Bacteria view from a microscope bacillus subtilis. Hay stick. Reproduction. How to grow a colony

Savustyanenko A.V.

Keywords

Bacillus subtilis / probiotic / mechanisms of action

annotation scientific article on medicine and health care, author of scientific work - Savustyanenko A.V.

The bacterium B. subtilis is one of the most promising probiotics studied in recent decades. The mechanisms of its probiotic action are associated with the synthesis of antimicrobial substances, strengthening of nonspecific and specific immunity, stimulation of the growth of normal intestinal microflora and the release of digestive enzymes. B. subtilis secretes ribosomal synthesized peptides, non-ribosomal synthesized peptides and non-peptide substances with a wide spectrum of antimicrobial activity, covering gram-positive, gram-negative bacteria, viruses and fungi. Resistance to these antimicrobial agents is rare. Strengthening of nonspecific immunity is associated with the activation of macrophages and the release of pro-inflammatory cytokines from them, an increase in the barrier function of the intestinal mucosa, the release of vitamins and amino acids (including essential ones). Strengthening of specific immunity is manifested by the activation of Ti B-lymphocytes and the release of the last immunoglobulins - IgG and IgA. B. subtilis stimulates the growth of normal intestinal microflora, in particular bacteria of the genera Lactobacillus and Bifidobacterium. In addition, the probiotic increases the diversity of the intestinal microflora. The probiotic releases all the main digestive enzymes into the intestinal lumen: amylases, lipases, proteases, pectinases and cellulases. In addition to digesting food, these enzymes break down anti-nutritional factors and allergenic substances found in incoming food. Listed mechanisms of action make reasonable the use of B. subtilis as part of complex therapy to combat intestinal infections; prevention respiratory infections during the cold season; prevention of antibiotic-associated diarrhea; for the correction of digestive disorders and the promotion of food of various origins (errors in diet, changes in diet, diseases gastrointestinal tract, disorders of the autonomic nervous system, etc.). B.subtilis does not usually cause side effects. This probiotic is characterized by a high ratio of efficacy and safety.

The text of the scientific work on the topic "Mechanisms of action of probiotics based on Bacillus subtilis"

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UDC 615.331:579.852.1

MECHANISMS OF ACTION OF PROBIOTICS BASED ON BACILLUS SUBTILIS

Summary. The bacterium B. subtilis is one of the most promising probiotics studied in recent decades. The mechanisms of its probiotic action are associated with the synthesis of antimicrobial substances, strengthening of nonspecific and specific immunity, stimulation of the growth of normal intestinal microflora and the release of digestive enzymes. B. subtilis secretes ribosomal synthesized peptides, non-ribosomal synthesized peptides and non-peptide substances with a wide spectrum of antimicrobial activity, covering gram-positive, gram-negative bacteria, viruses and fungi. Resistance to these antimicrobial agents is rare. Strengthening of nonspecific immunity is associated with the activation of macrophages and the release of pro-inflammatory cytokines from them, an increase in the barrier function of the intestinal mucosa, the release of vitamins and amino acids (including essential ones). Strengthening of specific immunity is manifested by the activation of T- and B-lymphocytes and the release of the last immunoglobulins - IgG and IgA. B. subtilis stimulates the growth of normal intestinal microflora, in particular bacteria of the genera Lactobacillus and Bifidobacterium. In addition, the probiotic increases the diversity of the intestinal microflora. The probiotic releases all the main digestive enzymes into the intestinal lumen: amylases, lipases, proteases, pectinases and cellulases. In addition to digesting food, these enzymes break down anti-nutritional factors and allergenic substances found in incoming food. These mechanisms of action justify the use of B.subtilis as part of complex therapy to combat intestinal infections; prevention of respiratory infections in the cold season; prevention of antibiotic-associated diarrhea; for the correction of disorders of digestion and promotion of food of various origins (errors in the diet, changes in diet, diseases of the gastrointestinal tract, disorders of the autonomic nervous system, etc.). B.subtilis does not usually cause side effects. This probiotic is characterized by a high ratio of efficacy and safety.

Key words: Bacillus subtilis, probiotic, mechanisms of action.

Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" . While the use of some of them (Lactobacillus, Bifidobacterium) has received much attention, others have been studied more recently, and their important therapeutic effect is only now becoming clear. One of the probiotics is the gram-positive bacillus Bacillus subtilis (B. subtilis).

Most bacteria of the genus Bacillus (including B. subtilis) are not dangerous to humans and are widely distributed in the environment. They are found in soil, water, air, and foods (wheat, other grains, baked goods, soy products, whole meats, raw and pasteurized milk). As a result, they constantly enter the gastrointestinal tract and Airways by seeding these departments. The number of bacilli in the intestine can reach 107 CFU / g, which is comparable to that of Lactobacillus. In this regard, a number of researchers consider bacteria of the genus Bacillus as one

from the dominant components of the normal intestinal microflora.

At the same time, the therapeutic administration of B. villii makes it possible to use this microorganism as a probiotic in four main areas: 1) for protection against intestinal pathogens; 2) from respiratory pathogens; 3) to eliminate dysbacteriosis during antibiotic therapy; 4) to enhance the digestion and promotion of food. A simplified scheme of the probiotic activity of B. villii in the pathology of the gastrointestinal tract is shown in fig. one.

Thus, in scientific works of recent decades, significant progress has been made in elucidating the spectrum of probiotic activity of B. villii, which makes this bacterium one of the most attractive probiotics for medical use. In this review, we present data from relevant experimental and clinical studies that allow us to form an impression of the therapeutic potential of B.villiv.

antimicrobial agents

Strengthening non-specific "and specific immunity

Isolation of 1 digestive enzymes

Figure 1. Simplified scheme of the probiotic activity of B.subtIIIs in the pathology of the gastrointestinal tract (based on figures from )

Survival of vegetative cells of Blillbv in the gastrointestinal tract

Probiotics based on RnbNBb are usually taken orally in the form of either spores or live bacteria (vegetative cells). The survival of spores in the gastrointestinal tract is beyond doubt due to their high resistance to various physicochemical factors, in particular extreme pH values. At the same time, the question of whether living bacteria are able to penetrate beyond the stomach and perform a probiotic function was discussed.

The situation was clarified by conducting a randomized, double-blind, placebo-controlled study in healthy volunteers (n = 81, age 18-50 years). All subjects were given live bacterium Vlybshv orally at a dose of 0.1 109; 1.0109 or 10109 cfu/capsule/day or placebo for 4 weeks. At the end of the study, the content of live bacteria in the feces was calculated. The figures obtained were 1.1 ± 0.1 1s^10 CFU/g1 in the placebo group and 4.6 ± 0.1 CFU/g; 5.6 ± 0.1 k^10 CFU/g; 6.4 ± 0.1 CFU/g for three increasing doses of VlySHv. Therefore, the survival of the vegetative RnLNB cells during the passage of the gastrointestinal tract was confirmed. At the same time, the effect was dose-dependent and significantly exceeded that of placebo (p< 0,0001) .

The similarity of the effects of B. uIIbv when taken in the form of spores and vegetative cells

In the cited literature, most of the experimental and clinical studies of RnbNb were performed with the introduction of either spores of these bacteria or their vegetative cells. In this regard, the question arises

1 Colony forming units (CFU) are numerically equal to the number of vegetative cells.

whether the effects obtained and the therapeutic results should be considered separately or can be combined.

In many works, when studying bacteria of the genus Bacillus, it was demonstrated that after oral intake spores are observed to germinate in the gastrointestinal tract into vegetative cells. Then re-transformation into spores (resporulation) is observed. These cycles are repeated several times. Ultimately, spores with fecal masses end up in the external environment. Similarly, after oral administration of vegetative cells, their sporulation in the gastrointestinal tract is observed. The cycles of germination and resporulation are repeated several times before being eliminated from the host.

Thus, whether B. subtilis-based probiotics are taken as spores or vegetative cells, both forms of the bacterium will be present in the recipient's body, and the observed effects and therapeutic effect will, apparently, be the same. This fact requires further confirmation in special studies.

Probiotic Mechanisms

B. subtilis activity

Synthesis of antimicrobial substances

As a rule, intestinal infections are caused by bacteria or viruses, less often by protozoa. In accordance with current recommendations, in most cases there is no need to prescribe antibiotics. A proper rehydration regimen should be maintained and the diarrhea will resolve on its own. However, in both mild and severe cases of intestinal infections, the doctor may decide to include probiotics in the treatment to increase its effectiveness.

