Atopic dermatitis, adaptation disorders and intestinal dysbiosis

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease manifested by intense itching, sympathic skin reaction, papular eruptions, and pronounced lichenification combined with other signs of atopy. AD typically arises in early childhood, has age-specific localization features, and is characterized by hypersensitivity to both allergens and non-specific irritants. AD significantly impacts quality of life, can cause sleep disturbances, reduced activity, neurotic states, and can lead to the development of bronchial asthma and, consequently, disability [1, 9].

Among the etiological factors leading to the development of AD, sensitization to food allergens is indicated, especially in childhood. This is associated with congenital and acquired impairments of digestive tract functions, improper feeding, early introduction of highly allergenic foods into the diet, intestinal dysbiosis, the presence of a high titer of conditionally pathogenic flora (CPF), impairment of the cytoprotective barrier, etc., which promotes the penetration of antigens from the food chyme through the mucous membrane into the internal environment of the body and the formation of sensitization to food products [6, 7, 10].

Most allergic problems are, to some degree, associated with the gastrointestinal tract (GIT). This is especially true for allergodermatoses, including AD. Over 90% of all antigens a person encounters are constantly present or pass through the intestines—this is where the main elements of anti-allergic defense are located, and the intestinal wall contains a huge number of immunocompetent cells, leading some researchers to consider the intestine one of the key organs of the immune system. If any disturbances occur in the barrier function of the GIT, various toxins and antigens, which have become allergens, begin to enter the bloodstream from the intestines.

Allergens can be the waste products of conditionally pathogenic flora [4] and parasites inhabiting the intestinal lumen, as well as food that has not been sufficiently broken down. They sensitize the patient's body, promote the production of specific IgE antibodies and the subsequent release of histamine from mast cells, which determines the clinical picture of food allergy. As is known, the environment is abundantly populated by microorganisms. Many of them are incapable of coexisting with the macroorganism, others are saprophytes, and still others are symbionts, i.e., organisms capable of coexisting with other biological species in an interconnected and mutually beneficial interaction. Symbionts are necessary for the normal functioning of the host organism.

Under normal physiological conditions, the human body contains hundreds of different microbial species. The term "normal microflora" unites microorganisms isolated from a healthy human body: from the skin, mucous membranes of the upper respiratory tract, GIT, and genitourinary system. The lower parts of the small intestine and especially the large intestine represent a reservoir of bacteria for the entire organism.

Normal flora is considered to be the totality of microbial associations typical for a specific biological species, whose natural life activity occurs in those organs and tissues of the macroorganism that communicate with the external environment. Normal flora performs crucial physiological and immunological functions in the macroorganism and forms a single whole with it.

The total number of gut bacteria reaches 10^14 cells, which is almost an order of magnitude greater than the number of cells in all the organs and tissues of the macroorganism. It has been shown that the natural form of existence for any microorganisms in nature is an immobilized state, i.e., 99.9% of bacteria in nature live in the form of microcolonies fixed to various surfaces [12]. .

The attachment of microbial cells to solid surfaces occurs in three stages: in the first stage, reversible adhesion occurs due to weak interactions; the second stage involves non-specific adhesion using fimbriae and pili, including the formation of hydrogen and ionic bonds; in the third stage, the production of extracellular material (polysaccharides) that enhances adhesion occurs. Thus, a biofilm is formed, through which contact between the intestinal lumen and the mucous membrane is mediated.

The biofilm covering the intestinal mucous membranes, in addition to microbial polysaccharides, consists of microorganism colonies and mucin produced by goblet cells. Microorganisms within the biofilm are tens to hundreds of times more resistant to adverse factors compared to when they are in a free-floating state [12]. Unlike free-living bacteria, representatives of the normal flora in an animal organism can only attach to specific receptors on the skin and mucous membranes. The most numerous and diverse in composition is the group of bacteria in the thick mucosal layer covering the inner surface of the digestive tract. The normal flora of the human GIT consists of bifidobacteria, lactobacilli, and Escherichia coli with normal enzymatic activity. Within the biofilm, these bacterial species should normally constitute up to 99% of the entire intestinal microflora.

In addition to normal flora, saprophytic and conditionally pathogenic flora can be present in the human intestine. Saprophytic flora is represented by epidermal and saprophytic staphylococci, enterococci, yeasts, Neisseria, and other bacterial species. The CPF of the intestine can be represented by hemolytic streptococci, Staphylococcus aureus, spore-forming anaerobes, lactose-negative enterobacteria, hemolytic E. coli, and fungi of the genus Candida. Normally, the amount of CPF should not exceed 10^3–10^6 CFU per 1 g of feces, or 10% of the total microbial count [5].

