Nestlé Nutrition Institute Symposium held at the 2018 European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) meeting, Geneva, Switzerland

Optimising the Approach to Cow’s Protein Allergy The aim of this symposium was to gain a deeper understanding of food allergies, recognising the importance of reaching an early diagnosis, and considering the optimal management strategies that can be applied. The symposium also explored the role of the gut microbiota and its importance in the development of the immune system.

State-of-the-Art in Food Allergy with Special IgE-mediated food allergy is the most common, and its diagnosis is straightforward as food-specific IgE testing or a skin prick test is typically Focus on Cow’s Milk Protein Allergy positive for immediate reactions. The best treatment is avoidance and self- administered epinephrine for emergencies. Professor Kirsi Järvinen-Seppo Division of Pediatric Allergy and Immunology and Center Diagnosis in non-IgE-mediated and mixed aetiology food allergies is not for Food Allergy, University of Rochester Medical Center, based on specific IgE. In allergic proctocolitis, blood streaked mucousy, loose Rochester, NY, USA stools appear up to six months of age in breast-fed or formula-fed infants who are otherwise well.5-7 The inflammation is eosinophil-dominant and cow’s Food allergy is an immune system-mediated adverse reaction, milk and soy are the most common triggers, although viruses can produce to food, which can be IgE-mediated, non-IgE-mediated or of mixed aetiology. a similar reaction. Bleeding resolves within three days following complete The IgE-mediated presentation is characterised by anaphylaxis, food- elimination of the allergen from the infant’s diet, and sometimes that of the dependent exercise-induced anaphylaxis, urticaria, angioedema, immediate mother. GI symptoms, bronchospasm and pollen food allergy syndrome. The non-IgE- Acute FPIES typically starts in early childhood and presents with emesis 2 to 4 mediated response is characterised by Coeliac disease, allergic proctocolitis hours after ingestion of the food protein, usually cow’s milk, soy, rice or oats. and food protein-induced enterocolitis (FPIES) all of which are commonly Diarrhoea may follow within 8 to 24 hours and there is often an appearance caused by cow’s milk. The mixed aetiology reactions typically present with eosinophilic oesophagitis or eosinophilic gastroenteritis, atopic dermatitis and of sepsis, with lethargy, limpness, and the risk of shock due to dehydration. asthma, commonly associated with consumption of cow’s milk. There is an increased white cell count, acidosis and methemoglobulinaemia in around 15% of cases. Around 6 to 8% of children are affected by food allergy, with cow’s milk, egg, and peanut being the most common. The prevalence of cow’s milk protein In chronic FPIES, which occurs earlier at around 1 to 3 months, there is allergy (CMPA) varies from 1 to 10% depending on the country or region,1,2 watery diarrhoea, failure to thrive, mucousy stools with intermittent emesis with self-reported allergy being up to four times as common as food-challenge associated with continuous exposure to cow’s milk, or soy formula. Blood confirmed allergy. The disparity between self-reported and confirmed food tests often reveal a low total protein. allergy is particularly noticeable for CMPA.3 Allergic eosinophilic gastroenteropathy affects either the oesophagus or the Children typically outgrow allergies to cow’s milk, egg, soy and wheat, lower GI tract. Allergic eosinophilic oesophagitis can present from infancy whereas allergy to peanuts, tree nuts, fish and shellfish typically persists until to adulthood with reflux symptoms, dysphagia, failure to thrive, irritability, adulthood, with a prevalence of about 3 to 4%. and vomiting. Allergic eosinophilic gastroenteritis generally appears up to adolescence and is characterised by vomiting, pain, anorexia, hematemesis, and even hypoalbuminaemia. The most common trigger for both is cow’s milk. Prevalence of Food Allergy At a molecular level, IgE-mediated allergy begins with digestion of the protein, followed