Human Milk Oligosaccharides (HMOs) have been proposed to be instrumental in building immune competence. To explore the role of HMOs in allergy prevention, twenty-one HMOs were quantified in breast milk samples and associated with sensitisation in infants. 2 '-fucosyllactose (2 '-FL) levels were positively associated with an increased risk of sensitisation, atopic dermatitis and recurrent skin rash. Interestingly, 2 '-FL levels, ranging from 1.35 to 1.95 g/L, were associated with a higher prevalence of non-allergic and non-sensitised infants. The role of 2 '-FL and lacto-N-neotetraose (LNnT) was further investigated in allergic sensitisation models in vivo. Oral administration of HMOs decreased allergic sensitisation. This was associated with gut microbiota and short-chain fatty acid (SCFA) production changes. Aligned with the clinical associations, the decreased sensitisation was not observed with lower and higher tested doses of the HMOs supporting a U-shape association between 2 '-FL and LNnT levels and allergic sensitisation risk reduction in humans and mice.Trial registration: ClinicalTrials.gov identifier: NCT02550236.

The human intestinal microbiota has been shown to be modulated during inflammatory conditions. Probiotic administration has been shown to affect the immune system and cytokine expression which can affect inflammation and health outcomes. There seems to be an association between the mother's intestinal microbiota and inflammation biomarkers, both of which may contribute to newborn early life immune and metabolic programming and impact short and long-term health outcomes. Probiotic supplementation during pregnancy has been shown to influence metabolic health, immunity, and gastrointestinal health of the mother, and can also have carry-over benefits to infants such as infant allergy risk reduction. Therefore, this review focuses on the evidence of probiotic administration in women of reproductive age, including during pregnancy and its impact on inflammatory markers and on maternal and infant health. We performed a PubMed search for articles published in English in the last 20 years. Immune markers were narrowed to serum and breast milk levels of TNF-α, IL-6 and TGF-β, IgA, and IL-10. Studies that investigated the beneficial effects of interventions in women with gestational diabetes mellitus, polycystic ovarian syndrome, and infant allergy management are summarized. These results show a beneficial or neutral effect on selected health outcomes and that it is safe for woman and their infants. The effect of probiotics on modulation of inflammatory markers was probiotic specific. More research is needed to further our understanding of the mechanisms underlying the effects of probiotics on inflammation and how these effects improve health outcomes.

Specific partially hydrolysed whey-based infant formulas (pHF-W) have been shown to decrease the risk of atopic dermatitis (AD) in infants. Historically, AD has been associated primarily with milk allergy; however, defective skin barrier function can be a primary cause of AD. We aimed to ascertain whether oral supplementation with pHF-W can improve skin barrier function. The effect of pHF-W was assessed on transepidermal water loss (TEWL) and antibody productions in mice epicutaneously exposed to Aspergillus fumigatus. Human primary keratinocytes were stimulated in vitro, and the expression of genes related to skin barrier function was measured. Supplementation with pHF-W in neonatal mice led to a significant decrease in TEWL and total IgE, but not in allergen-specific antibody levels. The whey hydrolysate was sufficient to decrease both TEWL and total IgE. Aquaporin-3 gene expression, linked with skin hydration, was modulated in the skin of mice and human primary keratinocytes following protein hydrolysate exposure. Skin barrier improvement may be an additional mechanism by which pHF-W may potentially reduce the risk of AD development in infants. Further human studies are warranted to confirm the clinical efficacy of these observations.

