Probiotics
The word probiotic means "to live" in Latin. Today, probiotic refers to live microbial foodstuffs that increase the microbial balance of the intestine and affect the benefit of the host animal or human. Probiotics help maintain a healthy balance in favor of beneficial bacteria in the gastrointestinal tract, stabilize the intestinal microflora, and support the function of flora. This flora is important in host defense against infections and prevents the proliferation of bacterial, viral and fungal agents.
Today, probiotic products are widely used in the form of baby food and fermented dairy products all over the world, particularly in Japan, Europe, the United States and Canada. Lactobacillus species are also available in Germany as tablets. Turkey in the name of probiotic products has begun to announce new. In this review, we examined the development, general characteristics and uses of probiotics.
HISTORY
People have probably consumed food containing probiotic bacteria since prehistoric times when they kept it dry or buried. Food stored in this way would be fermented with bacteria. However, as bacteria began to be considered as a source of disease, the use of bacteria in the preparation of food was discontinued and enzymes replaced bacteria [1] .
Ellie Metchnikoff first introduced the idea of bacterial replacement therapy in 1908. Metchnikoff reported that substances such as ammonia, amines and indole formed by intestinal bacteria as a result of protein hydrolysis lead to autointoxation in the host and the beneficial results of lactic acid bacteria that provide energy from carbohydrate fermentation instead of protein hydrolysis to reduce the number of these microorganisms [2] . However, bacterial replacement therapy was not widely accepted until 1921, when Rettger and Chaplin obtained beneficial results using Lactobacillus acidophilus strains in the treatment of constipation [3] .
In 1965, Lilly and Stillwell called "probiotics" substances that produced one of the two organisms cultured together and stimulated the other's reproduction. In 1974, Parker called the probiotic substances found in animal feeds, which affect the intestinal flora and produce beneficial effects in the animal. In the sense we use today, in 1989, Fuller described probiotics as "live microbial foodstuffs that regulate the microbial balance of the host animal and produce beneficial effects" [3,4] . In the last 20 years probiotic organisms have been studied for the treatment or prevention of many diseases and promising results have been obtained.
INTRODUCTION MICROFLORA AND CLINICAL IMPORTANCE
The idea that probiotics can benefit from the use of probiotics is based on experimental and clinical data showing that intestinal flora is protective against many diseases:
• Animals with impaired bowel flora become more susceptible to certain microorganisms than normal ones. For example, 10 10 Salmonella enteritidis must be administered to kill a normal flora mouse, while 10 microorganisms can kill a non-flora mouse.
• In animals and humans receiving antibiotic treatment, flora changes resulting from treatment are susceptible to some infections. Pseudomembranous enterocolitis (PMEC) associated with Clostridium difficile is the best example of this [3,4] . In addition, it was observed that the clinical picture improved with the administration of faecal suspensions from healthy subjects to patients with PMEC experimentally [5] .
• Some intestinal bacterial isolates inhibit pathogenic bacteria in vitro. Bifidobacteriae, Lactobacillus, Propionibacteriae species and enterococci isolated from the intestine inhibit C. difficile and C. botulinum growth in vitro [3] .
The first flora elements of the intestine, which are sterile during the intrauterine period, are lactic acid bacteria taken from the vaginal flora of the mother during childbirth. The flora content is then determined by factors belonging to the host (nutrition, etc.) and organisms (colonization ability, etc.) [4] . There are about 400 bacterial species in human intestinal flora. 30-40 of these make up 99% of flora. The dominant population has about 10 10 live bacteria. The organisms in this flora are shown in Table 1 [2-4] .
Intestinal flora may vary depending on many factors:
1. Food-related changes: Today, the etiology of many diseases has eating habits. Nutritional habits have changed significantly in the last 100 years, especially in western countries. Increased consumption of prepared food, especially prepared as sterile, makes the development of protective flora difficult [1] .
2. Changes due to environmental factors:
• Excess hygiene: Nowadays, the increase in caesarean deliveries and excessive hygiene applied during childbirth and neonatal care prevent or delay the development of protective flora in the newborn. In western countries, there is an approach to support newborns with probiotic formulas [1,6] .
• Antibiotic treatment
• Stress: Under stress, lactobacilli decrease, while coliforms tend to increase. Stress-induced hormonal changes can also affect mucus production, reducing the number of flora elements associated with mucus [4] .
PROBIOTICALLY USED MICROORGANISMS
Probiotics are mainly lactic acid bacteria. Yogurt-forming microorganisms L. bulgaricu s and Streptococcus thermophilus are all elements of the intestinal flora. The microorganisms used as probiotics are shown in Table 2 . A probiotic product may contain one or more of these microorganisms. As the number of microorganisms it contains increases, the probiotic usage area expands [2-4,7] .
Which microorganism will be selected as probiotic depends on the host. The microorganism to be used must be the flora element of that host [2] . There are 3 ways to choose:
1. Data collection with field work: It is a very time consuming, expensive and impractical method.
2. Selection according to laboratory test results: Bacterial colonization, reproductive properties and metabolites formed are considered. Today, the selection is based on these data.
