Atopy & the Microbiome

JACLYN CHASSE-SMEATON, ND 

Atopic dermatitis (AD) dramatically impacts pediatric health and quality of life of the family as a whole. Although the pathogenesis of AD has not been clearly elucidated, there are multiple factors at play, including genetic predisposition, environment, defects in innate and adaptive immune response, epidermal dysfunction, and the developing microbiota.¹ According to the Centers for Disease Control and Prevention (CDC) and the World Allergy Organization, the prevalence of both food (~5%) and respiratory (~17%) childhood allergies in the United States has increased in recent years.^2,3 But none so much as atopic dermatitis, which is currently estimated to affect up to 30% of American children (or approximately 10 million), one-third of whom experience significant symptom severity and prolonged course of disease.^4,5  

This article will review risk factors, the role of the maternal and infant microbiome, and the potential for therapeutic probiotics in the prevention and management of childhood eczema. 

Atopic Dermatitis: Early–Life Risk Factors 

Mode of delivery 

Cesarean-section birth rates have tripled since 1990 and show no sign of abating. Studies have shown that C-section-delivered children harbor less Bifidobacteria and Bacteroides, but more Clostridia, E coli, and S aureus compared to children delivered vaginally. They are also more likely to develop immune disorders including asthma and allergies.^6,7  

Breastfeeding 

Breast milk influences microbiota diversity, gut barrier function, and oral tolerance induction. Although 84% of US mothers begin breastfeeding, nearly 20% supplement with formula by day 2, and only 58% of US babies are breastfeeding at 6 months of age.⁸  

Antibiotic exposure 

Perinatal broad-spectrum antibiotic use has become common in modern obstetric/neonatal practice. But there is increased evidence that links early-life antibiotic exposure with inflammatory bowel disease, diabetes, obesity, and immune-modulated disease.⁹  

Infant Immune & Microbiome Development: Maternal Influence  

The gestational microbiome is distinct from non-pregnancy and evolves during the course of gestation, adapting for fetal tolerance. Regulatory T-cell (Treg) levels increase during pregnancy, with a shift away from Th1 and toward Th2 helper cells.^10,11 At the same time, cross-placental antibodies and growth factors instruct the developing infant immune system. Various studies have suggested that the reduction in Th1 may be a significant causative factor in the development of allergic disease.^12-14 More recent hypotheses, however, assign it a lesser importance in atopy. Rather, diversity of microbe exposure appears to be more instrumental. And, despite the fact that commensal maternal microbes begin to migrate across the placenta in the last trimester to help seed the infant microbiome,¹⁵ it is the mode of birth that has the greatest initial impact on infant microbiome development.¹⁶  

Vaginal birth is associated with enrichment of Bacteriodes and Bifodobacterium species in the early weeks of life, whereas infants born by C-section are primarily exposed to bacteria from the mother’s skin (eg, Staphylococcus spp).¹⁷ Although lack of Bacteriodes and Bifidobacterium is associated with the development of allergy and atopy, breastfeeding can help mitigate these risks. In fact, from 13 weeks, diet becomes the most important factor influencing infant microbiome development.⁶ Given our cultural trends toward shorter-term breastfeeding, it is important to note that premature cessation is also linked with an increase in Lachnospiraceae species, which is in itself positively correlated with the development of atopic dermatitis and asthma.⁶  

Support for the Developing Microbiome 

It is clear that the microbiome profile of children suffering from atopic dermatitis is distinctive compared to their healthy counterparts.¹⁸ This has led researchers to investigate the impact of the largest surface in the human body where microbes and their products interact with the immune system: the gut-associated lymphoid tissue (GALT). The primary proposed probiotic mechanisms of action focus on the ability of microbes to modulate immune response. Because the well-characterized probiotic species Bifidobacterium and Lactobacillus are often both found at lower concentrations in eczema,^19,20 the potential benefits of probiotic supplementation for prevention and treatment have been evaluated. But the results are mixed. 

A 2017 review and meta-analysis²¹ offers a glimpse into the heterogeneity of probiotic performance in atopic dermatitis (Table 1). Although not exhaustive, differences in study design, populations, and intervention (strains, formulations, doses) contribute to the variability of outcomes. 