Human clinical trials have shown that a specific partially hydrolyzed 100% whey-based infant formula (pHF-W) reduces AD risk in the first yeast of life. Meta-analyses with a specific pHF-W (pHF-W1) confirm a protective effect while other meta-analyses pooling different pHF-W show conflicting results. Here we investigated the molecular composition and functional properties of the specific pHF-W1 as well as the stability of its manufacturing process over time. This specific pHF-W1 was compared with other pHF-Ws. We used size exclusion chromatography to characterize the peptide molecular weight (MW), a rat basophil degranulation assay to assess the relative level of beta-lactoglobulin (BLG) allergenicity and a preclinical model of oral tolerance induction to test prevention of allergic sensitization. To analyze the exact peptide sequences before and after an HLA binding assay, a mass cytometry approach was used. Peptide size allergenicity and oral tolerance induction were conserved across pHF-W1 batches of production and time. The median MW of the 37 samples of pHF-W1 tested was 800 ± 400 Da. Further oral tolerance induction was observed using 10 different batches of the pHF-W1 with a mean reduction of BLG-specific IgE levels of 0.76 log (95% CI = −0.95; −0.57). When comparing pHF-W1 with three other formulas (pHF-W2 3 and 4), peptide size was not necessarily associated with allergenicity reduction in vitro nor oral tolerance induction in vivo as measured by specific IgE level (p < 0.05 for pHF-W1 and 2 and p = 0.271 and p = 0.189 for pHF-W3 and 4 respectively). Peptide composition showed a limited overlap between the formulas tested ranging from 11.7% to 24.2%. Furthermore nine regions in the BLG sequence were identified as binding HLA-DR. In conclusion, not all pHF-Ws tested have the same peptide size distribution decreased allergenicity and ability to induce oral tolerance. Specific peptides are released during the different processes used by different infant formula producers.

BackgroundNumerous studies have shown that specific components of breast milk, considered separately, are associated with disease status in the mother or the child using univariate analyses. However, very few studies have considered multivariate analysis approaches to evaluate the relationship between multiple breast milk components simultaneously.AimHere we aimed at visualizing breast milk component complex interactions in the context of the allergy status of the mother or the child.MethodsMilk samples were collected from lactating mothers participating in the Leipziger Forschungszentrum für Zivilisationskrankheiten (LIFE) Child cohort in Leipzig, Germany. A total of 156 breast milk samples, collected at 3 months after birth from mother/infant pairs, were analyzed for 51 breast milk components. Correlation, principal component analysis (PCA) and graphical discovery analysis were used.ResultCorrelations ranging from 0.40 to 0.96 were observed between breast milk fatty acid and breast milk phospholipids levels and correlations ranging from 0 to 0.76 between specific human milk oligosaccharides (HMO) were observed. No separation of the data based on the risk of allergy in the infants was identified using PCA. When graphical discovery analysis was used, dependencies between maternal plasma immunoglobulin E (IgE) level and the breast milk immune marker transforming growth factor-beta 2 (TGF-ß2), between TGF-ß2, breast milk immunoglobulin A (IgA) and TGF-ß1 as well as between breast milk total protein and birth weight were observed. Graphical discovery analysis also exemplifies a possible competition for the fucosyl group between 2'FL, LNFP-I and 3'FL in the HMO group. Additionally, dependencies between immune component IgA and specific HMO (6'SL and blood group A antigen tetraose type 5 or PI-HMO) were identified.ConclusionGraphical discovery analysis applied to complex matrices such as breast milk composition can aid in understanding the complexity of interactions between breast milk components and possible relations to health parameters in the mother or the infant. This approach can lead to novel discoveries in the context of health and diseases such as allergy. Our study thus represents the first attempt to visualize the complexity and the inter-dependency of breast milk components.

