 capsules will only have a total of this very minimum dose. However, significant clinical trials have shown that a dose of at least 1.5 grams per day, or 1,500 mg, is required to have a medically detectable effect. It is unnecessary to take below this amount. Of the products available in drugstores or ABC stores, you would often have to take 10 eyes a day to make it work, so the box price of HUF 1,500-3,000 is not so cheap anymore.



  • Manufacturers  in addition to the effective EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), other filler oils are used. Thus it is written that e.g. It contains 1,000 mg of fatty acids, of which only 500 mg is the medically effective form. You should always check the exact amount of EPA and DHA on the label.

  • Caught only from the North Sea, processed by a cold process  fish contain docosapentaenoic acid (DPA), which is of particular importance for endothelial  integrity  in the protection of.  

  • It is important to note that although quality omega-3 can contribute in the short term  to improve health, to be consumed continuously for at least 3-4 months to achieve full effect. Buying a single box will not have a relevant, clinically meaningful effect.



Polyphenols  inflammation  inhibitor  effect


The well-known and well-studied polyphenols in healthy foods, beverages and folk remedies can play a key role in inhibiting the production of transcription factors and inflammatory cytokines by a signaling pathway, thereby exerting an anti-inflammatory effect.  


The anti-inflammatory effects of a number of compounds used in traditional medicine or in healthy foods, such as resveratrol, curcumin or proanthocyanidins, have been the subject of laboratory and clinical studies. Because the solubility of these compounds is generally poor, the limitation of excellent pharmacological activity may be due to the low bioavailability of the agent. In addition, several new studies demonstrate that high-molecular polyphenols found in healthy foods and beverages (fruits, vegetables, chocolate, or red wine) are metabolized by the intestinal flora to lower-molecular phenolic acids and phenolaldehydes. This reinforces the hypothesis that microbial degradation products of polyphenols are more, but at least partially, responsible for the anti-inflammatory effect attributed to the original polyphenol. (29)


In activated macrophage cells, the nuclear kappa light chain enhancer factor NF-κB transcription factor plays a prominent role in mediating inflammatory processes induced by Gram-negative bacteria and inducing oxidative stress.  The anti-inflammatory effect of polyphenol is mediated by the inhibition of the transcription factor NF-κB and the regulation of inflammatory cytokines, TNFα, IL-1β, IL-6, IL-10.



Effect of elemental fibers on microbial function


Plant cell constituents that are resistant to hydrolysis of human digestive enzymes have previously been termed elemental fibers. In other words, the dietary fiber exerts its physiological effect by leaving the body undigested, ie in an unchanged state, with a kind of “gut cleansing” effect. 

Recent research, however, has shown that fibers in the gut become substrates for bacteria and undergo partial, sometimes almost complete, fermentation. The end products of fermentation are gases (hydrogen, carbon dioxide, methane, to a lesser extent hydrogen sulfide) and short-chain fatty acids (SCFAs), which are often referred to in the literature as butyrates. (20)   


Short-chain fatty acids (acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid) are the most important end products of the fermentation of fibers by intestinal bacteria, which are involved in the body's metabolic processes.

  • Short-chain fatty acids play a role in the metabolism of bile acids. Some of the primary bile acids are absorbed into the ileum (small intestine) and return to the liver. Unabsorbed cholic acid and deoxycholic acid enter the intestine and are dehydroxylated to secondary bile acids, dehydroxycholic acid and lithocholic acid, which are carcinogenic. The presence of SCFA lowers the pH of the intestinal contents. At lower pH, the formation of secondary bile acids is reduced or eliminated, reducing the amount of these risk factors for cancer. (21)

  • SCFAs increase intestinal motility, thus reducing transit time. During the shorter transit time, the possibility of the formation of carcinogenic compounds is reduced, and constipation (constipation) and diverticulosis (changes in the colonic mucosa) can also be avoided. The mechanism of action is not yet fully elucidated. (22) 

  • In addition, they are involved in the transport of inorganic ions in cells, especially the Na / H ion, thereby affecting the acid-base balance and intracellular pH of the cell. (23) 

  • Inhibition of cell proliferation is primarily attributable to butyric acid. Experiments have shown that SCFA inhibits the proliferation of tumor cells and causes a morphological change in them. When added to cancer cells, dedifferentiation occurs in the cell and the cells regain their original shape. (24)

  • A high-fiber diet can reduce serum cholesterol levels by an average of 5 to 10 percent. Cholesterol levels 1  percentage decrease results in a 2 percent decrease in coronary mortality at the population level. (28)

  • Fermentation in the colon is associated with various diseases; such as constipation, colon polyps and tumors, diverticulosis, and Crohn's disease, in which dietary fiber is beneficial. (28)


From a nutritional-physiological point of view, it is important to know what and how much short-chain fatty acid is produced as a result of intestinal fermentation through the fibers consumed in our daily diet. Consuming consciously prepared dietary fiber-containing foods can prevent some nutrition-related metabolic diseases and have a positive effect on their outcome. (25,26.27)

Literature used in the compilation


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  10. .Jeevendra Martyn, JA, Kaneki, M, Yasuhara, S: Obesity-induced insulin resistance and hyperglycemia. Anesthesiology 109: 137-148, 2008. 

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  12. Plomgaard, P, Nielsen, AR, Fischer, P, Mortensen, OH, Broholm, C, Penkowa, M, Krogh-Madsen, R, Erikstrup, C, Lindegaard, B, Petersen, AMW, Taudorf, S, Pedersen, BK: Associations between insulin resistance and TNF-α in plasma, skeletal muscle and adipose tissue in humans with and without type 2 diabetes. Diabetology 50: 2562-2571, 2007. 

  13. Franckhauser, S, Elias, I, Rotter Sopasakis, V, Ferré, T, Nagaev, I, Andersson, CX, Agudo, J, Ruberte, J, Bosch, F, Smith, U: Overexpression of IL6 leads to hyperinsulinemia, liver inflammation and reduced body weight in mice. Diabetologia 51: 1306-1316, 2008. 

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