Hundreds of products claiming to be probiotic, both foods and dietary supplements, are available in the marketplace today. Consumers are bombarded with information about these products and their potential benefits for human health. A 2011 survey found that 81% of Americans are aware of using probiotics to improve digestive health and 43% of Americans already consume probiotic foods. According to SPINS, a market research company for the natural products industry, consumers spent $1.2 billion on probiotic foods and supplements during the year ending September 2010, an increase of 27% from the previous year.
Probiotics are live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host. Several related terms (prebiotics, postbiotics, and synbiotics) are sometimes confused with probiotics. All four terms are defined in Table 1. Many probiotics have been isolated from the human gastrointestinal (GI) tract, but only those native commensal bacteria that have been shown to have health benefits can be called probiotic. Prebiotics are sometimes called food for bacteria because they stimulate the growth and activity of the probiotic within the human intestinal tract.
Probiotics have been proposed for treatment of a number of medical conditions, including allergic diseases, infections of a variety of types (respiratory, urinary tract infections (UTIs), bacterial vaginosis), and the prevention of dental caries. The most active area of interest and investigation is the use of probiotics to prevent and treat GI disorders. Scientific investigation of the medical uses for probiotics has increased markedly in recent years. It has been estimated that more than 5,000 articles about probiotics have been published in the medical literature in the past decade. Evidence that probiotics are useful for improving gut health and stimulating immune function is now available.
Probiotics are not new products. Live bacteria contained in food products have been known to confer health benefits for centuries. In the early 1900s, immunologist Élie Metchnikoff linked the longevity of Russian peasants to their consumption of fermented milk products containing lactic acid bacteria. He suggested that these beneficial bacteria coated the colon, decreased intestinal pH, and suppressed harmful bacteria. During World War I, a strain of Escherichia coli was isolated from the feces of a soldier who survived an outbreak of shigellosis without developing enterocolitis. The strain was successfully used to treat acute cases of infectious intestinal disease and it is still in use today. The term probiotic, meaning “for life” in Greek, was first used in the 1960s.
How Probiotics Work
The beneficial effects of probiotics are the result of complex, interacting immune mechanisms that are detrimental to intestinal pathogens in the intestinal tract and restore the balance between the good and the bad microorganisms. In addition to variations in mechanism of action, probiotics differ in their ability to withstand gastric acid and to colonize the intestinal tract. It is important to note that probiotic effects are strain specific: For example, there is evidence that Lactobacillus rhamnosus GG can reduce the duration of acute diarrhea in children; however, L rhamnosus GR-1 does not have the same effect. Proposed mechanisms include the following:
•Competition with the pathogen for binding sites on the intestinal wall and for essential nutrients
•Bacteriocidal actions, which may include
◦Lowering intestinal pH through the production of lactic, acetic, and/or propionic acids
◦Production of organic acids, bacteriocins, and hydrogen peroxide
•Immunomodulation, including enhanced phagocytic activity, production of immunoglobulin A, and stimulation of cytokine production
•Strengthening the intestinal barrier by stabilizing tight junctions between epithelial cells, decreasing permeability of the intestinal tract, and increasing production of mucins that form a protective barrier for the intestinal epithelium
•Metabolic mechanisms including:
◦Aiding digestion
◦Synthesizing vitamins
◦Increasing mineral absorption
◦Detoxifying carcinogens
Common Probiotic Organisms
The most commonly used probiotic organisms are the lactic acid-producing bacteria, bifidobacteria and lactobacilli. Bifidobacteria are the most abundant beneficial microorganisms in the large intestine. They are anaerobic, rod-shaped, gram-positive bacteria that produce broad-spectrum antimicrobial activity. Lactobacilli are gram-positive obligate and facultative anaerobes. They are much less abundant in the large intestine than bifidobacteria. Like bifidobacteria, lactobacilli produce a number of antimicrobial products. The yeast, Saccharomyces boulardii, is also used in probiotic products, as are a variety of other bacteria. Common probiotic organisms are listed in Table 2.
Manufacturers of probiotic products promote their products as supporters or regulators of digestive health. To support their claims, there is growing evidence regarding the use of specific probiotic products in the treatment of a variety of GI diseases; in fact, a number of meta-analyses have concluded that probiotics will produce a benefit during the treatment of these diseases. Gathering quality evidence is often difficult because of the inconsistency in testing methods; currently, data have been generated by small trials that are using a variety of probiotic strains and dosing regimens. The variability in study results have caused subsequent reviews to call for additional research to determine the best regimens by using specific probiotic strains in established regimens for specific patient groups.
