Probiotics, prebiotics and metabiotics: what's the difference

Probiotics are preparations containing live bacteria . Microbial cultures are able to correct the intestinal flora, which has a positive effect on the immune system and, accordingly, human health. Due to poor nutrition, stress, and the use of antibiotics, the intestinal microflora can gradually lose most of the “correct” bacteria, and their place will inevitably be taken by pathogenic flora. Probiotics will help save the situation by maintaining the balance of normal flora.

Prebiotics are substances that provide food for beneficial intestinal flora. As a rule, prebiotics consist of complex carbohydrates that are not absorbed in the upper intestines, but are stored until they enter the large intestine, where beneficial microorganisms live.

Probiotics and prebiotics play an important role in human health.

Use of probiotics and prebiotics

Probiotics are used to eliminate dysbiosis and the consequences of a course of antibiotics, strengthen the immune system , restore the normal balance of flora in the intestines, during and after digestive disorders, in case of obesity or exhaustion - in all cases where there are problems caused by a lack of beneficial or an excess of harmful bacteria in the intestines.

As a rule, special preparations are used, but ordinary foods also contain probiotics: fermented milk products, especially yoghurts, and some vegetables (for example, cabbage and pickles). However, for treatment it is better to use special preparations containing various strains of live bifidobacteria and lactobacilli . When consuming kefir, yogurt and other probiotic-containing products, most beneficial bacteria die without reaching the desired part of the intestine, whereas in specially manufactured probiotics this problem is solved.

Prebiotics , as already mentioned, are used to stimulate the growth and maintenance of intestinal flora. The presence of prebiotics and probiotics in the body is necessary for its proper functioning.

The nutrient medium for microflora is food components: inulin, polysaccharides, lactulose. In order for the necessary substances to enter the large intestine, and not be completely digested in the upper intestines, it is necessary to consume raw fruits and vegetables, plant fiber, wholemeal bread with bran - in fact, those foods that we consider the mainstay of a healthy diet.

What are probiotics

Probiotics, or eubiotics in other words, are beneficial live bacteria that, in the normal state of the intestines, create a healthy microflora. That is, these are substances necessary for the body that can suppress the negative effects of pathogenic and opportunistic microbes.

Such microorganisms have many beneficial properties:

1. ​Responsible for the synthesis of biotin, folic acid and vitamin K.
2. ​Promote the regeneration of the mucous membranes of the body and restore the microflora.
3. ​Prevent exposure to pathogenic and toxic substances.
4. ​Increase protective functions.

Changes in the composition and quantity of intestinal bacteria provoke disorders, causing dysbiosis and other diseases in children and adults.

Side effects

Probiotics contain bacteria that would normally already be present in the body. However, some problems can arise if probiotics are taken in the hope of quickly getting rid of unpleasant symptoms that accumulate over a long period of time. Chronic diseases, immunodeficiency, hormonal disorders, long-term treatment with antibiotics can create a situation in the body where probiotics will not have a very noticeable effect. In this case, step-by-step therapy should be carried out, including various measures to eliminate symptoms and restore the microflora.

Prebiotics should be used with caution for certain gastrointestinal diseases. Prebiotics can also cause enzymatic disorders in the intestines and an osmotic effect in the liver. Abuse of food containing prebiotics may result in diarrhea, flatulence, and intestinal colic.

Probiotics for the intestines: list of drugs

The most effective probiotic preparations for normalizing microflora and combating pathological conditions of the intestine are:

1. Bifidumbacterin is available in many dosage forms: tablets, suppositories, powder, capsules, ampoules, dry and liquid mixture. The composition contains bifidobacteria in various doses. A product is used to suppress the activity of pathogenic and opportunistic microbes. Prescribed for adults and children over 3 years of age.
2. Linex - presented in the form of capsules for oral administration. The active components of the probiotic are bifidumbacteria, enterococci and lactobacilli. They promote the formation of healthy flora, provoke the production of essential vitamins, cause an acidic environment and improve the functioning of digestive enzymes.
3. ​Biosporin is a second generation drug. Contains a large number of living bacteria - up to 2 billion. Available in the form of tablets and powder for further preparation of the solution. It has a broad therapeutic effect and can be used for the treatment and prevention of intestinal disorders in adults and children.
4. ​Colibacterin is available in powder form for oral administration. The basis of the probiotic is the dry mass of live E. coli. The pharmacological effect is to fight pathogenic microbes, improve immune status and produce the body necessary vitamins, enzymes, and amino acids. The drug has a detrimental effect on Proteus, Salmonella and Staphylococcus. Intended for the treatment of adults and children.
5. Acipol is an effective probiotic in capsules for all age groups. It has a complex and healthy composition, which includes live lactobacilli and kefir grains. Taking the medicine helps restore damaged flora, activates the synthesis of important biological substances and helps improve intestinal motility, preventing constipation. The list of indications is quite large.

