Skin biomarkers predict the development of food allergy in early life

Abstract

Background: Food allergy (FA) often occurs in early childhood with and without atopic dermatitis (AD). FA can be severe and even fatal. For primary prevention, it is important to find early biomarkers to predict the future onset of FA before any clinical manifestations.

Objective: Our aim was to find early predictors of future onset of FA in the stratum corneum (SC).

Methods: Skin tape strips were collected from the forearm of newborns (n = 129) at age 2 months, before any signs of clinical FA or AD. Children were clinically monitored until they reached age 2 years to confirm the presence or absence of FA and AD. Skin tape strips were subjected to lipidomic analyses by liquid chromatography-tandem mass spectrometry and cytokine determination by Meso Scale Discovery U-Plex assay.

Results: Overall, 9 of 129 infants (7.0%) developed FA alone and 9 of 129 infants (7.0%) developed FA concomitantly with AD. In the stratum corneum of children with future FA and concomitant AD and FA, absolute amounts of unsaturated (N24:1)(C18-sphingosine)ceramide and (N26:1)(C18-sphingosine)ceramide and their relative percentages within the molecular group were increased compared with the amounts and percentages in healthy children, with P values ranging from less than .01 to less than .05 according to ANOVA. The children with future AD had normal levels of these molecules. IL-33 level was upregulated in those infants with future FA but not in those with future AD, whereas thymic stromal lymphopoietin was upregulated in those with future AD but not in those with future FA. Logistic regression analysis revealed strong FA predicting power for the combination of dysregulated lipids and cytokines, with an odds ratio reaching 101.4 (95% CI = 5.4-1910.6).

Conclusion: Noninvasive skin tape strip analysis at age 2 months can identify infants at risk of FA in the future.

Keywords: Food allergy; protein-bound ceramides; skin lipids; stratum corneum; unsaturated ceramides.

Figure 1.. Stratum corneum unsaturated NS-ceramides as predictors of the future onset of FA and ADFA.

Increase in the absolute levels (A) and relative proportions (B) of unsaturated NS-ceramides N24:1(C18S)CER and N26:1(C18S)CER in the stratum corneum of infants with future development of FA or ADFA (A, B) or combined future FA and ADFA infants (C).

Figure 2.. Stratum corneum of future FA infants has increased levels of protein-bound OS-ceramides with ultra-long-chain omega-hydroxy fatty acids.

The separation of the future FA group from the healthy and ADFA group is best pronounced for OS-ceramide with C18-sphingosine (N32:0O)(C18S)CER (B). Note the decrease in OS-CER levels in infants with future AD (A-D).

Figure 3.. Unsaturated sphingomyelin species are not increased in the stratum corneum of infants with future FA.

The increase in absolute levels (A) and relative proportions (B) of 24:1- and 26:1-sphingomyelin molecular species in the SC of infants with future AD but not FA or ADFA. Note that the development of FA cancels the increase in 26:1-SM in the ADFA group.

Figure 4.. TSLP and IL-33 levels in the stratum corneum are unique for infants with future FA.

(A) TSLP is not increased in the skin of infants with future FA but increased in the skin of future AD and ADFA infants. IL-33 is increased in the skin of future ADFA infants but not in the skin of future AD infants. No selectivity in other cytokines measured was found. (B) IL-33 levels separate infants with future FA irrespective of AD status.

Figure 5.. Logistic regression analysis reveals the strong combinatorial power of STS cytokines and lipids to predict the future onset of FA by 24 months of age, irrespective of AD status.

The sole and combined effects of cytokines and lipids were evaluated by the estimates of odds ratios (ORs) from the logistic regression models. All study participants were included in the analysis. Dotted line – 2^x fold change