Treatment of Diarrhea
Probiotics have been studied in a variety of diarrheal illnesses. A systematic review of 63 probiotic studies involving adults and children showed that duration of acute antibiotic-associated diarrhea was shortened by a mean of 25 hours when a probiotic product was added to the regimen. Stool frequency was also reduced. The majority of the probiotics tested were lactic acid bacteria, with two studies using S boulardii. The probiotics were generally used in combination with rehydration therapy.
Systematic reviews of treatment for acute infectious diarrhea, particularly pediatric Rotavirus infection, have concluded that there is an overall decrease in diarrhea duration between 17 and 30 hours. These trials primarily used strains of lactobacillus, most commonly L rhamnosus GG (LGG) and VSL#3 (a mixture of 4 strains of lactobacilli, 3 strains of bifidobacteria, and 1 strain of Streptococcus thermophilus).
Meta-analyses of 12 studies using probiotics for the prevention of travelers’ diarrhea concluded that S boulardii and a combination of Lactobacillus acidophilus and B Bifidum reduced the risk of developing diarrhea. Another review concluded that the reduction in travelers’ diarrhea was 8%. The ability to demonstrate effectiveness in studies investigating the prevention of travelers’ diarrhea has been complicated by the use of different strains of probiotic organisms, as well as the variation in both trip destinations and the organisms to which patients were exposed.
Benefits of probiotics for acute diarrheal illness have been reported in at least one controlled trial for strains of L rhamnosus GG, Lactobacillus reuteri, and the combination of L acidophilus, and Lactobacillus bifidus.
Because the benefits reported are modest and the conditions are generally self-limiting in healthy children and adults, use of probiotics in acute infectious diarrheal illness is reasonable for healthy adults and children within the first 24 to 48 hours of symptoms to decrease the risk, stool frequency, and duration of diarrhea.
Clostridium difficile Infection (CDI)
C difficile can colonize the intestinal tract after normal GI flora are disrupted, often following antibiotic therapy. Patients with recurrent C difficile infection may have markedly diminished intestinal bacteria compared with patients who do not have C difficile. A review of six randomized, controlled trials suggested that S boulardii (3 X 1010 CFUs twice-a-day) in combination with either oral vancomycin or metronidazole, or both drugs, significantly decreased the recurrence of C difficile infection. Other probiotics were not found to be effective. Two other reviews found insufficient evidence to recommend S boulardii as adjunctive therapy to prevent CDI or decrease its recurrence. Based on this evidence, probiotics are not recommended for prevention or primary treatment of C difficile infection in most patients. Treatment with S boulardii may be considered for patients with no significant comorbidities who have recurrent disease.
Irritable Bowel Syndrome (IBS)
IBS is characterized by a group of symptoms, including abdominal pain, flatulence, and bloating. These symptoms have been attributed to possible alterations in the intestinal microbiota and elevated levels of cytokines. A meta-analysis of 16 randomized, controlled trials found methodological problems, including differences in probiotic strain, doses, duration of therapy, and outcomes measured, in many of the trials. Bifidobacterium infantis 35624 was the only probiotic to demonstrate efficacy in two appropriately designed trials. Both global and individual IBS symptoms were significantly improved without an increase in adverse events. B infantis increased the ratio of interleukin 10 to interleukin 12, suggesting an immunologic mechanism by which B infantis is producing a beneficial effect.
Inflammatory Bowel Disease (IBD)
IBD is a group of conditions characterized by inflammation along the GI tract. Symptoms include abdominal cramps, bloody diarrhea, weight loss, and fever. Crohn's disease, ulcerative colitis, and pouchitis are all forms of IBD. An imbalance in the intestinal microbiota may lead to the inflammatory symptoms seen in these diseases. Probiotics are being investigated for use in the treatment of IBD as an alternative to antibiotics, which are currently the mainstay of therapy. When added to standard therapy, probiotics do not provide additional benefit compared with standard therapy alone. Most probiotics tested to date are not more effective than placebo in inducing or maintaining IBD remission.
