The Effect of Prebiotics on Atopic Dermatitis

The human microbiota interacts with host immunity, leading to immune dysfunction associated with allergy and asthma.1 In particular, many studies revealed that gut microbiota plays an important role in the pathophysiology of atopic dermatitis (AD). In a comparative analysis between AD patients and healthy controls, the former group showed diminished levels of Bifidobacterium in the gut. Furthermore, an inverse correlation was identified between AD severity and percentages of Bifidobacterium.2 Low gut microbiota diversity (P = 0.004), particularly low diversity of the bacterial phylum Bacteroidetes (P = 0.02) and the genus Bacteroides (P = 0.01), at 1 month of age was significantly associated with AD until 2 years of age.3 When compared to the control group, a subgroup of AD showed lower functional genes related to host immune development and this finding was associated with reduced colonization of mucin-degrading bacteria (Akkermansia muciniphila, Ruminococcus gnavus, and Lachnospiraceae bacterium 2_1_58FAA) in the gut.4 The fecal samples at 6 months of age showed that the proportion of Streptococcus was significantly higher and Clostridium was significantly lower In infants with AD at 2 years of age.5 Overall, the development and persistence of AD are associated with alterations in the gut microbiome, and this effect may be mediated by the gut-skin axis through immunologic, metabolic, and neuroendocrine pathways.6, 7

Based on the relationship between gut microbiota and AD, many clinical trials have been conducted to prevent or treat AD by modulating host immunity through probiotics and prebiotics administration. At present, guidelines from the American Academy of Pediatrics and the European Academy of Allergy and Clinical Immunology do not recommend the use of probiotics or prebiotics to prevent the development of allergic diseases due to a lack of conclusive evidence.8, 9 The World Allergy Organization (WAO) guideline panel, on the other hand, suggests using probiotics in pregnant women at high risk for having an allergic child, in women who breastfeed infants at high risk of developing allergy, and in infants at high risk of developing allergy. However, the WAO notes that all recommendations are conditional and the evidence is very low quality.10

The therapeutic effect of probiotics on AD has been widely studied. In a meta-analysis of 25 randomized controlled trials (n = 1,599), a significant reduction in AD severity scores was observed in the probiotic group when compared to the control group. This effect was found in moderate–to-severe AD in children and adults, but not in infants.11 Another meta-analysis of 8 clinical trials by Zhao et al.12 showed that probiotics administration is beneficial for the treatment of AD in infants. In contrast, the Cochrane systematic review showed that the use of probiotics for AD treatment may not be evidence-based.13, 14 At present, whether probiotics are beneficial for the prevention and treatment of AD still remains controversial and requires further research.15

Prebiotics are non-digestible food substances that selectively promote the growth of intestinal microbes with benefits for the health of the host. Recently, this definition has evolved more simply to a substrate that is selectively utilized by host microorganisms conferring a health benefit.16 Prebiotics naturally exist in different dietary food products and are also manufactured on industrial large scales.17 There are many types of prebiotics including inulin, resistant starch, polydextrose (glucan with many branches), pectic oligosaccharides derived from pectin, etc., and among them, 2 important groups are fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS). Prebiotics are resistant to digestion and are not absorbed in the gastrointestinal tract. They are fermented by intestinal microbiota to produce short-chain fatty acids, including lactic acid, butyric acid, and propionic acid, which have beneficial effects on the host’s health.18 In addition, prebiotics directly supports intestinal epithelial barrier function and immune responses.19

