PROBIOTICS
Today, a growing appreciation of the importance of a healthy population of intestinal microbes and the health benefits provided by certain species has spurred interest in the consumption of probiotics, particularly those that contain lactobacilli and bifidobacteria. The ingestion of live bacterial cultures is not a new idea. Metchnikoff advocated such therapy at the turn of the 20 th century. He stated that “ingested lactobacilli can displace toxin-producing bacteria, promoting health and prolonging life.”12 ,13 Probiotics is a topic of major interest nearly 100 years later, as evidenced by a probiotics keyword search of the National Library of Medicine’s Pub Med database that yielded more than 100 papers published in the first 4 months of 2005.
As mentioned above, a population imbalance favoring harmful microbes can result in a variety of serious disease conditions. It is not surprising, then, that studies have demonstrated the potential use of probiotics in the treatment of these conditions. For example, therapy with probiotics has improved conditions of patients with various gastrointestinal conditions and protozoal infections, and helped prevent the onset or recurrence of certain inflammatory conditions and allergies. This will be discussed more thoroughly later.
Safety of probiotics
The thought of ingesting living microbes probably sounds bizarre at first; however, the safety of probiotics has been well-established, as would be expected, since they are non-pathogenic and normally found in the human gut. In fact, many probiotic studies have been performed in infants. For example, a study in which infants aged 3-24 months were fed a milk-based formula supplemented with Bifidobacterium lactis and Streptococcus thermophilus for up to 210 days not only showed no adverse effects, but demonstrated a reduction in colic and irritability, and a lower frequency of antibiotic use.43 Between 1961 and 1998 143 clinical trials with 7,526 human subjects were performed, during which not a single adverse event was reported.44
One is wise to remember, however, that nothing is 100% safe, as is evidenced by an article that reports of a child with short bowel syndrome who experienced bacteremia after taking Lactobacillus GG (LGG) supplements. Genetic testing verified that the infection was related to the ingested LGG.45 Probiotics are thus considered very safe for healthy people, but certain individuals, such as those who are seriously ill or who are immunocompromised, would be prudent to consult with their physicians before consuming probiotics.
Probiotics and GI diseases
Diarrhea
Studies with specific strains of probiotic bacteria have shown promise for use in patients with various gastrointestinal diseases. Bifidobacterium lactis strain Bb 12 provided some protective effect against acute diarrhea in healthy infants, and LGG shortened the course of acute diarrhea in children.46 ,47 Patients who took LGG and erythromycin had fewer cases of diarrhea than those who took erythromycin alone.48 Enterococcus SF 68 significantly reduced both the incidence of antibiotic-associated diarrhea, and duration of diarrhea in patients.49 Patients with recurrent Clostridium difficile infection experienced a significant reduction in incidence of diarrhea when given the antibiotic vancomycin with Saccharomyces boulardii, a species of non-pathogenic yeast, compared to those who took vancomycin alone (16.7% vs 50%).50 LGG reduced duration of diarrhea in rotavirus-positive and rotavirus-negative children. In addition, duration of rotavirus excretion in stools was significantly reduced.51 ,16
Serum antibody response to toxin A, produced by C. difficile, is associated with protection against recurrence of diarrhea.52 Mice that were given S. boulardii experienced a significant increase in intestinal anti-toxin A antibody levels, thus providing a possible mechanism for the protective effects of S. boulardii against C. difficile disease.53
Helicobacter pylori infections
H. pylori is a bacterium that is a major cause of stomach ulcers. Bifidobacterium lactis Bb 12 demonstrated the ability to inhibit H. pyloriin vitro. Lactobacillus brevis (CD2), L. acidophilus La5 and B. lactis Bb12 given to H. pylori-positive patients reduced urea breath test delta values, which suggested a decrease in the H. pylori population of the stomach. Thus, probiotics could have utility in both prevention and treatment of H. pylori infection.54 ,55 ,56
Inflammatory bowel diseases
