Nutrition in Clinical Practice

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Nutrition in Clinical Practice http://ncp.sagepub.com

Probiotics for Preventive Health Anil Minocha Nutr Clin Pract 2009; 24; 227 DOI: 10.1177/0884533608331177 The online version of this article can be found at: http://ncp.sagepub.com/cgi/content/abstract/24/2/227

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The American Society for Parenteral & Enteral Nutrition

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Invited Review

Nutrition in Clinical Practice Volume 24 Number 2 April/May 2009 227-241 © 2009 American Society for Parenteral and Enteral Nutrition 10.1177/0884533608331177 http://ncp.sagepub.com hosted at http://online.sagepub.com

Probiotics for Preventive Health Anil Minocha, MD Financial disclosure: none declared. Gut flora and probiotics have potential to affect health and disease far beyond the gut. There is increasing evidence that probiotics have beneficial effects in preventing a wide range of conditions and improving health. Randomized, double-blind studies have provided evidence of the effectiveness of probiotics for preventing various diarrheal illnesses as well as allergic disorders. Evidence for their efficacy for use in the prevention and treatment of bacterial vaginosis and urinary tract infections is also mounting. In addition, probiotics may be useful for preventing respiratory infections, dental caries, necrotizing enterocolitis, and certain aspects of inflammatory bowel disease. Data also suggest that probiotics may promote good health in day care

and work settings, and may enhance growth in healthy as well as ill and malnourished children. Results from meta-analyses and systematic reviews that combine results of studies from different types of probiotics to examine the effects in any disease state should be interpreted with caution. Specific strains are effective in specific disease states. No 2 probiotics are exactly alike; we should not expect reproducible results from studies that employ different species or strains, variable formulations, and diverse dosing schedules. (Nutr Clin Pract. 2009;24:227-241)

oman historian Plinio promoted the use of fermented milk for gastrointestinal (GI) infections. Later, based on his observations of longevity associated with certain Bulgarians consuming fermented products, Metchnikoff hypothesized that fermented products seed the gut with healthy bacteria, suppressing the harmful ones, preventing illness, and healing the body systems. The intestinal microbiota is the largest source of microbial stimulation that has potential for both harmful as well as beneficial impact in human health and sickness. About 60%–80% of immune system components can be found in the gut. Low-level gut inflammation may have far-reaching effects, including and not limited to the brain. As such, attention has been focused on the role of probiotics in boosting immunity to prevent or treat infections, chronic inflammatory diseases, and allergic disorders. Probiotics benefit the host animal by improving intestinal microbial balance and promoting health benefits. Lactobacilli and bifidobacteria are the 2 most common bacteria used. However, not all strains are alike. The effects of any probiotic depend on the particular strain used. Use of each probiotic strain results in a unique pro-

file of cytokines secreted by lymphocytes, enterocytes, or dendritic cells interacting with a particular bacterium. Research suggests that probiotics have a broader spectrum of influence in the body than is commonly considered for these unique substances. This article reviews preventive and health maintenance effects of probiotics; prebiotics are mentioned wherever relevant studies are available.

Keywords:

R

probiotics; prevention; Saccharomyces; Lactobacillus

Boosting Immunity and Preventing Infections Rationale Innate immunity acts as a microbe sensor and represents the first-line defense against assault by invading pathogens. As such, the mucosal lining of the GI tract is able to sense and distinguish between molecular patterns shared by pathogens and nonpathogenic commensal microbes. Any imbalance in the war between good and bad bacteria (eg, a relative reduction in beneficial bacteria or increase in number of pathogenic bacteria in the colon) provides a greater opportunity for pathogenic bacteria to assert themselves and cause disease. The concentration of beneficial bacteria can be boosted by probiotic supplementation and potentially fight off infections. Numerous animal studies have documented the immune-boosting properties of probiotics. For example, McVay et al1 demonstrated that formula acidified with live Lactococcus lactis formula provided superior protection

From the Louisiana State University Health Sciences Center and VA Medical Center, Shreveport, Louisiana. Address correspondence to Anil Minocha, MD, VA Medical Center, Medical Service, 510 E. Stoner Ave, Shreveport, LA 71101; e-mail: [email protected]

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against pulmonary and GI bacterial colonization as well as translocation in rabbits. However, the immune modulatory responses of probiotics in healthy or sick persons depend on the probiotic strain used. Certain probiotics may elicit a faster immune response to vaccinations and, as such, may be useful as adjuvants to the humoral immune response following oral vaccination.2

Preventing Infections in Day Care Facilities Breastfed infants develop a probiotic-rich intestinal microbiota compared with the GI microbiota of formulafed infants. When children attending child care centers take probiotics, it reduces infections, suggesting that probiotics impede the spread of infections.3,4 Weizman et al3 investigated the effect of 2 different probiotics in preventing infections in infants attending child care centers in a multicenter, double-blind, placebo-controlled, randomized trial. Healthy, term infants 4–10 months old (n = 201) were recruited and received formula supplemented with Bifidobacterium lactis (BB-12), Lactobacillus reuteri, or no probiotics for 12 weeks. The mean daily formula volume consumed was similar in the 3 groups. The controls, compared with those fed B. lactis or L. reuteri, suffered significantly more mean febrile (0.41 [confidence interval (CI) 0.28-0.54] vs 0.27 [CI 0.17-0.37] vs 0.11 [CI 0.04-0.18]) and diarrheal episodes (0.31 [CI 0.22-0.40] vs 0.13 [CI 0.05-0.21] vs 0.02 [CI 0.010.05]). The L. reuteri group displayed superior results compared with both B. lactis and controls with regard to the number of days with fever, clinic visits, child care absences, and antibiotic prescriptions. However, there was no impact of probiotics on the frequency or duration of respiratory illnesses. Another randomized, controlled trial4 examined the efficacy of a milk product containing probiotics and prebiotics (CUPDAY milk) in healthy children 1–3 years old (n = 496) attending day care centers over 5 months. Treatment was undertaken for 41,745 child-days. The authors found that the children consuming the CUPDAY drink had a 20% reduction in the number of diarrheal days of 4 or more stools per day.