by absorption and processing by antigen presenting cells before •Affects more than 1-2%, but less than 10%1-2 •Meta-analysis (EuroPrevall)3: presentation to T cells. The T cells, particularly Th2 type cells orchestrate Milk Egg Peanut Fish Shellfish the B cells to produce specific IgE antibodies to milk protein which are then bound by high affinity IgE receptors on mast cells. Upon re-exposure to the Self-reported 12-13% 3.5% 1% 0.75% 0.6% 1.1% same foods, parts of these allergens (epitopes) cross link consecutive IgE Symptomatic/sensitized 3% 0.6% 0.9% 0.75% 0.2% 0.6% molecules, resulting in the release of lipid mediators such as histamine and OFC-confirmed 3% 0.9% 0.3% n/a 0.3% n/a tryptase, which are responsible for the typical manifestations of flushing, vasodilation, pruritus, bronchoconstriction and vascular permeability. 1Chafen JAMA 2010, 2Sicherer JACI 1011, 3Rona et al JACI 2007 T cells also synthesise lipid mediators such as IL-4 which is responsible for The most important milk allergens are caseins and proteins, including mast cell up-regulation. IgA and IgG antibodies can suppress this reactivity ß-lactoglobulin and -lactalbumin. Most people with are multi- by blocking antibodies and neutralising food antigens, and by T regulatory sensitised, and express IgE antibodies to a number of proteins. There is a high cells which suppress Th2 and mast cell activity. These molecules are key to level of cross-reactivity between the proteins of cow, and , but developing tolerance to food allergens. 1 2 3 lessChafen so between JAMA 2010, cow, Sicherer camel, JACI and1011, pig Rona milk et al and JACI even 2007 less between cow, horse The non-IgE-mediated presentation has much more variable aetiology and is and .4 not so well understood.

Satellite Symposium Proceeding for ESPGHAN 2018 1 Geneva, May 11th, 2018 Food allergies are a growing clinical problem, with a doubling of peanut ESPGHAN guidelines for the diagnosis and management of CMPA26 cases in the US from 1997 to 2003, and a further doubling to 2008,8,9 and an 18% increase in all food allergies.10 There is similar data for Canada, United Kingdom, and Australia.11-13 The main increase is seen for peanut and tree nuts (three to four-fold), compared to a two-fold increase for milk and egg allergy. A 2016 paper proposed three different hypotheses to account for the increase in food allergy.14 One hypothesis suggests that reduced levels of vitamin D may be responsible for the development of more allergic diseases and asthma. The hygiene hypothesis proposes that exposure to a less diverse microbiological environment might induce intolerance to allergens. The dual allergen exposure hypothesis proposes that competing routes of exposure have opposite effects on the development of sensitisation and tolerance. Normal development of CD103+ dendritic cells induces tolerance in the GI tract, therefore most people become tolerant to ingested food through the development of T regulatory cells. However, skin allergen exposure can also contribute to sensitisation especially in those with filaggrin mutation, or significant eczema. Through daily exposure to food proteins, dendritic cells in questions on medical cases. people with abnormal skin barrier function, can up-regulate IL-4 cytokines in Over 2500 completed assessments were returned. There were more females the Th2 type memory. Although a person may rigorously avoid exposure via (72%), and the largest age group was 55 to 64 years, both of which are the oral route there can be continuing allergen exposure through the skin, representative of the respective societies. The majority, 72%, worked in which can be particularly sensitising when oral exposure is limited. paediatric practice, and had more than 20 years’ experience. There were Introduction of peanuts to the diet of high risk infants with significant eczema very few sub-specialists, only 4% were allergy specialists, so the majority can be a powerful tool for inducing tolerance.15 However, it is not known of responders would be the first point of contact for children suspected of whether the same applies to other food allergens. Most