Editorial comment on the Special Issue “Omics in Food
Allergy”
Riccardo Castagnoli1,2, Ivan
Taietti1,2,*, Agnes Sze-Yin Leung3,
Philippe Eigenmann4
1. Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and
Pediatric Sciences, University of Pavia, Pavia, Italy
2. Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia,
Italy
3. Department of Paediatrics, Faculty of Medicine, The Chinese
University of Hong Kong, China
4. Pediatric Allergy Unit, Department of Pediatrics, Gynecology and
Obstetrics, University Hospitals of Geneva, Geneva, Switzerland
ORCID:
- Riccardo Castagnoli: 0000-0003-0029-9383
- Ivan Taietti: 0000-0002-0372-523X
- Agnes Sze-Yin Leung: 0000-0001-8249-4478
- Philippe Eigenmann: 0000-0003-1738-1826
Corresponding author:
Ivan Taietti, MD;
Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and
Pediatric Sciences, University of Pavia, 27100 Pavia, Italy.
ivan.taietti@gmail.com; +39
340 7092400.
Food allergy (FA), defined as an adverse reaction to food mediated by
the immune system, is a significant public health issue with increasing
prevalence over the past decades. Although FA affects up to 10% of
children, the precise mechanisms underlying FA development and
persistence remain inadequately understood1. Food
immunotherapy has been successful in increasing the threshold of
tolerance in individuals with persistent FA (desensitization), and in a
subset, sustained unresponsiveness (remission) can be achieved. A
combination of environmental and genetic factors is considered to be
involved in the tolerance induction to food allergens. However, to date,
it has been difficult to fully dissect the complexity of the biological
determinants involved in FA.
The emergence of “omics” sciences, including genomics,
transcriptomics, proteomics, and metabolomics, is revolutionizing the
basic and translational research approach, allowing for the
comprehensive study of biological processes through analyzing and
integrating multiple datasets from various biological perspectives.
Moreover, epigenetic studies that evaluate the role of gene expression
modifiers are deepening our understanding of the interaction between
genetic predisposition and environmental influences.
The Special Issue “Omics in Food Allergy” aims to present current
knowledge and future perspectives in the field of FA through the lenses
of omics sciences.
Chun et al. and Lehmann et al. provide a detailed overview of epigenetic
mechanisms involved in FA, including DNA methylation and microRNA
(miRNAs)2,3. DNA methylation refers to the covalent
addition of a methyl group, typically to a cytosine in a CpG
dinucleotide in DNA. This limits access for transcription, frequently in
the promoter region, leading to reduced gene expression. Moreover,
miRNAs are small RNAs transcribed from intergenic or intronic genomic
loci that decrease gene expression by mRNA degradation and translational
inhibition. Of note, Chun et al. described two different approaches in
investigating FA mechanisms: (i) the epigenome-wide research approach
and (ii) candidate-gene investigations. The epigenome-wide research
approach identified genomic regions differently methylated and
regulated, involved in FA causation, antigen presentation, T cell
development, and reaction severity. Candidate-gene investigations
focused on Th1, Th2, T regulatory, and innate genes of interest in FA,
highlighting the importance of methylation changes in specific candidate
genes. In this context, for cow’s milk allergy (CMA), the attention is
focused on novel genetic loci involved in Th1/Th2 differentiation
pathways and potential B-cell dysfunction4. Of note,
miRNA seems to be involved in CMA as demonstrated by the downregulation
of mi193a-5p, a post-transcriptional regulator of IL-4 expression, in
infants with CMA5. Moreover, methylation levels in
peripheral blood mononuclear cells for IL-4, IL-5, IL-10, and IFN-γ
negatively correlate with their respective serum cytokine concentrations
and vary according to CMA status (active, resolved, or non-CMA).
Finally, Chun et al. reviewed ongoing research aimed at finding DNA
methylation predictors of food challenges. Initial work based on the
concept of epigenetic markers as biomarkers of disease and treatment
demonstrated promise for applying DNA methylation markers to potentially
improve how we assess and manage patients with FA, but further
validation in larger cohorts and work to practically translate such
biomarkers to clinical practice is advocated2.
Metabolomics may reflect the integration of genetic, transcriptomic, and
proteomic variations with environmental factors, thus reflecting
molecular processes of diseases. A metabolome approach would facilitate
the identification of surrogate metabolite markers correlating with the
disease activity and prognosis. Lee et al. reported an updated overview
of metabolomics’s current application in the FA field. Alterations to
the gut microbiota induced by Western dietary patterns are likely to
profoundly affect host immunity and play a significant role in FA.
Metabolites of interest include short-chain fatty acids (SCFAs), bile
acid metabolites, and tryptophan metabolites due to their essential
roles in normal immune development and homeostasis. SCFAs appear to be
reduced in FA patients. Of note, it has been shown that bacterial SCFAs
could protect against FA as a consequence of a high-fiber diet in mice.
