|Year : 2013 | Volume
| Issue : 3 | Page : 219-228
Probiotics: Nature's medicine
Amit Kumar1, Vandana2
1 Department of Pharmacology, RIMS, Ranchi, India
2 Department of Physiology, M.G.M. Medical College, Jamshedpur, Jharkhand, India
|Date of Submission||23-Nov-2012|
|Date of Acceptance||24-Jan-2013|
|Date of Web Publication||10-Jul-2013|
House No. 6, Durga Path Via Mohan Path, Bhatia Basti, Kadma, Jamshedpur, Jharkhand - 831 005
Source of Support: None, Conflict of Interest: None
| Abstract|| |
There has been renewed interest in the natural and alternative therapy, for holistic management of various complex diseases, in the recent past. Clinical application of probiotics in such cases is a very promising field. Probiotics are one of the finest natural tools for maintaining the delicate balance between disease and health. Many clinical trials have shown that probiotics are not only useful in various forms of diarrhea, but are also showing promising results in other diseases like immunological diseases, allergies and some cancers. However, more robust studies are warranted to evaluate their efficacy before mass application.
Keywords: Alternative therapy, biotherapeutics, diarrhea, immunological diseases, probiotics
|How to cite this article:|
Kumar A, Vandana. Probiotics: Nature's medicine. Int J Nutr Pharmacol Neurol Dis 2013;3:219-28
| Introduction|| |
The concept behind probiotics was introduced in the early 20 th century, when Nobel laureate Elie Metchnikoff, known as the "Father of Probiotics," proposed that ingestion of micro-organisms could have substantial health benefits for humans. Working on his theory, scientists were able to isolate, in 1935, certain strains of Lactobacillus acidophilus (L. acidophilus). These strains were observed to be very active when implanted in the human digestive tract. Several studies were carried out using this organism and encouraging results were obtained especially, in the relief of chronic constipation.
In 1953, Werner Kollath came up with the term "Probiotic," which is derived from the Greek word pro (for) and bios (life).  In 1989, in one of his works, Roy Fuller suggested a definition for probiotics as "A live microbial feed supplement, which beneficially affects the host animal by improving its intestinal microbial balance," but the most accepted definition of probiotics was given by Food and Agriculture Organization of the United Nations/World Health Organization (FAO/WHO) expert committee in 2001. According to which, probiotics are: "Live micro-organisms, which when administered in adequate amount confer a health benefit on the host." In day-to-day practice, probiotics are commonly described as "friendly," "beneficial," or "healthy" bacteria.
Probiotics are mainly lactic acid producing bacilli, mostly Lactobacilli (L. acidophillus0 DDS-1, Lactobacillus casei (L. casei), L. lactis, L. rhamnosus, L. salviarius) and Bifidobacteria (B. longum, B. infantis, B. bifidum), and also the yeasts Sacharomyces boulardii (Brewer's yeast) and Sacharomyces cervisiae (Baker's yeast).
Lactic acid is a carboxylic acid with the chemical formula C 3 H 6 O 3. It is produced by fermentation of complex sugar molecules present in partially digested food of the intestine. Besides lactic acid, other bioactive soluble molecules (such as organic acids, fatty acids, hydrogen peroxide, bacteriocine, and bacteriocin-like substances) are also produced. These bioactive molecules alter the micro-environment of gut favorably to exert their beneficial effects. Lactic acid, in particular, creates an acidic environment, hence inhibiting other pathogenic bacteria and also helps in absorption of iron and other minerals.
S. boulardii is the only probiotic fungus, which has been successfully used for curing the intestinal infections, especially diarrhea.  Other organisms used as probiotics are Bacillus coagulans, Enterococcus faecium, Streptococcus thermophillus. At least five of the 12 main probiotic species should be present in order to make an effective probiotic combination. 
| Critera|| |
A successful probiotic agent must fulfill the following criteria:
- It must be of human source and non-pathogenic
- It must be resistant to the gastric, bile, and pancreatic digestion
- It must be able to adhere and colonize the enterocytes
- It must be able to remain metabolically active once it reaches the gastrointestinal tract
- It must be able to nullify the effect of disease causing (pathogenic) bacteria
- It must balance PH levels in the colon
- It must have favorable immunomodulation properties
- It must have the ability to influence metabolic activities.