One of the most promising bacteria in this respect is B.subtilis. The uniqueness of the bacterium lies in the fact that 4-5% of its genome encodes the synthesis of various antimicrobial substances. According to published reviews, by 2005 about 24 such substances were isolated from different strains of B. subtilis, and by 2010 - 66, and the list continues to grow. Most of the antimicrobial substances are represented by ribosomal and nonribosomal synthesized peptides. In smaller quantities, non-peptide substances are found, for example, polyketides, amino sugars and phospholipids. Some of the antimicrobial substances B. subtilis are given in table. 1. It can be seen that the activity of many of them is directed against gram-positive bacteria. In addition, the spectrum of action covers gram-negative bacteria, viruses and fungi. Therefore, virtually all pathogens that can cause enteric infections are covered.

An example is the results of a study of one of the new strains of B. subtilis VKPM B-16041 (DSM 24613). High antagonistic activity against St.aureus and C.albicans, medium or low - against C.freundii, E.coli,

Table 1. Some antimicrobial agents synthesized and secreted by B. subtilis

Ribosomal synthesized peptides Bacteriocins: - type A lantibiotics - type B lantibiotics Subtilin Ericin S Mersacidin For 2 substances: formation of pores in the cytoplasmic membrane Inhibition of cell wall synthesis Gram-positive bacteria Gram-positive bacteria, including methicillin-resistant strains of Staphylococcus aureus and vancomycin-resistant strains of Enterococci

Nonribosomal synthesized peptides Lipopeptides Surfactin Bacilizin Bacitracin Dissolution of lipid membranes Inhibition of glucosamine synthase involved in the synthesis of nucleotides, amino acids and coenzymes, which leads to lysis of microbial cells Inhibition of cell wall synthesis Viruses, Mycoplasma Staphylococcus aureus, Candida albicans Gram-positive bacteria

Non-peptide substances Difficidin Impaired protein synthesis Gram-positive bacteria, Gram-negative bacteria

K.pneumoniaе, P.vulgaris, P.aeruginosa, Salmonella spp., Sh.sonnei, Sh.flexneri IIa.

Different strains of B.subtilis secrete a different set of antimicrobial substances. However, in any case, the spectrum of antagonism against enteric pathogens covered is quite wide. For example, the strain B. subtilis ATCC6633 secretes subtilin, which is an antibiotic against gram-positive bacteria. Another strain of B.subtilis A1/3 does not produce subtilin. Instead, it releases the antibiotic ericin S, which has the same mechanism of action and spectrum of activity as subtilin. So, whichever of these strains is used in the production of a probiotic, the spectrum of gram-positive bacteria will be covered.

The antimicrobial peptides secreted by B. subtilis have a huge advantage over conventional antibiotics. The fact is that they are close to antimicrobial peptides secreted in the human body and are part of its innate immunity. Similar Substances have been identified in a wide range of tissues and epithelial surfaces, including the skin, eyes, ears, oral cavity, intestines, immune, nervous and urinary systems. The best known of these are defensin, lysozyme, cathelicidin, dermcidin, lectin, histatin, and others. B. subtilis secrete similar substances, so resistance to them rarely occurs, and side effects are usually absent. The lack of resistance to human and B. subtilis antimicrobial peptides is associated with the fact that their action is more often directed to the formation of membrane pores, leading to the death of bacteria. The activity of traditional antibiotics is more focused on the metabolic enzymes of bacteria, which facilitates the formation of resistance.

Strengthening of nonspecific and specific immunity

V.mishk enhances protection against intestinal and respiratory pathogens by stimulating nonspecific and specific immunity. Nonspecific immunity is defined as a defense system that works in the same way in relation to a wide variety of microorganisms. Specific immunity works on the “key to the lock” principle - special cells or antibodies are produced for a specific pathogen. Nonspecific immunity is usually considered as the first phase of the body's defense reaction, and specific - the second phase.

Nonspecific immunity

The most important cells involved in nonspecific immunity are macrophages. They phagocytose the pathogen by digesting it. In addition, the antigens of the pathogen are aligned on the surface of their own membranes - the so-called presentation, which is necessary to start the second phase of the body's defense reaction.

It has been demonstrated in numerous studies that the administration of BHHNII induces macrophage activation. In activated macrophages, the synthesis and release of pro-inflammatory cytokines is enhanced: tumor necrosis factor a, interferon-y (N-7), interleukin (II 1p, III-6, III-8, III-10, III-12, macrophage inflammation protein- 2. As a result, a complex inflammatory response develops, aimed at destroying the pathogen.For example, 1KK-y activates macrophages and protects cells from viral infection.III-6 stimulates the proliferation and differentiation of B-lymphocytes responsible for the synthesis of antibodies.III-8 is a powerful chemotactic and paracrine mediator for neutrophils.

activated neutrophils plays an important role in maintaining inflammation and oxidative stress. IL-12 regulates the growth, activation, and differentiation of T lymphocytes.

The mechanisms by which B.subtilis activates macrophages continue to be studied. In one of the works, it was shown that the exopolysaccharides of the probiotic are responsible for this.

The next important component of nonspecific immunity is the barrier function of the epithelium. Epithelial tissues are the first to meet the attack of pathogens, and the course of the disease largely depends on their resistance.

Researchers have found that bacteria communicate with each other within the same species and between different species using a special group of substances called quorum-sensing molecules. One such molecule, isolated from B.subtilis, is called the competence and sporulation factor (CSF). The transfer of CSF to intestinal epithelial cells activates critical signaling pathways required for the survival of these cells. First of all, these are the p38 MAP kinase pathway and the protein kinase B/AI pathway. In addition, CSF induces the synthesis of heat shock proteins (Hsps), which prevent the development of oxidative stress in epithelial cells. Both of these effects - improving the survival of epithelial cells and reducing oxidative stress in them - lead to an increase in the barrier function of the intestinal mucosa. It becomes less vulnerable to pathogens.

The factors of nonspecific immunity also include the content of a number of metabolic substances that affect the overall resistance of the body to infections.

It was found that B. subtilis synthesizes a number of vitamins, in particular thiamine (B1), pyridoxine (B6) and menaquinone (K2). Different strains of B. subtilis secrete a different set of amino acids, some of which are essential, such as valine.

specific immunity

Specific immunity is a more powerful defense system because it selectively targets a particular pathogen. It distinguishes between cellular and humoral immunity. Cellular immunity provide T-lymphocytes, directing their fight against viruses. Humoral immunity is associated with the functioning of B-lymphocytes that secrete antibodies (immunoglobulins). In this case, the fight is directed against bacteria.

Many studies have confirmed the ability of B.subtilis to cause the activation and proliferation of T- and B-lymphocytes. This occurs both in the peripheral blood (both cell types) and in the thymus (T-lymphocytes) and spleen (B-lymphocytes). As discussed above, this is made possible by the release of cytokines from macrophages. In addition, a direct ability to stimulate lymphocytes due to the cell walls, peptidoglycans and teichoic acids of B. subtilis was found.

Figure 2. Probiotic B.subtilis significantly increased the content of lgA in saliva in elderly patients

Note: the probiotic was taken in 4 visits for 10 days, between which there were breaks of 18 days. Data are presented as of the end of the study (43) - after 4 months.

Ш B.subtilis □ Placebo

and o GO o Q. L

Figure 3. Probiotic B.subtilis significantly increased the content of 1dA in the feces of elderly patients

Note: the probiotic was taken in 4 visits for 10 days, between which there were breaks of 18 days. Data are presented as of baseline (VI), 10 days after first probiotic intake (VI + 10 days), and post-study (43) 4 months later.

The consequence of the effect on B-lymphocytes is an increase in the content of immunoglobulins (IgG and 1&L) in the blood serum and 1&L - on the surface of the mucous membranes. For example, in one of the studies, an increase in the content of 1&L in feces was found, which characterizes an increase in immunity against intestinal infections, as well as in saliva, which is important for enhancing protection against acute respiratory infections (Fig. 2, 3). As is known, 1&L

is one of the main molecules that protect the epithelium from pathogens entering from outside.

Stimulation of the growth of normal intestinal microflora

Normal microflora occupies various sections of the intestinal tube, from the oral cavity to the large intestine. There are about 1014 such bacteria in the human body, which is 10 times the number of human cells. The total metabolic activity of bacteria exceeds that of our cells.

The number of bacterial species that make up the normal intestinal microflora was determined in two ways. An older method based on the cultivation of bacteria from stool samples has identified over 500 species. Newer methods based on DNA analysis indicate that in fact there are more than 1000 such species. The figure has grown due to the fact that in the normal microflora there are those bacteria that cannot be cultivated in the usual way.

The main functions of the normal intestinal microflora are to protect against colonization and growth. pathogenic microbes, stimulation of nonspecific and specific immunity, digestion food components. As can be seen, these functions coincide with those discussed in relation to the B.subtilis probiotic in this review.