Preventing Infections in the Elderly Aging is generally associated with impaired immunity and greater predisposition to infections. A controlled pilot study (n = 360) examined the effect of supplementation with milk fermented with yogurt cultures and Lactobacillus casei DN-114001 over a period of 3 weeks. Although there was no difference in the incidence of infections during the winter between groups, the duration of all pathologies was significantly lower in the treatment

than in the control group (7.0 ± 3.2 days vs 8.7 ± 3.7 days; P = .024), as was maximal temperature (38.3 ± 0.5°C treatment group vs 38.5 ± 0.6°C control; P = .01). The authors concluded that there was potential for a 20% reduction in the duration of winter infections in the elderly as a result of probiotic therapy.5 Fukushima et al6 conducted a double-blind feeding trial to elucidate the effect of fermented milk containing Lactobacillus johnsonii La1 on infections and nutrition status in 24 enterally-fed elderly inpatients aged over 70 years. All participants were administered 900 kcal/d of enteral nutrition (EN) for 12 weeks. For 12 weeks, participants in the probiotic group were administered 89 kcal/d of probiotic-fermented milk after feeding of 811 kcal/d of EN. In the control group, 89 kcal/d was replaced from the fermented milk. In the probiotic group, the percentage of days with infections during the run-in observation period was 15.4% (SD 17.3), which significantly decreased to 5.7% (SD 8.1) during the intervention period (P = .018); the reduction was larger than that of the control group (P = .047). There was a significant increase in blood hemoglobin and a trend toward an increase in serum albumin concentration accompanied by a decline in proinflammatory cytokines in the probiotic group. The authors concluded that L. johnsonii La1 may help suppress infections by improving nutrition and immunological status in the elderly.

Preventing Infections in Healthy Adults Regular intake of probiotics can reduce potentially pathogenic bacteria in the upper respiratory tract, suggesting a linkage of the lymphoid tissue between the gut and the upper respiratory tract.7 de Vrese et al8 conducted a randomized, double-blind, placebo-controlled trial to examine if the consumption of Lactobacillus gasseri PA 16/8, Bifidobacterium longum SP 07/3, and Bifidobacterium bifidum MF 20/5 (5 × 107 colony-forming units [CFU]/tablet) affected the severity of symptoms as well as the incidence and duration of the common cold during 3 winter months in healthy adults (ages 18-67 years; n = 479). The study was conducted over 2 winter/spring periods. Participants received daily vitamins and minerals with or without the probiotic bacteria. The total symptom score (79.3 ± 7.4 vs 102.5 ± 12.2 points, P = .056), the duration of common cold episodes (7.0 ± 0.5 vs 8.9 ± 1.0 days, P = .045), and days with fever during an episode (0.24 ± 0.1 vs 1.0 ± 0.3 days, P = .017) were lower in the probiotic-treated vs control group. This was accompanied by a significantly greater enhancement of cytotoxic plus T suppressor cells and T helper cells in the probiotic-treated group vs the control group. Thus, the ingestion of probiotic bacteria significantly shortened common cold episodes by almost 2 days and reduced the severity of symptoms.

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Health and sickness at the workplace directly affect the economy and thus the socioeconomic fabric of the society. A randomized, controlled trial examined the effect of Lactobacillus reuteri protectis on its ability to improve workplace health.9 Healthy participants (n = 181) were randomized to receive either a daily dose of a probiotic of 108 CFU of L. reuteri or placebo for 80 days. Compared with the control group, fewer participants from the probiotic group needed sick leave for defined causes (11% vs 26%; P < .01). In addition, the frequency of sick days was also significantly lower in the probiotic vs control group (0.4% vs 0.9%; P < .01). The differences were even more pronounced among the 53 shift workers, where 33% in the placebo group reported sick during the study period compared with none in the L. reuteri group (P < .005). Heavy exercise has been associated with an increased risk of upper respiratory tract infections as well as bowel symptoms. Tiollier et al10 examined the effect of probiotic supplementation on a group of French commandos in a double-blind, randomized, controlled trial. Cadets received 300 mL per day of either a probiotic (milk fermented by yogurt cultures and with L. casei strain DN-1 14 00 1) or nonfermented milk as placebo supplementation during the study period (3-week training followed by a 5-day combat course). Although the probiotic administration did not have any impact on respiratory tract infections, there was a greater increase in dehydroepiandrostane sulfate in the probiotics group, leading authors to suggest that the benefits of probiotic supplementation in a multistressor environment rely mainly on its capacity to prevent the infection from spreading throughout the respiratory tract. Another randomized, double-blind study investigated the effect of Lactobacillus rhamnosus GG (LGG) on marathon runners (n = 141) over a 3-month training period.11 Although LGG had no effect on the incidence of respiratory infections or GI symptom episodes, it seemed to shorten the duration of GI symptom episodes (1.0 vs 2.3 days; P < .05) following the marathon.

Preventing Infections After Vaccinations Gut flora support and stimulate the immune system and, as such, probiotics have potential to enhance the effectiveness of vaccinations. Olivares et al12 studied the coadjuvant capability of oral consumption of Lactobacillus fermentum for an anti-influenza vaccine in a randomized, double-blinded, placebo-controlled fashion in 50 human volunteers. Volunteers received an oral daily dose of methylcellulose (placebo) or probiotic bacteria (1 × 1010 CFU/d) 2 weeks before vaccination and 2 weeks after vaccination. The authors found a significant increase in the proportion of natural killer cells in the probiotic group

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but not in the placebo group. The vaccination induced an increase in cytokines in both groups, although the probiotic group showed a significantly higher induction in many of these parameters. In addition, the probiotic group demonstrated a significant increase in antigen-specific immunoglobulin A. More noteworthy was the fact that the incidence of an influenza-like illness during the 5 months after vaccination was significantly reduced in the probiotic group, suggesting that oral administration of L. fermentum potentiates the immunologic response of an anti-influenza vaccine and may provide enhanced systemic protection from infection by increasing the T helper type 1 response and virus-neutralizing antibodies.