Any generation of probiotics must be taken correctly, it is advisable to consult your doctor first. This will help avoid negative consequences and increase the therapeutic effect of the drugs.

Benefit

Probiotics can effectively eliminate dysbiosis , help prevent the occurrence of intestinal infections and eliminate their consequences, increase immunity and make it possible for newborns, including premature babies and those suffering from lactose intolerance, to acquire their own resistance. Probiotics are also used to prevent recurrences of bacterial and fungal infections.

Prebiotics contain substances that feed beneficial flora; they are not suitable for pathogenic flora. With the help of prebiotics, you can effectively maintain the state of intestinal microflora .

How to choose a probiotic and prebiotic

Probiotics. It is important to pay attention to:

• best before date;
• the presence of living strains of bacteria;
• mandatory presence of lacto- and bifidobacteria ;
• a combination of several strains of beneficial microorganisms.

There is ongoing debate about the best form to take probiotics: liquid or dry powder capsules. The thing against dry matter is that probiotics undergo additional processing, which reduces the viability of bacteria.

Prebiotics , according to experts, include carbohydrates that:

• cause active growth of beneficial intestinal bacteria, selectively fermented by colon microflora;
• are not absorbed in the upper parts of the digestive system;
• have the ability to influence the balance of intestinal microflora in the direction of increasing the number of beneficial microorganisms.

Classification of probiotics

There is a whole classification of drugs that improve intestinal microflora:

1. ​First generation - only one type of microorganism is present. Representatives are Bifidumbacterin, Dactobacterin, Colibacterin and others.
2. ​Second generation - such probiotics contain yeast fungi and bacilli, which, upon penetration into the body, have a therapeutic effect and help normalize normal intestinal flora. Effective representatives of the second row: Biosporin, Bactistatin, Sporobacterin.
3. The third generation consists of drugs that contain a whole range of beneficial strains of bacteria and various additives. These drugs include: Acipol, Bifiliz, Linex, Lebenin.
4. ​The fourth generation is a probiotic medicine based on bifidumbacteria with a pronounced sorbing effect. Representatives are: Probifor, Bifidumbacterin Forte, Florin Forte.

There are currently a lot of probiotic manufacturers. However, it is recommended to choose products that are manufactured by domestic pharmaceutical companies, since such preparations contain beneficial bacteria that are adapted to the climate in Russia. While foreign drugs often have low therapeutic properties.

Also, before you start taking probiotics, you should familiarize yourself with the procedure for taking them. All features are described in the instructions or you can consult a doctor. It is impossible to take drugs uncontrollably, as they can cause severe pathological disorders. Improper use of probiotics can cause weight gain, an allergic reaction, an imbalance of cytokines in the body, and the formation of stones in the urinary and gall bladder.

The term “probiotics” was first introduced in 1954 by F. Vergio, who in his monograph “Antiund Probiotika” compared various compounds that have both antimicrobial and positive effects on the intestinal microflora. Subsequently, DM Lilly and RH Stilvell (1965) proposed to understand the term “probiotics” as “substances produced by some microorganisms to stimulate the growth of others” [50], but now a more precise definition is used: “probiotics are live microorganisms that, when prescribed in adequate quantities have a beneficial effect on the health of the macroorganism by changing the properties of normal microflora” [56]. The term “probiotics” should be used to refer to live microorganisms that have been shown to benefit human health in controlled studies. At the International Congress of Gastroenterologists (Montreal, 2005), probiotics were defined as drugs based on intestinal commensals that are capable of exercising biological control in the body and have regulatory, trigger properties [51].

Probiotics are live microorganisms that can be included in various types of foods, including medications and dietary supplements. The most common strains of lactobacteria and bifidobacteria are used as probiotics. The yeast Saccharomyces cerevisiae and some strains of Escherichia coli may also serve this role.

The main probiotics are microorganisms that produce lactic acid (bifidobacteria and lactobacilli), which are among the most typical representatives of normal human microflora. Lactobacilli are facultative, bifidobacteria are obligate anaerobes.