Lactobacilli mainly reside in small intestine whereas Bifidobacteria (marker of healthy micro-flora) mainly reside in large intestine and form 90% of total colonic beneficial micro-flora.
| Natural Source of Probiotics|| |
Probiotics are found in fermented food e.g., yogurt, dairy drinks, and kefir. There are other fermented foods that are good natural sources of probiotics like aged cheese, beer, kimchi, fermented soy product (miso, temph, tamari, shoyu), pickled ginger, sauerkraut, etc.
The probiotics in yogurt include Lactobacillus bulgaricus, L. acidophilus, S. thermophiles, and Bifidobacteria.
Kefir is a creamy dairy drink similar to yogurt. It contains probiotics not usually found in yogurt, such as Lactobacillus caucasus.
Cottage cheese also contains Bifidobacterium lactis and L. acidophilus. Buttermilk is often cultured with the probiotic Streptococcus lactis. Certain non-dairy fermented foods are also rich in probiotics, including sauerkraut (fermented cabbage), kimchi (Korean spicy cabbage), tempeh (a fermented soybean product) and soy sauce. The probiotics found in non-dairy fermented foods include Lactobacillus planatarum, Lactobacillus brevis, and L. acidophilus. Breast milk contains some oligosaccharides and bifidogenic substances, which promote the growth of Bifidobacteria in breast-fed infants.
Beer, bread, cider, wine, malt beverages, sour dough bread, fruit skin (especially grapes, plumbs), grape juice, and yeast extracts are the good sources of probiotic yeasts.
Certain substances, which help in survival and proliferation of these healthy bacteria are known as prebiotics.
Prebiotics are substances, which enhance the proliferation and development of probiotic micro-organisms. They act as a catalyst to promote the growth of host indigenous colonies of helpful bacteria. Prebiotics are typically oligosaccharides, especially, Galacto-Oligosaccharides, Fructo-Oligosaccharides (FOS), inulin, Xylo-Oligosaccharides, etc., They remain undigested or partially digested in the gastro-intestinal tract and act as a substrate for the micro-flora.
Natural sources of prebiotics are: Breast milk, Jerusalem artichoke, chicory root, raw dandelion greens, leeks, onions, garlic, asparagus, whole grains, beans, banana, psyllium husk, germinated seeds, etc.
Adding prebiotics to probiotics increases production of gut short-chain fatty acids (SCFA). Human colonic bacteria ferment Non-Starch Polysaccharides (NSP; major components of dietary fibers and prebiotics) to SCFA, mainly acetate, propionate, and butyrate. SCFA stimulates colonic blood flow and fluid and electrolyte up-take. Butyrate is a preferred substrate for colonocytes and appears to promote a normal phenotype in these cells. 
Study of probiotics and prebiotics resulted in a new concept: Synbiotics. Synbiotics are products containing both prebiotics and probiotics.
| Mechanisms of Acyion of Probiotics|| |
Various mechanisms of action of probiotics can be discussed under the following headings [Figure 1]:
Anti-microbial actions of probiotics
- Modification of micro-flora: Several studies suggested that ingestion of certain lactobacilli and Bifidobacteria species decrease the fecal concentrations of clostridia, Bacteroides, and Escherichia coli increasing the endogenous levels of lactobacilli and Bifidobacteria. They have also proposed that probiotics more importantly affect the metabolic activities of the flora by decreasing the production of carcinogenic substances such as faecal azoreductase, nitroreductase, and β-glucoronidase. 
- Production of anti-microbial factors such as:
- SCFAs, which lower the colonic pH and prevent the growth of pathogenic organisms. 
- Bacteriocins, anti-microbial proteins elaborated by probiotic organisms, are especially effective against Gram-positive organisms. 
- Certain soluble substances with anti-viral effect, produced by L. rhamnosus GR-1, and L. fermentum RC-14, have the capacity to inactivate adenovirus and the vesicular stomatitis virus. 
- Anti-microbial substances such as lactic acid, hydrogen peroxide, and pyroglutamate, produced by Lactobacillus GG (LGG) inhibits the growth of several Gram-positive and Gram-negative bacteria. 
- A non-bacteriocin and non-lactic acid anti-microbial substance is produced by L. acidophilus strain LA1 against a variety of Gram-negative and Gram-positive bacteria. 