Preventing Recurrent Otitis Media in Kids Studies suggest that children with recurrent acute otitis media have significantly lower quantities of α-hemolytic streptococci (AHS) in the nasopharynx than healthy children. Tano et al13 performed a randomized, placebo-controlled, double-blind clinical study to determine whether a nasal spray containing AHS could be an alternative to tympanostomy tube insertion. Children younger than 4 years of age (n = 36; 16 probiotic and 20 control) were included in the study. The result showed no significant differences regarding the number of recurrences (7/16 vs 8/20) of acute otitis media, and there were no significant changes in the nasopharyngeal flora. Another double-blind, placebo-controlled, randomized trial studied the effect of ingesting 1 probiotic capsule (LGG and LC705, Bifidobacterium breve 99, and Propionibacterium freudenreichii JS) or placebo daily for 24 weeks by otitis-prone children (n = 309).14 Probiotic treatment did not reduce the occurrence (72% vs 65%, P = NS) or the recurrence (3) of acute otitis media episodes (18% vs 17%, P = NS). The median duration of acute otitis media episodes was also similar (5.6 vs 6.0; P = NS). However, there was a trend toward a reduction in recurrent (4-6) upper respiratory infections (URIs) in the probiotic group (OR for 4 URIs: 0.56, 95% CI: 0.31-0.99, P = .046; OR for 6 URIs: 0.59, 95% CI 0.34-1.03, P = NS). In contrast to the above, beneficial results of probiotic use have been reported in children with secretory otitis media characterized by persistent fluid in the middle ear cavity of unknown etiology. Skovbjerg et al15 conducted a double-blind, randomized, controlled study in 60 children with longstanding secretory otitis media. Children scheduled for insertion of tympanostomy tubes were randomized to nasal spray treatment with Streptococcus sanguinis, L. rhamnosus, or placebo for 10 days before surgery. Complete or significant clinical recovery occurred in 7/19 patients treated with S. sanguinis compared to 1/17 patients in the placebo group (P < .05).

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Preventing Urinary Tract Infections Data suggest a promising role for probiotics for preventing urinary tract infections (UTIs) in patients with neurogenic bladders. Bacterial inoculation of the bladder with probiotics can result in secretion of substances that inhibit or kill pathogens, blockage of the binding sites on uroepithelium, and alterations in the nutrient/pH environment in the bladder. Darouiche et al16 examined the role of the topical use of probiotics in patients (n = 27) with a neurogenic bladder in a double-blind, placebo-controlled trial. After inserting a new catheter and emptying the bladder, 30 mL of 106 CFU/mL of a probiotic (Escherichia coli 83972) or normal saline was instilled into the bladder and allowed to dwell for 2 hours. Inoculation was done twice daily for 3 days. Urine samples were obtained 1 week after the inoculation and then every month for a period of 1 year. Local instillation of the benign strain of E. coli into the bladder resulted in decreased rates of recurrent UTIs (mean 1.6 episodes in the probiotic group vs 3.5 episodes in the control group; P = .036), especially in those in whom the bladder was successfully colonized with the probiotic bacteria. Another study17 examined urinary catheters coated with a probiotic (E. coli HU2117) in patients with neurogenic bladders (n = 12) requiring indwelling urinary catheters as a means to establish asymptomatic colonization. After completion of 1 week of antibiotic therapy, a urinary catheter that had been incubated in broth with E. coli HU2117 for 48 hours was inserted. Eighty-three percent were successfully colonized with E. coli HU2117 for 14 days or more after inoculation by insertion of a study catheter, the median being 48.5 days. All participants remained colonized with other species while colonized with E. coli HU2117. Symptomatic UTI appeared in only 1 patient during a total of 648 patient days of colonization. Thus, the rate of symptomatic UTI was reduced to 0.15 cases per 100 patient days, as compared to published mean rates of 2.72 cases per 100 patient days in such patients.

Preventing Vulvovaginal Infections Hilton et al18 conducted a crossover trial over 1 year to examine the effect of daily ingestion of yogurt containing Lactobacillus acidophilus for prevention of vulvovaginal candidal infections. Participants (n = 13) received 8 oz of yogurt-free or a yogurt-containing diet for 6 months each. Consumption of yogurt containing L. acidophilus resulted in a 3-fold reduction in infections. The mean number of infections per 6 months was 2.54 ± 1.66 in the control period compared with 0.38 ± 0.51 per 6 months in the yogurt period (P < .01). This was associated with a decline in candidal colonization, with a mean number of infections of 3.23 ± 2.17 per 6 months in the

control period to 0.84 ± 0.90 per 6 months in the yogurt period (P < .01).

Preventing Infections During Infancy Ortiz-Andrellucchi et al19 conducted a double-blind, randomized, controlled trial to determine if probiotic intake would modulate the immune system in women (n = 124) who had recently delivered and were breastfeeding. The probiotic treatment (L. casei) was administered for 6 weeks after birth, and the infants were followed for first 6 months of their lives. Probiotic treatment resulted in a significant increase in natural killer cells and a nonsignificant increase in T and B lymphocytes. This was accompanied by a decrease in the proinflammatory cytokine tumor necrosis factor α (TNF-α) in maternal milk as well as fewer GI disturbances in the breastfed child of the mothers who consumed probiotic. On the other hand, administration of prebiotics GOS/lcFOS (3 times daily; 3 g GOS/lcFOS at a ratio of 9:1 or maltodextrin as placebo from week 25 of gestation until delivery) to women during pregnancy resulted in increased proportions of bifidobacteria in the maternal gut, without any impact on the neonate intestinal flora or immune parameters.20

Preventing Infections in Children at Risk for Allergies A randomized, placebo-controlled, double-blind trial examined the effect of feeding a synbiotic mixture of 4 probiotic species (LGG and LC705, B. breve Bb99, and P. freudenreichii ssp shermanii) plus 0.8 g of galactooligosaccharides to moms pregnant with infants at high risk of allergies.21 The moms were given the synbiotic during the last 4 weeks of pregnancy, and then the newborns continued to receive the same for a period of 6 months. In total, 925 infants completed the 2-year follow-up. During the 6 months of synbiotic consumption, antibiotics were prescribed less often in the synbiotic group than in the placebo group (23% vs 28%). Throughout the 2-year period, respiratory infections occurred less frequently in the synbiotic vs control group (geometric mean: 3.7 vs 4.2 infections). Authors concluded that feeding synbiotics to newborn infants is safe and increases resistance to respiratory infections during the first 2 years of life.21