Probiotics include Bacillus subtilis and Bacilluscereus, saprophytic spore-forming anaerobes, the probiotic activity of which has not been precisely established when using spores [56], as well as the yeast fungi Saccharomyces boulardii [42].

Main probiotic strains:

1. Lactobacillus – L. acidophilus, L. casei, L. crispatum, L. delbrueckii subtype bulgaricus, L. fermentum, L. gasseri, L. johnsonii, L. paracasei, L. plantarum, L. lactis, L. reuteri, L. rhamnosus, L. salivarius.
2. Bifidobacterium – B. bifidum, B. breve, B. infantis, B. lactis, B. longum, B. adolescentis.
3. Other microorganisms – Escherichia coli Nissle, Enterococcus faecium, Enterococcus faecalis, S. boulardii, S. cerevisiae, Streptococcus thermophilus *, Streptococcus salivarius, Streptococcus cremoris, Streptococcus lactis, Streptococcus diacetylactis, Streptococcus intermedius, B. subtilis *, B. cereus * , Propionibacterium acnes, Lactococcus spp. cremonis, L. lactis spp. Lactis, Clostridium butiricum (* The probiotic activity of the microorganism has not been precisely established) [1].

Probiotics are a heterogeneous group of non-pathogenic bacteria. As defined by the WHO working group, these include living microorganisms that, when administered in adequate quantities, cause an improvement in the health of the host.

Modern probiotics must meet the following criteria [17]:

• contain microorganisms whose probiotic effect has been proven in randomized controlled trials;
• have stable clinical effectiveness;
• be pheno- and genotypically classified;
• to be kept alive;
• be non-pathogenic and non-toxic, do not cause side effects with long-term use;
• have a positive effect on the host organism (for example, increase resistance to infections);
• have colonization potential, i.e. persist in the gastrointestinal tract (GIT) until the maximum positive effect is achieved (be resistant to high acidity, organic and bile acids, antimicrobial toxins and enzymes produced by pathogenic microflora);
• be acid-resistant or encapsulated in an acid-resistant capsule
• be stable and retain viable bacteria during long-term storage [15, 32].

Fundamental requirements are also imposed on the bacterial strains on the basis of which probiotics are created.

They have to:

• be isolated from healthy people and identified to species based on pheno- and genotypic characteristics;
• have a genetic passport;
• have a wide range of antagonistic activity against pathogenic and opportunistic microorganisms;
• should not inhibit normal microbiocenosis;
• be safe for humans, including immunological safety;
• production strains must be stable in biological activity and meet technological requirements.

Classifications of probiotics are based on the number of microorganisms included in the drug, their genus, or the presence of additional components in the composition of the drug. Probiotics are divided into monocomponent (monoprobiotics), monocomponent sorbed, polycomponent (polyprobiotics), combined (synbiotics); in composition - bifido-, lacto-, coli-containing, consisting of spore bacteria and saccharomycetes (self-eliminating antagonists) [11].

Currently, all probiotics are divided into three groups:

• drugs;
• biologically active additives (dietary supplements; parapharmaceuticals or nutraceuticals);
• functional food products containing live probiotic microbes.

In Russia (Drug Directory “Russian Medicines”, 2011) 34 pro- and synbiotic drugs, as well as 16 prebiotic drugs, are registered as medicinal products. In the “Dietary Supplements – Probiotics and Prebiotics” section, 229 products with 127 trade names are registered.

The most common strains of lactobacilli and bifidobacteria used in Russia for the production of probiotics and functional food products:

• L. acidophilus 100АШ; NK1; K3Ш24; Er317/402;
• L. fermentum 90-TC-4;
• L. plantarum 8RA-3;
• B. bifidum 1; 791; LVA-3;
• B. longum B379M;
• B. breve 79119; 79-88;
• B. infantis G 73-15; 79-43;
• B. adolescentis 7513; MC-42; G013.

There are four generations of probiotics [9]. The first generation includes monocomponent preparations (Colibacterin, Bifidumbacterin, Lactobacterin) containing one strain of bacteria.

Second generation drugs (Baktisubtil, Biosporin and Sporobacterin) are based on microorganisms that are not specific to humans and are self-eliminating antagonists. They must be used in mandatory combination with bifido- and lactose-containing probiotics, which are necessary to normalize the intestinal microbiocenosis.

III generation preparations include multicomponent probiotics containing several symbiotic strains of bacteria of the same species (Acilact, Acipol) or different species (Linex, Bifiform), with a mutually reinforcing effect. They differ from first generation drugs in a more balanced composition [9].