Background: Eosinophilic esophagitis (EoE) is commonly associated with concomitant atopic diseases including atopic dermatitis (AD) and allergic airway (AA) diseases including asthma. Despite this link and the shared pathologic features across these three disorders, detailed analyses of the unifying molecular pathways are lacking. Objectives: We sought to investigate the mRNA expression profile overlap between EoE, AA, and AD and to identify the involvement of interleukin 13 (IL-13) in modulating gene expression. Methods: Whole-genome mRNA expression analyses were performed on tissue specimens (biopsies or nasal brushes) from patients with EoE, AD, and AA, and IL-13-stimulated primary human epithelial cells from the esophagus, the skin, and the airways. Results: By human disease expression profiles, EoE evidenced a significantly higher overlap (p = 0.0006) with AD (181 transcripts; 10%) than with AA (124 transcripts, 7%). Only 18 genes were found to be commonly dysregulated among the three diseases; these included filaggrin, histamine receptor H1, claudin 1, cathepsin C, plasminogen activator urokinase receptor, and suppressor of cytokine signaling 3. Ontogenetic analysis revealed a common immune/inflammatory response among the three diseases and a different epithelial response (epidermal cell differentiation) between EoE and AA. The overlap between the IL-13-stimulated epithelial cell transcriptome and the respective disease transcriptome was 22, 9, and 5% in EoE, AD, and AA, respectively, indicating a greater involvement of the IL-13 pathway in EoE than AA (p = 0.0007) or AD (p = 0.02). Conclusion: EoE, AD, and AA share a common set of disease-specific transcripts, highlighting common molecular etiology. Their comparative analysis indicates relatively closer relationships between EoE and AD, particularly centered around IL-13-driven pathways. Therefore, these findings provide an increased rationale for shared therapeutic strategies.

Background: Gut microbial fermentation products, short-chain fatty acids (SCFAs) have recently been described to play a beneficial role in asthma and allergic airway inflammation. The mechanisms behind this remain partly unclear. Aims: To investigate presence of SCFAs in airway fluids of healthy controls and people with asthma and the effect of SCFAs on airway epithelium. Methods: Targeted metabolomics (GC-MS) was used in two different studies to assess the presence of SCFAs. In the first study, bronchial alveolar lavage (BAL) samples from healthy controls (n=10) and people with mild to moderate asthma (n=28) were assessed, whereas in the second study, sputum samples from people with asthma (n=102) were evaluated. Additionally, the response of normal human bronchial epithelial cells (NHBE) to SCFAs was investigated. Results: The three main SCFAs (acetate, propionate and butyrate) were detected in µM concentrations in BAL samples of healthy controls and people with asthma, with acetate being significantly higher in people with asthma compared to healthy controls (P=0.0308). Presence of SCFAs in sputum samples was 5-times more abundant than in BAL samples of people with asthma. Furthermore, treatment of bronchial epithelial cells with similar concentrations of acetate and propionate to those found in sputum samples, resulted in decreased gene expression of SCFA receptors and increased expression of IL-6 and eotaxin-3. Conclusions: We report significantly increased concentrations of acetate in the airways of people with asthma compared to the airways of healthy controls. Our in vitro work suggests that treatment with SCFAs may induce a pro-inflammatory response in human bronchial epithelial cells.

Significant efforts are necessary to introduce new dietary protein sources to feed a growing world population while maintaining food supply chain sustainability. Such a sustainable protein transition includes the use of highly modified proteins from side streams or the introduction of new protein sources that may lead to increased clinically relevant allergic sensitization. With food allergy being a major health problem of increasing concern, understanding the potential allergenicity of new or modified proteins is crucial to ensure public health protection. The best predictive risk assessment methods currently relied on are in vivo models, making the choice of endpoint parameters a key element in evaluating the sensitizing capacity of novel proteins. Here, we provide a comprehensive overview of the most frequently used in vivo and ex vivo endpoints in murine food allergy models, addressing their strengths and limitations for assessing sensitization risks. For optimal laboratory-to-laboratory reproducibility and reliable use of predictive tests for protein risk assessment, it is important that researchers maintain and apply the same relevant parameters and procedures. Thus, there is an urgent need for a consensus on key food allergy parameters to be applied in future food allergy research in synergy between both knowledge institutes and clinicians.