children who develop having a food allergy. CMPA also have eczema: if there is early introduction to the allergen in the first “In which circumstances would you switch a 3-month old formula-fed weeks of life this may help to develop tolerance. infant with suspected CMPA from a normal infant formula to a special There may be a window of opportunity that includes not just infant feeding therapeutic formula?” practices, decreasing C-sections and early life antibiotics, but also maternal exposure, environment, pets, lifestyle, diet, allergen and microbial exposures A number of possible responses were given and multiple answers were that can shape the immune system to become tolerant or sensitised.16 There allowed. is good data to suggest that farm life can protect from the development of Of the given options, failure to thrive (poor feeding, weight loss of 300g over asthma and allergic rhinitis. It is not clear whether this also protects from food the previous three weeks) was most appropriate to the guidelines and was allergy, although our work is continuing on this topic. selected by 53% of respondents. Forty-three percent also voted for moderate ß-lactoglobulin is found in very small concentrations in some women’s breast atopic eczema on the face and trunk. However, the most popular choice, 60%, milk, and is related to maternal diet.17-20 ß-lactoglobulin induces symptoms was blood-streaked stools for one week. such as eczema and rashes in some highly sensitised babies.20-22 When Rectal bleeding is an alarming symptom. However it is seen in breast-fed cow’s milk is eliminated from the mother’s diet, the eczema clears, while and non-breast-fed infants without any other signs of organic disease.27 re-exposure to milk protein through the maternal diet causes the rashes to Studies have found that in the majority of young infants, rectal bleeding is re-appear. of short duration without any intervention.27,28 When children with short-term It is possible that low levels of antigen in could bring about rectal bleeding were examined it was found that the majority did not have 27,28 sensitisation, but if they are ingested along with tolerance-inducing breast eosinophilic colitis and had normal histology and macroscopic findings. milk immune factors such as IgA, TGFß and HMOs, the effect could be to About 20% were subsequently found to have CMPA. develop tolerance.21,22 This subject is still under investigation. Excessive crying was chosen by 25% but a recent systematic review of crying patterns in infants found that two hours is quite normal for a baby of The prognosis for CMPA is generally favourable. Eighty per cent of children three months.29 If the crying were to persist beyond four months of age or is outgrow their IgE-mediated CMPA by early adolescence and recurrence accompanied by other symptoms, it would be sensible to investigate further. is extremely uncommon.23 Development of tolerance is probably due to 24 recognition of linear epitopes on milk proteins: tolerance of is a “A 10 month old infant has a history of chronic diarrhoea and failure 25 good prognostic sign. Non-IgE-mediated manifestations such as proctocolitis to thrive. Which investigation is most useful to rule out a diagnosis of are usually outgrown by 1 year, FPIES by 3 to 4 years. However, the prognosis CMPA?” for eosinophilic oesophagitis is more variable and poorly understood. Only one answer was allowed and most respondents, 68%, chose the correct The Challenge of Correct Diagnosis and answer which is to eliminate products from the diet and to carry out a challenge test if the infant appears to improve. A negative blood test for Management of Cow’s Milk Protein Allergy IgE specific for cow’s milk protein does not rule out CMPA, and it is not possible to exclude or prove CMPA using skin prick tests: it must be followed Professor Sibylle Koletzko by an elimination and re-challenge procedure. Endoscopy with small bowel Dr von Hauner Children’s Hospital, Ludwig-Maximilian biopsies and elimination of lactose from the diet were only selected by a few University, Munich, Germany respondents and are not recommended.

