Prebiotics and probiotics for treatment of allergic disease

INTRODUCTION — The rapid increase in immune-mediated disorders such as allergic disease is strongly linked to reduced early microbial exposure [1,2]. The gut microbiota represents the greatest microbial exposure by far and is central to the development of immune regulation. The specific composition of the gut microbiota may affect the risk of developing allergic disease [3]. This finding provided the foundation for intervention studies designed to modify gut microbial composition for the treatment of allergic disease. The effects of beneficial bacteria (probiotics) or resistant starches or fiber (prebiotics) that selectively stimulate a limited number of beneficial bacteria have been evaluated in allergy treatment studies.

This topic examines the evidence for prebiotics and probiotics in the treatment of allergic disease [4-8]. The evidence for prebiotics and probiotics in the prevention of allergic disease is presented separately. The definitions of prebiotics, probiotics, and synbiotics; proposed mechanisms of action; rationale for use in allergic disease; and side effects and safety are also discussed separately. (See "Prebiotics and probiotics for prevention of allergic disease".)

TERMINOLOGY — Prebiotics are nondigestible carbohydrates that stimulate the growth and/or activity of beneficial colonic bacteria. Probiotics are live microorganisms that benefit the host. Synbiotics are a combination of prebiotics and probiotics. (See "Prebiotics and probiotics for prevention of allergic disease", section on 'Definitions'.)

CLINICAL TREATMENT STUDIES USING PREBIOTICS — Randomized, controlled trials evaluating the effects of prebiotics for treatment of allergic disease are scarce, and further studies are needed before any conclusions can be drawn.

The effect of kestose, a fructo-fructooligosaccharide (FOS), was assessed in a trial that randomized 29 infants and children under three years of age with eczema to daily ingestion of kestose or maltose (placebo) for 12 weeks [9]. Median SCORAD (SCORing Atopic Dermatitis) scores were significantly lower at 6 and 12 weeks in the prebiotic group compared with placebo. Another trial found no reduction in SCORAD in infants fed galacto-oligosaccharides (GOS) in a formula with hydrolyzed protein compared with the same formula without any addition [10].

CLINICAL TREATMENT STUDIES USING PROBIOTICS — Initial meta-analyses suggest no benefit of oral probiotics in the treatment of eczema or asthma. One meta-analysis reported a beneficial effect of probiotics in the treatment of allergic rhinitis, but it was not conclusive, and further studies are needed.

Caution is advised when using probiotics in immunocompromised patients, including premature infants, due to an increased risk of adverse effects and, in rare cases, infection caused by fungal contamination [11,12].

Eczema — There are a number of meta-analyses on using probiotics for eczema treatment [5,13-16]. Most have concluded that there is no consistent evidence that live oral probiotics are useful for the treatment of established eczema. Additional subgroup analyses according to evidence of allergen sensitization or eczema severity did not affect this conclusion. Subsequent trials have been consistent with these findings [17], although a small trial reported reduced SCORAD (SCORing Atopic Dermatitis) and improved quality-of-life measures in adults with eczema following 16 weeks of treatment with a Lactobacillus salivarius strain compared with placebo [18]. (See "Treatment of atopic dermatitis (eczema)".)

However, there are problems with the quality of some studies. In addition, the high degree of heterogeneity, which includes marked differences in probiotic preparations, study populations, and outcome measures, hampers direct comparison of studies. Lactobacillus rhamnosus GG (LGG) is the most extensively studied strain to date in the treatment of atopic dermatitis, with both positive and negative results [19-25]. Three other probiotic strains, Lactobacillus fermentum VR1-003PCC, Lactobacillus sakei KCTC 10755BP, and Lactobacillus plantarum CJLP133, have reduced SCORAD scores significantly in more limited trials [26-28]. Preliminary data suggest that dead probiotic microorganisms given orally or administered topically may be effective in the treatment of eczema, but further trials are needed [29-31].

The effect of probiotics in the treatment of allergic disease was first studied in infants with eczema, with or without associated food allergy. The initial study targeted infants with eczema and cow's milk allergy [25]. In that study, 27 infants were randomized to extensively hydrolyzed whey formula (eHF) with or without LGG for four weeks. The SCORAD score reductions were similar in the LGG and control groups.

In another early study by the same group, infants fed eHF with added LGG or Bifidobacterium lactis had a more rapid improvement of eczema compared with placebo (eHF alone) [19]. In contrast, there was no effect of LGG administration on eczema in a study with a comparable design [20]. Other groups have reported no benefit of LGG on SCORAD, medication requirements [21,22], or subjective parameters [21].