Pouchitis
Pouchitis is an inflammation in the lining of an intestinal pouch, resulting from surgery for ulcerative colitis. This condition can occur in up to half of patients who undergo the surgery within 5 years. Decreased levels of lactobacilli and bifidobacteria may contribute to the condition. The combination product, VSL#3, has provided the best evidence to date of effectiveness in preventing and treating pouchitis. Several prospective clinical trials using VSL#3 for 9 to 12 months have shown a consistent decrease in the incidence and relapse of pouchitis. One uncontrolled trial involving patients with mild active pouchitis who were treated with VSL#3 showed a remission rate of 69%; while trials investigating treatment with LGG for 3 months failed to show efficacy. A 2010 meta-analysis concluded that VSL#3 is more effective than placebo for preventing the onset and relapse of pouchitis.
Ulcerative Colitis (UC)
Several studies have suggested that probiotics may be effective in the induction and remission of UC. However, most studies have been hampered by the use of different probiotic strains, a short duration of trial, and a small number of patients. Several small trials, all with a short duration of therapy and with a variable standard of care, showed improvement in various measures of disease activity and cytokine profiles. Studies comparing the efficacy of E coli Nissle 1917 with mesalazine found the therapies to be similar in the ability to maintain remission. A Cochrane database systematic review concluded that probiotics when combined with other therapies did not improve remission rates, but showed a reduction in disease activity in mild-to-moderately severe UC. A small study using a 4 week course of S boulardii showed a 68% success rate in achieving clinical remission. In another small trial, a 6-week course of VSL#3 effectively induced remission or produced a response in 77% of patients formerly unresponsive to standard therapies. All of these studies support the idea that specific probiotics may be effective for the short-term treatment of patients with UC.
Crohn’s Disease (CD)
The literature about the use of probiotics as induction therapy, as well as its use as a maintenance therapy during remission, in patients with CD is mixed. Again, methodological problems exist regarding trials, particularly the low numbers of patients involved. Data about the prevention of relapse following surgical intervention failed to show benefit; meta-analyses and systematic reviews have shown that probiotics were ineffective as maintenance therapy during remission for patients with CD.
Lactose Intolerance
Probiotic bacteria may produce lactase that degrades lactose in the intestine and stomach and prevents symptoms of lactose intolerance. Streptococcus thermophilus and Lactobacillus bulgaricus were shown to improve lactose digestion and reduce symptoms related to lactose intolerance in studies using yogurt with live cultures.
Patients with milk allergy or lactose intolerance should check probiotic labels for the presence of lactose or milk products. Some products contain milk protein or lactose and can cause symptoms in lactose intolerant patients.
The effects of probiotics on several other GI disorders are currently under study. These conditions include Helicobacter pylori infection, colon cancer prevention, obesity, and diabetes. To date, study results are variable and too preliminary to draw any reliable conclusions about the benefits of using probiotics.
Future – Additional randomized, controlled trials are needed to determine the most effective strains of probiotics to treat a variety of GI diseases. These investigations may include the following: a determination of optimal doses and the optimal duration of treatment; the use of single versus combination products; and the use of products combining probiotics with prebiotics. There should also be further investigation to determine the safety of probiotics for the treatment of debilitated patients and in patients with compromised gut epithelial integrity. Guidelines have been suggested for evaluating probiotics as a food or as a dietary supplement product. The probiotic must be identified by genus, species, and strain; it should be characterized functionally and a safety assessment should be conducted. Phase I, II, and III human studies should be conducted, including comparisons of probiotic regimens with standard treatment for the proposed use. The following issues should be considered when performing these studies:
•Probiotic species, genus, and strains may have different effects on individuals with different disease states.
•Probiotics may produce metabolites, or postbiotics, that contribute to the probiotic’s action by inducing cytokine secretion. These additional actions should be considered when determining a probiotic’s effectiveness.
•Few studies have documented the survival of a probiotic as it travels through the intestine, which can be done by performing a fecal recovery study. Results from one probiotic strain may not be transferable to other probiotics, even within the same species.
•Method of delivery, such as food product versus supplement tablet, may alter the viability and stability of CFUs. The vehicle for the organism, as well as other components of the preparation, can affect probiotic activity. Studies should be done using the specific dosage form available for purchase by consumers.
•The optimal dose in number of CFUs for each bacterial strain used to treat a specific condition should be determined. Doses used in human trials should be based on doses used in animal studies. Dose–response studies have not been performed for most probiotics.
•Optimal length of probiotic treatment and duration of response are not known for most probiotics. How long it takes for a specific probiotic strain to colonize, alter the microbiota, and impact the immune system determines onset and duration of activity.