Imbalance of the intestinal microflora occurs in the case of intestinal infections, as pathogenic bacteria competitively suppress the vital activity of normal bacteria. We mentioned intestinal infections above when considering antimicrobial substances isolated from B.subtilis. In addition, an imbalance occurs during the course of antibiotic treatment of therapeutic and surgical diseases. In this case, the route of administration of the antibiotic does not matter - it can be either oral or parenteral. The incidence of antibiotic-associated diarrhea depends on the type of antibiotic used and ranges from 2 to 25%, less often up to 44%. The antibiotic inhibits the vital activity of normal microflora, which leads to the growth pathogenic bacteria.

Many studies have demonstrated the positive effect of B. subtilis on the maintenance of normal intestinal microflora. The probiotic increased the amount of Lactobacillus and reduced the content of Escherichia coli in the intestines and feces, increased the level of Bifidobacterium and reduced - Alistipes spp., Clostridium spp., Roseospira spp., Betaproteobacterium in feces (Fig. 4). Consequently, the introduction of B. subtilis changed the ratio of intestinal microflora towards an increase in the number of normal bacteria and a decrease in pathogenic strains.

The mechanisms of this phenomenon continue to be studied. Evidence to date points to two possibilities. On the one hand, B.subtilis due to the release of antimicrobial substances

Influence on the content of Lactobacillus

o w n o (I t S

Figure 4. Probiotic B.subtilis at the highest administered dose significantly increased the content of Lactobacillus in the feces of piglets

inhibits the development of pathogenic microflora, which creates conditions for filling the released niche with normal bacteria. This mechanism is indirectly indicated by the results of a study in which the antibiotic neomycin sulfate was administered to piglets. This tool is characterized by the fact that it inhibits the growth of Escherichia coli, but does not affect Lactobacillus. As a result, taking the antibiotic expectedly led to a decrease in the content of Escherichia coli in the feces, but at the same time to an increase in Lactobacillus. This phenomenon is possible only if the normal intestinal microflora begins to develop due to the suppression of pathogenic bacteria. The same thing happens when B. subtilis releases its anti-microbial agents.

The second possibility is related to the direct stimulation of B.subtilis normal intestinal microflora, such as Lactobacillus and Bifidobacterium. This is indicated by the results of in vitro experiments on the creation of mixed probiotics containing B.subtilis and Lactobacillus. It was found that the viability of lactobacilli in such combinations increased significantly. The results of one of the works indicate that this may be due to the release of catalase and subtilisin from B.subtilis.

Another discovered circumstance is of interest. Some studies have shown that B. subtilis enhances the diversity of the normal intestinal microflora. It is believed that this has a positive effect on the health of the host organism. In particular, B. subtilis increased the diversity of the intestinal microflora due to bacteria such as Eubacterium coprostanoligenes, L. amylovorus, Lachnospiraceae bacterium, L. kitasatonis.

At one time, the question of whether probiotics could harm the host's body, changing the microflora that had been established for him for years to alien, artificially introduced bacteria from outside, was widely discussed. However, later it was found that any probiotics taken for medical purposes do not linger in the gastrointestinal tract after the end of the course.

treatments are completely withdrawn from it. With regard to B. subtilis, it is important to take into account one more circumstance. This bacterium, although it constantly enters the digestive canal from soil, water, air and food products, however, does not colonize it (unlike Lactobacillus and Bifidobacterium). B. subtilis is a kind of transit bacterium, constantly coming in and out of the alimentary canal. Therefore, B. subtilis cannot take root in the intestines and change the stable composition of our microflora.

Enhancement of digestion and promotion of food

Exists a large number of diseases and conditions leading to impaired digestion and movement of food. An example would be errors in the diet, changes in diet, diseases of the gastrointestinal tract (cholecystitis, pancreatitis, etc.), disorders of the autonomic nervous system (leading to functional disorders) etc.

B. subtilis based probiotic can enhance digestion and secondary food promotion through the release of digestive enzymes. In studies, it was found that these bacteria synthesize all groups of enzymes necessary for the successful breakdown of food: amylases, lipases, proteases, pectinases and cellulase. The high activity of these enzymes is evidenced by the fact that B. subtilis is used in the food industry for the enzymatic processing of manufactured products.

Food contains substances called anti-nutritional factors. They got this name because their presence reduces the availability of one or more food components from the food consumed. It was found that B. subtilis enzymes destroy anti-nutritional factors, reducing their content in food. This, in particular, concerned the total phenols, tannins and caffeine. This increases the availability of food components for the host organism.

Food also contains substances that can cause allergic reactions in some sensitive individuals. However, B. subtilis enzymes are able to break down these substances, reducing the allergenic potential of the food. A study was conducted in which a similar effect of the probiotic was found in relation to gliadin (found in wheat) and p-lactoglobulin (present in cow's milk).

Examples of clinical studies

It is not our intention in this section to provide an exhaustive overview of all available clinical studies on B.subtilis. Rather, there was a desire to confirm the work of all those probiotic mechanisms that were described above using clinical examples.

Intestinal infections. In the study by Gracheva et al. included patients with salmonella

Frequency of antibiotic-associated diarrhea

o w n o (H t S

30 25 20 15 10 5 0

Figure 5. Probiotic B.villbv significantly reduced the incidence of diarrhea in outpatients treated with oral and intravenous antibiotics

disease, food poisoning and dysentery. One of the selected groups of patients received B. subtilis along with another probiotic ( total- 2109 live microbial cells) 2 times a day for 4-10 days. According to the results of the study, a pronounced therapeutic effect of the drug was found, which consisted in the accelerated normalization of stools, the disappearance of abdominal pain and a decrease in intestinal dysbiosis.

Antibiotic associated diarrhea. In a randomized, double-blind, placebo-controlled clinical trial, T.V. Horosheva et al. included outpatients > 45 years of age who received one or more oral or intravenous antibiotics for at least 5 days. One of the groups of patients (n = 90) received B. subtilis probiotic (2109 live microbial cells) 2 times a day, starting 1 day before the initiation of antibiotic therapy and ending 7 days after antibiotics were discontinued. As a result, it was found that in the probiotic group, antibiotic-associated diarrhea developed only in 7.8% (7/90) of patients, while in the placebo group this figure was 25.6% (23/90) (p< 0,001) (рис. 5). Пробиотик достоверно снижал частоту появления тошноты, рвоты, метеоризма и абдоминальной боли.

Strengthening the digestion and promotion of food. In a study by Y.P. Liu et al. included elderly (74 ± 6 years) outpatients and inpatients with functional constipation. One of the treatment groups (n = 31) received live B. subtilis microbial cells for 4 weeks. At the end of the study, it was found that the probiotic was effective in 41.9% (13/31) of patients.

Respiratory infections. This indication may seem somewhat unusual, given that B. subtilis is a probiotic that works in the gastrointestinal tract. However, when considering the mechanisms of the probiotic action of the bacterium, we mentioned that its ability to influence respiratory pathogens is associated with stimulation of the immune system.

In 2015, the Cochrane community published the results of a systematic review on the use of probiotics for the prevention of acute respiratory infections (ARIs). The authors concluded that probiotics were 47% more effective than placebo in reducing ARI episodes. In addition, probiotics reduced the duration of ARI by 1.89 days. Probiotics may slightly reduce the frequency of antibiotic use and the number of days missed from school. Side effects of probiotics were minimal, with more common gastrointestinal symptoms.

Safety

The safety of B. subtilis has been tested in three main areas: for the presence of pathogenic genes, antibiotic resistance, and the accuracy of microbial identification.

pathogenic genes. The presence of such genes is dangerous because they lead to the formation of toxins and other harmful substances that adversely affect the intestinal wall and the body as a whole. The authors report that these genes were not found in B. subtilis. Moreover, the cultivation of this probiotic in vitro with intestinal epithelial cells and its administration in vivo most different types animals did not lead to the development of harmful effects and side effects.

Antibiotic resistance. This parameter is dangerous in that if the probiotic has genes capable of conferring antibiotic resistance, then they can eventually be transferred to pathogenic bacteria that will also become resistant to antibiotics. The good news is that when tested in 3 studies, the B. subtilis probiotic proved to be sensitive (non-resistant) to all major antibiotics used in medicine. Therefore, B. subtilis cannot transmit resistance to pathogenic bacteria.

Accuracy of microbial identification. In 2003, a study was published demonstrating that 7 probiotics marketed as containing B. subtilis actually contained other closely related bacteria. Nevertheless, microbiologists report that today there are all conditions for the reliable identification of B.subtilis. Therefore, the correctness of the composition of the probiotic depends on the responsibility of the manufacturer releasing it.

It should be remembered that, like other probiotics, B. subtilis is not prescribed to patients with severe immunodeficiency (weakening of the body after severe infections, radiation and chemotherapy, patients with HIV / AIDS, etc.) due to the possibility of generalization of infection and the development of sepsis .