Background/Aims: Atopic dermatitis (AD) is a common disease in infancy, for which topical steroids are the first-line therapy but have side effects. Innovative approaches are needed to reduce the burden of AD and corticosteroid usage in infants. Methods: The once-daily consumption of heat-treated probiotic Lactobacillus paracasei GM-080 or placebo for 16 weeks as supplementary approach to topical treatment with fluticasone propionate cream was compared in AD infants aged 4-30 months. Outcomes were SCORAD and its subscores, TEWL, Infants' Dermatitis Quality of Life Index (IDQOL), corticoid "sparing effect," CCL17/TARC, and IgE status. Results: SCORAD, objective SCORAD, itching, and IDQOL decreased significantly (p < 0.001) over the treatment period in both treatment groups. Slight decreases (ns) were noted in TEWL in lesional and unaffected skin and CCL17 levels. There were no differences between the treatment groups. Total IgE increased over the treatment period in both groups, with significantly higher increase in the heat-treated probiotic group (p = 0.038). There was no evidence of a corticoid "sparing effect" by the probiotic. Conclusions: In this design, the probiotic L. paracasei was not beneficial as a complementary approach to topical corticosteroids in infants with AD. However, slight beneficial effects may have been masked by the moderate potency corticoid. (c) 2019 S. Karger AG, Basel

Basel • Freiburg • Hartford • Oxford • Bangkok • Dubai • Kuala Lumpur • Melbourne • Mexico City • Moscow • New Delhi • Paris • Shanghai • Tokyo Founded 1950 by D. Harley, P. Kallós, W. Löffler and F.W. Wittich Continued by E.A. Brown (1952–1954), W. Kaufman (1955–1967), F. Hahn (1961–1972), H.C. Goodman (1963–1975), R.R.A. Coombs (1955–1984), Z. Trnka (1972–1987), P. Kallós (1950–1988), G.B. West (1959–1991), J. Bienenstock (1990–1991), L.Å. Hanson (1981–1991), K. Kano (1982–1991), F. Milgrom (1965–1991), K. Rother (1982–1991), G. Wick (1991–1997), B. Grubeck-Loebenstein (1991–1997), D. Kraft (1998–2002) R. Valenta (2003–2017), B. Bohle (2013–2017) Official Journal of the

Basel • Freiburg • Hartford • Oxford • Bangkok • Dubai • Kuala Lumpur • Melbourne • Mexico City • Moscow • New Delhi • Paris • Shanghai • Tokyo Founded 1950 by D. Harley, P. Kallós, W. Löffler and F.W. Wittich Continued by E.A. Brown (1952–1954), W. Kaufman (1955–1967), F. Hahn (1961–1972), H.C. Goodman (1963–1975), R.R.A. Coombs (1955–1984), Z. Trnka (1972–1987), P. Kallós (1950–1988), G.B. West (1959–1991), J. Bienenstock (1990–1991), L.Å. Hanson (1981–1991), K. Kano (1982–1991), F. Milgrom (1965–1991), K. Rother (1982–1991), G. Wick (1991–1997), B. Grubeck-Loebenstein (1991–1997), D. Kraft (1998–2002) R. Valenta (2003–2017), B. Bohle (2013–2017) Official Journal of the

Limited evidence is available regarding the effect of partially hydrolyzed whey-based formula (pHF-W) on growth and atopic dermatitis (AD) risk reduction in infants within the general infant population, and without a familial history of allergy as an inclusion or exclusion criterion. We reviewed the current evidence available from studies using pHF-W in the general population and summarized the data on safety (growth) and efficacy outcomes (reduction of AD), comparing the studies side by side. A total of 8 clinical trials were identified from the literature search, 7 of which used the same pHF-W. Six out of 8 studies indicated a reduction of atopic manifestations using a specific pHF-W versus cow's milk formula (CMF) in the first years of life. Data were summarized and compared side by side for growth (3 studies) and efficacy (5 studies). In these diverse general populations, the results on growth and AD were consistent with the previous findings reported on infants with a family history of allergy, but numerous limitations to these studies were identified. This literature review confirms that pHF-W supports normal growth in infants, and suggests that the risk of AD may be reduced in not-fully breastfed infants from the general population when supplemented with a specific pHF-W when compared to CMF during the first 4-6 months of life. Further studies are warranted to confirm these results. (C) 2018 The Author(s) Published by S. Karger AG, Basel