Preventing Infections in Patients With Abdominal Surgeries Several randomized, controlled trials have demonstrated the positive effect of probiotics in preventing postoperative infections after major abdominal surgeries22,23 and

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liver transplantation.24 A recent prospective, randomized, double-blind trial in 80 patients following pyloruspreserving pancreatoduodenectomy23 studied the effect of enteral formula composed of 4 lactobacilli and 4 fibers (1010 Pediacoccus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei subspecies paracasei F19, and Lactobacillus plantarum 2362 plus 4 bioactive fibers: 2.5 g of each betaglucan, inulin, pectin, and resistant starch for a total of 10 g per dose or 20 g per day) administered twice daily. The control group received enteral formula containing the fibers only. The treatment started 1 day preoperatively and continued during the first 8 days after surgery. The results showed that the probiotic plus fiber group had a lower incidence of postoperative bacterial infections (12.5%) than with fibers only (40%). This was associated with a shorter duration of antibiotic therapy. Another similar prospective, randomized, doubleblind trial in 66 liver transplant recipients24 demonstrated that the combination of 4 probiotics and fiber for 14 days resulted in a lower incidence of postoperative bacterial infections (3%) compared with a 48% rate of infection with the fibers-only group. This was also associated with a reduced duration of antibiotic therapy in the probiotic group.

Preventing Infections in Patients With Severe Pancreatitis Studies examining the role of probiotics in preventing infections in patients with severe pancreatitis have yielded mixed results.25 Initially, several studies demonstrating a beneficial effect of probiotics in preventing complications in severe pancreatitis led to a great deal of excitement.26,27 However, a recent multicenter, randomized, double-blind, placebo-controlled trial found that the use of multispecies probiotic preparation did not reduce the risk of infections; rather, probiotic prophylaxis was associated with a more than 2-fold increase (16% vs 6%) in mortality.28 Nine patients in the probiotics group developed bowel ischemia (8 with fatal outcome) compared with none in the placebo group (P < .01). In addition, a recent meta-analysis by Sun et al29 concluded that enteral feeding with probiotic does not reduce the infected necrosis and mortality in severe pancreatitis.

Preventing Helicobacter pylori Infections Long-term intake of probiotics may have a favorable effect on Helicobacter pylori infection in humans, thus reducing the risk of gastritis and potentially functional dyspepsia, peptic ulcer disease, and gastric malignancy. A recent epidemiologic study documented a protective effect of yogurt consumption on the prevalence of

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H. pylori infection.30 Furthermore, multiple studies have documented that probiotic therapy reduces the side effects induced by anti–H. pylori therapy.31-33

Preventing Infections in Hospitals Studies on the use of probiotics in medical, surgical, and pediatric intensive care units for prevention of infections and improvement in outcomes have yielded mixed results. Recently, McNabb and Isakow34 reviewed the current evidence for probiotics in preventing nosocomial infections, particularly pneumonia, in a diverse population of critically ill patients. They concluded that currently there are insufficient data to determine whether probiotics are beneficial in the prevention of nosocomial infections, particularly nosocomial pneumonia. A related article by Koretz in this issue evaluates the use of probiotics in critically ill patients.

Preventing Necrotizing Enterocolitis The pathogenesis of necrotizing enterocolitis (NEC) remains to be established, although infections have been implicated as a factor, and broad-spectrum antibiotics are used as part of management of the infections. A recent Cochrane review concluded that enteral supplementation of probiotics reduces the risk of severe NEC and mortality in preterm infants; this supports a change in practice in premature infants greater than 1000 g at birth.35 The topic of probiotics in pediatric patients was discussed in more detail in an article by Wallace in the previous issue of this journal.36

Conclusion Although many studies on the use of probiotics to boost immunity and fight infections appear convincing, making a sweeping call in favor of any particular individual or probiotic combination is difficult. Regarding the use of single probiotics, L. casei and L. reuteri appear to be promising. There is a paucity of direct evidence demonstrating a benefit of prebiotics for boosting immunity and fighting infections; use of FOS/GOS and/or inulin holds the most promise.

Preventing Allergic Disorders Rationale The composition of the intestinal microflora may be different in patients with allergic diseases compared with the flora of healthy controls; in fact, such differences may precede the development of allergies. Probiotics differentially

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modulate peripheral immune parameters in healthy participants and patients with allergic disorders such as atopic dermatitis.37 There can be beneficial interactions between the intestinal immune system and specific bacterial probiotic strains. An altered microbial exposure may be at least in part responsible for an increase of allergic diseases in affluent societies. Probiotics have the potential to shift the balance toward normalization and, as such, may prevent or aid in healing such conditions.

Preventing Food Allergies The interest in modulating commensal bacterial flora with prebiotics and probiotics to prevent and treat food allergy has multiplied in recent years. Modulation of commensal bacteria of the gut with probiotics has been shown to modulate the immune system and positively affect both the prevention and treatment of food allergy.38 The effects have been highly variable depending on the mode of treatment, and even though the literature is promising, the optimal treatment remains to be established.

Preventing Sensitization and Atopic Dermatitis Huurre et al39 demonstrated that infants of atopic mothers, specifically when breastfed exclusively over 2.5 months or totally over 6 months, had a higher risk of sensitization at the age of 12 months and that this risk could be reduced by the use of probiotics during pregnancy and lactation, partly by resulting in a beneficial composition of the breast milk. Supplementation of L. casei and B. lactis to hydrolyzed formula does not accelerate cow’s milk tolerance in patients with cow’s milk allergy.40 Perinatal administration of the probiotic LGG (ATCC 53103) has been shown to reduce the incidence of atopic eczema in at-risk children during the first 2–4 years of life without any impact of the probiotic on skin prick test reactivity.41 Investigators42 recently extended the results of their previous study from a 4-year to 7-year follow-up. The authors found that the cumulative risk for developing eczema during the first 7 years of life was significantly lower in the LGG group than in the placebo group (42.6% vs 66.1%; relative risk [RR] = 0.64; 95% CI: 0.45-0.92). In contrast to the above studies, Kopp et al43 conducted a double-blind, placebo-controlled, prospective trial and reported that supplementation with LGG during pregnancy and early infancy neither reduced the incidence of atopic dermatitis nor altered the severity of atopic dermatitis in affected children but was associated with an increased rate of recurrent episodes of wheezing bronchitis. Conversely, a double-blind, randomized, placebocontrolled trial by Abrahamsson et al44 found that when mothers received L. reuteri daily from gestational week 36