It is very important to arrive at a correct diagnosis for cow’s “The same child is diagnosed with CMPA but refuses to take the milk protein allergy (CMPA), to ensure appropriate treatment extensively hydrolysed formula. Which alternatives may be given to the and monitoring, however, symptoms can be very broad and non-specific. In child?” 2012 ESPGHAN published practical diagnostic and management guidelines for CMPA.26 The three correct options are soy-based formulas (chosen by 51%), amino- We carried out a survey to assess awareness of the guidelines, whether acid based formula (62.5%) and milk-free rice-based baby cereals (56.5%). they were followed, and whether they were useful. Paediatricians in 13 It is of concern that 11% selected goat’s milk formula, as there is a high European countries were invited via their medical associations to answer degree of cross reaction to cow’s and goat’s milk: 90% of children with CMPA some basic demographic questions, and to respond to a number of also react to milk, which is therefore a dangerous option. A partially

2 Satellite Symposium Proceeding for ESPGHAN 2018 Geneva, May 11th, 2018 hydrolysed infant formula is also not safe in children with CMPA since many The Gut Microbiome in Infants with Cow’s Milk have an allergic reaction to the whey protein and peptides in these formulas.30 Protein Allergy – Implications for Treatment “A ten-week old exclusively breast-fed child with frequent regurgitation (4 to 5 times per day) is reported to have pain and to be uncomfortable. Doctor Christina West Clinical examination is normal, while length is within the 75th percentile Department of Clinical Sciences, Pediatrics, Umeå University, Sweden and weight within the 50th percentile. How would you proceed?” The greatest microbial influence to which the neonate is Three-quarters of respondents chose the recommended option which was to exposed is the maternal microbiota during delivery, although see the child again in two weeks for re-examination. Frequent regurgitation there is emerging evidence that the process of exposure may begin in the without any alarm symptoms in a ten week old is not a sufficiently strong womb, imprinting the microbiota of the offspring and the immune system reason to switch to a hydrolysed or amino acid formula (selected by 8%). A in preparation for birth.32 During infancy the baby continues to be exposed trial of acid suppressive therapy has been found to be no better than placebo to the maternal microbiota through breast milk. The microbial colonisation in this population.31 of the mucosal surfaces in the baby’s gastrointestinal tract will have a large influence on immune maturation. “A five-month old breast-fed infant develops swelling of the lips A number of maternal factors influence establishment of the baby’s and eyelids after drinking his second bottle of infant formula. Which microbiota, including maternal antibodies and nutrients, the transference of alternative milk or infant formula would you recommend?” which influence expansion of the gut innate immune cells, development of intestinal epithelial cells, mucus development and the expression of anti- The recommendation is to go back to complete breast-feeding (selected by microbial peptides and the secretion of antibodies.33 Together, these will only 26% of respondents). The most common choice (46%) was to recommend prevent translocation of the endogenous microbiota and avoid hyper-reactivity breast-feeding, but also to advise the mother to eliminate dairy from her own to micro-organism derived compounds and ultimately, food antigens. diet. As there is no risk of anaphylaxis through ingestion of the mother’s milk, we recommend the mother remain on a normal diet. If the baby subsequently In a healthy breast-fed baby the development of the microbiome is quite has a skin reaction then she should consider reducing or eliminating milk predictable. The early gut microbiota is abundant in Bifidobacteria and the from her own diet. But small amounts of dairy in the maternal diet may induce microbes that characterise the early stages of development are more capable of metabolising nutrients associated with breast-feeding, such as simple tolerance in the infant and therefore may be beneficial in the long run. carbohydrates. In the later stages the infant will have a gut microbiota that Other options were an extensively hydrolysed formula, an amino-acid