Table 1. Probiotic Intervention in Atopic Dermatitis²¹  

Year	Cohort Size	Age	Outcome	Citation
2005	220	1.4-11.9 months	Positive findings in IgE-sensitized infants only	Viljanen M, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy. 2005;60(4):494-500.
2005	56	6-18 months	Positive findings in food-sensitized children only	Weston S, et al. Effects of probiotics on atopic dermatitis: a randomised controlled trial. Arch Dis Child. 2005;90(9):892-897.
2006	54	1-55 months	No significant difference	Folster-Holst R, et al. Prospective, randomized controlled trial on Lactobacillus rhamnosus in infants with moderate to severe atopic dermatitis. Br J Dermatol. 2006;155(6):1256-1261.
2007	102	3-12 months	No significant difference	Grüber C, et al. Randomized, placebo-controlled trial of Lactobacillus rhamnosus GG as treatment of atopic dermatitis in infancy. Allergy. 2007;62(11):1270-1276.
2010	90	1-3 years	Significant SCORAD decrease	Gerasimov SV, et al. Probiotic supplement reduces atopic dermatitis in preschool children a randomized, double-blind, placebo-controlled, clinical trial. Am J Clin Dermatol. 2010;11(5):351-361.
2010	75	2-10 years	Significant SCORAD decrease	Woo SI, et al. Effect of Lactobacillus sakei supplementation in children with atopic eczema-dermatitis syndrome. Ann Allergy Asthma Immunol. 2010;104(4):343-348.
2011	41	1-36 months	No significant difference	Shafiei A, et al. Synbiotics could not reduce the scoring of childhood atopic dermatitis (SCORAD): a randomized double blind placebo-controlled trial. Iran J Allergy Asthma Immunol. 2011;10(1):21-28.
2012	60	2-14 years	Significant SCORAD decrease	Wu KG, et al. Lactobacillus salivarius plus fructo-oligosaccharide is superior to fructo-oligosaccharide alone for treating children with moderate to severe atopic dermatitis: a double-blind, randomized, clinical trial of efficacy and safety. Br J Dermatol. 2012;166(1):129-136.
2012	133	3-6 months	No significant difference	Gore C, et al. Treatment and secondary prevention effects of the probiotics Lactobacillus paracasei or Bifidobacterium lactis on early infant eczema: randomized controlled trial with follow-up until age 3 years. Clin Exp Allergy. 2012;42(1):112-122.
2012	83	1-13 years	Significant SCORAD decrease	Han Y, et al. A randomized trial of Lactobacillus plantarum CJLP133 for the treatment of atopic dermatitis. Pediatr Allergy Immunol. 2012;23(7):667-673.
2012	39	1-12 years	Significant SCORAD decrease	Yesilova Y, et al. Effect of probiotics on the treatment of children with atopic dermatitis. Ann Dermatol. 2012;24(2):189-193.
2015	220	1-28 years	Significant SCORAD decrease	Wang IJ, et al. Children with atopic dermatitis show clinical improvement after Lactobacillus exposure. Clin Exp Allergy. 2015;45(4):779-787.

An earlier meta-analysis found slightly more positive findings: In one subgroup, in particular, prenatal probiotic administration, followed by continued postnatal supplementation, was more protective than postnatal probiotic supplementation alone.²²     

Although promising, these reviews do not offer robust evidence of the efficacy of general probiotic supplementation in the prevention and resolution of atopy. Alternatively, these studies emphasize the importance of selective strain identification (validated immune-modulatory effects) and demonstrated efficacy of specific final formulations and dosing regimen. 

Selecting a Probiotic Formulation for AD Efficacy 

Strain Significance 

Research has elucidated a number of commensal microbe immune-supporting pathways, including inhibition of pathogenic bacteria, production of defensins, and degradation of a variety of endotoxins, including lipopolysaccharides. However, microbes also play a direct role in the regulation of innate and immune response through intestinal barrier integrity (which is impaired in AD children²³), and the short-chain fatty acid (SCFA) modulation of dendritic cell, macrophage, and T/B lymphocyte functions.²⁴ In the case of AD, specifically, the ability to down-regulate Th2 cytokine production and induce regulatory T-cell cytokines also plays a role.²⁵ Yet, these capabilities are highly strain-specific. It is therefore incumbent on probiotic formulation developers and manufacturers to identify the right players, in the right combination, to ensure the highest probability of efficacy. 

Synergistic Performance 

Beyond the individual strain components, the performance of a final, indication-targeted probiotic formulation is only clearly demonstrated through data. Niers et al offered a unique view into the efficacy of a multi-species probiotic for AD prevention in high-risk children, with an initial study demonstrating significantly less AD development in the probiotic group at 3 months compared to the control group.²⁶ Subsequent NMR spectroscopic analyses of the same children’s fecal samples found lower levels of succinate, phenylalanine, and alanine, and higher levels of glucose, galactose, and lactose in children who later developed eczema.²⁷ These findings highlight the role of select bacterial metabolites in the development of the immune system even prior to clinical AD presentation.  

Summary 

In summary, select probiotic strains and formulations offer promise in the prevention and amelioration of atopic dermatitis; however, not all strains or available probiotic formulations will perform at similar levels of efficacy. Digging deep is the route to confidence. 

Caveat emptor: Always understand the quality of evidence behind your recommendations. 

References:

1. Dharmage SC, Lowe AJ, Matheson MC, et al. Atopic dermatitis and the atopic march revisited. Allergy. 2014; 69:17-27.     

2. Centers for Disease Control and Prevention. Trends in Allergic Conditions Among Children: United States, 1997–2011. Number 121, May 2013. Last reviewed November 6, 2015. CDC Web site. https://www.cdc.gov/nchs/products/databriefs/db121.htm. Accessed February 7, 2021. 

3. Pawankar R, Holgate ST, Canonica RW, et al, eds. White Book on Allergy: Update 2013. World Allergy Organization. WAO Web site. https://www.worldallergy.org/UserFiles/file/WhiteBook2-2013-v8.pdf. Accessed February 7, 2021.  