Accordingly, a reduction in Bifidobacterium during infancy, with
a consequent reduction in SCFA levels is associated with an increased
risk of allergy6. In peanut allergy, oral dysbiosis,
reduced oral SCFA levels, and increased oral mucosal Th2 cytokine
secretion characterize patients affected, and low fecal SCFAs at a young
age could raise the risk of developing FA. Bile acid levels in stool
seem to be involved in FA development and persistence, but blood level
measurements are advocated to better characterize their role. Moreover,
sphingolipids may modulate the function of invariant natural killer T
cells and contribute to maintaining intestinal balance and protecting
against FA through the modulation of the mast cells’ responsiveness.
Sphingolipid dysmetabolism is involved in FA development as a
consequence of immune dysregulation in modulating the differentiation of
regulatory T cells and Th17 cells that is relevant in FA. Interestingly,
some fecal sphingolipids seem to confer protection against FA while
reduction of other of them seems to be associated with increased risk of
FA, likewise the reduction in serum sphingolipids. Unfortunately, no
definitive evidence is available to distinguish whether the
sphingolipids modulating this FA effect are dietary or
microbial-derived. Metabolites of tryptophan from kynurenine and indole
pathways are linked to the function of the intestinal barrier and
mucosal immune responses (mainly T regulatory cells) and contribute to
intestinal homeostasis. A reduction in these pathways is linked to
multiple FA in children. To date, the role of omega-3-polyunsaturated
fatty acids metabolites is not clearly defined in FA. However,
17-hydroxy-docosahexaenoic acid (17-HDHA) has been reported to inhibit
IgE production by B cells and to suppress the differentiation of naïve B
cells into IgE-secreting cells7.
The gut microbiome (GM) and its metabolic product, as previously
mentioned, play an important role in FA development. TheBifidobacteriaceae family and bacteria of theLactobacillales order are consistently reported lower in CMA
children. At the same time, the Firmicutes phylum, primarily
associated with the Clostridia class, is consistently increased
in mice and human studies. It seems discordant with the observation that
infants with resolved CMA were reported to have enrichedClostridia class at 3-6 months but with non-conclusive data.
However, Savova et al. showed that GM with enriched Clostridiaclass, reduced Lactobacillales order, and reducedBifidobacterium genus is associated with CMA in early life.
Emerging evidence shows that prebiotics, probiotics, and symbiotics, may
be a promising adjuvant in promoting tolerance acquisition. ElevatedBifidobacterium genus and reduced Clostridia class members
were consistently observed post-treatment with Bifidobacteriumstrains probiotics or after lactose-supplemented extensively hydrolyzed
formula (EHF) treatment strategy but with decreased levels ofLactobacillus genus in those treated with Bifidobacteriumstrains probiotics. Gaps remain in understanding the relationship
between microbiome and immune response and between transcriptomics
(including genes related to the immune response) and GM. In vivo ,Bifidobacterium bifidum has been shown to reduce allergy
symptoms, lower serum IgE and raise IgG2 levels, decrease the
pro-inflammatory cytokines (TNFα, IL- 1β, and IL-6), and increase the
anti-inflammatory cytokine IL-10 in CMA-patients8.
Recently, fiber diet has been shown to modulate the disease course of FA
through diet-driven changes in the GM9. It is
necessary to conduct further research on the impact of GM on FA
development and persistence.
Lastly, oral immunotherapy (OIT) may provide an active treatment that
enables to increase the amount of food that the patient can intake
without reaction during treatment (i.e., desensitization), and reduces
the risk of potential life-threatening allergic reaction in the event of
accidental ingestion10 Unfortunately, there are still
significant gaps in understanding the immune mechanisms following OIT,
but increasing knowledge about transcriptional pathways associated with
its outcomes is available to date11. Ashley et
al.12 show that OIT-induced remission of FA is linked
to the anergic T cell state mediated by anergy of memory T cells
associated with mantained T regulatory cell activity. Suppression of the
Th2 transcriptional signals in Th2A-like cells was linked to
desensitization following OIT. Moreover, the dampened Th2 and Th1
signatures in effector cells are linked with FA remission, while
baseline inflammatory signals in Th1 and Th17 effector cells were
associated with poorer outcomes following OIT. Type I interferons were
recently identified as potential regulators of remission following OIT
because of their key role in the suppression of the Th2 antigen response
through regulatory action on GATA3 and the high-affinity IgE
receptor. Moreover, an early transient increase in TGF-β producing cells
one year into treatment seems to be associated with good clinical
outcomes. In addition, persistent activation of FOXP3, expressed by T
regulatory cells, may be a critical requirement for lasting persistence
of remission12.
Comprehensive multi-omics studies are essential to understand FA
mechanistically, as highlighted by this Special Issue. “Omics” studies
of FA are of great interest as they allow for a thorough understanding
of the complexity of FA development and therapeutic outcomes. This has a
fundamental impact on approaches to precision medicine.