One publication listed the attributes of a "good" probiotic. To them, among other things, the authors attributed the ability of bacteria to exert

a positive effect on the host organism, for example, to increase resistance to diseases. The probiotic must be non-pathogenic and non-toxic. It must be able to survive and develop inside the gastrointestinal tract - that is, to be resistant to low values pH and organic acids. As follows from this review, all these properties are inherent in the probiotic bacterium B.subtilis.

According to experimental and clinical studies, there are a number of indications when the appointment of a probiotic based on B. subtilis is appropriate. First of all, this is the inclusion of a probiotic in the complex therapy of intestinal infections, including travelers' diarrhea, as well as its use for the prevention of respiratory infections in the cold season. The probiotic will be useful in the course of oral or parenteral antibiotic therapy for the prevention of antibiotic-associated diarrhea. The appointment of these bacteria will be important in case of violations of digestion and promotion of food of various origins associated with errors in diet, changes in diet, diseases of the gastrointestinal tract, disorders of the autonomic nervous system, etc.

Probiotics based on B. subtilis are characterized by a high ratio of efficacy and safety.

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Prepared by Ph.D. A.V. Savustyanenko ■

Savustyanenko A.V.

MEKHASHMI DM PROBYUTIEV ON OCHOBi BACILLUS SUBTILIS

Summary. The bacterium Vybnsh is one of the most promising prospects for probing, which has grown in the remaining ten. Mechashzmi 11 is a trial! dc sov "yazash 1s synthesis of anti-organic speeches, strengthening of non-specific 1 specific 1 mush-tetu, stimulating growth normally! Mzhroflori intestines and visions of herbal enzymes. - timzhrobno!

specific immunity pov "yazane with activating macrofaps i see 1 of them pro-inflammatory cytosis, pschvischennyam bar" erno! slime function! shellfish to the intestines, vidshennyam vggamshv i amshokislot (including non-suede). The strengthening of the specific immune system is manifested by the activating T-i B-lsh-fotsitsh and the manifestations of the stagnation of immunoglobulins - IgG and IgA. B.subtilis stimulates rut normally! intestinal microflora, zocrema bacterium genus Lactobacillus i Bifidobacterium. In addition, probutik zbshshue riznomanitnist mzhroflori intestines. Probutik is seen in the intestinal lumen and the main trace enzymes: amshazi, lshazi, protease, pectin-

zi i cellulase. In addition to the digestion "well qi enzyme ruin aHraxap40Bi factor and allergens of speech, to go to sleep. it's time to rock; prevention of antibutanesotsshovano"! diarrhea; for correction piston

digestion and prostitution of izhi of various genesis (errors in diet, dietary malnutrition, ailments of the mucosal-intestinal tract, vegetatively damaged! nervous system! B. subtilis does not sound like side effects. For which pro-biotic is characteristic high security efficiency.

Key words: Bacillus subtilis, probutik, dp mechanisms.

Savustyanenko A.V.

MECHANISMS OF ACTION OF PROBIOTICS BASED ON BACILLUS SUBTILIS

summary. The bacterium B. subtilis is one of the most promising probiotics studied in recent decades. Mechanisms of its probiotic action are associated with the synthesis of antimicrobial agents, increasing of non-specific and specific immunity, stimulation of growth of normal microflora of the intestine and the releasing of digestive enzymes. B.subtilis releases ribosomally synthesized peptides, non-ribosomally synthesized peptides and non-peptide substances with a broad spectrum of antimicrobial activity covering Grampositive, Gram-negative bacteria, viruses and fungi. Resistance to these antimicrobial agents is rare. Enhancement of non-specific immunity is associated with macrophage activation and the release of pro-inflammatory cytokines from them, increasing of barrier function of the intestinal mucosa, releasing of vitamins and amino acids (including essential ones). Enhancement of specific immunity manifests by activation of T- and B-lymphocytes and the release from the latter of immunoglobulins - IgG and IgA. B. subtilis stimu-

lates the growth of normal intestinal flora, in particular, bacteria of the genus Lactobacillus and Bifidobacterium. Furthermore, probiotic increases the diversity of intestinal microflora. Probiotic secretes all major digestive enzymes to the intestinal lumen: amylases, lipases, proteases, pectinases and cellulases. In addition to digestion, these enzymes destroy antinutritional factors and allergenic substances contained in the food. These mechanisms of action make reasonable the use of B.subtilis in the combination therapy to treat intestinal infections; prevention of respiratory infections during the cold season; prevention of antibiotic-associated diarrhea; for the correction of food digestion and movement impairments of various origins (errors in the diet, changes in the diet, diseases of the gastrointestinal tract, disorders of the autonomic nervous system, etc.). B. subtilis does not usually cause side effects. This probiotic is characterized by a high efficacy and safety ratio.

Key words: Bacillus subtilis, probiotic, mechanisms of action.

The invention relates to biotechnology, veterinary medicine and can be used to obtain a drug from the group of probiotics. The bacterial strain Bacillus subtilis BKM B-2287 was isolated from the soil. The cells are gram-positive, do not form capsules, form round spores, the type of respiration is aerobic. Hydrolyzes glucose, mannitol, lactose. Does not ferment sucrose, inositol, sorbitol, maltose. Does not form gas during fermentation. Suppresses the growth of staphylococci, Escherichia coli, enterobacteria, citrobacteria, aeromonas. The strain is used as a production strain to obtain a probiotic preparation, named by the authors "Subtilis+". The drug normalizes the activity of the gastrointestinal tract of farm animals, poultry, fish; promising in the treatment and prevention of bacterial infections. 1 tab.

The invention relates to biotechnology and can be used in the microbiological industry to obtain a probiotic preparation used in veterinary medicine in the treatment and prevention of gastrointestinal diseases in animals, poultry and fish.

Known strain of Bacillus subtilis 534 - producer of the probiotic "Sporobacterin", which is intended for the prevention and treatment of the gastrointestinal tract, dysbacteriosis. SU 1708350, class. A 61 K 35/66.

The disadvantage is the short shelf life, tk. contains live bacteria that cannot retain their properties for a long time, low purity of the preparation, which has a narrow scope - as a feed additive for animals. The strain is also sensitive to antibiotics, with the exception of polymyxin, which limits the scope of the drug.

A strain of Bacillus subtilis 3H (GISK No. 248) is known, which has the property of antibiotic resistance, used to obtain the probiotic preparation "Bactisporin", which is used in conjunction with antibiotics for the treatment and prevention of dysbacteriosis, enzyme deficiency of the digestive organs, purulent infections, food allergies. RU 2067616 C1, class. A 61 K 35/74, 10.10.1996.

Known strain of Bacillus subtilis TPAXC-KM-117, which exhibits inhibitory activity against pathogenic microorganism species and has multidrug resistance. The strain is resistant to tetracycline, rifampicin, alenicillin, chloramphenicol, aprectomycin. On its basis, an antibiotic-resistant probiotic is prepared for the treatment and prevention of infectious diseases with the same antibiotic therapy (RU 2118364 C1, class C 12 N 1/20, 27.08.1988).

Known strain of Bacillus subtilis VKM B-2250 (RU No. 2184774, class A 61 K 35/74, 10.07.02), which is the basis of the drug for veterinary purposes and fisheries.

The problem to which the invention is directed is the identification of a new effective strain-producer of a probiotic preparation for veterinary purposes and fisheries.

The technical result achieved in the implementation of the invention is to increase the effectiveness of treatment, increase the digestibility of feed, productivity and weight gain of animals, birds, fish through the use of a probiotic preparation based on the proposed producer strain, stability of the preparation during storage in a wide range of ambient temperatures.

The Bacillus subtilis B-9 strain was isolated from the soil, deposited in the All-Russian Collection of Microorganisms (IBFM named after K.G. Skryabin) under the number VKM B-2287.

The strain of Bacillus subtilis VKM B-2287 can be stored in a lyophilized state for several years or on shoals with an agar medium based on meat-peptone broth with obligatory reseeding at least 1 time in 2 months on the same medium.

Characteristics of the strain.

Cultural and morphological features. Sticks. The size of a one-day agar culture is 3-5 µm. Cells stain positively according to Gram, form round spores, single, central diameters are less than the diameter of the cell. The colonies on the MPA are white, the pigment is not isolated into the medium.

Physiological signs. Aerobe, optimum growth temperature 37°C and pH 3.5-8.0. Growth is possible in the temperature range of 4-50 ° C. Relation to NaCl - growth at a content of up to 3%.

biochemical signs. Breaks down glucose, lactose, mannitol. Non-fermentable carbon compounds: sucrose, inositol, sorbitol, maltose, lactose. Utilizes citrate and acetate. Does not form gas during fermentation. Produces oxidase, catalase.

antagonistic signs. Bacillus subtilis BKM B-2287 strain inhibits the growth of staphylococci, Proteus, Klebsiella, Escherichia coli, enterobacteria, citrobacteria, aeromonas, yeast fungi.