Inflammatory bowel diseases (IBD) include Crohn’s disease and ulcerative colitis (UC). Crohn’s disease can affect any or all of the GI tract while UC affects the colon only. They are both characterized by chronic inflammation and discomfort. Persistent diarrhea is common; bloody diarrhea is the hallmark of UC. Fistulas and abscesses can occur, and in colonic Crohn’s disease and UC, the risk of colorectal cancer increases. The exact causes of IBD are not known, but there are definite genetic differences between the two. In addition, it is now well-established that the intestinal microbiota is intimately involved in the etiology of IBD. Either an imbalance toward pathogenic bacteria, or an abnormal immune response to gut microflora is at play.57 ,58 ,59 ,60 Animal studies implicate an overgrowth of clostridia species with concurrent decrease in populations of lactobacilli and bifidobacteria.61 A human study also demonstrated a decrease in colonic bifidobacteria, and, interestingly, identified peptostreptococci only in the colons of UC patients.62
Probiotics have been studied in patients with IBD. Crohn’s disease sufferers who were given the yeast S. boulardii in combination with standard therapy (mesalamine) experienced a significant reduction in relapse compared to patients who took mesalamine alone (6.25% vs 37.5%).63 E. coli strain Nissle 1917 (N. S.) was as effective as standard therapy (mesalazine) in preventing relapse of UC flares.64 VSL#3, a “cocktail” of lactic acid probiotics, when given in combination with another standard therapeutic agent (balsalazide), was significantly superior to either balsalazide or mesalazine alone in obtaining remission in patients with mild-to-moderate UC.65
As mentioned earlier, short-chain fatty acids are produced by intestinal bacteria as by-products of fermentation of complex polysaccharides. One of these acids, butyrate, appears to reduce inflammation by several means, including suppression of IL-8 secretion, reduction of production of inflammatory mediators by macrophages, and inhibition of leukocyte adhesion to endothelial cells. 66 ,67 ,68 Butyrate also enhances the activation of peroxisome proliferator-activated receptor, which may inhibit inflammation and help prevent UC.69
Colon cancer
Approximately 70% of colorectal cancer is associated with environmental factors, especially diet.70 Animal studies consistently demonstrate the effectiveness of probiotics in reducing the incidence and/or extent of chemically induced colon cancer.70 ,71 The means by which this is accomplished is still under investigation; however, the effects of beneficial microbes on certain enzymes produced by other colonic bacteria are thought to play a significant role.
Some intestinal bacteria produce β-glucuronidase, nitroreductase and azoreductase, enzymes that have been implicated in the generation of carcinogens, mutagens, and tumor-promoting agents. In a clinical trial, consumption of L. acidophilus significantly reduced by up to 4-fold the activities of these three enzymes. This effect lasted only as long as ingestion of the probiotic continued.3 ,72 ,73 , Healthy volunteers who consumed a diet including fried meat (known to be a major risk for colorectal cancer) showed significantly reduced fecal bacterial β-glucuronidase and nitroreductase activities while consuming L. acidophilus-fermented milk.74 ,75 Although risk factors and markers of colorectal cancer have been shown to be reduced, a direct correlation has not yet been demonstrated with probiotic use and reduction in human colorectal cancer. Future studies will hopefully provide more definitive information in this regard.
Miscellaneous benefits
Phagocytosis of E. coli, a potential pathogen, was enhanced when individuals consumed a fermented product containing adherent strains of either L. acidophilus or B. bifidum.76 Lactobacillus supplementation significantly reduced incidence and severity of respiratory illness in children and the need for antibiotic treatment. This resulted in fewer missed days from day care due to illness.77
Probiotics have demonstrated cholesterol-lowering effects in both in vitro and in vivo studies. Several strains of lactobacilli, as well as streptococcus and bifidobacteria, are able to assimilate cholesterol from growth cultures.78 ,79 ,80 Human clinical trials have verified that lactobacilli and bifidobacteria can produce a moderate reduction in serum cholesterol. Proposed mechanisms of action include 1) fermentation of carbohydrates to short-chain fatty acids which can inhibit cholesterol synthesis by the liver or cause a redistribution of cholesterol from the plasma to the liver, 2) interference by some bacteria with cholesterol absorption from the gut, or 3) direct use of cholesterol as a food source by bacteria.81
Some investigators believe that probiotic therapy may have a place in treatment of major depressive disorder (MDD). MDD patients have elevated levels of proinflammatory cytokines, increased oxidative stress, altered GI function, and lowered micronutrient and omega-3 fatty acid status. Stress, a major factor in MDD, lowers levels of lactobacilli and bifidobacteria. Probiotics can reduce systemic inflammatory cytokines, decrease oxidative stress, improve nutritional status, and correct small intestine bacterial overgrowth. Intestinal bacteria also appear to be able to communicate with the central nervous system, even in the absence of an immune response.82