The fourth generation includes preparations of bifid-containing probiotics immobilized on a sorbent (Bifidumbacterin forte, Probifor). Sorbed bifidobacteria effectively colonize the intestinal mucosa, providing a more pronounced protective effect than unsorbed analogues.

There are also metabolic probiotics (Hilak forte) [12].

Due to a more balanced effect, it is currently recommended to give preference to combined probiotics of the third generation. Among them, the most widely used drug is Linex, which satisfies almost all of the above criteria [13].

Probiotics impact the gastrointestinal ecosystem by stimulating mucosal immune mechanisms and non-immune mechanisms through antagonism with potential pathogens. The symbiosis between the microflora and the host can be optimized through pharmacological or nutritional interventions in the gut microbial ecosystem using probiotics.

The immunological effects of probiotics are:

• activation of local macrophages to increase the presentation of B antigens to lymphocytes and enhance the production of secretory immunoglobulin A (IgA) locally and systemically;
• modulation of cytokine profiles;
• causing a hyperresponse to food allergens. The non-immunological effects of probiotics are:
• digestion of food and competition for nutrients with pathogens;
• changing local pH to create an unfavorable local environment for pathogen development;
• production of bacteriocins to suppress pathogens;
• elimination of superoxide radicals;
• stimulation of epithelial mucin production;
• strengthening intestinal barrier function;
• competition with pathogens for adhesion to the epithelium of the mucous membrane;
• modification of pathogenic toxins.

The effect of probiotics is not limited to simply colonizing the intestines, as is often imagined. Their influence is more complex and multifaceted - it is competition with pathogenic and opportunistic microflora; adhesion to the intestinal mucosa and interaction with epithelial cells; immunomodulatory effect [8].

The mechanism of action of probiotics at the molecular level is being actively studied. Almost all microorganisms interact with the cells of the macroorganism through the so-called. Toll-like receptors (TLRs) are a family of membrane glycoproteins present on macrophages, neutrophils, and dendritic cells. There are 10 types of TLRs. The structure of TLR is quite simple: there is a cytoplasmic domain and a domain that is located on the outer membrane of the cell and directly interacts with antigens. The cytoplasmic TLR domain consists of 200 amino acids, the homologous regions of which make up 3 separate regions necessary for signal transmission into the cell (signal transduction).

All probiotics are thought to interact with TLRs located on the membrane. TLR is activated, and then through a complex system of various intracellular factors (myeloid differentiation protein 88 - MyD88, family of interleukin-1 [IL-1] receptor-associated kinases - IRAK, receptor-associated factor 6 - TRAF6) nuclear factor κB (NF -κB), which induces genes that determine the antimicrobial and proinflammatory response, in particular the production of proinflammatory cytokines (tumor necrosis factor α, IL-1b, IL-6, IL-8). Probiotics “unblock” the function of TLR-4, which, against the background of activation of receptors interacting with peroxisome proliferator, leads to the cessation of the effects of NF-κB and, accordingly, stopping the synthesis of pro-inflammatory cytokines [10].

The most important property of probitics is their ability to adhere to the intestinal epithelium. The probiotic attaches to the epithelium through glycoconjugated receptors, thereby providing colonization resistance and preventing adhesion and invasion of pathogens. Using a culture of Ca-co-2 colonocytes [22], it was shown that living strains of probiotics adhere to the epithelium and thereby cause strengthening of the cytoskeleton of intestinal epithelial cells (the expression of tropomyosin TM-5, the synthesis of actin and occlusin are enhanced); decreased permeability (increased phosphorylation of protein of intercellular junctions); increased mucin synthesis (stimulation of the MUC-3 gene); stimulation of synthesis and activation of the epithelial growth factor receptor (EGF); increased synthesis of polyamines, which are hormone-like substances that enhance epithelial regeneration processes. All these mechanisms ultimately contribute to increased epithelial resistance, enhancing its barrier functions and protection. The ability to adhere in vitro differs among different representatives of probiotics; it has been proven in L. acidophilus and Bifidobacteriae [38].

It has been proven that probiotics take part in the formation of free amino acids, organic acids, oligosaccharides, short-chain fatty acids (SCFA), bioactive peptides, bacteriocin, help reduce cholesterol levels, competitively interact with adhesion molecules for pathogenic bacteria, have antioxidant, immunostimulating effects, and neutralize food carcinogens, affect the synthesis of vitamins (biotin, vitamin K, etc.). In addition, a number of possible positive effects of probiotics are being actively studied: anticarcinogenic (reducing the risk of intestinal cancer, breast cancer, etc.), antidiabetic, antiallergic, anti-inflammatory (for Crohn's disease, ulcerative colitis), etc. [53].