- Certain specific micro-flora isolated from an infant, were found to be bactericidal against Salmonella typhimurium. 
- Competition with pathogens to prevent their adhesion to the intestine:
Probiotics competitively inhibit adhesion of pathogenic bacteria to intestinal epithelium. Binding of probiotics causes colonization resistance which prevents the attachment of pathogens. For example, LGG and Lactobacillus plantarum 299V competitively inhibit the attachment of enterohemorrhagic E. coli 0157:H7 to HT-29 cells. S. boulardii inhibits the attachment of Entamoeba histolytica trophozoites to erythrocytes in vitro.  Certain strains of lactobacilli are also capable of blocking receptor sites preventing the invasion of pathogens.
- Competition for nutrients necessary for survival of pathogen: Probiotics compete with pathogens for nutrients. For example, consumption of monosaccharides by a probiotic may reduce the growth of Clostridium difficile, which is dependent on monosaccharides for growth. 
- Anti-toxin effect: Probiotics also modify toxin receptors through an enzymatic mechanism, which has been seen with S. boulardii through its effect on the C. difficile toxin A receptor. 
Effects of probiotics on intestinal epithelium
- Enhance the barrier function of intestinal epithelium by
- Activation of tight junction proteins - Probiotic bacteria such as Streptococcus hermophilus and L. acidophilus enhance activation of tight junction proteins avoiding the development of a leaky intestine. 
- Prevention of inflammation and programmed cell death of lining of intestinal epithelial cells, e.g., L. rhamnosus GG 
- Decreasing the mucosal permeability - An effect on barrier function with a lactobacillus strain has been demonstrated by decreased mucosal permeability to mannitol in germfree rats. 
- Enhance the production of defensive molecules such as mucins:
Mucins produced by the host constitute one of the defense mechanisms against pathogens, and MUC2 and MUC3 mRNA expression is increased in response to lactobacilli. This protects the intestinal cells against the adhesion of pathogenic bacteria.
- Increase brush border enzyme production:
On ingestion, S. boulardii increases brush border enzymes in jejunal mucosa and at the same time enhances intestinal enzyme expression by producing polyamines.
Effects of probiotics on immune system
- Probiotics act as vehicles to deliver anti-inflammatory molecules to the intestine: Probiotic agents, e.g., lactobacilli, can be genetically manipulated to secrete interleukin 10 (IL-10) (an anti-inflammatory cytokine). IL-10 is released locally at the inflamed area in gastrointestinal tract, on ingestion of these genetically engineered probiotic agents. The primary mechanism of the IL-10 regulated anti-inflammatory response is to selectively inhibit transcription of the specific inflammatory genes and to limit cytokine and chemokine production from the activated macrophages and dendritic cells. 
- Probiotics enhance signaling in host cells to reduce inflammatory response: Toll-like receptor-9 (TLR9) signaling is essential in mediating the anti-inflammatory effect of probiotics. DNA obtained from a mixture of probiotic strains was shown to attenuate colitis in an animal model, an effect that was dependent on TLR-9.  A study by Petrof et al., demonstrated that probiotics inhibited the pro-inflammatory nuclear factor kappa B (NF-κB) pathway and triggered the expression of cell protective heat shock proteins in the intestinal cells. The resulting inhibition of NF-κB and increased expression of heat shock proteins may account for the anti-inflammatory and cytoprotective effects reported for probiotics and may be a novel mechanism of microbial-epithelial interactions. 
- Switch in immune response to reduce allergy: Probiotic bacteria appear to modulate the non-specific immune receptors differently in healthy and hypersensitive subjects. They have immune-stimulatory effect in healthy subjects. On the other hand, they down-regulate the response in hypersensitive subjects. 
- Induce antibody response to reduce infection: Many probiotic agents have the capability to induce specific antibody response. L. casei strain GG has been known to stimulate rotavirus specific immunoglobulin A (IgA) antibody responses. L. rhamnosus GG or L. acidophilus CRL 431, induces an immunologic response toward poliomyelitis vaccine virus by affecting the production of virus neutralizing antibodies.  Furthermore, ingested B. bifidum significantly increased the number of immunoglobulin (IgM, IgG, and IgA) secreting cells. 