until delivery, and then the babies continued with the same product from birth until 12 months of age, there were less incidences of IgE-associated eczema in the treatment vs control group during the second year (8% vs 20%).44 This suggests that the treated infants possibly run a reduced risk of developing later respiratory allergic disease. Although a meta-analysis of 5 studies reporting the outcomes of 1477 infants found a significant reduction in infant eczema associated with probiotic ingestion (typical RR = 0.82, 95% CI: 0.70, 0.95), a recent Cochrane review concluded that there is insufficient evidence to recommend the addition of probiotics to infant feeds for preventing allergic disease or food hypersensitivity.45 Recently, Lee et al46 conducted a meta-analysis on studies examining the prenatal and postnatal probiotic supplementation for the prevention and treatment of pediatric atopic dermatitis. The authors concluded that current evidence is more convincing for probiotics’ efficacy in prevention than treatment of pediatric atopic dermatitis. In contrast, Betsi et al47 concluded that more randomized controlled trials (RCTs) are needed to determine whether probiotics are useful for the treatment or prevention of atopic dermatitis. The composition of flora can be altered not just by probiotics but also by prebiotics for beneficial results. Arslanoglu et al48 demonstrated that early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first 2 years of life. Compared with infants in a control group, infants receiving prebiotics had significantly fewer episodes of overall infections, URIS, and fever as well as fewer antibiotic prescriptions.

Preventing Allergic Rhinitis Studies examining the role of probiotics in allergic rhinitis have yielded promising results.49,50 In one study, administration of L. casei Shirota (LcS) in participants with allergic rhinitis49 resulted in a significant reduction in antigen-induced interleukin (IL)-5, IL-6, and interferon gamma (IFN-γ) production associated with an increase in specific immunoglobulis G (IgG) and a decrease in IgE levels. This probiotic-induced immunomodulation in allergic rhinitis may have the potential to alleviate symptoms. In a separate randomized, double-blind, placebocontrolled study in patients with allergic rhinitis triggered by Japanese cedar pollen, researchers found that although the ingestion of fermented milk containing LcS for 8 weeks did not affect nasal and ocular symptoms, the subgroup of patients with moderate to severe nasal symptom scores showed reduced nasal symptoms.50 Another randomized, prospective, double-blind, controlled trial to examine the effect of long-term consumption

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of L. casei on the health status of children suffering from allergic asthma and/or rhinitis51 found that although the probiotic did not affect outcome measures in the kids with asthma, the annual number and duration of rhinitis episodes were significantly reduced.

Conclusion The results of studies on the use of probiotics for allergic disorders provide a mixed picture, and different expert reviews/meta-analyses have come to different conclusions varying from “insufficient evidence” to “positive evidence.” The above notwithstanding, there is potential for interactions between probiotic and nutrition intake. L. casei, L. reuteri, and LGG (ATCC 53103) show promise for primary prevention of allergic disorders. Increased intakes of retinol, calcium, and zinc, with perinatal administration of probiotics, reduce the risk of atopic eczema, whereas an increase in the intake of ascorbic acid increases the likelihood of atopic eczema.52 As such, the cumulative impact of nutrients and probiotics must be considered in active prevention and management strategies for allergic diseases.

Enhancing Growth and Development Rationale The GI tract is the locus of not only nutrient digestion and absorption but also the GI flora and gut immune system that, in turn, affects systemic immune status. Infants and children who suffer fewer infections, feeding intolerances and colics,53 orodental sickness, and allergies during the formative years are more likely to grow and develop fully than their sicker counterparts. Probiotics indirectly (by enhancing the immunity and preventing allergies and chronic inflammatory states) may enhance the potential for growth.

Clinical Studies Saran et al54 conducted a controlled trial to investigate the effect of probiotic supplementation on morbidity and growth of poor children with growth retardation. The experimental group received yogurt containing L. acidophilus, whereas the control group received an isocaloric supplement daily for 6 months. There was a significant increase in weight and height in the probiotic group compared with the control group; this was associated with fewer cases of diarrhea and fever. This finding suggests that failure to thrive occurs, at least in part, as a result of damage to the GI epithelium during repeated episodes of GI infections. Probiotic-induced healing of the damaged gut epithelium may counter the deleterious effects and promote growth.

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Another randomized, controlled trial found that yogurt supplementation decreased the incidence and duration of upper respiratory infection and diarrhea in preschool children; this was accompanied by enhanced growth and development in the yogurt-supplemented vs control group.55 The results of the 2 above-mentioned studies were confirmed in a double-blind, RCT demonstrating that the children receiving LGG-supplemented formula had superior changes in their length and weight compared with those receiving regular formula.56 In addition, the LGG group also had a significantly higher defecation frequency, and more frequent colonization with lactobacilli compared with the control group. In contrast to the above studies, a double-blind RCT57 reported that infants fed formulas containing probiotics (B. longum, L. rhamnosus) or synbiotics (probiotics plus galactooligosaccharide and short-chain fructooligosaccharide) showed a similar rate of weight gain compared with those fed the control formula. Similar lack of effect of probiotics on growth and metabolism was seen in human immunodeficiency virus (HIV)negative infants of HIV-infected mothers in a double-blinded RCT.58 Indrio et al59 randomly assigned 30 preterm newborns in a double-blind manner to receive either L. reuteri or placebo for 30 days. The authors found that although weight gains per day were similar, newborns receiving probiotics showed a significant decrease in regurgitation and mean daily crying time and a larger number of stools compared with the newborns in the placebo group.

Conclusion Data about the use of probiotics for enhancing growth and development, although promising, are too preliminary to make specific recommendations.