The conclusion about the safety of probiotics is based on the appropriate production conditions, the results of clinical studies and use in real practice. The likelihood that they can cause infectious complications, adverse metabolic activity, excessive stimulation of the immune system, or gene transfer is very low. Several cases of systemic infections with their use have been reported, although this relationship is disputed [40].

Overall, research shows that probiotics have many beneficial properties. However, a specific effect can only be attributed to the strain(s) being tested and not to the species or entire group of probiotics. Results from studies on specific strains cannot be used as evidence of the effectiveness of untested strains. This also applies to probiotic doses [51].

Indications for the use of probiotics are quite extensive [17]: diseases associated with Helicobacter pylori infection (HP), chronic diffuse liver diseases, irritable bowel syndrome, diarrhea syndrome, constipation syndrome, treatment and prevention of antibiotic-associated diarrhea, helminthiases, vaginosis, colpitis, endocervicitis and other urogenital diseases, dermatoallergoses, premature and newborn children at risk.

The topic of using probiotics in clinical practice is currently so relevant, primarily because the number of scientific works devoted to various aspects of this problem is rapidly increasing. At the same time, more and more studies are being conducted that meet the high requirements of evidence-based medicine: randomized controlled trials, meta-analyses and systematic reviews. Thus, if from 1996 to 2005 in the MEDLINE database there were 2748 works aimed at studying probiotics (MB De Morais, CM Abe Jacob, 2006), then in 3 years (2006–2008) their number already exceeded 2000, and after the last one was 2010 – 1500. And these scientific researches bring tangible results: today more than 15 proven effects of probiotics are already known. The clinician should remember that a number of drugs that affect microbiocenosis are medicinal products in Russia and their prescription must be justified by specific indications developed in accordance with the principles of evidence-based medicine. An analysis of the effectiveness of probiotics [30], which used the levels of evidence in the field of treatment/prevention developed by the Oxford Center for Evidence-Based Medicine, determined the current state of knowledge on the use of probiotics with the results of clinical studies:

Level of Evidence 1A:

• treatment of acute infectious diarrhea in children;
• prevention of intra- and community-acquired diarrhea in children;
• prevention of antibiotic-associated diarrhea;
• treatment of lactose malabsorption. Level of Evidence 1B:
• prevention of pauchitis (inflammation of the surgically created small intestinal reservoir after resection of the colon) and maintenance of remission;
• prevention of postoperative infections;
• prevention and treatment of atopic diseases in children. Level of Evidence 2B:
• prevention of traveler's diarrhea;
• prevention of septic conditions in acute pancreatitis;
• maintaining remission of ulcerative colitis;
• diseases associated with HP infection;
• lowering blood cholesterol levels.

A number of studies have shown that the addition of probiotics to standard anti-Helicobacter therapy regimens slightly increased the frequency of HP eradication, but in addition significantly reduced the frequency of side effects and increased patient adherence to treatment. In addition to the protective effect against the development of intestinal dyspepsia syndrome, probiotics also have an additive effect with eradication drugs. A culture or preparations made from cultures of lactobacilli and a number of other microorganisms inhabiting the human gastrointestinal tract can suppress the vital activity of HP; probiotics can prevent the adhesion of HP to cell membranes and the proliferation of HP [14, 24, 34].

When choosing a probiotic drug, several problematic issues arise, the first of which is survival. As stated above, only living microbes have probiotic properties. Moreover, a number of studies have shown that a dose of at least 107 CFU can be considered minimally sufficient and capable of producing a significant effect [54].

The survival rate of bacteria depends on the production technology and storage conditions of the drug. For example, adding bifidobacteria to kefir does not guarantee their safety and ability to vegetate, and the viability of the microflora in both liquid and simple dry forms of preparations may be lost before the official deadline. Most probiotics, especially liquid dosage forms, require special storage conditions, such as a certain temperature. The destructive effect of gastric juice on unprotected flora should be taken into account. It has been proven that only a small number of strains of lacto (L. reuteri, L. plantarumNCIB8826, S. boulardii, L. acidophilus, L. caseiShirota) and bifidobacteria are acid-resistant; most microbes die in the stomach. Therefore, probiotics enclosed in an acid-resistant capsule are preferred. According to A. Bezkorovainy [21], only 20–40% of selective strains survive in the stomach. D. Pochart [43] demonstrated that out of 108 CFU of lactobacilli taken in an acid-fast capsule, 107 CFU were found in the intestines, after taking the same amount in yogurt - 104 CFU, and after taking the same dose in open form in powder form, microbes in the intestines are not detected at all.