- Reduce the production of inflammatory substances: Certain probiotic bacteria decrease the synthesis of potent proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ, IL-12 and also platelet activating factor, by inhibiting the NF-κB mediated DNA transcription. Probiotics also inhibit TNF-α-induced IL-8 secretion. On the other hand, they enhance the production of anti-inflammatory cytokines such as IL-10. The increased IL-10 production is accompanied by an increase in transforming growth factor-β (TGF-β) through ligation of certain probiotic antigens to TLRs. , Some in vitro studies show that certain probiotics can activate an anti-inflammatory defense system. For example, Voltan et al. showed that Lactobacillus crispatus down regulated expression of pro-inflammatory genes through production of H 2 O 2 -induced peroxisome proliferator. 
Effects of probiotics on allergic disorder
Various studies have suggested the role of probiotics in strain-specific, anti-allergic effects. In a double-blind placebo study, LGG was observed to alleviate atopic eczema in infants who were IgE sensitized.  In children with atopic dermatitis, lactobacilli stabilizes the intestinal barrier function and decreases gastrointestinal symptoms. 
Probiotic bacteria reduce CD34+ hemopoietic pre-cursor cells, which are increased in allergic subjects.
In infants with cow milk allergy, interferon-γ secretion can be increased with LGG.  Specific strains of Bifidobacterium and Lactobacillus have shown to be useful in the treatment and prevention of eczema and dermatitis in infants and children. 
L. casei Shirota, can enhance innate immunity by increasing the number of natural killer cells.  Other animal studies also indicate toward the immunity modifying properties of probiotics.
Anti-proliferative effect of probiotics on cancer
Recently, much concentration has focused on declining the threat of colon cancer through growing intake of dietary fiber and this has incorporated understanding in the use of prebiotics and probiotics.  Probiotic use has resulted in direct anti-proliferative effect on tumor cells and immune cells.  Probiotics affects several intestinal functions such as detoxification, colonic fermentation, transit, and immune status. This prevents the development of colon cancer. Lactobacilli and Bifidobacteria, have the ability to modify gut flora and decrease β-glucuronidase and carcinogen levels. Intestinal instillation of probiotic, L. casei shirota has shown a reduction in bladder cancer.  Although, a lot of study remains to be done in order to show the use of probiotics in limiting tumor growth still the data received show promising results.
Effects of probiotics on distant mucosal sites
It is a very interesting fact that the good effects of probiotics go beyond the gastrointestinal tract to distant areas, such as urinary and respiratory tracts. LGG has been used, with considerable success, for treating and preventing urinary tract infections, vulvo-vaginal candidiasis, otitis media  and bacterial vaginosis.  Probiotics have proved to be of modest benefit in prevention and reduction of severity of respiratory infections as well.
| Uses of Probiotics|| |
Acute infectious diarrhea
Probiotic-treated children have been observed to produce higher levels of IgA antibodies. The strongest evidence of a beneficial effect of probiotics has been established with L. rhamnosus GG and B. lactis BB-12 for prevention and Lactobacillus reuteri SD2222 for treatment of acute rotavirus diarrhea in children. ,, The beneficial effects of probiotics have been demonstrated in infectious diarrhea in adults as well.
Antibiotic associated diarrhea
It can range from mild diarrhea to colitis and even to pseudo-membranous enterocolitis (PMC). PMC can be due to toxin produced by C. difficle, altered bowel flora due to prior antibiotic treatment and impaired host immunity. Use of Probiotic agents can has shown to replenish the gut flora. Probiotics also have anti-toxin effect. S. boulardii is the most studied probiotic in this respect. S. boulardii releases a 54-kDa protease, which digests the C. difficile toxin A and B molecules and brush border membrane receptors. 
Neonatal necrotizing enterocolitis (NEC)
Prophylactic probiotic to preterm babies, especially Bifidobacteria has been observed to decrease neonatal necrotizing enterocolitis (NEC) incidence and severity. The intestinal microbiota in low-birth-weight premature infants can be dominated by many pathogens such as Enterococcus faecalis, E. coli, Staphylococcus epidermidis, Enterobacter cloacae, Klebsiella pneumoniae, and Staphylococcus haemolyticus. These increase the risk of NEC in such infants. Studies have indicated that Bifidobacteria not only colonize the gut of animals, they possibly also help to exclude pathogens; they also reduce endotoxemia and appear to modulate the inflammatory cascade. 