Probiotics and allergy
Benefits seen in the GI tract with probiotic use are not all that surprising. Of great interest, however, is the effect that probiotics have on patients who suffer with various allergies. For example, Lactobacillus paracasei-33 improved the quality of life in patients with perennial allergic rhinitis.83 In another study LGG given for 1 month to infants with atopic eczema and cow’s milk allergy alleviated signs and symptoms of both conditions. LGG given prenatally to mothers who had at least one first-degree relative with atopic disease, and postnatally for 6 months to their infants, significantly decreased the incidence of atopic disease in the at-risk infants compared to placebo, and the benefit continued past infancy for at least the 2 years of follow-up.37 ,84
The mechanism by which this bacterium confers this protection is not known, but probably involves several factors. Serum interleukin-10 (IL-10) levels are lower than normal in food allergy patients with late-reacting cases. LGG significantly elevated IL-10 in a study of children with atopic dermatitis, which would be expected to reduce inflammation.85 In addition, LGG has been shown to prevent permeability defects and help control antigen absorption in the colon.86 It has been noted that colonic bacterial populations of allergic individuals have microbial patterns different from those of healthy individuals. Probiotics may be employed to generate bacterial populations that more closely resemble those of healthy individuals, and can be used to prevent the onset of atopic allergies in children.87
Probiotic development and use
When developing effective probiotic products, it is understood that only a handful of microbes can be used, because only a very few that are known to be beneficial can be cultivated. However, it appears that a small number is sufficient to make a significant contribution to the health of the individual. To illustrate, a summary of the benefits provided by just two species of lactobacillus should suffice. LGG is a strain of Lactobacillus rhamnosus. LGG has been shown to reduce effects of traveler’s diarrhea, antibiotic-associated diarrhea, infantile diarrhea (rotavirus gastroenteritis), and C. difficile-associated colitis. LGG-fermented milk reduces mucosal barrier defects caused by exposure to cow’s milk and rotavirus infection. It enhances intestinal immunity by stimulating local release of interferon and by increasing the numbers of cells of the mucosa that secrete IgA and other antibodies. It provides an adjuvant effect with oral vaccines and facilitates antigen transport to underlying lymphoid cells. In an animal model, LGG reduced the incidence of chemically induced colon cancer.16 ,47 ,48 ,51 ,88
The second species, L. plantarum, is thought to have been the most common bacterium in the food of our ancestors. It is the dominant species in sourdough, sauerkraut, green olives, and natural wines and beers. L. plantarum has been used as a food preservative. For example, an inoculum of one million cells/g of food was shown to completely inhibit anaerobic bacteria such as Enterobacteriaceae, enterococci, and S. aureus, even when found in large amounts.12 In addition to the above, it increases the content of important nutrients such as omega-3 fatty acids in foods during storage.
L. plantarum also produces nitric oxide (NO). NO is essential for GI tract functions such as bacteriostasis, stimulation of immune defenses, mucus secretion and others. The amount of NO produced by L. plantarum is sufficient to control pathogens such as E. coli, Candida albicans, Salmonella and Shigella, H. pylori, ameba and other parasites.12 L. plantarum (299v) also demonstrated reduction in cardiovascular disease risk factors (systolic blood pressure, leptin and fibrinogen) in heavy smokers.89
Currently marketed probiotics contain monocultures or mixed cultures of up to nine species of microbes. The most common probiotic bacteria are those of the Lactobacillus and Bifidobacterium genera. Much is yet to be determined, such as which species, or even strains, of microbes to employ to help assure good health, or to address specific disease conditions. Therapeutic dosages and regimens for taking probiotics remain to be determined. Studies have demonstrated that a daily dose of 109–1010 organisms can be effective in management of diarrhea, lactose intolerance, and colon cancer biomarkers. Future studies will determine specific regimens required for desired responses.