The Bacillus subtilis BKM B-2287 strain is not pathogenic for plants, animals, fish and humans.

The data in Table 1 show the antagonistic activity of test strains of microorganisms (delayed antagonism method).

For cultivation of the strain Bacillus subtilis BKM B-2287 use a liquid nutrient medium containing casein hydrolyzate - 5 cm 3 · DM -3 (N aM =300 mg%); corn extract - 80 cm 3 dm -3 (N am \u003d 290 mg%), MnSO 4 5H 2 O - 0.250 g-dm -3; MgSO 4 7H 2 O - 0.300 g-dm -3; FeSO 4 7H 2 O - 0.015 g-dm -3; CaCl 2 2H 2 O - 0.052 g-dm -3; NaCl - 11,000 g-dm -3 , distilled water.

Preliminary dry biomass of microorganisms is sown in a test tube with broth. When visible growth appears, the colonies are subcultured on meat-peptone agar in test tubes.

Typical colonies are selected and subcultured onto a liquid medium in vials. After 22 hours, the entire grown mass is transferred to a 20-liter bottle with 10 liters of nutrient medium and cultivated for 26 hours at 37-39 ° C, obtaining inoculum.

A nutrient medium based on casein hydrolyzate is placed in a biological reactor, sterilized for 60 minutes at 1 atm, cooled to 39°C, and inoculated with inoculum from a bottle in a ratio of 1:9.

In the process of aerobic cultivation, the pH of the medium is maintained within the range of (6.8-7.2) units. pH, feeding the medium with (10-15)% glucose to a final concentration of (0.1-0.2)%. Upon reaching the biological concentration of BC (15-20) 10 9 cells.cm -3 and (8-10) 10 9 cells.cm -3 BKt stop adding glucose to lower pH 4.0 and turn off the air supply. Then the heating of the reactor is turned off, the medium is cooled to (15-19) ° C. The resulting cooled culture is pumped into containers or packaged in vials.

With the specified cultivation method, a probiotic preparation is obtained in the form of a liquid form containing (80-95)% spores and live vegetative cells of bacteria of the Bacillus subtilis VKM B-2287 strain.

The proposed probiotic preparation is harmless, does not contain extraneous microflora. Harmlessness was tested on white mice weighing (18-20) g, which were orally administered the drug in a volume of 1.0 ml.

The drug has a specific activity: the number of cells in one dose of the drug (8-20)10 9 cells.cm -3 antagonistic activity - the growth inhibition zone of test microorganisms is from 10 to 38 mm.

Thus, the proposed strain of Bacillus subtilis VKM B-2287 can be used as a production strain for obtaining a probiotic preparation recommended for the prevention and treatment of gastrointestinal diseases in animals, poultry, and fish.

The invention is illustrated by examples.

Example 1. Tests of the proposed probiotic preparation on newborn calves and piglets.

The effectiveness of the drug based on the proposed strain of Bacillus subtilis VKM B-2287 was tested on newborn calves and piglets diagnosed with diarrhea, which occurred against the backdrop of a difficult epizootic situation on the farm. The control groups of calves and piglets were kept according to the technology adopted in the farm. The calves and piglets of the experimental groups were additionally given a drug based on the proposed strain of Bacillus subtilis BKM B-2287 orally with a small amount of water 20 minutes before feeding in a single dose per head of 15 ml for calves and 20 ml for piglets three times a day for three days . Observations showed that in the experimental groups, one day after giving the drug, the general condition of all animals improved, diarrhea stopped, and two days later all animals were practically healthy. The condition of the animals in the control groups was characterized by the continuation of the state of diarrhea, the death rate was 10% in calves and 22% in piglets.

Example 2. Addition of the probiotic preparation "Subtilis+" to the feed of aquarium fish.

The reared juveniles of goldfish (oranda) were fed with extruded feed with the addition of the probiotic preparation Subtilis+. The amount of food was 10 kg, added probiotic 1 ml. The number of fish in the experimental and control groups was 250 specimens each. Feeding was carried out 4-6 times a day. The food was eaten willingly. The growth rate of juveniles in the experimental group compared to the control group was 22%. The output of fish in the experimental - 98%, in the control - 78%. The water in the aquariums did not deteriorate, there was no turbidity.

Example 3. The safety of chickens in the first weeks.

“Subtilis+” was tested on chickens of a broiler poultry farm (5 poultry houses in the experimental and control groups). The waste of chickens in the control group that did not receive the probiotic was 4%, experimental - 0.2%. In the experimental groups, chickens gained weight more intensively. After the first three days, the average weight of a chicken in the control group was 61 g, in the experimental group - 70 g.

The conducted tests have shown the effectiveness of the drug "Subtilis+", obtained on the basis of the proposed strain of Bacillus subtilis BKM B-2287.

CLAIM

The bacterial strain Bacillus subtilis BKM B-2287 used to obtain a probiotic preparation intended for the prevention and treatment of gastrointestinal diseases in animals, poultry and fish.

Formula, chemical name: no data.
Pharmacological group: organotropic agents/ gastrointestinal agents/ antidiarrheals; immunotropic agents / immunomodulators / other immunomodulators.
Pharmachologic effect: broad spectrum antibacterial, immunostimulating, antidiarrheal.

Pharmacological properties

The active substance Bacillus subtilis is a lyophilized microbial mass of a live antagonistically active strain of Bacillus subtilis 3H, which was selected for chromosomal resistance to rifampicin from the production strain of Bacillus subtilis 534. One dose medicinal product contains from one to five billion living bacteria. Bacillus subtilis have antagonistic activity, secrete broad-spectrum antibacterial substances that inhibit the growth of opportunistic and pathogenic fungi and bacteria. At the same time, the growth of saprophytes, including the normal intestinal microflora, is not inhibited. Due to the release of Bacillus subtilis proteolytic enzymes (including lipases, lysozyme, amylases and others), the drug promotes the breakdown of fats, proteins, fiber, carbohydrates, improves digestion and absorption of food, and helps cleanse wounds and inflammatory foci from necrotic tissues. Bacillus subtilis has a pronounced immunostimulating effect, including on the digestive and absorption activity of phagocytic blood cells. Bacillus subtilis also have a moderate anti-allergic effect.

Indications

Intestinal dysbacteriosis of various origins (including complicated by allergic dermatosis and food allergies); acute bacterial intestinal infections (including salmonellosis, acute dysentery and others); bacterial vaginosis; bacterial vaginitis; osteomyelitis (in the absence of large sequesters); surgical soft tissue infections; treatment and prevention of purulent-septic complications caused by conditionally pathogenic and pathogenic microorganisms during obstetric-gynecological and surgical operations in the postoperative period.

Method of application of bacillus subtilis and doses

Bacillus subtilis is applied orally 30-40 minutes before meals, intravaginally, in the form of irrigations or applications (on a tampon). When taken orally, Bacillus subtilis is pre-dissolved with boiled, cooled water. Dosage, method of administration, duration of treatment are set individually depending on the indications and age of the patient.
Treatment of acute bacterial intestinal infections, including acute dysentery, salmonellosis, continues for 7-10 days.
Treatment of dysbiosis after bacterial infections or the use of antibiotics continues for 20 days.
Treatment of allergic dermatoses continues for 10-20 days.
Treatment of bacterial vaginosis, vaginitis continues for 5 to 10 days.
Prevention of purulent-septic complications in the postoperative period: within 5 days before surgery and 5 days after surgery or injury.
Treatment and prevention surgical infection soft tissues continues for 7-10 days.
If necessary, the course of treatment can be repeated.
When using Bacillus subtilis according to the indications in the recommended doses, no adverse reactions were detected. In case of development adverse reactions they completely disappear within a day when the dose is reduced or the drug is discontinued.
The effect of Bacillus subtilis on women during pregnancy has not been studied.
The diluted powder of Bacillus subtilis cannot be stored.
With caution, bacillus subtilis is prescribed for polyvalent drug allergies.
Bacillus subtilis is not used in case of violation of the integrity of the package, changes in physical properties, presence of impurities, lack of labeling.
The use of Bacillus subtilis has no effect on the performance of potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

Contraindications for use

Hypersensitivity (including to the auxiliary components of the drug).

Application restrictions

Polyvalent drug allergy, childhood.

Use during pregnancy and lactation

The effect of Bacillus subtilis on women during pregnancy has not been studied. Bacillus subtilis can be used as prescribed by the attending physician during breastfeeding.

Side effects of bacillus subtilis

Digestive system: diarrhea, abdominal pain.
Others: fever, chills, skin rash.