based can digest solid foods.34 or a soy-based formula. These are acceptable choices if the mother cannot In the early years there is a successive establishment of the gut microbiota. resume breast-feeding. The facultative anaerobes such as E coli and Streptococcus species that “The mother in the previous case wishes to start weaning the child. dominate in the first few days, are followed byBifidobacteria, Bacteroides 35 What would you advise?” and Clostridium species due to oxygen deprivation. This is followed by successive establishment of new bacterial taxa and increased diversity which Fifteen and 25% of respondents respectively would avoid other potential progresses into the school years. allergens such as eggs or fish, or would not introduce complementary Several maternal factors influence susceptibility to allergic disease in infancy, feeding before six months. But recent guidelines suggest that there is no including the allergy phenotype, the maternal microbiota, mode of delivery reason to delay the introduction of solid foods in children with CMPA. The of the infant, and breast-feeding. There is increasing evidence that dysbiosis recommended approach is to introduce complementary feeding in the same of the intestinal microbiota in infancy, and reduced diversity precedes the way as with non-allergic infants, but to avoid any products with cow’s milk clinical manifestations of sensitisation, eczema, food and respiratory allergies. protein (chosen by 53%). However, a causal relationship has not been established.35 The establishment of the microbiota parallels the development of innate and “The child in the case above undergoes a blood test which is negative adaptive immune pathways. In individuals with high biodiversity there is an for specific IgE. Can the mother re-introduce dairy products to the increase in short-chain fatty acid (SCFA) production that has both nutritive child’s diet?” and inflammatory effects and brings about induction of the T regulatory cells. In individuals with low biodiversity and dysbiosis, IgE production and pro- A negative test for cow’s milk specific IgE does not always indicate an absence inflammatory responses are enhanced.36 of allergy, so dairy products should not be re-introduced on this basis (selected The CHILD (Canadian Healthy Infant Longitudinal Development) study by 7%). Thirty-six percent of respondents chose to recommend elimination of compared the gut microbiome of 166 children through faecal sampling at dairy products for the first year on the basis of the acute reaction experienced three and 12 months and looked at how this might be related to sensitisation to by the child. However, the recommended advice (chosen by 46%) is first food substances.37 Skin prick testing at one year identified twelve infants who to confirm the diagnosis with elimination of dairy products and then to re- were sensitised to at least one common food allergen. In the gut microbiota challenge in children with a negative test for specific IgE. If the challenge is of food-sensitised infants, Enterobacteriaceae were over-represented, while positive a therapeutic elimination diet until one year of age is justified. Bacteroidaceae were under-represented. The authors concluded that low gut In a child with a clear acute reaction, and a positive skin prick test, there is microbiota richness and an elevated Enterobacteriaceae / Bacteriodaceae no need for a challenge before proceeding with therapeutic elimination. But if ratio in early infancy are associated with subsequent food sensitisation. the test is negative then confirmation is needed to rule out other alternatives, An interesting area of current study is that of the toll-like receptors (TLRs) such as a reaction to cereal, porridge or other products. that we believe are the ancient “gate keepers” of innate immunity. They are To summarise: CMPA is common, affecting 2 to 3% of children, but diagnosis expressed on epithelial cells, endothelial cells and on leukocyte subsets in can be difficult. Symptoms are non-specific, such as eczema (50% of cases), the blood. TLRs have evolved in mammals to recognise conserved structural gut dysmotility (diarrhoea and constipation), frequent regurgitation, abdominal molecules unique to microbes, allowing them to detect the presence of pain, refusal to feed, malabsorption and failure to thrive. Diagnostic proof is infection and to induce activation of