•Age of the patient population is relevant. Composition of colonic bacterial microbiota appears to change as patients age, particularly for patients older than 60 years of age.
•Combination probiotic products may interact and have a different cumulative effect on host intestinal flora than single probiotic preparations.
USE OF PROBIOTICS IN INFANTS
There is evidence that human milk contains mononuclear cells that transport intestinally derived bacterial components from the mother to her infant. These bacterial components are thought to influence an infant’s developing immune system through a process called bacterial imprinting. An infant’s early diet and intestinal microbial environment are thought to serve as pivotal factors in overall health. Exposure to nonbeneficial microorganisms and antimicrobial agents in the newborn may result in immune dysregulation and lead to some chronic disease states. Production of secretory IgA, or obtaining it from breast milk, helps to protect the newborn from pathogens during the perinatal period. Addition of probiotic bacteria to formula may stimulate the natural production of IgA. A growing number of studies have evaluated the use of probiotics in children for common conditions, including infectious gastroenteritis. The evidence suggests potential benefit from LGG, L bulgaricus, L acidophilus, S thermophilus and B bifidum. According to the American Academy of Pediatrics, confirmatory well-designed clinical studies supporting the addition of probiotics to powdered infant formulas do not currently exist; therefore, the Academy does not recommend this practice. Addition of prebiotic oligosaccharides to infant formula also lacks evidence of clinical efficacy. However, probiotics, with or without prebiotics, are increasingly being added to infant formulas and other food products marketed for use by children. Two infant formulas currently contain a probiotic; one contains Bifidobacterium lactis and the other contains LGG.
Probiotics should not be given to children who are seriously or chronically ill until the safety of administration has been established; its long-term impact on the gut microbiota of children is currently unknown. It also remains to be established whether there are significant biological benefits to the administration of probiotics during pregnancy.
SAFETY AND ADVERSE EFFECTS OF PROBIOTICS
Probiotics, particularly the lactic acid bacteria, have maintained a good safety record for the last 100 years. As long as the strain has no transferable genes for antibiotic resistance, Lactobacillus and Bifidobacterium are considered very safe. Reports of infection are very rare and those reports have occurred primarily in patients with preexisting infections, dental surgeries, or obstetrical procedures, where the infection is likely to have occurred from native sources. Some species or strains of Streptococcus, Enterococcus, and Escherichia may be pathogenic, so correct identification of the strain being used is essential to maintain the safe use of probiotics.
A few cases of sepsis have occurred in conjunction with the administration of S boulardii. Contamination of intravenous lines may have been a factor in these cases. Another potential risk is the induction of D-lactate acidosis by probiotic bacteria that produce D-lactic acid. While this condition has never been linked to probiotic administration, it has occurred in patients with short-bowel syndrome; therefore, it is recommended to avoid use of probiotics when treating these patients. The unpredictability of immunomodulation in some disease states is a potential issue with the use of probiotics. Worsening of CD in patients taking probiotics has been reported.
Since no formal clinical trials assessing the safety of probiotics are required prior to marketing, the majority of information about safety has been obtained from individual case reports.
In summary, probiotics have been shown to be safe in healthy, immunocompetent patients who receive the product in an outpatient setting. Caution should be exercised when administering probiotics to pregnant women, infants, immunocompromised patients, or patients with chronic diseases because of the lack of information about safety in regard to these populations.
Probiotics are generally well tolerated. The most commonly reported adverse effects are abdominal discomfort, flatulence, and bloating. These effects are more likely to occur during the first week of use of a probiotic and are usually self-limiting.
FORMULATION AND DELIVERY OF PROBIOTIC PRODUCTS
Probiotics are marketed in a wide variety of formulations. The probiotics market in Europe consists primarily of food products including yogurt, fermented milk products, juices and other fortified food and beverage items. These products are sometimes referred to as functional foods. The U.S. probiotic market is primarily dietary supplements rather than food products although food products enriched with probiotics are growing in number and popularity. The following characteristics are considered to be essential when formulating a probiotic product (Table 3):
•Known genus, species, and strain of the product
•Established safety – the organism cannot be pathogenic or carry antibiotic resistance genes and it cannot degrade the intestinal mucosa or conjugate bile acids
•Resistant to degradation by acid or bile and survival in transit through the GI tract to its site of action
•Adherence to mucosa and ability to colonize the intestine for a period of time
•Evidence of health benefit established by scientific studies
•Stability of organism during the manufacturing process and storage prior to sale
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