4. National Eczema Association. Eczema Stats. Available at: https://nationaleczema.org/research/eczema-facts/. Accessed February 7, 2021. 

5. Kim BS. What is the global prevalence of atopic dermatitis (eczema)? June 3, 2020. Medscape Web site. https://www.medscape.com/answers/1049085-4692/what-is-the-global-prevalence-of-atopic-dermatitis-eczema. Accessed February 7, 2021. 

6. Galazzo G, van Best N, Bervoets L, et al. Development of the Microbiota and Associations With Birth Mode, Diet, and Atopic Disorders in a Longitudinal Analysis of Stool Samples, Collected From Infancy Through Early Childhood. Gastroenterology. 2020;158(6):1584-1596. 

7. Lee SY, Lee E, Park YM, Hong SJ. Microbiome in the Gut-Skin Axis in Atopic Dermatitis. Allergy Asthma Immunol Res. 2018;10(4):354-362. 

8. Centers for Disease Control and Prevention. Breastfeeding Report Card: United States, 2020. Last reviewed September 17, 2020. CDC Web site. https://www.cdc.gov/breastfeeding/data/reportcard.htm. Accessed February 7, 2021. 

9. Eck A, Rutten NBMM, Singendonk MMJ, et al. Neonatal microbiota development and the effect of early life antibiotics are determined by two distinct settler types. PLoS One. 2020;15(2):e0228133.  

10. Borzychowski AM, Croy BA, Chan WL, et al. Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells. Eur J Immunol. 2005;35(10):3054-3063. 

11. Reinhard G, Noll A, Schlebusch H, et al. Shifts in the TH1/TH2 balance during human pregnancy correlate with apoptotic changes. Biochem Biophys Res Commun. 1998;245(3):933-938. 

12. Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299(6710):1259-1260. 

13. Bloomfield SF, Stanwell-Smith R, Crevel RW, Pickup J. Too clean, or not too clean: the hygiene hypothesis and home hygiene. Clin Exp Allergy. 2006;36(4):402-425. 

14. Strannegård O, Strannegård IL. The causes of the increasing prevalence of allergy: is atopy a microbial deprivation disorder? Allergy. 2001;56(2):91-102. 

15. Walker RW, Clemente JC, Peter I, Loos RJF. The prenatal gut microbiome: are we colonized with bacteria in utero? Pediatr Obes. 2017;12 Suppl 1(Suppl 1):3-17. 

16. Robertson RC, Manges AR, Finlay BB, Prendergast AJ. The Human Microbiome and Child Growth – First 1000 Days and Beyond. Trends Microbiol. 2019;27(2):131-147.  

17. Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107(26):11971-11975.  

18. Kalliomäki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet. 2001;357(9262):1076-1079. 

19. Zheng H, Liang H, Wang Y, et al. Altered Gut Microbiota Composition Associated with Eczema in Infants. PLoS One. 2016;11(11):e0166026. 

20. Melli LCFL, Carmo-Rodrigues MSD, Araújo-Filho HB, et al. Gut microbiota of children with atopic dermatitis: Controlled study in the metropolitan region of São Paulo, Brazil. Allergol Immunopathol (Madr). 2020;48(2):107-115. 

21. Huang R, Ning H, Shen M, et al. Probiotics for the Treatment of Atopic Dermatitis in Children: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Cell Infect Microbiol. 2017;7:392. 

22. Panduru M, Panduru NM, Sălăvăstru CM, Tiplica GS. Probiotics and primary prevention of atopic dermatitis: a meta-analysis of randomized controlled studies. J Eur Acad Dermatol Venereol. 2015;29(2):232-242. 

23. Rosenfeldt V, Benfeldt E, Valerius NH, et al. Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr. 2004;145(5):612-616.  

24. Yan F, Polk DB. Probiotics and immune health. Curr Opin Gastroenterol. 2011;27(6):496-501.  

25. Kim NY, Ji GE. Effects of probiotics on the prevention of atopic dermatitis. Korean J Pediatr. 2012;55(6):193-201. 

26. Niers L, Martin R, Rijkers G, et al. The effects of selected probiotic strains on the development of eczema (the PandA study). Allergy. 2009;64(9):1349-1358. 

27. Kim HK, Rutten NB, Besseling-van der Vaart I, et al. Probiotic supplementation influences faecal short chain fatty acids in infants at high risk for eczema. Benef Microbes. 2015;6(6):783-790. 

Jaclyn Chasse-Smeaton, ND, is a licensed naturopathic physician focused on infertility, reproductive, and genitourinary health. Her practice, Perfect Fertility, has helped thousands of couples grow their families, and her passion to share this knowledge has led her to teach integrative fertility care to thousands of doctors. Dr Smeaton also works as VP of Medical Education for Emerson Ecologics, the largest provider of vitamins and supplements into the medical community. Dr Smeaton is the past-president of the AANP, and has served on the boards of several organizations, including the Integrative Health Policy Consortium, the American Herbal Products Association, and many others.