3. Genetic manipulation: By using molecular techniques and PCR, detailed analysis of the effect of probiotic product on bacterial populations in the intestine can be performed. These techniques, which are currently in development, will be the most commonly used methods in the near future [4] .
The properties of microorganisms used as probiotics are:
• It should be reliable and should not cause any side effects in the animals and animals.
• be stable; Low pH in the intestine should be metabolised without being affected by adverse environmental conditions such as bile salts.
• It must be able to attach to colon and colonize.
• An antagonist must be effective against carcinogenic and pathogenic bacteria.
• It should produce antimicrobial substances.
• Be capable of producing beneficial effects such as increased resistance to diseases in the host.
• be resistant to antibiotics; should not be affected by antibiotics in the intestine, as it may be used to correct intestinal flora in patients with antibiotic-induced diarrhea.
• Since the minimum effective doses are unknown, they should be present in large quantities in living cells.
• It must be suitable for industrial treatment and should remain viable and stable for a long time under storage conditions [2,4] .
EFFECT MECHANISMS OF PROBIOTICS
The mechanisms of action of probiotics can be examined under three headings:
1. Direct Antagonistic Effect
a. Antibacterial effect: Probiotics have effects such as altering metabolism or toxin production of pathogenic bacteria or reducing the number of viable cells [3] . After the administration of a probiotic product containing L. acidophilus to mice developed Escherichia coli diarrhea, it was observed that the clinic improved after the 3rd day.
Fatty acids produced by lactic acid bacteria in the intestine prevent colonization of the intestine by Shigella sonnei and enteropathogenic E. coli [3] . The lowering effect of organic acids such as lactic and formic acid produced by probiotics as a result of metabolism and primary metabolites such as hydrogen peroxide also contribute to antibacterial effect [4] .
It has been observed that lactic acid bacteria produce antibiotic-like, high molecular weight substances in vitro. These include acidoline, lactocidine, acidophylline, diplocoxin and nisin. The presence of these substances has not yet been demonstrated in the intestine [3,4,7,9] .
b. Competition for nutrients: In vitro studies have shown that intestinal bacteria compete with C. difficile for intestinal nutrients such as monomeric glucose, N-acetyl glucosamine and sialic acid, and S. flexneri for carbon sources [10,4] .
c. Competition for adhesion receptors: Many pathogens need to attach to the intestinal wall to cause disease. Probiotic microorganisms compete with pathogenic bacteria for these sites and prevent their attachment [11] .
2. Influencing Microbial Metabolism
Suppression of beta-glucronidase, nitroreductase and azoreductase activity in the intestine has been observed in humans fed L. acidophilus [12] . L. rhamnosus GG strain suppresses fecal hydrolase activity [1] . Urease activity decreases with probiotic treatment [13] . Studies in both mice and humans have shown increased beta-galactosidase activity during treatment [14] .
3. Immune System Stimulation
The intestinal mucosa has a special antigen transport system formed by Peyer's plaques to assimilate antigens. In physiological conditions, very few antigen fractions can cross the defense barrier of enterocytes. This defense barrier dietary antigens, pathogen microorganisms, chemicals and so on. and many allergens and pathogens have found entry into the body [13,15] .
Probiotics are capable of stimulating both components of the immune system:
a. Macrophage activation: Since most probiotic bacteria are gram-positive bacteria, the cell walls are mainly composed of peptidoglycan. Muramyl peptides, which are among the degradation products of peptidoglycan, provide direct macrophage activation [2] .
It has been suggested that for systemic effect with probiotic bacteria, the bacteria must be translocated. Lactobacilli may be translocated and survive for several days in the spleen, liver and lungs [4] . However, bacterial translocation is rare in healthy people, so they should be able to stimulate the immune system without leaving the lumen. Today, enterocytes are known to be involved in the immune response by producing cytokines. Interleukin-8 (IL-8), tumor necrosis factor-a (TNF-a), monocyte chemotactic protein-1 (MCP-1) and granulocyte-macrophage, which, when confronted with certain bacteri The expression of genes encoding colony stimulating factor (GMCSF) is increased [2] .
b. Increase in antibody levels: An increase in total and specific IgA levels was detected in probiotic-fed animals and humans. Total IgA and antipolio virus IgA levels in stool samples of babies fed with formula containing bifidobacteriae were significantly higher than controls [16] . During Lactobacillus GG use, an increase in the number of cells secreting sIgA against rotavirus and serum IgA levels was detected [17] .
CLINICAL USE OF PROBIOTICS
1. Lactose Intolerance
Lactose intolerance is characterized by the congenital absence of beta-galactosidase enzyme that breaks down lactose in the intestine. It has been observed that people with lactose intolerance tolerate lactose in yogurt better than that in milk [18] . Bacteria taken with yogurt and producing lactase upon arrival in the intestine were held responsible for this effect. Lactose intolerance improved with milk containing L. acidophilus [3,14] . Probiotics can also be used to improve lactase activity in the gut in children with Giardia lamblia infestation [19] .