Preventing Recurrences in Inflammatory Bowel Disease Rationale Intestinal bacteria play an important role in the pathogenesis of inflammatory bowel disease (IBD).60 Mucosaassociated microbiota of patients with active colitis differs from that of non-IBD controls. Bacterial patterns are also different between the active and inactive phases in the identical patients.61 Probiotics have the potential to alter the intestinal flora in favor of beneficial bacteria, thus affecting the immune and inflammatory response. The mechanisms may include enhancing epithelial barrier function, modulating epithelial cytokine secretion into an anti-inflammatory dominant profile, altering mucus

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Table 1. Disorder

Evidence for Probiotics in Preventing Orodental Disorders Probiotic

Study Design

Results

Dental caries

Lactobacillus reuteri lozenge (1.1 × 108 CFU) once daily for 10 days

Dental caries

Bifidobacterium lactis Bb-12 in ice cream; 100 mL (53 g) once daily L. reuteri ATCC 55730 once daily as tablets or through straw for 3 weeks

Randomized, double-blind, placebo-controlled study (n = 20 women) Double-blind, randomized crossover study (n = 24) Placebo-controlled study design with parallel arms (n = 120)

Dental caries (Caglar et al83)

Bifidobacterium DN-173 010 in 200 g yogurt once daily

Double-blind, randomized crossover study (n = 21)

Gingivitis and plaque (Krasse et al84)

L. reuteri formulations (LR-1 or LR-2) at a dose of 2 × 108 CFU per day for 2 weeks Streptococcus salivarius K12 or placebo lozenges × 1 week

Randomized, placebo-controlled, double-blind study (n = 59) Placebo-controlled study (n = 23)

Dental caries (Caglar et al82)

Halitosis (Burton et al85)

Significant reduction in salivary Streptococcus mutans levels (P < .05) Significant reduction in salivary S. mutans levels (P < .05) Significant reduction of the S. mutans levels after ingestion of the probiotic bacteria via the straw (P < .05) and the tablets (P < .01) Significant reduction of salivary S. mutans after the probiotic yogurt consumption Significant reduction in gingival and plaque index 85% of the K12-treated group and 30% of the placebo group had substantial (>100 ppb) reductions of volatile sulfur compound

ppb, parts per billion.

production, changing bacterial luminal flora, modifying the innate and systemic immune system, and inducing regulatory T cell effects.62

Preventing Recurrences in Ulcerative Colitis Zigra et al63 performed a systematic review of clinical trials comparing the effect of probiotics with the effect of anti-inflammatory treatment or placebo in the remission of ulcerative colitis (UC). Nine studies met the inclusion criteria. The authors concluded that there are a limited number of randomized trials published in the field of probiotics used for the remission of UC, and the existing studies suggest a similar safety and efficacy of probiotics compared with anti-inflammatory drugs.

Preventing Acute Pouchitis Although studies on the effect of probiotics for treatment of acute pouchitis have been mixed, multiple studies have documented a beneficial effect of probiotics (especially VSL#3; VSL Pharmaceuticals, Gaithersburg, MD) in preventing pouchitis. Elahi et al64 performed a meta-analysis of current evidence on the effect of probiotics in preventing pouchitis after restorative ileal pouch anal anastomosis. Five randomized, placebo-controlled clinical trials were included in the meta-analysis, yielding an odds ratio of 0.04 (95% CI: 0.01-0.14) in favor of the treatment group.

Conclusions Probiotics (especially VSL#3) are effective for preventing pouchitis. Although probiotics are probably helpful in preventing recurrences of UC (E. coli Nissle 1917), they do not appear to have any role in Crohn’s disease.

Preventing Diarrhea Rationale Probiotics play an important role in preventing diarrhea. Prevention of infectious diarrhea such as traveler’s diarrhea can potentially prevent irritable bowel syndrome because many of these cases are preceded by GI illness. The underlying mechanism appears to be impact on intestinal permeability. Issues related to preventing antibiotic-induced diarrhea65 and recurrent Clostridium difficile colitis66 were discussed in the previous issue.67,68

Preventing Acute Diarrhea Sazawal et al69 performed a meta-analysis to evaluate the evidence for the use of probiotics in the prevention of acute diarrhea. The meta-analysis included 34 masked, randomized, placebo-controlled trials. The authors concluded that probiotics significantly reduced the risk of antibiotic-associated diarrhea, traveler’s diarrhea, and acute diarrhea of diverse causes. Probiotics reduced the

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Table 2.

235

Probiotics for Improving Immunity in Immunocompromised Patients Design and #

Variable studied

Outcome

Children 2-12 years of age with HIV (n = 77) (Trois et al89)

Double-blind randomized controlled trial (RCT) for 2 months

Probiotics resulted in significant increase in CD4 counts [+118 cells mm3 vs –42 cells mm3; P < .05).

Women 18-44 years of age with HIV (n = 24) (Anukam et al90)

Controlled prospective study; patients consumed 100 mL of conventional or supplemented yogurt per day × 15 days

Children with cystic fibrosis (n = 30), healthy controls (n = 30), and inflammatory bowel disease patients (n = 15) (Bruzzese et al91) Children with cystic fibrosis (n = 19) (Bruzzese et al92)

Controlled, prospective study

Formula containing Bifidobacterium bifidum with Streptococcus thermophilus–2.5 × 1010 CFU Conventional yogurt fermented with Lactobacillus delbruekii var bulgaricus and S. thermophilus was supplemented with probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14. Lactobacillus GG (LGG)

A prospective, randomized, placebo-controlled, crossover study × 1 year

LGG or oral hydration solution for 6 months

Alcoholic cirrhosis (n = 12) and healthy participants (n = 13) (Stadlbauer et al93)

Open-labeled trial × 4 weeks

Lactobacillus casei Shirota (6.5 × 109 CFU) 3 times daily

Patients

Mean CD4 cell count remained the same or increased in 11/12 probiotic-treated patients compared with 3/12 in the control group. Diarrhea resolved in 100% of probiotics vs 17% of controls.