Helicobacter pylori infection
Helicobacter pylori is a Gram-negative bacteria responsible for type B gastritis and peptic ulcers and may be a risk-factor for gastric cancer. Studies have shown that probiotics can play a role in inhibiting or killing these bacteria. Some in vitro and animal data indicate that lactic acid bacteria can inhibit the pathogen's growth and decrease the urease enzyme activity necessary for it to survive in the acidic environment of the stomach.  In humans, there is also evidence that probiotic strains can suppress infection and lower the risk of recurrences. 
Inflammatory bowel disease
Role of probiotics is not very well established in case of ulcerative colitis. However, beneficial effects of probiotics have been observed in case of pouchitis. A probiotic mixture of eight bacterial species is effective in the treatment and prevention of pouchitis following ileo-anal pouch creation.  Decreased rate of recurrence has been observed in Crohn's disease. Administration of probiotics to IL-10 deficient mice with bowel inflammation decreased the levels of proinflammatory cytokines TNF-α and IL-12 and reduced intestinal inflammation. In children, the most widely used probiotic is LGG. The addition of LGG to prednisone decreased disease activity in a small study of children with Crohn's disease. In a larger study of children, however, there was no difference in remission rate observed over 2 year. 
Irritable bowel syndrome (IBS)
Probiotics have been observed to decrease the symptoms of irritable bowel syndrome (IBS). Reduction in abdominal bloating and flatulence, as a result of probiotic use, has been quite a consistent finding in several studies. The basal IL-10:IL-12 ratio that is low prior to the probiotic treatment can become normal after probiotic treatment. 
Lactase deficiency is a very frequent phenomenon in children, with digestive complaints related to the consumption of milk and dairy products. These complaints can include flatulence, diarrhea, and abdominal distension. Probiotic bacteria (especially, L. reuteri) are capable of digesting lactose that would otherwise remain poorly digested, thereby alleviating the symptoms of lactase deficiency in susceptible subjects. 
Gliadin has toxic amino-acid sequences that are responsible for the symptoms of gluten-sensitive enteropathy in immunologically susceptible subjects. These epitopes, including the 33-mer peptides corresponding to 57-89 of α2-gliadin, are very resistant to digestion. The prolyl endopeptidase of probiotic bacteria origin is able to digest these 33-mer peptides. A mixture of probiotic strains contains the entire portfolio of peptidases that are able to degrade gliadins. 
Food protein hypersensitivity
The probiotic flora stimulates development of gut-associated lymphoid tissue and is important for the development of oral tolerance to food antigens. Even before the development of allergy, the intestinal flora of atopic children have markedly reduced reservoir of commensals e.g., Bifidobacteria, which are markers for healthy intestinal environment. Probiotics have been observed to reverse the increased permeability and enhance specific IgA responses that are frequently defective in children with food allergy. 
| Some Other Uses of Probiotics|| |
Besides the above mentioned uses of probiotics, there are several others where probiotics are showing promising results.
The use of lactic acid bacteria, such as L. plantarum NCIMB 8826, to deliver vaccines is under investigation.  Studies are also being designed to explore the extent to which lactobacilli can immunize against various pathogens that attack the mucosal surfaces of the mouth, intestine, vagina, and respiratory tract.
Probiotics use in surgical site infections
Probiotics use for treatment of surgical site infections is under investigation. Emergence of vancomycin-resistant strains of multidrug-resistant S. aureus, is posing a lot of difficulties in hospital settings. A series of animal studies have shown that L. fermentum RC-14 and proteins produced by these organisms tend to prevent severe Staphyoloccus aureus surgical implant infection.  Although this study is still in a preliminary stage and proves nothing regarding human efficacy, the concept puts forward a totally new concept of wound infection management. Further studies are needed to consolidate this study.
| Factors Affecting Viability of Probiotics in Food|| |
Certain factors, both intrinsic and extrinsic, may influence the survival of probiotics in food. These factors are needed to be kept in mind in all stages of probiotic food manufacturing. ,
- Physiological state of the added probiotic in the food, i.e., whether live bacteria or dry spores are used. The bacteria should be metabolically stable and active in the product, survive passage through the upper digestive tract in large numbers and have beneficial effects when in the intestine of the host. The standard for any food sold with health claims from the addition of probiotics is that it must contain per gram at least 10 6 -10 7 cfu of viable probiotic bacteria (FAO/WHO, 2001).