Interaction of Bacillus subtilis with other substances

When sharing bacillus subtilis with antibiotics, the therapeutic efficacy of bacillus subtilis may decrease.
When sharing bacillus subtilis with sulfonamides, it is possible to reduce the therapeutic efficacy of bacillus subtilis.
It is allowed to use Bacillus subtilis in conjunction with other drugs in consultation with the attending physician.

Thesis

Gataullin, Airat Gafuanovich

Academic degree:

PhD in Biology

Place of defense of the dissertation:

VAK specialty code:

Speciality:

Microbiology

Number of pages:

LITERATURE REVIEW

Chapter 1. Microbial antagonism - the basis for the creation of biotherapeutic drugs for the correction of dysbiotic conditions

Chapter 2. Spore probiotics and their impact on the macroorganism

2.1. Preparations from bacteria of the genus Bacillus

2.2. Modern ideas about the mechanisms of the therapeutic and prophylactic action of probiotics from bacteria of the genus Bacillus

2.3. Biologically active substances produced by aerobic spore-forming bacteria

2.4. Pathogenicity factors of bacteria of the genus Bacillus 34 OWN RESEARCH

Chapter 3. Objects and methods of research

3.1. Research objects

3.2. Research methods 43 3.2.1. Equipment and methods

Chapter 4. Characteristics of isolated strains

4.1. The study of morphological and physiological biochemical properties strains

4.2. Antagonistic and adhesive activity of B. subtilis strains in in vitro experiments

4.3. Definition antibiotic resistance and plasmid profile of B.subtilis strains

Chapter 5

5.1. Study of toxicity, toxigenicity, virulence and probiotic activity of B.subtilis 1719 strain in experiments in vivo

5.2. Study of the influence of B. subtilis 1719 strain on immunity parameters in experiments in vivo with experimental dysbiosis

Chapter 6

6.1. Evaluation of growth properties on various liquid nutrient media

6.2. Study of the viability and antagonistic activity of the B. subtilis 1719 strain during storage

Chapter 7 Comparative characteristics properties of the B.subtilis\l\9 strain and the strains that form the basis of some commercial probiotic preparations. CONCLUSION

Introduction to the thesis (part of the abstract) On the topic "Biological properties of Bacillus subtilis strains, promising for the creation of new probiotics"

Relevance of the problem

At the present stage in medical microbiology, new data have appeared that justify the use of saprophytic microflora, which is capable of producing biologically active substances (BAS) during its life activity that inhibit the growth of pathogenic microorganisms, malignant tumors and normalize various pathological and biochemical processes in the human body.

In the last decade, biological preparations based on live microbial cultures have been widely used for the prevention and treatment of diseases of the gastrointestinal tract. spore-forming

Bacteria of the genus Bacillus, one of the most diverse and widespread groups of microorganisms, are important components of the exogenous flora of humans and animals.

The genus Bacillus has attracted the attention of researchers since ancient times. The accumulated knowledge in the field of microbiology, physiology, biochemistry, genetics of bacteria testify to the advantages of Bacillus as producers of biologically active substances: enzymes, antibiotics, insecticides. High adaptability to various conditions of existence (presence or absence of oxygen, growth and development in a wide range of temperatures, use of various organic or inorganic compounds as food sources, etc.) contribute to the spread of bacilli in soil, water, air, food and other environmental objects, as well as in humans and animals.

The diversity of metabolic processes, genetic and biochemical variability, resistance to lytic and digestive enzymes, served as a rationale for the use of bacilli in various fields medicine. The U.S. Food and Drug Administration has awarded Bacillus subtilis the status of GRAS (generally regarded as safe) - completely safe organisms, which is prerequisite for the use of these bacteria in the manufacture of drugs.

The activity of bacilli is manifested in relation to a wide range of pathogenic and conditionally pathogenic microorganisms. Thanks to the synthesis of various enzymes and other substances, they regulate and stimulate digestion, have anti-allergic and anti-toxic effects. When using bacilli, the nonspecific resistance of the macroorganism increases significantly. These microorganisms are technologically advanced in production, stable during storage, and, most importantly, environmentally safe.

Therapeutic and prophylactic preparations based on live non-pathogenic microbes, capable of exerting natural way the introduction of beneficial effects on the physiological and biochemical functions of the host organism through the optimization of its microbiological status, are currently referred to as probiotic preparations.

Of the bacilli, strains of B. subtilis are of the greatest interest. According to the study of genetic and physiological properties, they take second place after E. coli. The great potential of B. subtilis in biotechnology is evidenced by the creation of a data bank on the molecular genetics of this strain - SubtiList, in which all information about the bacterial genome is entered.

Based on live bacteria of the genus Bacillus, probiotic preparations have been created that are harmless to the macroorganism, have a wide range of therapeutic and prophylactic effects and environmental safety. Of great scientific and practical importance are the results on the use of live microbial cultures of the genus Bacillus for the treatment of gastrointestinal diseases in humans and farm animals.

Currently, well-known probiotic preparations are widely used in practical healthcare: bactisubtil, sporobacterin, biosporin, bactisporin, subalin, cereobiogen, enterogermin and others.

The indications for therapeutic use and the therapeutic efficacy of these drugs are limited by the properties of the strains used for their production. In this case, the spectrum of antagonistic activity against pathogenic and opportunistic microorganisms, which are the cause of microecological disturbances in various biotopes of the human or animal body, is of decisive importance. In addition, one cannot ignore the ability of bacilli to produce biologically active substances (polypeptide antibiotics, enzymes, etc.) and their antibiotic resistance.

Diversity and emerging antibiotic resistance microorganisms involved in the development of dysbiotic disorders, on the one hand, as well as the variability biosynthetic opportunities in different strains of B. subtilis, on the other hand, determine the expediency of continuous monitoring of strains that have directed probiotic activity and/or are producers of various biologically active substances.

Objective:

To study the biological properties of the isolated strains of B. subtilis and evaluate the possibility of their use for the development of the original spore probiotic.

Research objectives:

1. To study the morphological, physiological, biochemical, antagonistic, adhesive and other properties of isolated B. subtilis cultures in in vitro experiments and choose the most promising strain for further research.

2. Evaluate the probiotic activity of the selected strain of B. subtilis in experiments in vivo.

3. Choose a nutrient medium that is optimal for the accumulation of the biomass of the studied B.subtilis strain.

4. Determine the viability and antagonistic activity of the selected B. subtilis strain during storage.

5. Compare the properties of the original strain of B. subtilis and the cultures used for the manufacture of commercial probiotic preparations.

Scientific novelty.

Based on the study of morphological, physiological, biochemical, genetic and other biological properties of the isolated strains, a plasmid-free strain B.subtilis 1719 was selected, which exhibits antagonism against opportunistic and pathogenic microorganisms of various taxonomic groups with low adhesive activity, resistant to gentamicin, polymyxin and erythromycin.

Approaches to the creation of a production technology were experimentally substantiated, including the study of the growth properties of the B. subtilis 1719 strain on original nutrient media, the conditions for stabilizing its viability and antagonistic activity as stages in obtaining a new probiotic preparation.

An application for an invention has been filed (No. 2005111301 dated April 19, 2005): "The bacterial strain Bacillus subtilis 1719 is a producer of antagonistically active biomass against pathogens, as well as proteolytic, amylolytic and lipolytic enzymes."

Practical significance.

The isolated and identified strain B. subtilis 1719 was deposited in the State Collection of Cultures of the GISK named after. JI.A. Tarasevich under No. 277 and can be recommended for the development of an industrial technology for the production of an original biotherapeutic probiotic preparation.

The main provisions for defense:

1. The isolated three strains of bacterial cultures according to morphological, physiological, biochemical and other properties correspond to the species B. subtilis. They do not contain plasmids, are antagonistically active against opportunistic and pathogenic bacteria of different taxonomic groups, have a low or medium level of adhesion.

2. The B.subtilis 1719 strain has probiotic properties, manifested in the elimination of opportunistic and pathogenic microorganisms with the restoration of the quantitative and qualitative composition of the normal microflora in experimental dysbiosis, and also has an immunomodulatory effect on the macroorganism.

3. According to the technological characteristics, the B.subtilis 1719 strain can be recommended as a candidate for creating an original probiotic preparation.

LITERATURE REVIEW

Dissertation conclusion on the topic "Microbiology", Gataullin, Airat Gafuanovich

1. On the basis of morphological and physiological-biochemical properties, the isolated strains were identified as B.subtilis. No plasmids were found in DNA preparations of B. subtilis strains, which apparently indicates chromosomal control of antibiotic resistance.

2. The probiotic activity of the B.subtilis 1719 strain, which manifests itself in the elimination of opportunistic and pathogenic microorganisms with the restoration of the qualitative and quantitative composition of the normal microflora, is shown on the model of dysbiosis in white mice.