The evidence on the effect of prebiotics on AD is limited. In a prospective, randomized, double-blind, placebo-controlled study of 134 infants with a parental history of atopy, the cumulative incidence for AD at age 2 years was higher in the placebo group (n = 68) than in the intervention group (n = 66) who were fed a mixture of neutral shot-chain GOS and long-chain FOS for 6 months after birth (27.9% vs. 13.6%, P < 0.05).20 In another double-blind, placebo-controlled, randomized prospective intervention study of infants with low atopy risk, AD occurred less frequently in infants receiving the prebiotic formula than in those receiving the regular formula without prebiotics (5.7% vs. 9.7%, P = 0.04) during the first year of life. The hazard ratio for the incidence of AD in the prebiotic group was 0.56 (95% confidence interval, 0.323–0.971, P = 0.039) when compared to the control group.21 In contrast, a parallel-group, randomized, double-blind, placebo-controlled trial in infants with a family history of allergic disease demonstrated that partially hydrolysed whey formula containing oligosaccharides did not prevent eczema in the first year of life.22 The WAO guideline panel reviewed 18 randomized trials and developed clinical recommendations following the Grading of Recommendations Assessment, Development and Evaluation approach. It suggests prebiotic supplementation for infants who are not exclusively breastfed, both at high and at low risk for developing allergy, although it emphasizes that the recommendation is conditional and the evidence is very low certainty.23 Taken together, there is insufficient evidence to strongly recommend the prebiotic supplement for the primary prevention of AD.

The therapeutic effect of prebiotics on AD has been investigated in limited numbers. In a randomized, double-blind, placebo-controlled study of Japanese children aged < 3 years, children receiving kestose, the smallest component of FOS, every day for 12 weeks (n = 15) showed significantly lower SCORing Atopic Dermatitis (SCORAD) scores (median) than those receiving placebo (n = 14) on week 6 (25.3 vs. 36.4, P < 0.01) and week 12 (19.5 vs. 37.5, P < 0.001).24 A randomized controlled trial of kestose for 6 weeks demonstrated a significant positive correlation between an increase in the fecal Faecalibacterium prausnitzii counts and the improvement of SCORAD score in the 2- to 5-year-old infants with AD (rs = 0.52, P < 0.05). Of note, this effect was not observed in infants aged < 1 year.25 Although kestose seems to have a clinically beneficial effect in the treatment of AD, those studies do not yet provide strong evidence because of the limitations including the small number of patients, insufficient clinical improvement, and lack of mechanism studies.

In the dinitrochlorobenzene (DNCB)-induced AD mice model, oral administration of GOS in combination with Bifidobacterium longum for 21 days significantly reduced dermatitis score, decreased transepidermal water loss, and attenuated the epidermal thickness than the administration of DNCB alone. Of interest, serum IgE concentrations, and the gene expression of IL-4 and IL-13 in the skin were reduced when the combination of GOS and B. longum was administered, while epidermal barrier protein such as filaggrin was upregulated. Moreover, this effect of B. longum plus GOS was greater than B. longum alone.26 This study provides the possible therapeutic effect of GOS in AD.

In this issue of the Allergy Asthma Immunol Res, Kang et al.26 used prebiotics (β-glucan and inulin) in an oxazolone (OX) AD-like mouse model to examine the therapeutic and preventive effects of prebiotics on AD. For investigating the therapeutic effect, they induced an AD-like model in 8-week-old female SKH-1 hairless mice by sensitizing with 1% OX once daily for 1 week and then challenging with 0.1% OX once daily for 5 weeks. Prebiotics (β-glucan only, inulin only, or in combination) were administered orally for 3 weeks from weeks 4 to 6. They found that prebiotics markedly reduced AD severity and mRNA expression of calprotectin, IL-4, IL-13, and IL-1β in the skin. Histologically, they also demonstrated that epidermal thickness, the number of mast cells, and the expression of filaggrin and loricrin were reduced by prebiotic treatment. In the preventive study, mice were sensitized with 1% OX at week 3 for 1 week and challenged with 0.1% OX at week 4 for 1 week. While the prebiotic was orally administered for 5 weeks from weeks 0 to 5. In this experiment, it seems that pre-administration of β-glucan or inulin did not completely prevent AD development. However, prebiotics significantly inhibited the increase in clinical scores, epidermal thickness, and the downregulation of filaggrin and loricrin. Although not many studies have been done yet, this study supports the possible therapeutic effect of prebiotics in AD.

Considering animal experiments cannot represent human AD with various phenotypes and there is a lack of clinical trials, further investigations are needed to determine how effectively the prebiotics can be used in clinical practice. In particular, lots of questions remain, such as which type of prebiotics are effective, how long to administer, how many doses to use, and whether there are any adverse effects from long-term administration.