In the small intestine, probiotics are exposed to bile acids and pancreatic enzymes. As a result, many microbes, for example L. fermentum KLD, L. lactis MG1363, almost completely die. This may be explained by increased permeability of the bacterial cell membrane, which occurs in response to exposure to bile acids. The survival of most bacteria depends on how they are taken: in a protective capsule, in the form of yogurt, with milk, or without any protection. Thus, according to K. Kailasapathy [38], many strains of lactobacilli from fermented milk products either do not reach the intestine or survive in it for only a few days. These data call into question the effectiveness of unprotected and non-acid-stable probiotics.

Only a few drugs, in particular Linex, have these properties. It contains L. acidophilus, B. infantis, E. faecium, the content of which is at least 107 microbial bodies. The microorganisms that make up the drug are enclosed in a capsule that opens in the stomach. However, due to the high acid resistance of all components of the drug, bacteria are not destroyed in the stomach and the drug is able to have a probiotic effect at all levels of the gastrointestinal tract. The combination of lacto- and bifidobacteria in the drug with proven probiotic properties provides a symbiont effect during colonization of the large intestine, and the presence of an aerobic microorganism, enterococcus, contributes to the active immunomodulatory and bactericidal effect of the drug at the level of the stomach and small intestine. The microbes that make up Linex are resistant to most antibiotics, which allows the drug to be used against the background of antibacterial therapy. The resistance of the resulting strains is maintained upon repeated inoculation for 30 generations and in vivo. Linex studies have shown that transfer of resistance to other microorganisms does not occur [19]. If necessary, Linex can be used simultaneously with antibacterial and chemotherapeutic agents.

The effectiveness of Linex components, their combinations and the drug itself has been proven in clinical studies for various gastrointestinal diseases [4, 6, 7, 13, 16, 18].

The advantage of Linux is its high security. With widespread long-term use of the drug, no side effects have been recorded. Linex does not have a teratogenic effect. Its safety and good tolerability make it possible to use the drug in patients at risk - pregnant and breastfeeding women, children, including newborns, the elderly, etc. The quality of Linex is also guaranteed by its production technology, which meets all the requirements for the production of probiotics.

Unfortunately, probiotic strains, despite numerous beneficial effects, are not equivalent to our own indigenous microflora and are not able to multiply in the intestines. One of the reasons for this may be bioincompatibility with resident bacteria of the host [5]. Even the most effective probiotics are effective only during the course of treatment and are detectable in stool only for 3–7 days after treatment [39].

Therefore, to achieve a sustainable therapeutic effect, firstly, long-term or even constant use is necessary, which is practically impossible. Secondly, it is desirable that the probiotic preparation represents normobiota strains that are maximally compatible with resident strains and the local immune system [8].

In addition to biological agents of the probiotic class, the class of prebiotics, which are closely and organically related to probiotics, is no less popular in medical practice. Despite the fact that the term “prebiotics” entered medical terminology in the mid-1990s, this important and fruitful area of ​​scientific research dates back nearly 50 years and was pioneered by the Austrian pediatrician F. Petuely. It was he who first described in 1957 the properties of lactulose as a prebiotic, that is, a disaccharide with a pronounced bifidogenic effect. A study conducted by F. Petuely showed that if formula-fed children received a milk formula containing lactulose 1.2 g/100 kcal, then an almost pure culture of bifidobacteria was formed in the intestines, and the microbiocenosis of bottle-fed children was practically no different from the intestinal biocenosis of children, who are breastfed [47, 48].

Among prebiotics, the most popular are poly- and oligofructans, soy oligosaccharides, galactooligosaccharides, isolated from natural sources or obtained by biotechnological or synthetic methods. The definition of prebiotics was first given by GR Gibson [29] - he proposed to understand this term as a non-digestible food ingredient that can improve human health by selectively stimulating the growth and/or activity of one or a limited number of bacterial species in the colon. Subsequently, MB Roberfroid (2007) defined prebiotics as food ingredients selectively fermented by intestinal microorganisms, specifically changing the composition and/or activity of microflora, which leads to improved well-being and human health [52].