Results from a larger study [23] suggested that immunoglobulin E (IgE) sensitized individuals might be more likely to benefit from probiotic treatment. In that study, there was a reduction in SCORAD scores in infants with IgE-associated eczema who had received LGG compared with placebo, even though there was no overall effect. These findings are consistent with another study that reported significant SCORAD improvement with probiotics in a subgroup of food-sensitized children, while there was no overall effect in the whole study population [24].

The definition of probiotics indicates that the microorganisms should be alive to exert their effects (see "Prebiotics and probiotics for prevention of allergic disease", section on 'Definitions'). However, there is some evidence that dead probiotic microorganisms may also exert beneficial effects [29]. In one trial, 60 children (1 to 12 years of age) with eczema were randomized to heat-inactivated Lactobacillus acidophilus L-92 or placebo for eight weeks [30]. Both groups showed an improvement in eczema severity (as assessed by the Atopic Dermatitis Area and Severity Index), but the improvement was greater in the group assigned to L. acidophilus L-92. In a study of 50 participants >16 years of age with atopic dermatitis, intake of heat-killed L. acidophilus L-92 led to reduced severity of eczema using both objective and subjective assessments compared with a placebo group [32]. A much earlier study was also designed to compare the effect of viable or heat-inactivated LGG with a placebo in the treatment of eczema and cow's milk allergy [33]. However, this trial was terminated prematurely due to adverse effects (gastrointestinal symptoms) in the group of infants that received heat-inactivated LGG. Therefore, no firm conclusions can be drawn. Future research is needed to establish if inactivated microorganisms are effective in the treatment of eczema.

Most studies have used oral ingestion of probiotics, but there are limited studies on topical use. In one randomized trial, the topical application of a lysate of Vitreoscilla filiformis, a nonpathogenic gram-negative bacterium, led to a significant reduction in both SCORAD scores and cutaneous Staphylococcus aureus colonization compared with placebo [31]. These preliminary results need further validation.

Allergic rhinitis and asthma — Most studies using probiotics in the treatment of respiratory allergic disease have evaluated the effects of probiotics in the treatment of allergic rhinitis in adolescents and adults with conflicting results. A few studies report that certain probiotic strains such as Bifidobacterium longum (BB536) [34], Lactobacillus paracasei Lp33 [35], and L. acidophilus L-92 [36] lessen symptoms of allergic rhinitis and improve quality of life, while there was no benefit of LGG [37] or Lactobacillus casei strain Shirota [38].

Meta-analyses have identified that marked heterogeneity among studies makes direct comparison difficult. Even though probiotics may improve symptoms and quality of life in patients with allergic rhinitis, evidence is still limited because of heterogeneity in study design and outcome measures [39]. A trial published after this meta-analysis reported that a probiotic combination of one Lactobacillus and two Bifidobacterium strains improved quality of life in adults with allergic rhinitis compared with placebo; however, there was no effect on IgE concentrations or regulatory T cell (Treg) percentages [40]. In addition, a trial in 63 children aged 7 to 12 years with confirmed house dust mite allergy and moderate-to-severe allergic rhinitis published after the first meta-analysis demonstrated that levocetirizine plus a Lactobacillus johnsonii strain was superior to levocetirizine alone for improving nasal peak expiratory flow [41]. No benefit of probiotics was seen in the meta-analysis of four studies of probiotics in the treatment of asthma. This meta-analysis did not include a subsequently published study that showed a benefit of Lactobacillus gasseri on objective airway measurements [42].

Allergic rhinitis often coexists with asthma. Therefore, a few studies have included subjects with both asthma and allergic rhinitis. One randomized trial of 187 preschool children with respiratory allergic disease (asthma and/or allergic rhinitis) evaluated the effects of long-term consumption of fermented milk with the addition of a L. casei strain compared with nonfermented milk (placebo) [43]. Episodes of rhinitis were fewer in the probiotic group during the 12-month intervention, but there was no reduction in episodes of asthma. However, it was not confirmed if the rhinitis episodes were of allergic or viral origin.

Another study randomized 118 children aged 6 to 12 years with mild-to-moderate persistent asthma and persistent allergic rhinitis to daily intake of L. gasseri or placebo for eight weeks [42]. Both groups reported a reduction in the clinical severity of asthma and allergic rhinitis following treatment, but the number of patients with an improved score was higher in the probiotic group. There was an increase in forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), FEV₁/FVC, and postbronchodilator FEV₁ following five weeks of treatment in children receiving probiotics compared with placebo, demonstrating an effect on objective airway measurements.