3. The optimal medium for the accumulation of biomass when cultivating the B. subtilis 1719 strain is VK-2 medium with the addition of glucose or sucrose as a source of carbohydrates.

4. It has been established that the B.subtilis 1719 strain retains viability and antagonistic activity in a lyophilized state with a sugar-gelatin stabilizer for at least 4 years (observation period), in a liquid form stabilized with a 7% NaCl solution - 2 years, and 1 year in the presence of distilled water or 10% glycerol solution.

5. Antagonistically active, low adhesive, a plasmid-free, non-toxic strain of B. subtilis 1719, which has probiotic and immunomodulatory activity, is deposited in the State Collection of Cultures of the GISK named after. J1.A. Tarasevich.

6. The B.subtilis 1719 (277) strain, in terms of biological properties and main technological characteristics, is promising for use in the development of new probiotic preparations.

CONCLUSION

Discoveries and achievements of modern biological and medical science made it possible to develop and introduce into practice new biological products - probiotics. These medicines are based on live microbial cultures. The therapeutic effect of these drugs is based on a pronounced microbial antagonism against pathogenic and conditionally pathogenic strains - pathogens. In the process of treatment, the immunomodulatory activity of probiotics is no less important. The undeniable advantages of preparations from live bacteria over drugs synthesized by chemical means are harmlessness, their physiological nature for the human body, and the absence of allergic reactions. Already, probiotics have taken a leading position in the correction of the microflora of the gastrointestinal tract, metabolic disorders, the treatment of the consequences of antibacterial, chemotherapy, hormonal and radiation therapy. As a result of studying the phenomenon of bacterial translocation, it has been shown that probiotics can successfully replace antibiotics and proteolytic enzymes in the prevention and treatment of various surgical infections.

In the last decade, biological preparations based on live microbial cultures have been widely used for the prevention and treatment of diseases of the gastrointestinal tract. spore-forming bacteria.

The variety of metabolic processes, genetic and biochemical variability, resistance to lytic and digestive enzymes, served as a rationale for the use of bacilli in various fields of medicine. These microorganisms are technologically advanced in production, stable during storage, and, what is essential, environmentally safe.

High activity of strains against one set of test cultures does not guarantee its activity against others. In this regard, the use of spore probiotic is limited to specific medicinal purposes. The variability of nosological forms of purulent-septic diseases and the variety of microorganisms etiologically significant for the development of dysbiotic disorders determine the requirements for the biological product used. This encourages researchers to continually screen for antagonist strains with desired properties.

The strains studied by us had morphological and physiological-biochemical properties typical of representatives of B. subtilis and were characterized by a set of enzymes that decompose various substrates.

According to the literature, B.subtilis has pronounced antagonistic properties against a wide range of pathogenic microorganisms and high enzymatic activity, due to which they normalize digestion processes, and also provide antitoxic and antiallergic effects.

The studied strains of B.subtilis had wide range antagonistic activity, low (B. subtilis No. 1719) or medium (B. subtilis No. 1594, B. subtilis No. 1318) level of adhesion.

Thus, the strains studied by us were characterized by high probiotic activity. However, the study of biochemical properties showed that the B.subtilis 1719 strain had a higher enzymatic activity (protease, amylase, lipase), which was expressed in the largest zone of hydrolysis of the studied substrates. In addition, the low level of adhesive activity of the B. subtilis 1719 strain and, apparently, its natural antibiotic resistance, controlled by the chromosome, made it possible to conclude that further study of this culture is promising.

In our opinion, the prospects for expanding the industrial production of drugs based on the genus Bacillus are very high.

Bacilli are able to secrete many enzymes into the culture fluid. They serve as an important industrial facility for the production of proteolytic and amylolytic enzymes used in the production of foodstuffs, detergents and biomedical substances. In the last decade, a number of new antibiotics, bacterial insecticides and other biologically active substances have been obtained with their participation.

Despite the fact that B. subtilis have GRAS status, there are isolated reports in the literature of the presence of pathogenicity factors in some strains of B. subtilis. It is indicated that this is not a permanent feature, since it disappears during reseeding. It has been suggested that the pathogenic properties of bacteria are related to the presence of plasmids in them. For example, Le H. and Anagnostopoulos C. isolated plasmids from 8 strains of B. subtilis in 83 patients. Plasmid DNA was detected only in cells of toxigenic strains of B. subtilis and was not found in cells of other strains of the same species that do not have toxigenicity. Elimination of plasmids from toxigenic strains under the influence of eliminating agents led to the elimination of the toxigenic properties of culture filtrates. However, the genetic role of plasmids is not well understood.

In our studies, no plasmids were found in the isolated DNA preparations of the three B. subtilis strains studied.

The authors, who studied the effect of bacilli on the body of warm-blooded animals, came to the conclusion that B. subtilis strains are completely harmless to humans and animals. The proof of harmlessness for the macroorganism is the experimental data that already a few days after parenteral administration, B.subtilis is eliminated from the body. The mechanisms of the therapeutic action of these cultures were studied in animals. Currently, it is believed that the therapeutic effect of spore probiotics is determined by a complex of factors, including: the production of bacteriocins by B. subtilis cultures that inhibit the growth of pathogenic and conditionally pathogenic microorganisms; synthesis of highly active enzymes: proteases, ribonucleases, transaminases, etc.; production of substances that neutralize bacterial toxins.

The study of the properties of the selected strain in mice showed that it is avirulent, does not have toxicity and toxigenicity.

Factors positive impact probiotics on a macroorganism are various products of microbial synthesis: amino acids, polypeptide antibiotics, hydrolytic enzymes and a number of other biologically active substances of lesser importance. Therefore, the study and isolation of protective substances produced by microorganisms of the genus Bacillus, and the creation of biomedical preparations on their basis, is an urgent need.

In the gastrointestinal tract, a direct antagonistic effect of bacilli is manifested, which is predominantly selective in relation to pathogenic and conditionally pathogenic microorganisms. At the same time, they are characterized by the absence of antagonism against representatives of the normal microflora.

In our studies, when correcting experimental dysbiosis induced by the administration of the antibiotic doxycycline, the culture of B. subtilis 1719 contributed to the normalization of the composition and abundance of the intestinal microflora, as well as the elimination of conditionally pathogenic microorganisms in the parietal and luminal microflora.

It follows from the literature data that industrial strains of the genus Bacillus have a low index of adhesive activity to erythrocytes and weak or moderate adhesiveness to intestinal epithelial cells. B. subtilis 534 and 3N strains have more adhesins to enterocyte receptors, B. licheniformis strain - to colonocytes, i.e. different strains appear to have adhesins to receptors on different intestinal cells.

Their activity is carried out in the intestinal lumen and is directed against pathogenic microorganisms, without having an antagonistic effect on representatives of the normal microflora. When taking spore probiotics, the possibility of restoring autoflora in various loci of the intestine is realized, and after 3-5 days the number of lactobacilli, bifidobacteria, Escherichia coli, etc. increases, and then recovers to normal levels.

The results of our studies on the adhesion of microorganisms on enterocytes make it more likely that the adhesive ability of intestinal cells depends on the quantitative and qualitative composition of the normal microflora. In dysbiotic conditions, receptors open on the surface of enterocytes, on which conditionally pathogenic and pathogenic microorganisms, and when correcting dysbiosis, colonization of the intestine by normal microflora occurs and a decrease in the number of enterocyte receptors capable of adhering non-indigenous microorganisms to their surface occurs.

It is known that the normal microflora plays an important starting role in the mechanism of the formation of immunity and specific protective reactions in the postnatal development of the macroorganism.

The role of microflora in the development of the immune response is due to its universal immunomodulatory properties, which include immunostimulation and immunosuppression. It has been established that bacterial lipopolysaccharides (LPS) have an immunoregulatory effect on the Ig A immune response and play the role of adjuvants. The microflora ensures the development of a complex of non-specific and specific immunological reactions, forming adaptive-protective mechanisms.

No matter how high antimicrobial activity a drug has, a decisive role in the elimination of an infectious pathological status. The creation of drugs that are effective in terms of antimicrobial indicators and stimulate immune responses is an important task. Therefore, a large number of studies are aimed at studying the effect of drugs - probiotics on different parts of the immune system of humans and animals.

Administration of live cultures of aerobic bacilli markedly stimulates in vivo production of serum interferon and interferon induced in vitro by Newcastle disease virus.

A number of works indicate that probiotic preparations have an immunomodulatory effect, restoring the immune status disturbed by pathology, increasing the production of endogenous interferon, enhancing the functional activity of macrophage cells, increasing the phagocytic activity of blood leukocytes - monocytes and neutrophils.