- Physicochemical conditions of food processing. e.g., mechanical stress (during high-speed blending or homogenization), extreme temperature conditions (during spray and freeze drying), composition of growth medium, composition of freezing and drying media, presence of toxic by-products, high dissolved oxygen content, etc., may result in cell disruption and losses in viability.
- Physical conditions of product storage, like temperature and water activity (moisture content) of the product. Higher the temperature and moisture levels, lower will be the survival of probiotics. The loss of viability is possibly due to increase of metabolic and cellular activity that led to exhaustion of nutrients stored within the cell. Freeze-dried probiotic products stored at frozen temperature have maximum bacterial counts.
- Chemical composition of the product and host environment. e.g., presence of fermentable sugars and prebiotic compounds, oxygen stress, pH (acidity of carrier food, highly acidic conditions in stomach, bile salts and alkalinity of small intestine), enzymatic activities, competition with other organisms in the product etc., also affect the viability. Most of the probiotic species survive poorly at pH levels below 4.6. Lactobacilli are able to grow and survive at pH values between 3 and 4, while Bifidobacteria tend to be less acid tolerant.
Different approaches that increase the resistance of these sensitive micro-organisms against adverse conditions have been proposed, including appropriate selection of acid and bile-resistant strains, use of oxygen-impermeable containers, two-step fermentation, stress adaptation, incorporation of micro-nutrients such as peptides and amino acids, and micro-encapsulation.
| Safety Profile of Probiotics|| |
Assessment of safety must take into account the nature of the microbe being used, method of administration, level of exposure, health status of users and physiological functions they are called on to perform [Figure 2]. 
Largely, probiotics are considered quite safe. Side effects with probiotics are rare and generally limited to constipation, increased thirst and flatulence. However, certain warnings have been issued regarding occurrence of bacteremia and endocarditis in immunocompromised (e.g., human immunodeficiency virus/cancer chemotherapy patients) and critically ill persons (e.g., patients with impaired intestinal barrier function as occurs with multi organ failure/severe acute pancreatitis and patients on central venous catheter). The Norwegian Scientific Committee for Food Safety evaluated the safety of use of probiotics for hospitalized patients and concluded that probiotics should not be used for critically ill patients, including those with antibiotic-associated diarrhea, including C. difficile infection.  There has been a case report of L. rhamnosus sepsis in a patient with corticosteroid immunosuppression in association with live yogurt biotherapy and also a case report of endocarditis. 
These clinical experiences suggest that the patients who are immunosuppressed or have pre-existing heart valve disease should avoid probiotic preparations containing L. rhamnosus and invasive surgical procedures involving the G.I tract (which naturally has a large population of lactic acid bacteria) should be avoided in these patients.
Probiotics containing Lactobacilli and Bifidobacteria are probably safe whilst Enterococcus strains should be avoided, because a few enterococci are associated with the development of antibiotic resistance. Similarly, fungaemia has been observed with Saccharomyces, especially in patients on central venous line. 
There may be potential transfer of virulence and/or resistance factors to antibiotic agents from probiotic micro-organism to commensal gut flora. Probiotics may be unsafe in immunodeficient neonates. So infant formulas enriched with probiotics should be used only in immunocompetent infants of more than 4-5 months of age. Some lactobacilli may potentially contribute to dental caries probably due to production of organic acid and decalcification of dental material.
Specific strain can have a beneficial effect when given alone, whereas, this effect may vanish when given as a mixture of probiotic. Allergy to certain prebiotic compounds (FOS, inulin, etc.), used in preparation of probiotic mixture, can occur.
Latest researches have associated probiotics with development of auto-immune diseases like rheumatoid arthritis (Science Daily June 18, 2010) and multiple sclerosis ("Multiple Sclerosis is triggered by friendly bacteria residing in the gut;" Christine Stomes. Healthy Living; October 30, 2011). Studies are going on in order to consolidate these findings and it will be very premature to conclude that probiotics are unsafe. Still, caution and common sense should be used while evaluating the need to take probiotic supplements.