2. Pseudomembranous Enterocolitis
Fecal enemas taken from healthy individuals improve the condition. Some types of lactobacilli also prevent relapses in PMEC [20] . Prophylactic use of probiotics is recommended especially for risky patients.
3. Intestinal Infections
Some probiotics have been shown to prevent and treat some bacterial and viral infections in clinical and laboratory studies [21] . Intestinal flora, E. coli, Campylobacter jejuni, Clostridium perfringens, Clostridium botulinum, Salmonella spp. and Yersinia enterocolitica [4] . Use of Lactobacillus GG prevents rotavirus diarrhea in children and shortens disease duration [17,22] . Similar results were obtained with L. casei Shirota strain and B. bifidum [13] . The administration of oral nonenteropathogenic E. coli strains to preterm and term newborns prevented the establishment of pathogenic strains and protected infants against E. coli diarrhea [23] . Lactobacillus and Saccharomyces species were found to be effective on tourist diarrhea [24,25] . Saccharomyces boulardii yeast prevents antibiotic-induced diarrhea and PMEK attacks [26] . Preparations of L. acidophilus and Bifidobacterium reduce radiation-induced diarrhea and intestinal side effects [13] .
4. Constipation
Positive results were obtained in the treatment of constipation with the use of L. acidophilus [4] .
5. Antitumor Effect
In 1962, Bogdanov et al . Observed that L. bulgaricus produced substances that prevent tumor growth, and many studies have been conducted on this subject [12,27,28] . Anticarcinogenic effects of lactobacilli are tried to be explained by 3 mechanisms:
Inhibition of tumor cells: L. casei Shirota has an inhibitory effect on chemically induced tumors in animals. Although Lactobacillus GG inhibits initiation and early development stages in tumorigenesis, it has no effect on the tumor. Lactic acid bacteria form butyrate and butyric acid by column fermentation. Butyrate slows growth in vitro in cultured colon cancer cells [13] .
• Inhibition of fecal microbial enzymes, such as beta-glucronidase, beta-glucosidase, azoreductase, and urease, which produce carcinogens from various complexes [4,13] .
• Suppression of nitroreductase involved in degradation and synthesis of nitrosamines [10,12] .
6. Anticholesterolemic Effect
The effects of yogurt and L. acidophilus milk on blood cholesterol are variable. Yogurt intake in humans reduces blood cholesterol, but this effect is more pronounced with fermented milk. Bacterial metabolites in fermented milk are thought to suppress cholesterol synthesis in the body. Some lactobacilli have a direct effect on cholesterol levels by assimilating cholesterol in reproductive media [4,29] .
7. Food Allergy
It is attributed to disruption of antigen transport in the intestinal mucosa. Lactobacillus GG strengthens the immune barrier by stabilizing the mucosal barrier and provides a proportional passage through Peyer's plaques [6,13,30] .
8. Atopic Dermatitis
It is a chronic skin disease which is frequently seen especially in children and goes on with exacerbations. The increase in IL-4 production caused by food allergens such as macromolecular absorption and casein in these children is responsible for the clinical picture. Lactobacillus GG can break down food allergens such as bovine casein and thus reduce IL-4 production [6,13] .
9. Inflammatory Bowel Diseases
In these patients, an exaggerated increase in immune system reaction and a decrease in the barrier function of the intestinal epithelium have been identified [30] . Probiotic use in the maintenance treatment of patients may support the immune barrier function of the intestine [30,31,13] .
10. Rheumatoid Arthritis
Urease activity was found to be high in patients with juvenile chronic arthritis. Probiotic therapy suppresses urease activity [13] .
11. Urinary System Infections
In women with uncomplicated lower urinary tract infection, weekly intravaginal Lactobacillus treatment has been found to reduce the frequency of infectious episodes [32] . Since the ascending pathway is important in the development of urinary tract infections, increased lactobacilli in the intestine may prevent episodes of urinary tract infection [33] .
12. In Farm Animals
Probiotic Use
Probiotics are used to accelerate growth and increase ovulation in livestock [4] .
PROBIOTICS 'ADVANTAGES ON ANTIBIOTICS
• Does not induce resistance to antibiotics in a way that disrupts treatment.
• Non-toxic. No side effects and no toxic residues in slaughter animals.
• Stimulates the immune system.
• Does not predispose to other infections since it does not disturb flora.
• It is much cheaper than antibiotics.
PROBLEMS IN PROBIOTIC USE
• Poor quality control.
• Dosing problem.
• Necessity of continuous use: The effects of probiotics can only be sustained by continuous use. The effects cease soon after use is discontinued.
RESULT
The World Health Organization, in Geneva in 1994, aimed at limiting the use of antibiotics to accelerate growth in animals; in humans, vaccines, bacterial interactions, serum therapy and the use of macrophages have been suggested to prevent infections by increasing immunity [1] . Probiotics attract attention as agents that can provide these effects. However, there is little evidence yet about the use of probiotics. Therefore, they cannot replace antibiotics at least for now, but they can repair flora damage and resistance to infections due to food and environmental factors. In order for probiotics to be widely used in therapeutic medicine, more studies are needed on them.
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