Whatever combinations are used, probiotics should become a part of the daily diet because the increase in populations of beneficial microbes seen with probiotics is temporary, as are the benefits seen after their discontinuation (except in perinatal therapy and prevention of atopy). LGG was shown to colonize the GI tract for 1-3 days in most individuals, and up to 7 days in about 30% of those tested. But, the numbers returned to baseline within days after discontinuation of the probiotic.88 A daily probiotic diet would appear to be natural. It is estimated that our ancestors employed a diet than included as much as one million times more microbes than does our modern diet.12
The intestinal microflora is so important to good health that it is considered to function as a separate organ.7 With time, more specific uses of probiotics will certainly be identified. In the meantime, addressing the needs of this “organ” with constant replenishment is prudent. With the growing population and the aging of the Baby Boomer generation will come increased incidence of both acute and chronic diseases, with concurrent increased cost for health care. With this in mind, and considering the safety and potential health benefits of probiotics, there is little doubt that their use will gain popularity.
DISCUSSION
That probiotics are beneficial in a variety of disease conditions is well-established. The exact mechanisms by which these benefits are produced are a matter of conjecture, although some are fairly well-accepted. Certain bacteria benefit patients with inflammatory bowel disease by means of mucosal barrier protection, prevention of pathogenic bacterial growth, and/or altering immunoregulation (decreasing proinflammatory molecules and increasing protective ones).90 ,91 Food allergy and atopic dermatitis patients experience mucosal barrier protection and a rise in anti-inflammatory cytokines such as IL-10.
Colonic bacteria generally must be adherent to the mucosa to provide long-term health-promoting benefits. Bacteria commonly found in milk and yogurt (most L. acidophilus strains, L. bulgaricus, most bifidobacteria, etc.), however, do not adhere to mucosa. Some strains that adhere do not colonize and vice versa. L. plantarum 299 and LGG both adhere to mucosa, but LGG does not colonize well. The good news is that some bacteria can provide benefit as they pass through the GI tract, without colonizing it.12
The sugars fucose and mannose are important in adhesion of some bacteria to the intestinal wall. Both appear to serve as modulators of intercellular communication between certain beneficial bacterial species and the host for regulation of the bacterial population of the intestinal surface.92 Beneficial bacteria can thus either prevent adherence of pathogenic microbes to the mucosa, or interrupt their colonization.
Studies have shown that aging affects the makeup of the colon’s microbial population, with a shift toward higher numbers of enterobacteria and lower numbers of anaerobes and bifidobacteria. This may help explain the increase in incidence of gastrointestinal infections suffered by the elderly. Clostridium difficile-associated diarrhea is a common nosocomial (hospital) infection in the elderly. Standard therapy includes antibiotics, which can drastically reduce or eliminate lactobacilli from the intestinal microflora. Lactobacilli and S. boulardii have demonstrated efficacy in treatment of this affliction.93 LGG is able to repopulate the colons of individuals during treatment with erythromycin. In addition to long-term antibiotic therapy, abusive dietary habits, alcohol consumption and stress can also disturb the microbial ecology of the gut.94 For those who may be subject to these situations, the daily ingestion of probiotics may be invaluable.
GLOSSARY
Anaerobic: Aerobic microbes must have oxygen to survive, whereas anaerobes live in the absence of oxygen.
Carcinogenesis: The development of cancer.
Facultative: Able to live under more than one specific set of environmental conditions.
Genera: Plural of genus. The binomial nomenclature system, commonly used to classify living organisms, consists of genus and species. Thus, Homo sapiens, the classification of man, where Homo is the genus and sapiens is the species.
Glycosidic bonds: Bonds that hold monosaccharides together to form oligo- or polysaccharides.
Glycosylhydrolases: Enzymes that specifically hydrolyze carbohydrates, resulting in simpler sugar molecules.
Gnotobiotic: Germ-free; or an organism that was formerly germ-free with a fully defined microbial population.
Hydrolyze: To break chemical bonds by hydrolysis. Hydrolysis is the chemical process whereby a compound is broken down into two or more simpler compounds (molecules) by the uptake of a hydrogen (H) atom on one side of the broken bond, and a hydroxyl (OH) group on the other side of the broken bond. Thus, one molecule of water (H2O) is added in the process. Hydrolysis is usually performed by the actions of acids, bases or enzymes.
Oligosaccharide: A sugar chain composed of a small number of monosaccharides (oligos, Greek for “few.”)
There is so much study going on now in the area of health and wellness from a company based in TExas called Mannatech.Mannatech pride themselves on being a world leader in the area of glyconutrients.
Mannatech does not sit still when it comes to research and developing new products. the Probiotic used in this study was provided by Mannatech.
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