Our studies have shown that the culture of B. subtilis 1719 significantly changed the metabolic activity of neutrophils during the correction of dysbiosis and did not cause changes in the functional activity of neutrophils in the normal state of the indigenous microflora. In addition, it was found that dysbiosis was accompanied by an increase in the level of TNF-a, which indicated a pronounced phagocytic, cytotoxic, and adhesive activity of macrophages, lymphocytes, as well as endothelial and epithelial cells of the small intestine.

Increased secretion of a pro-inflammatory cytokine in mice with dysbiosis probably reflects the activation of immunocompetent cells (T-lymphocytes, monocytes/macrophages). Under the influence of culture B.subtilis 1719 * observed a decrease in the production of TNF-a. The introduction of culture to intact animals did not cause changes in the level of TNF-a production.

Considering that TNF-a is a marker of inflammatory reactions, it was concluded that the probiotic plays an important role in increasing the anti-inflammatory activity of immunocompetent cells in animals.

Studies on the dynamics of cytokine production under the influence of the B. subtilis 1719 strain showed that the culture had no effect on the production of cytokines in the first hours after administration, except for IL-lp, the amount of which accumulated gradually. The level of other studied cytokines (IL-2, IL-4, IL-6, IL-10, IL-12, IFN-y) increased significantly in the range from 12 to 24 hours.

Thus, modulation of cells of the immune system and changes in the potential of cytokines may be one of the mechanisms by which the culture of B. subtilis 1719 contributes to the correction of dysbiosis.

An analysis of the results of scientific research conducted in our country and abroad indicates the extent of the use of bacteria of the genus Bacillus to obtain products from the biomass of bacteria or their metabolites. Known ways cultivation bacteria of the genus Bacillus are the basis for the technology for obtaining a number of bacterial and enzyme preparations. .

When studying the growth properties of the B. subtilis 1719 culture on various liquid nutrient media, it was found that for the maximum accumulation of biomass, the VK-2 medium with the addition of glucose or sucrose can be considered the most adequate substrate for cultivating the strain.

Currently, when selecting and characterizing production cultures of microorganisms, the following indicators of biological characteristics are mainly taken into account: the spectrum and level of antagonistic activity, manufacturability, i.e. ability to rapidly accumulate bio*mass, resistance to freeze-drying, viability during storage. Particular attention is paid to the criteria for the degree of safety of the used microorganisms for human health.

In studies conducted to assess the viability of B. subtilis 1719 microbial cells during storage in the presence of liquid stabilizers, it was found that the optimal stabilizer is a 7% NaCl solution, which allowed maintaining the viability and antagonistic properties of the strain for 2 years. To preserve the properties of the culture for 1.5 years, it is possible to use a 10% solution of glycerol, 1 year - distilled water, while it was found that these fillers did not have statistically significant effects on the antagonistic properties of the B.subtilis 1719 strain. It should be noted that important fact is the ability of the B.subtilis 1719 strain to maintain antagonistic activity against S.sonnei and S.aureus in liquid stabilizers for a long time -36 months. (observation period).

Freeze drying with a sucrose-gelatin stabilizer maintained the viability and antagonistic activity of the B. subtilis 1719 strain for 4 years (observation period).

Currently, well-known probiotic preparations are widely used in practical healthcare: bactisubtil, sporobacterin, biosporin, bactisporin, subalin, cereobiogen, enterogermin and others.

Comparative study of strain B.subtilis 1719 in terms of antagonistic and adhesive activity with commercial cultures of the following probiotic preparations: Sporobacterin, Russia (B. subtilis 534), Cereobiogen, China (B. cereus DM423), Subtil, Vietnam (B. cereus var. vietnami), Baktisubtil, France (B.cereus IP5832), Nutrolin, India (B.coagulans), showed that the isolated strain is original and can be recommended as a production strain when obtaining a new probiotic preparation.

Thus, according to the physiological and biochemical properties, the B.subtilis 1719 strain has clearly distinguishable individual characteristics, which are entered in the culture passport when deposited in the collection of cultures of the GISK named after. JI.A. Tarasevich. In addition, the dominant position of the isolated B. subtilis 1719 strain in terms of antagonistic activity indicates the prospects for using this culture for the development of a probiotic preparation based on it.

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Bacillus subtilis or hay stick(lat. Bacillus subtilis) is a species of gram-positive spore-forming aerobic bacteria, representatives of the genus Bacillus ( bacillus). Bacillus subtilis- one of the most well-studied microorganisms.

Name hay stick is due to the fact that earlier Bacillus subtilis isolated exclusively from hay decoctions. Bacillus subtilis It has the appearance of a colorless straight rod, approximately 0.7 microns in thickness and 2-8 microns in length. Bacillus subtilis can reproduce by division and spores. Sometimes individual Bacillus subtilis, after transverse division, remain connected in the thread.

Bacillus subtilis(hay stick), due to the produced antibiotics and the ability to acidify the environment, is an antagonist of pathogenic and opportunistic microorganisms such as salmonella, proteus, staphylococci, streptococci, yeast fungi; produce enzymes that remove the products of putrefactive decay of tissues; synthesize amino acids, vitamins and immunoactive factors. Some strains Bacillus subtilis are producers of hyaluronic acid.

Bacillus subtilis may cause food poisoning in humans (ICD-10 code A05.4).

Bacillus subtilis - the active ingredient of drugs

Bacillus subtilis (Bacillus subtilis) - the active substance of some drugs. In this context, the term "Bacillus subtilis" refers to a specific strain (s) of bacteria of the species Bacillus subtilis. According to the pharmacological index, Bacillus subtilis belongs to the groups "Antidiarrheals" and "Other immunomodulators". The ATC code for Bacillus subtilis is A07FA Antidiarrheal organisms. Indications for use of Bacillus subtilis:

acute intestinal infections in children
intestinal dysbacteriosis of various nature
bacterial vaginosis
prevention of purulent-septic complications in the postoperative period.

As the active substance of drugs, a lyophilized microbial mass of a live antagonistically active strain is used. Bacillus subtilis 534 or strain Bacillus subtilis 3H,

selected on the basis of chromosomal resistance to the antibiotic - rimfapicin from the production strain Bacillus subtilis 534. Russian enterprises of the 48th Central Research Institute of the Ministry of Defense of Russia FGU, Yekaterinburg, CJSC "Biopharma" and several Ukrainian enterprises produce the drug Biosporin containing a mixture Bacillus subtilis strain 2335 (also called Bacillus subtilis 3) and Bacillus licheniformis 2336 (also called Bacillus licheniformis 31) in a ratio of 3:1.

Russia also registered (were registered) medicines in which the main active ingredient was Bacillus subtilis:(strain 534), Baktisporin (strain N 3H).

Preparations based on hay sticks Bacillus subtilis(Sporobacterin, Biosporin, Bactisporin) and a similar microorganism Bacillus cereus(Bactisubtil) have antimicrobial activity and can be used for bacterial infections when antibiotics are not available or for selective decontamination of the small intestine in bacterial overgrowth syndrome. The spores of these bacteria, turning into active forms in the large intestine, produce acidic metabolites - organic acids - in the course of life. At the same time, the pH in the colon shifts to the acid side and the growth of pathogenic and opportunistic microorganisms is suppressed (Belousova E.A., Zlatkina A.R.).

The composition of the drug Enzymtal, which has permission for use on the territory of Ukraine (later withdrawn), contains fungal amylase, an amylolytic enzyme obtained from mushrooms Aspergillus oryzae and non-pathogenic bacterial cultures Bacillus subtilis(Kirik D.L., Polyakova I.F.).

Bacillus subtilis - probiotic

In addition to the probiotic drugs listed above, strains Bacillus subtilis included in food supplements. In Russia, dietary supplements containing Bacillus subtilis: Bactistatin, Supradin Kinder gel (manufactured in Germany), Vetom and others.

BAA Bactistatin contains metabolites of cell-free culture fluid Bacillus subtilis strain 3 (including vitamin E), carrier zeolite, fermented soy flour hydrolyzate, anti-caking agent calcium stearate (or aerosil), capsule ingredients (medical gelatin, titanium dioxide, indigotin). Baktistatin is recommended by different authors, in particular, for the correction of mild bacterial overgrowth syndrome (Loginov V.A.), as additional funds: with intestinal insufficiency syndrome (Levchenko S.A.), H. pylori- associated gastritis (Grishchenko E.B.) and others.

Strains Bacillus subtilis are used in a number of medicines and products for veterinary medicine and agriculture. In particular, the probiotic "Subtilis" (liquid form "Subtilis-J" and powder "Subtilis-S"), which includes a microbial mass of live bacterial spores Bacillus subtilis and Bacillus licheniformis used in animal husbandry, poultry farming, fish farming for the prevention and treatment of diseases of the gastrointestinal tract of bacterial etiology, dysbacteriosis, lung infections, increasing productivity, obtaining healthy offspring, suppressing the growth of pathogenic and conditionally pathogenic microorganisms (