It is expected that by 2010, global production of prebiotics will reach hundreds of thousands of tons. They are sold independently in the form of fortifying additives to a variety of food products, as well as in combination with probiotic microorganisms (synbiotics) [17, 35, 36, 41, 46, 57].

In addition to the listed prebiotic substances, various adhesion blockers and growth inhibitors of pathogenic and opportunistic microorganisms are also used (lectins, antiadhesins, modulators of the synthesis of secretory immunoglobulins, defensins of various types, structural components of probiotic microorganisms, their metabolites, etc.).

Quite strict requirements are imposed on prebiotics in their pure form: they should not be hydrolyzed by human digestive enzymes, should not be absorbed in the upper parts of the digestive tract, and should selectively stimulate one species or a specific group of microorganisms resident in the colon [2].

Main types of prebiotic compounds:

• •monosaccharides, alcohols (xylitol, melibiose, xylobiose, raffinose, sorbitol, etc.);
• •oligosaccharides (lactulose, lacitol, soy oligosaccharide, latitololigosaccharide, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, dixilooligosaccharide, etc.);
• polysaccharides (pectins, pullulan, dextrin, inulin, chitosan, etc.);
• enzymes (β-microbial galactosidases, Saccharomyces proteases, etc.);
• peptides (soy, dairy, etc.);
• amino acids (valine, arginine, glutamic acid, etc.);
• antioxidants (vitamins A, C, E, α-, β-carotenes, other carotenoids, glutathione, ubiquinol, selenium salts, etc.);
• unsaturated fatty acids (eicosapentaenoic acid, etc.);
• organic acids (propionic, acetic, citric, etc.);
• plant and microbial extracts (carrot, potato, corn, rice, pumpkin, garlic, yeast, etc.);
• others (lecithin, para-aminomethylbenzoic acid, lysozyme, lactoferrin, gluconic acid, starch syrup, etc.).

Lactulose is a synthetic disaccharide used as a drug in the treatment of constipation and hepatic encephalopathy. Prebiotic oligofructose occurs naturally in many foods, such as wheat, onions, bananas, honey, garlic and leeks. Oligofructose can also be isolated from chicory root or enzymatically synthesized from sucrose.

Fermentation of oligofructose in the colon causes many physiological effects, including:

• increased number of bifidobacteria;
• increased calcium absorption;
• increase in stool volume;
• reduction of transit time through the gastrointestinal tract;
• a decrease in blood lipid levels is likely.

Based on his research, F. Petuely named lactulose “bifidus factor” (Der Bifidusfactor) and devoted almost 30 years to studying this compound [47, 49]. The term “bifidus factor” has become widely used to refer to nutrients that promote the growth of bifidobacteria and normalize the composition of intestinal microflora. The chemical structure and method of synthesis of this compound were described in 1929 by E. Montgomery and C.S. Hadson under the name “lactoketose.” Lactulose is a disaccharide consisting of galactose and fructose (4-0-β-D-galactopyranosylD-fructose).

The prebiotic effect of lactulose has been proven in numerous studies [20, 31, 44, 55]. A randomized, double-blind, controlled study on 16 healthy volunteers (lactulose for 6 weeks) showed a significant increase in the number of bifidobacteria in the colon [25].

An increase in the production of SCFAs by intestinal bacteria normalizes the trophism of the colon epithelium (due to the production of butyrate), improves its microcirculation (propionate effect), ensuring effective motility, absorption of water, magnesium and calcium. As part of medications (Duphalac®), lactulose can be effectively used for functional constipation in both adults and children. The incidence of side effects of lactulose is significantly lower compared to other laxatives and does not exceed 5%, and in most cases they can be considered minor. The safety of lactulose determines the possibility of its use even in premature infants, proven in clinical trials [3]. For the same purpose, lactulose can be included in formulas for feeding children in the first year of life.

SCFAs formed as a result of the metabolism of saccharolytic microflora reduce the pH in the intestinal lumen, which leads to a decrease in the concentration of secondary bile acids and their salts. In addition, the resulting SCFAs are utilized by the macroorganism, which is accompanied by the absorption of water and a decrease in the volume of colonic contents [27]. Based on this, it can be argued that the laxative effect of lactulose is primarily associated with its prebiotic ability and is due to an increase in the volume of bacterial mass, as well as the positive effect of microbial metabolic products on the intestinal wall.