Calprotectin and nitric oxide concentrations were reduced after probiotic administration, suggesting that intestinal inflammation in cystic fibrosis is reduced by probiotics. LGG treatment showed a reduction of pulmonary exacerbations (median 1 vs 2; P < .01) and of hospital admissions (median 0 vs 1; P < .01). LGG also resulted in a greater increase in FEV1 (3.6% ± 5.2% vs 0.9% ± 5%; P = .02) and body weight (1.5 ± 1.8 kg vs 0.7 ± 1.8 kg; P = .02). Neutrophil phagocytic capacity normalized in 100% of patients (P < .05). This was associated with significant lowering of endotoxinstimulated levels of sTNFR1, sTNFR2, and IL-10 (P < .05).

CFU, colony forming units; HIV, human immunodeficiency virus; IL, interleukin; RCT, randomized, controlled trial; STNFR, soluble tumor necrosis factor-receptor

associated risk of acute diarrhea among children by 57% (35%-71%) and by 26% (7%-49%) among adults. The protective effect did not vary significantly among the probiotic strains Saccharomyces boulardii, LGG, L. acidophilus, Lactobacillus bulgaricus, and other strains used alone or in combinations of 2 or more strains. Probiotics for acute infectious diarrhea in children seem to be especially helpful for treating watery diarrhea and viral gastroenteritis; however, data are nonexistent for benefits of probiotics with invasive, bacterial diarrhea. Szajewska and Mrukowicz70 concluded that randomized, controlled trials provide evidence of a very modest effect

of some probiotic strains (LGG, L. reuteri, B. lactis) on the prevention of community-acquired diarrhea.

Preventing Traveler’s Diarrhea Traveler’s diarrhea occurs in 5%–50% of travelers depending on the destination. Despite several decades of research providing information about the etiology and pathogenesis of the disease, the rate of illness and consequences remain unchanged. McFarland71 recently published the results of a meta-analysis on the role of probiotics for the prevention of traveler’s diarrhea. Twelve

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Table 3.

Potential Uses of Probiotics for Disease Prevention

Disorder

Rationale

Studies

Cardiovascular disease

May lower cholesterol

Infantile colic Musculoskeletal disorders

Affect GI motility Impact on mineral absorption, metabolism, bone composition, and architecture Better recovery from fatigue and immune enhancement Alteration of intestinal microflora Improving nutrient absorption

Fatigue in athletes Hepatic diseases Malnutrition in lactose intolerance Aging processes Restless leg syndrome

Obesity

Maniac depressive disorder

Attention-deficit hyperactivity disorder (ADHD) HIV and sexually transmitted diseases

Inhibiting immunosenescence and lowering chronic inflammation Inhibiting small bowel bacterial overgrowth, which may be a common denominator in chronic pain syndromes Intestinal flora vary in ability for nutrient extraction, and probiotics alter the “obese microbiota” to “lean” Altered intestinal microflora to affect proinflammatory cytokines, oxidative stress, and improved nutrition ADHD may be an allergic disorder, and probiotics may prevent allergy Genital mucosa serves as the main port of entry for infection. Probiotics may prevent HIV and sexually transmitted infections in women by treating and preventing recurrent bacterial vaginosis, or directly by secreting endogenous (eg, hydrogen peroxide) and exogenous substances that block infections.

Bouhnik et al,94 Greany et al,95,96 Kekkonen et al,97 Xiao et al98 Savino et al,53 Indrio et al59 Scholz-Ahrens et al109 Hatakka et al110 Nichols112 Ewaschuk et al,112 Gerbitz et al113 Parra and Martínez de Morentin,116 Parra and Martínez117 Guigoz et al,118 Candore et al,119 Schiffrin et al120 Weinstock et al121

DiBaise et al115

Logan and Katzman122

Pelsser et al123 Bolton et al89

HIV, human immunodeficiency virus

of 940 screened studies met the inclusion and exclusion criteria. The results indicated a significant reduction in relative risk, suggesting that probiotics significantly prevent traveler’s diarrhea. He concluded that several probiotics (S. boulardii and a mixture of L. acidophilus and B. bifidum) are effective for this indication.

Preventing Radiation-Induced Diarrhea Radiation enteritis is difficult to manage, and optimal treatment remains elusive to this day. Most management strategies are based on anecdotal evidence or case series. Probiotics have the potential to affect the deleterious effects of radiation on the GI wall, preventing long-term damage. Delia et al72 conducted a double-blind, placebocontrolled trial to investigate the efficacy of a high-potency probiotic preparation on prevention of radiation-induced diarrhea in cancer patients. Four hundred and ninety patients who underwent adjuvant postoperative radiation therapy after surgery were assigned to either the high-potency probiotic

preparation VSL#3 (1 sachet 3 times daily) or placebo starting from the first day of radiation therapy. There was a higher incidence of radiation-induced diarrhea in the placebo group compared with the VSL#3 patients (51.8% vs 31.6%; P < .01). In addition, more patients given placebo suffered grade 3 or 4 diarrhea compared with VSL#3 recipients (55.4% and 1.4%; P < .01). Daily bowel movements were reduced in the probiotic group (5.1 ± 3 vs 14.7 ± 6; P < .05). The mean time to the use of loperamide was also significantly shorter for the placebo group vs the group receiving VSL#3 (86 min vs 122 min). Another multicenter, randomized, placebo-controlled nutrition trial reported that yogurt containing L. casei DN114 001 significantly improved the consistency of stool, as measured by the Bristol scale, without reducing the incidence of radiation-induced diarrhea.73

Preventing Feeding Tube Diarrhea Diarrhea is a common and serious complication of enteral tube feeding, and multiple factors have been implicated.