| Probiotics: The Future Prospects|| |
Recent times have brought to light several ongoing and several proposed studies on probiotics. The observations made in these studies have proved, to a great extent, the utility of these helpful microbes. Still, molecular tools are being used to further understand and manipulate the probiotic flora for our benefit. The critical step, in order to popularize the use of probiotic, is to make them available in specific, safe and clinically proven formulations. They should be made easily available to both physicians and consumers. Also, further research should be done in order to specify the safety profile of various strains used for probiotic preparations.
| References|| |
|1.||Hamilton-Miller JM, Gibson GR, Bruck W. Some insights into the derivation and early uses of the word 'probiotic'. Br J Nutr 2003;90:845. |
|2.||Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, van Belle G. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterology 1989;96:981-8. |
|3.||Branski D, Wilschanski M, Kliegman. Probiotics in gastrointestinal disorders. Nelson Textbook of Pediatrics. 18 th ed. Philadelphia: Saunders; 2007. p. 1618-21. |
|4.||Topping DL, Clifton PM. Short-chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiol Rev 2001;81:1031-64. |
|5.||Wollowski I, Rechkemmer G, Pool-Zobel BL. Protective role of probiotics and prebiotics in colon cancer. Am J Clin Nutr 2001;73:451S-5. |
|6.||Michail S. The mechanism of action of probiotics. Pract Gastroenterol 2005;XXIX: 29-47. |
|7.||Røssland E, Langsrud T, Granum PE, Sørhaug T. Production of antimicrobial metabolites by strains of Lactobacillus or Lactococcus co-cultured with Bacillus cereus in milk. Int J Food Microbiol 2005;98:193-200. |
|8.||Cadieux P, Burton J, Gardiner G, Braunstein I, Bruce AW, Kang CY, et al. Lactobacillus strains and vaginal ecology. JAMA 2002;287:1940-1. |
|9.||Liévin V, Peiffer I, Hudault S, Rochat F, Brassart D, Neeser JR, et al. Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial activity. Gut 2000;47:646-52. |
|10.||Reid G, Jass J, Sebulsky MT, McCormick JK. Potential use of probiotics in clinical practice. Clin Microbiol Rev 2003;16:658-72. |
|11.||Resta-Lenert S, Barrett KE. Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut 2003;52:988-97. |
|12.||Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem 2002;277:50959-65. |
|13.||Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000;289:1352-5. |
|14.||Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, et al. Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 2004;126:520-8. |
|15.||Petrof EO, Kojima K, Ropeleski MJ, Musch MW, Tao Y, De Simone C, et al. Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology 2004;127:1474-87. |
|16.||Ezendam J, van Loveren H. Probiotics: Immunomodulation and evaluation of safety and efficacy. Nutr Rev 2006;64:1-14. |
|17.||Park JH, Um JI, Lee BJ, Goh JS, Park SY, Kim WS, et al. Encapsulated Bifidobacterium bifidum potentiates intestinal IgA production. Cell Immunol 2002;219:22-7. |
|18.||Matsuzaki T, Chin J. Modulating immune responses with probiotic bacteria. Immunol Cell Biol 2000;78:67-73. |
|19.||Iordache F, Iordache C, Chifiriuc MC, Bleotu C, Pavel M, Smarandache D, et al. Antimicrobial and immunomodulatory activity of some probiotic fractions with potential clinical application. Archiva Zootechnica 2008;11:41-51. |
|20.||Voltan S, Martines D, Elli M, Brun P, Longo S, Porzionato A, et al. Lactobacillus crispatus M247-derived H2O2 acts as a signal transducing molecule activating peroxisome proliferator activated receptor-gamma in the intestinal mucosa. Gastroenterology 2008;135:1216-27. |
|21.||Viljanen M, Savilahti E, Haahtela T, Juntunen-Backman K, Korpela R, Poussa T, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: A double-blind placebo-controlled trial. Allergy 2005;60:494-500. |
|22.||Rosenfeldt V, Benfeldt E, Valerius NH, Paerregaard A, Michaelsen KF. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr 2004;145:612-6. |