The normal intestinal flora participates in many vital processes of the macroorganism, which, in turn, serves as its habitat.

The etiology and pathogenesis of AD involve not only immune disorders but also disturbances in the gastrointestinal microecology (referred to as intestinal dysbiosis), for which there is considerable evidence. Examination of a large number of children with various allergodermatoses revealed that disturbances in intestinal microflora were noted in 92.8% of children, with more pronounced deviations in the biocenosis composition corresponding to a more severe course of the allergodermatosis—this is associated with the accelerated penetration of food and microbial antigens into the blood and sensitization of the body [8].

A link has been proven between non-atopic eczemas and infectious agents, particularly staphylococcal, streptococcal infections, fungi of the genus Candida, hemolytic E. coli, and other representatives of CPF. Some studies have obtained data that the breakdown products of staphylococcal enterotoxin and other microorganisms are highly homologous to the IgE receptor. Microbial enterotoxins bind to B-lymphocytes, which stimulates IgE synthesis, causing secondary hypersensitization. This plays an important role in maintaining skin inflammation in atopic dermatitis. Furthermore, the waste products of microorganisms—toxins—can accumulate in the human body [7]. In healthy individuals, they are inactivated by normal flora bacteria. Under conditions of intestinal dysbiosis, these toxins cause reactive inflammation of the pancreas and liver, impairing the function of these organs, which leads to even more pronounced intestinal dysbiosis. This, in turn, disrupts the breakdown and absorption of vital nutrients. Moreover, large molecules damage the biofilm, exacerbating dysbiosis, and, upon absorption, directly affect mast cells, causing their degranulation via a pseudoallergy mechanism. Incidentally, GIT diseases can also contribute to the development of respiratory allergies.

Dysbiosis is of two types: with a decrease in the amount of normal intestinal microflora or with an increase in the amount of CPF (Table 1) [3]. Both types of dysbiosis can lead to the formation of AD. In the first type (deficiency of beneficial bacteria), allergic problems arise due to thinning of the biofilm, which disrupts the barrier function of the GIT—food sensitization develops. A decrease in bifidobacteria is particularly unfavorable for the body, as they constitute at least 95% of the biofilm—their significant deficiency is always a third-degree dysbiosis, regardless of the quantity of other representatives of the normal flora. In the second type of dysbiosis (excessive amount of CPF), a large number of infectious antigens enter the mucous membrane and then the systemic bloodstream, ultimately leading to sensitization of the body. The combination of a deficiency of beneficial bacteria with an overgrowth of CPF particularly strongly contributes to sensitization and the development of AD.

Table 1

Grouping of Microbiological Deviations in the Intestine by Type and Degree

The treatment strategy for dysbiosis differs depending on the type and degree of microbiological disturbances. For Type I dysbiosis with reduced normal flora, the prescription of probiotics is indicated.

Microbiological Correction for Type I Dysbiosis

• I Degree. Dry (Bifidumbacterin, Bificol, Acilact, Linex, Primadophilus, etc.) or liquid (Normoflorins, Gabriflorins, Euflorins, etc.) probiotics in a maintenance dose (5 doses/day). The use of dietary supplements (BАDs) or therapeutic nutrition ("Bifilife," "Narine," "Evita," etc.) is possible. Treatment course: 10–30 days.
• II Degree. Use of lactobacillus preparations (Acilact, Lactobacterin, Normoflorin-L, Biobakton-Lacto, etc.) in a therapeutic dose (10 doses/day). Simultaneous use of a bifidobacteria preparation in a maintenance dose is possible. Treatment course: 30 days.
• III Degree. Preference for liquid probiotics in a therapeutic dose. Treatment course: 30 days. Subsequently, the use of BАDs or dry probiotics in a maintenance dose is possible. Course: 10–30 days.

For Type II dysbiosis with an elevated level of CPF, the question of prescribing antimicrobial drugs, as well as immune correction with a complex immunoglobulin preparation (CIP), is considered. The efficacy of CIP monotherapy against lactose-negative enterobacteria is 95%, and against other CPF—75–80% [2].