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Table 4. Cancer Type

237

Probiotics for Primary and Secondary Prevention of Cancer

Study Design

Variable Studied

Colon cancer (Rafter et al104)

Double-blind RCT in colon cancer (n = 37) and polypectomized (n = 43) patients

Colon cancer (Roller et al108)

Double-blind RCT in colon cancer (n = 34) and polypectomized (n = 40) patients

Bladder cancer (n = 58) (Aso and Akazan102) Bladder cancer (n = 138) (Aso et al101)

Prospective RCT in superficial bladder cancer after transurethral resection Double-blind RCT superficial transitional cell carcinoma of the bladder following transurethral resection Randomized controlled study following transurethral resection of the bladder tumor Case control study

Bladder cancer (n = 58) (Aso et al101) Bladder cancer (Ohashi et al100) (180 cases, 445 controls) Breast cancer Saccharomyces cerevisiae–induced (Ghoneum apoptosis; breast and cancer MCF-7 cell line Gollapudi106) Breast cancer Mice injected with breast tumor cells (de Moreno de LeBlanc et al107)

Control

Synbiotic food (oligofructoseenriched inulin + LGG and Bifidobacterium lactis Bb12) 1 × 1010 CFU of LGG and 1 × 1010 CFU of B. lactis Bb12 [Bb12] plus 10 g of inulin enriched with oligofructose Oral Lactobacillus casei plus intravesical instillation of epirubicin

Placebo

Oral L. casei preparation or BLP

Placebo

Higher bifidobacterium and lactobacillus concentrations plus favorable impact on several colorectal cancer biomarkers.

Controls Intervention group showed minor received stimulatory effects on the systemic encapsulated immune system. maltodextrin and 10 g of maltodextrin Intravesical instillation of epirubicin

Oral (3 g/day) L. casei preparation or BLP

Higher 3-year recurrence-free survival rate in experimental group than eoirubicin alone (74.6% vs 59.9%), although progression-free survival and overall survival were similar. BLP showed a better prophylactic effect in patients with primary multiple tumors, recurrent single tumors, and recurrent multiple tumors. Fifty percent recurrence-free interval was prolonged by probiotics (350 days) to 1.8 times that in the control group (195 days). Intake of fermented milk products was 0.46 (0.27-0.79) for 1 to 2 times/week and 0.61 (0.38-0.99) for 3 or more times/week, respectively.

L. casei, taken as fermented milk by history

Arabinoxylan rice bran (MGN-3/Biobran)

Milk fermented by Lactobacillus helveticus R389

Outcome

Mice not injected with tumor cells

Yeast-induced apoptosis of MCF-7 cells occurs in a time-dependent manner and is enhanced in the presence of MGN-3. Mice fed with probiotic and injected with tumor cells had increased IgA and CD4-positive cells in mammary glands (tumor control increased CD8 + cells).

BLP, biolactis powder; CFU, colony forming units; LGG, Lactobacillus rhamnosus GG; RCT, randomized controlled trial.

Probiotics and prebiotics may be effective because of their suppression of colonization by enteropathogenic bacteria, immune stimulation, and modulation of colonic metabolism. Prebiotics increase the concentration of fecal bifidobacteria in healthy subjects consuming enteral formula.

Several experts have recommended the use of probiotics in feeding formula.74 Bleichner et al75 studied 128 patients receiving enteral tube feeding in a prospective, randomized, placebo-controlled fashion. S. boulardii 500 mg 4 times a day or placebo was administered. Treatment with S. boulardii reduced the mean percentage of days with

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diarrhea per feeding days from 18.9% to 14.2% (OR = 0.67, 95% CI: 0.50-0.90, P = .0069). In contrast, a study by Heimburger et al76 (n = 41) found that use of L. acidophilus and L. bulgaricus does not alter the risk for diarrhea in patients receiving enteral tube feeding. Whelan77 suggests that further trials of the efficacy of probiotics and prebiotics, alone and in combination, in preventing diarrhea in this patient group are warranted.

Preventing Chemotherapy-Induced Diarrhea VSL#3 is effective in reducing chemotherapy-induced diarrhea in rats.78 Osterlund et al79 conducted an RCT to examine the effect of lactobacillus and fiber supplementation in 5FU chemotherapy patients. Patients were randomly allocated to receive or not receive LGG supplementation (1-2 × 1010 CFU/d) and fiber (11 g guar gum per day) during chemotherapy treatment. The authors found that patients who received lactobacillus had less grade 3 or 4 diarrhea (22% vs 37%, P < .05), reported less abdominal discomfort, needed less hospital care, and had fewer chemotherapy dose reductions due to bowel toxicity compared with the control group.

Preventing Diarrhea in Nursing Homes A randomized, double-blind, placebo-controlled trial conducted in 2 nursing homes in Finland assessed the impact of a fermented oat drink with 2 selected B. longum strains on bowel movements among elderly nursing home residents.80 The authors found that use of probiotics helped to normalize bowel movements in frail nursing home patients.

Conclusion Much of diarrheal illness, irrespective of the inciting agent, is associated with dysbiosis. Evidence on the beneficial effect of probiotics in such conditions is accumulating. Trials of single probiotics or as part of various combinations, including S. boulardii, LGG, and L. acidophilus, may be worth the cost in many cases depending on the indication and the product used.

Other Potential Uses Table 1 shows the positive preventive impact of probiotics in orodental illnesses such as caries, gingivitis, and halitosis.81-88 As shown in Table 2, many probiotics are considered safe for immunocompromised patients and have the potential to boost immunity.89-94 Tables 3 and 4 outline preliminary evidence suggesting that probiotics may be helpful in preventing cardiovascular disease by reducing cholesterol,95-99 various kinds of cancers,100-108 musculoskeletal disorders,109-111 fatigue in athletes,112 hepatic diseases,113,114 obesity,115

malnutrition,116,117 aging processes,118-120 restless leg syndrome,121 maniac depressive disorder,122 attention-deficit hyperactivity disorder,123 and so on.

Conclusion The mechanisms of action of probiotics in health and sickness are multifactorial. In addition to their impact on the health of the individual by acting as a digestive aid and boosting the immune response, the fundamental action involves their potential to restore the gut barrier function by modifying the bacterial balance in favor of the beneficial ones. Ingestion of a healthy diet combined with probiotics has the potential to affect health and disease far beyond the gut, including reducing risk for cancer.124 The probiotics with the greatest number of proven benefits are LGG and S. boulardii. Results from meta-analyses and systematic reviews that combine all probiotic bacteria into a single category to examine the effects in any disease state should be interpreted with caution. Specific strains are effective in specific disease states. No 2 probiotics are exactly alike; as such, we should not expect reproducible results from studies that employ different species or strains, variable formulations, and diverse dosing schedules.

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