|23.||Pohjavuori E, Viljanen M, Korpela R, Kuitunen M, Tiittanen M, Vaarala O, et al. Lactobacillus GG effect in increasing IFN-gamma production in infants with cow's milk allergy. J Allergy Clin Immunol 2004;114:131-6. |
|24.||Kalliomäki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 2003;361:1869-71. |
|25.||Reveneau N, Geoffroy MC, Locht C, Chagnaud P, Mercenier A. Comparison of the immune responses induced by local immunizations with recombinant Lactobacillus plantarum producing tetanus toxin fragment C in different cellular locations. Vaccine 2002;20:1769-77. |
|26.||Saini R. Role of probiotics in colorectal cancer. Int J Nutr Pharmacol Neurol Dis 2011;1:81-2. |
|27.||Lee JW, Shin JG, Kim EH, Kang HE, Yim IB, Kim JY, et al. Immunomodulatory and antitumor effects in vivo by the cytoplasmic fraction of Lactobacillus casei and Bifidobacterium longum. J Vet Sci 2004;5:41-8. |
|28.||Tagg JR, Dierksen KP. Bacterial replacement therapy: Adapting 'germ warfare' to infection prevention. Trends Biotechnol 2003;21:217-23. |
|29.||Golledge CL, Riley TV. "Natural" therapy for infectious diseases. Med J Aust 1996;164:94-5. |
|30.||Guandalini S, Pensabene L, Zikri MA, Dias JA, Casali LG, Hoekstra H, et al. Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: A multicenter European trial. J Pediatr Gastroenterol Nutr 2000;30:54-60. |
|31.||Shornikova AV, Casas IA, Isolauri E, Mykkänen H, Vesikari T. Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children. J Pediatr Gastroenterol Nutr 1997;24:399-404. |
|32.||Szajewska H, Kotowska M, Mrukowicz JZ, Armañska M, Miko³ajczyk W. Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants. J Pediatr 2001;138:361-5. |
|33.||Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005;147:192-6. |
|34.||Felley CP, Corthésy-Theulaz I, Rivero JL, Sipponen P, Kaufmann M, Bauerfeind P, et al. Favourable effect of an acidified milk (LC-1) on Helicobacter pylori gastritis in man. Eur J Gastroenterol Hepatol 2001;13:25-9. |
|35.||Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, et al. Prophylaxis of pouchitis onset with probiotic therapy: A double-blind, placebo-controlled trial. Gastroenterology 2003;124:1202-9. |
|36.||Sanders ME, Akkermans LM, Haller D, Hammerman C, Heimbach J, Hörmannsperger G, et al. Safety assessment of probiotics for human use. Gut Microbes 2010;1:164-85. |
|37.||Wald A, Rakel D. Behavioral and complementary approaches for the treatment of irritable bowel syndrome. Nutr Clin Pract 2008;23:284-92. |
|38.||Ojetti V, Gigante G, Gabrielli M, Ainora ME, Mannocci A, Lauritano EC, et al. The effect of oral supplementation with Lactobacillus reuteri or tilactase in lactose intolerant patients: Randomized trial. Eur Rev Med Pharmacol Sci 2010;14:163-70. |
|39.||Osborn DA, Sinn JK. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev 2007; Oct 17;(4):CD006475. |
|40.||Gan BS, Kim J, Reid G, Cadieux P, Howard JC. Lactobacillus fermentum RC-14 inhibits Staphylococcus aureus infection of surgical implants in rats. J Infect Dis 2002;185:1369-72. |
|41.||Crittenden R. Incorporating probiotics into food. In: Lee YK, Salminen S, editor. Handbook of Probiotics and Prebiotics. 2 nd ed. New Jersey: Wiley; 2009. p. 60-7.44. |
|42.||Mortazavian A, Razavi SH, Ehsani MR, Sohrabvandi S. Principles and methods of microencapsulation of probiotic microorganisms. Iran J Biotechnol 2007;5:1-18. |
|43.||The use of probiotics for patients in hospitals. A benefit and risk assessment. Opinion of the steering committee of the norwegian scientific committee for food safety, 2009. Available from: http://www.vkm. no/dav/009488e0b8.pdf. [Last accessed 2012, vol-7/112-FINAL: 6-23]. |
|44.||Vancanneyt M, Huys G, Lefebvre K, Vankerckhoven V, Goossens H, Swings J. Intraspecific genotypic characterization of Lactobacillus rhamnosus strains intended for probiotic use and isolates of human origin. Appl Environ Microbiol 2006;72:5376-83. |
|45.||Lolis N, Veldekis D, Moraitou H, Kanavaki S, Velegraki A, Triandafyllidis C, et al. Saccharomyces boulardii fungaemia in an intensive care unit patient treated with caspofungin. Crit Care 2008;12:414. |
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