Eosinophilic esophagitis (EoE) represents a chronic, local immune-mediated esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Other systemic and local causes of esophageal eosinophilia should be excluded. Clinical manifestations or pathologic data should not be interpreted in isolation. EoE was first described as a distinct disease entity in 1993. Most patients are diagnosed with underlying food allergies. The first diagnostic and therapeutic guidelines were published in 2007 with a first update in 2011. In 2017, new international guidelines were published based on the GRADE methodology. These guidelines provide, among many other topics, insights on the role of proton pump inhibitor-responsive esophageal eosinophilia. Over the last two decades, considerable progress was made by stakeholders regarding the understanding of EoE's pathogenesis, genetic background, natural history, allergy workup, standardization of assessment of disease activity, evaluation of minimally invasive diagnostic tools, and new therapeutic approaches. This brief review provides further insights into latest diagnostic and therapeutic advances.

Basel • Freiburg • Hartford • Oxford • Bangkok • Dubai • Kuala Lumpur • Melbourne • Mexico City • Moscow • New Delhi • Paris • Shanghai • Tokyo Founded 1950 by D. Harley, P. Kallós, W. Löffler and F.W. Wittich Continued by E.A. Brown (1952–1954), W. Kaufman (1955–1967), F. Hahn (1961–1972), H.C. Goodman (1963–1975), R.R.A. Coombs (1955–1984), Z. Trnka (1972–1987), P. Kallós (1950–1988), G.B. West (1959–1991), J. Bienenstock (1990–1991), L.Å. Hanson (1981–1991), K. Kano (1982–1991), F. Milgrom (1965–1991), K. Rother (1982–1991), G. Wick (1991–1997), B. Grubeck-Loebenstein (1991–1997), D. Kraft (1998–2002) R. Valenta (2003–2017), B. Bohle (2013–2017) Official Journal of the

OBJECTIVES:For technical reasons, the histologic characterization of eosinophilic esophagitis (EoE)-specific alterations is almost exclusively based on those found in the esophageal epithelium, whereas little is known about subepithelial abnormalities. In this study, we aimed to systematically assess the nature of subepithelial histologic alterations, and analyze their relationship with epithelial histologic findings, endoscopic features, and symptoms. METHODS:Adult patients with established EoE diagnosis were prospectively included during a yearly follow-up visit. Patients underwent assessment of clinical, endoscopic, and histologic disease activity using EoE-specific scores. RESULTS:We included 200 EoE patients (mean age 43.5±15.7 years, 74% males) with a median peak count of 36 intraepithelial eosinophils/hpf (IQR 14-84). The following histologic features were identified in the subepithelial layer: eosinophilic infiltration (median peak count of 20 eosinophils/hpf (IQR 10-51)), eosinophil degranulation (43%), fibrosis (82%), and lymphoid follicles (56%). Peak intraepithelial eosinophil counts were higher, identical, and lower when compared to the subepithelial layer in 62.5%, 7%, and 30.5% of patients, respectively. Anti-eosinophilic treatment at inclusion did not influence the relation between subepithelial and epithelial peak eosinophil counts. Subepithelial histologic activity correlated with epithelial histologic activity (rho 0.331, P<0.001), endoscopic severity (rho 0.208, P=0.003), and symptom severity (rho 0.179, P=0.011). Forty percent (21/52) of patients with <15 intraepithelial eosinophils/hpf had subepithelial peak counts of ≥15/hpf. CONCLUSIONS:There is a significant but modest correlation between subepithelial histologic activity and epithelial histologic activity, endoscopic severity, and symptom severity. The long-term clinical impact of assessing subepithelial alterations in EoE needs to be further elucidated.