inflammatory and antimicrobial innate essential: improvement must be seen upon elimination of cow’s milk products, immune responses. Recently it has been shown that T regulatory cells also followed by an adverse response to a cow’s milk protein re-challenge after express TLRs. When these TLRs are activated they can increase or decrease symptoms have subsided. Endoscopy and histology can be helpful but are the suppressor activity of T regulatory cells providing an important link rarely needed. A positive specific IgE or skin prick test is indicative but does between innate and adaptive immunity. not provide a diagnosis; while a negative test for specific IgE does not exclude It has been reported that allergic children show exaggerated inflammatory the diagnosis. Our survey results demonstrated that not all paediatricians are responses to TLR-activation before the onset of allergic disease, but these aware of these points and further education is needed. exaggerated responses decrease with age. The early hyper-responsiveness

Satellite Symposium Proceeding for ESPGHAN 2018 3 Geneva, May 11th, 2018 fails to translate into a corresponding maturation of TH1 function which The aim of intervening to treat food allergy and CMPA is to induce a tolerogenic remains attenuated compared to that seen in non-allergic subjects.38 It has environment in the gut. This can be achieved by dietary interventions such as also been demonstrated that allergic children have immature T regulatory the addition of fibre, pre-, pro-, and synbiotics or lactose to infant formula. functions.39 Human milk is plentiful in lactose and complex carbohydrates which have We hypothesised that this deviant innate immune maturation might be many bioactive properties, so the addition of lactose and human milk dependent on microbial exposure. In a nested case control study in a high oligosaccharides (HMOs) can also be beneficial. The interventions should risk cohort in Australia, stool samples were taken from atopic mothers in the increase mucus production, reinforce gut barrier integrity, stimulate the third trimester of pregnancy and their infants were followed for the first two production of SCFAs, stimulate or dampen the innate immune responses, 40,44 and a half a years of life.40 Stool samples were taken from the infants at one induce T regulatory cells and dampen reactive clones. week, and at one and twelve months and the infants were clinically assessed To summarise, variations in the gut microbiota have been implicated in at repeated intervals until two and half years of age. The development of the development of CMPA and microbial signatures have been associated the microbiome in children that were sensitised to milk, egg, or peanuts and with tolerance acquisition. However at this stage meta-genomic studies also had eczema, was compared to that of healthy controls, who had no are needed to enable higher resolution of the microbes involved and for sensitisation, eczema, or other allergic manifestations. the understanding of functional relevance. Prebiotics (including lactose), Blood samples were taken at six months and were cultured with specific probiotics and synbiotics may influence gut microbiota composition in cow’s microbial ligands for TLR2, a principle receptor for Gram positive bacteria, and milk allergy and HMOs may have therapeutic potential in the treatment of TLR4 which is the principle receptor Gram negative bacteria. With infants who CMPA. developed IgE associated eczema and food sensitisation, it was found that the mothers also had a lower -diversity of the main bacterial group, Bacteroidetes, in their stool. There was also a reduced abundance of Enterobacteriaceae References: in the infants who developed atopic eczema, and an inverse association 1. Chafen et al. JAMA 2010;303:1848-56. between levels of Enterobacteriaceae TLR-4 induced TNF- . This suggests 2. Sicherer SH. JACI 2011;127:594-602. that when there is a reduced abundance of potentially immunomodulatory 3. Rona et al. JACI 2007;120:638-46. bacteria in the gut this may be associated with exaggerated inflammatory 4. Järvinen et al. Curr Opin Allergy Clin Immunol 2009;9:251-8. cytokine responses to TLR ligands and may influence the development of 5. Arvola et al. Pediatrics 2006;117:e760-8. innate immune response patterns. 6. Lake AM. JPGN 2000;30:S58-60. 