SYNBIOTICS FOR TREATMENT OF ALLERGIC DISEASE — A few studies have used probiotics in combination with prebiotic oligosaccharides (synbiotics). One systematic review and meta-analysis examined six treatment studies and two prevention studies of synbiotics for atopic dermatitis [44]. The pooled change in SCORAD (SCORing Atopic Dermatitis) scores at eight weeks was greater in the synbiotic group than then placebo group, an effect that was only significant in the subgroup analysis when mixed strains of bacteria were used and treated children were ≥1 year of age. In one of the included studies, for example, 90 children one to three years of age with moderate-to-severe atopic dermatitis were randomly assigned to daily intake of a synbiotic mixture with L. acidophilus DDS-1 and B. lactis UABLA-12 plus fructooligosaccharides (FOS) or placebo for eight weeks [45]. The decrease in SCORAD score was greater in the synbiotic compared with the placebo group.

In another trial, 90 infants under seven months of age with atopic dermatitis were randomized to receive an extensively hydrolyzed whey formula (eHF) with or without synbiotics (Bifidobacterium breve M-16V and a mixture of 90 percent galacto-oligosaccharides [GOS] and 10 percent FOS) for 12 weeks [46]. Overall, there was no difference in SCORAD improvement between the two groups, but the SCORAD improvement was significantly greater in the synbiotic group than the placebo group in the subgroup of infants with IgE-associated eczema. This is consistent with a few probiotic treatment studies that reported no overall effect but found a benefit in infants and children with evidence of IgE sensitization to foods [23,24].

One study has evaluated if synbiotics are superior to prebiotics alone [47]. In this trial, 60 children aged 2 to 14 years with moderate-to-severe eczema were randomized to synbiotics (Lactobacillus salivarius plus FOS) or FOS alone for eight weeks [47]. SCORAD scores following treatment were significantly lower in the synbiotic group compared with prebiotic therapy, in conjunction with a reduction in eosinophilic cationic protein (ECP) levels and frequency of medication use.

Synbiotics in the treatment of asthma were evaluated in a trial that randomized 29 adults with asthma and house dust mite allergy to synbiotics (B. breve M-16V and a mixture of 90 percent GOS and 10 percent FOS) or placebo for four weeks [48]. Peak expiratory flow and systemic T helper type 2 (Th2) cytokines were reduced in the synbiotic group compared with placebo, but there was no effect on bronchial inflammation. These results are preliminary and need confirmation in other clinical settings.

SUMMARY AND RECOMMENDATIONS

●Prebiotics are nondigestible carbohydrates that stimulate the growth and/or activity of beneficial colonic bacteria. Probiotics are live microorganisms that benefit the host. Synbiotics are a combination of prebiotics and probiotics. (See "Prebiotics and probiotics for prevention of allergic disease", section on 'Definitions'.)

●There is evidence from animal models and in vitro studies that gut microbiota modulate immune programming, promote oral tolerance, and are important in inhibiting the development of the allergic phenotype. However, the therapeutic effect of prebiotics or probiotics may be reduced once colonization and the allergic phenotype are established compared with treatment at younger ages when there is greater plasticity. (See "Prebiotics and probiotics for prevention of allergic disease", section on 'Rationale for prebiotics and probiotics in allergic disease' and "Prebiotics and probiotics for prevention of allergic disease", section on 'Proposed mechanisms'.)

●There are several limitations that have hampered direct comparison of probiotic studies, including the quality of some studies and significant heterogeneity, such as marked differences in probiotic preparations, study populations, and outcome measures. (See 'Clinical treatment studies using probiotics' above.)

●There is no definitive evidence that prebiotics, probiotics, or synbiotics have efficacy in the treatment of any allergic conditions. Several meta-analyses suggest no benefit of probiotics in the treatment of eczema or asthma. Two meta-analyses reported a beneficial effect of probiotics in the treatment of allergic rhinitis, and studies evaluating prebiotics and synbiotics in the treatment of allergic disease show some promise. However, further studies are needed before any definitive conclusions can be drawn. (See 'Clinical treatment studies using prebiotics' above and 'Clinical treatment studies using probiotics' above and 'Synbiotics for treatment of allergic disease' above.)