Microbiological and Immunological Correction for Type II Dysbiosis

• I Degree. CIP, 1 dose once daily. Course: 5 days.
• II Degree. If CPF sensitivity to bacteriophages is present—the corresponding bacteriophage in an age-specific dosage. Course: 5 days. CIP, 1 dose once daily. Course: 5–10 days. The use of intestinal antiseptics (nifuroxazide, chlorophyllipt, furazolidone, etc.) is possible. Course: 7–10 days.
• III Degree. CIP, 1 dose once daily. Course: 10 days. Bacteriophages. Course: 7–14 days. After using the bacteriophage, the prescription of intestinal antiseptics is possible. Course: 7–10 days.

For combined dysbiosis, probiotics, antimicrobial drugs, and immune correction are used depending on the degree of microbiological deviations of each type. In this case, it is possible to prescribe drugs from different groups simultaneously or sequentially. However, simultaneous use of CIP with drugs from other groups (based on personal experience) gives a more pronounced clinical and microbiological effect.

Often, inflammatory skin rashes are due to impaired intestinal peristalsis (spastic colitis), which leads to severe constipation and is often a consequence of intestinal dysbiosis. Remaining in the intestine sometimes for several days, fecal matter decomposes, forming ammonia and ammonia acids, which, in turn, also creates an endotoxemia syndrome.

Food allergy is most significant in the development of AD in young children, and the causally significant allergens are proteins from cow's milk, eggs, and fish [6]. Accordingly, one of the main postulates of treatment is the exclusion of a huge number of products from the child's diet.

Very often, doctors, upon the appearance of single skin rashes, exclude valuable nutritional components from the child's diet without replacing them with anything, which leads to a pronounced disturbance of all types of metabolism and the functional state of many body systems, which require sufficient amounts of proteins, fats, and carbohydrates to function. At the same time, an exacerbation of the disease is often caused not by the product itself, but by a violation of its breakdown and absorption. The normal intestinal flora is responsible for the complete breakdown and absorption of food products. In most cases of food sensitization, strict diets can be avoided, and effective treatment will be the normalization of the GIT condition, including comprehensive treatment of dysbiosis.

The role of treating dysbiosis and concomitant functional disorders of the GIT in AD is confirmed by personal experience, on the basis of which recommendations for the management of patients with AD can be given.

Nutritional Recommendations: Elimination diets are not always required. In most cases of AD, cure is possible without excluding products such as: breast milk, cow's milk protein, lean meat, fish, and most other products that a child can receive according to their age. At the same time, certain rules for introducing new products must be observed: introduce gradually, one at a time, and assess the individual reaction to the new product. Avoid premature introduction of complementary foods. Do not use hydrolysates, as they negatively affect the intestinal microflora (promote the development of dysbiosis), suppress the development of the digestive system and the immune system, which ultimately exacerbates the course of AD and leads to even greater impairment of adaptation processes. Personal experience shows that the gradual replacement of hydrolyzed formulas, prescribed to infants for "cow's milk protein allergy," with regular milk formula, in 99% of cases not only does not worsen the course of AD but, on the contrary, leads to significant improvement due to the normalization of processes occurring in the GIT.

Recommendations for Treating Functional GIT Disorders: Treatment should be comprehensive. Microbiological and immunological correction is carried out according to the type and degree of dysbiosis. Concomitant therapy is applied simultaneously: enzyme therapy, choleretic agents, prebiotics, etc.

AD is characterized by a wavy course—alternating periods of exacerbation and remission. During the treatment of dysbiosis, temporary worsening may occur, associated with the restructuring of the adaptation system and the expulsion from the body of waste products and breakdown products of CPF. Exacerbation of dermatitis occurs especially often at the beginning of treatment during the use of bacteriophages or intestinal antiseptics: CPF microorganisms are destroyed by the action of the drugs, releasing a large amount of toxins, which the body eliminates through the intestines and through the skin, leading, among other things, to an intensification of the clinical manifestations of AD. Such worsening does not require discontinuation or correction of the main therapy. For exacerbation of AD, antihistamines and enterosorbents are used.

Restoring normal intestinal microbiocenosis and the normal adaptation system is not a quick process. Patients should be explained that time will be required to achieve a clinical effect (usually 3–4 weeks from the start of treatment). More than one course may also be needed. At the same time, the absence of measures to normalize the adaptation systems associated with the intestinal microflora, as a rule, leads to a chronic, torpid course of AD and the necessity for constant use of various anti-allergic agents and elimination diets, significantly worsening the quality of life.

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