7. Ohtsuka et al. JACI 2012;129:1676-8. There are also some interesting associations between the gut microbiome and 8. Sicherer et al. JACI 2003;112:1203-7. cow’s milk protein allergy (CMPA). An observational study carried out by the 9. Sicherer et al. JACI 2010;125:1322-6. Consortium of Food Allergy study involved 226 children who were enrolled in 10. Branum et al. Pediatrics 2009;124:1549-55. infancy. All of the involved children had IgE-mediated CMPA, and the children 11. Grundy et al. JACI 2002;110:784-9. were followed with clinical evaluation, milk-specific IgE levels, skin prick test 12. Mullins RJ. Med J Aust 2007;186:618-21. and stool samples at entry, 6 months, 12 months and then annually until eight 13. Ben-Shoshan et al. JACI 2010;125:1327-35. years of age. Milk allergy had resolved at this age in 56.6% of the children.41 14. Du Toit et al. JACI 2016;137:998-1010. Using principal coordinate analysis (PCoA) there was a distinct gut microbiome 15. Du Toit et al. NEJM 2015;372:803-13. in three to six month old subjects whose allergy had resolved, compared to 16. Cho et al. Nat Rev Genet 2012;13:260-70. those whose allergy persisted. This was not seen in subjects sampled later on 17. Høst et al. Acta Paediatr Scand 1988;77:663-70. at seven to 12 months. Taxa within the Clostridia class in the Firmicutes phylum 18. Høst et al. Clin Exp Allergy 1990;20:383-7. were enriched in children with resolution of milk allergy, while Bacteroidetes 19. Sorva et al. JACI 1994;93:787-92. and Enterobacter were seen in subjects whose milk allergy did not resolve. 20. Järvinen et al. J Pediatr 1999;135:506-12. This demonstrates that early microbiome composition is associated with the 21. Järvinen et al. JACI 2015;135:1390-3. development of tolerance versus persistence of milk allergy. However, the 22. Seppo et al. JACI 2017;139:708-11. resolution of this analysis was low. In a more recent study there have been 23. Skripak et al. JACI 2007;120:1172-7. efforts to attempt a higher resolution. In a study of 82 children with atopic 24. Järvinen et al. JACI 2002;110:293-7. dermatitis, with and without food allergy, faecal samples were analysed using 25. Nowak-Wegrzyn et al. JACI 2008;122:342-7. 16S rRNA microbial analysis.42 Four microbial species were found to be under- 26. Koletzko et al. J Pediatr Gastroenterol Nutr 2012;55:221-9. represented in children with confirmed food allergy:Bifidobacterium breve, 27. Arvola et al. Pediatrics 2006;117:e760-8. Bifidobacterium adolescentis, Faecalibacterium prausnitzii, and Akkermansia 28. Molnar et al. World J Gastroenterol 2013;19:3824-30. muciniphila. Notably, in one of our recent studies, Faecalibacterium prausnitzii 29. Wolke et al. J Pediatr 2017;185:55-61. was associated with a tolerogenic systemic immune response.43 30. Giampietro2018 et al. Pediatr-05- 08Allergy Immunol 2001;12:83-6. It is clear that post-natal exposure will promote development of oral tolerance 31. Orenstein et al. J Pediatr 2009;154:514-20. through colonisation of the gut and the introduction of food antigens. Human 32. West et al. Exp Review Clin Immunol 2016;12:625-39. milk has a plentiful supply of bioactive factors with immunomodulating 33. Macpherson et al. Nat Rev Immunol 2017;17:508-17. capacity. 34. Subramanian et al. Cell 2015;161:36-48. 35. Garn et al. JACI 2013;131:1465-78. 36. Simonyté Sjödin et al. Curr Opin Allergy Clin Immunol 2016;16:390-5. POSTNATAL EXPOSURES PROMOTE 37. Azad et al. Clin Exp Allergy 2015;45:632-43. TOLERANCE DEVELOPMENT 38. Tulic et al. JACI 2011;127:470-8. 39. Smith et al. JACI 2008;121:1460-6. 40. West et al. Clin Exp Allergy 2015;45:1419-29. Colonization Food antigens 41. Bunyavanich et al. JACI 2016;138:1122-30. 42. Fieten et al. Int Arch Allergy Immunol 2018;175:77-84. 43. Simonyté Sjödin et al. Allergy 2018 https://doi.org/10.1111/all.13485. 44. Heine. Ann Nutr Metab 2018;72:33-45. ORAL TOLERANCE

Immunomodulating capacity – Human milk

UMEÅ UNIVERSITY 4 Satellite Symposium Proceeding for ESPGHAN 2018 Geneva, May 11th, 2018

AIM OF INTERVENTIONS

Induce a tolerogenic • Increase mucus production environment in the gut and Reinforce gut barrier integrity to promote tolerance • acquisition • Stimulate the production of SCFA MICROBIAL MODULATORS • Stimulate/dampen innate • Diet (fiber) immune responses o Probiotics • Induce Tregulatory cells o Prebiotics Dampen reactive clones o Synbiotics o o Human milk oligosaccharides

UMEÅ UNIVERSITY

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