The prebiotic effect of lactulose has significant metabolic consequences. A decrease in pH in the lumen of the colon increases the colonization resistance of the entire microbial community, and also promotes the ionization of ammonia and its excretion in the form of ammonium ions. The latter effect of lactulose has long been used in clinical practice for the purpose of detoxification in liver failure (hepatic encephalopathy) of various origins. The growth of bifidobacteria and lactobacilli while taking lactulose leads to a decrease in the activity of urease, which converts urea into ammonia. Urease activity is also suppressed by a decrease in pH, since the optimal pH for β-glucuronidase is 7.0, and for nitro- and azoreductase is 7.8. A placebo-controlled study showed a significant decrease in fecal concentrations of phenol, cresol, indole and skatole when taking lactulose [20].

Lactulose reduces the alcohol dehydrogenase activity of intestinal microflora, significantly reducing the concentration of acetaldehyde in the colon, which is believed to have carcinogenic activity [58].

Lactulose, stimulating the growth of normal intestinal microflora, helps maintain the anti-infective defense of the macroorganism against Shigella, Salmonella, Yersinia and rotaviruses [28].

In 1960, the Dutch company BV Philips-Duphar began producing lactulose syrup under the name Duphalac®. Since 1964, Duphalac® has been widely used in the Netherlands, and from 1967 to the present day it has been effectively used by doctors in many countries around the world. The drug Duphalac® contains 66.7 g/100 ml of lactulose and has a wide range of indications for use, including the treatment of constipation and hepatic encephalopathy. A relatively rare side effect may be the development of flatulence, the manifestations of which in most cases are eliminated by reducing the dose, and in some children it goes away on its own after a few days of taking the drug - as the intestinal microflora “adapts” to it. Contraindications to the use of lactulose are galactosemia, intestinal obstruction and individual intolerance to the components of the drug.

The current state of knowledge on the use of lactulose determines, based on the results of clinical studies, level of evidence A [23, 26, 33, 37] regarding its use for constipation of various etiologies and hepatic encephalopathy.

So, lactulose (Duphalac®) is one of the most powerful prebiotics in terms of its effect on bacterial metabolism, which is confirmed by many years of experience in its use for the treatment of hepatic encephalopathy. It is in this condition that powerful stimulation of the growth of bifidobacteria and lactobacilli, which use ammonia to build the cell wall, is required, and the rate of stimulated growth is sufficient to effectively relieve hepatic encephalopathy.

Due to not only its effectiveness, but also high safety and good tolerability, Duphalac® is a drug that can be prescribed to young and middle-aged children. In many countries, lactulose is added to the milk of infants to increase their bifid flora levels. Often the very first meal of solid food creates problems associated with constipation. In such cases, lactulose, prescribed even in very low doses, helps prevent the development of constipation.

More than one million pregnant women received lactulose. However, no data were obtained that would indicate the need to limit the use of lactulose during pregnancy (or lactation). Because of this, lactulose is the laxative most commonly used during pregnancy.

Duphalac® is widely used to restore impaired motility during constipation, being metabolized by intestinal microflora to monosaccharides (fructose and galactose), and then to SCFAs, which restore intestinal motor function. SCFAs increase osmotic pressure in the intestinal lumen and reduce pH, which stimulates intestinal motility. Thus, Duphalac® is a physiological and safe regulator of intestinal motor function.

In general, using modern pro- and prebiotic drugs or their combinations, a practicing physician has the opportunity in a short time to obtain the necessary sanogenic reaction, potentiation of the clinical effect of the main treatment for most pathological processes in the body, especially those occurring in the gastrointestinal tract (HP-associated pathology, hepatobiliary diseases system, pancreas, small and large intestines of both functional and organic origin).

Information about the authors:

Maev Igor Veniaminovich – Doctor of Medical Sciences, Professor, Head of the Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education MGMSU Roszdrav. Tel., e-mail; Plotnikova Ekaterina Yuryevna – Doctor of Medical Sciences, head of the gastroenterology course at the department of postgraduate training of primary care and emergency physicians, Kemerovo State Medical Academy. Tel. 8 (3842) 642-003, e-mail Aleksey Andreevich Samsonov – Doctor of Medical Sciences, Professor of the Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education MGMSU Roszdrav. Tel., e-mail: [email protected] ; Nikushkina Irina Nikolaevna – Doctor of Medical Sciences, Professor of the Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education MGMSU Roszdrav. Tel.; Ivashkina Natalya Yurievna – Candidate of Medical Sciences, Associate Professor of the Department of Propaedeutics of Internal Diseases and Gastroenterology of the State Educational Institution of Higher Professional Education MGMSU Roszdrav. Tel.;