Molecularly defined adult-type hypolactasia in school-aged children with a previous history of cow's milk allergy

AIM： To assess the role of lactase non-persistence/per- sistence in school-aged children and their milk-related symptoms. METHODS： The genotypes for the C/T-13910 variant associated with lactase non-persistence/ persistence were determined using PCR-minisequencing in a group of 172 children with a mean age of 8.6 years （SE = 0.02, 93 boys） participating in a follow-up study for cow＇s milk allergy. The parents were asked to assess their children＇s milk consumption and abdominal symptoms. RESULTS： The presence of allergy to cow＇s milk was not associated with the C/C-13910 genotype related with a decline of lactase enzyme activity during childhood （lactase non-persistence）. The frequency of the C/C-13910 genotype （16%） was similar to published figures for the prevalence of adult-type hypolactasia in Finland. The majority of the children （90%） in this series consumed milk but 26% of their families suspected that their children had milk-related symptoms. Forty-eight percent of the children with the C/C-13910 genotype did not drink milk at all or consumed a low lactose containing diet prior to the genotyping （P〈 0.004 when compared to the other genotypes）. CONCLUSION： Analysis of the C/T-13910 polymorphism is an easy and reliable method for excluding adult-type hypolactasia in children with milk-related symptoms. Genotyping for this variant can be used to advise diets for children with a previous history of cow＇s milk allergy.

Milk fat globule membrane supplementation protects againstβ-lactoglobul-ininduced food allergy in mice via upregulation of regulatory T cells and enhancement of intestinal barrier in a microbiota-derived short-chain fatty acids manner

Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects and possible underlying mechanisms of MFGM on cow’s milk allergy(CMA)in aβ-lactoglobulin(BLG)-induced allergic mice model.MFGM was supplemented to allergic mice induced by BLG at a dose of 400 mg/kg body weight.Results demonstrated that MFGM alleviated food allergy symptoms,decreased serum levels of lipopolysaccharide,pro-inflammatory cytokines,immunoglobulin(Ig)E,Ig G1,and Th2 cytokines including interleukin(IL)-4,while increased serum levels of Th1 cytokines including interferon-γand regulatory T cells(Tregs)cytokines including IL-10 and transforming growth factor-β.MFGM modulated gut microbiota and enhanced intestinal barrier of BLG-allergic mice,as evidenced by decreased relative abundance of Desulfobacterota,Rikenellaceae,Lachnospiraceae,and Desulfovibrionaceae,while increased relative abundance of Bacteroidetes,Lactobacillaceae and Muribaculaceae,and enhanced expressions of tight junction proteins including Occludin,Claudin-1 and zonula occludens-1.Furthermore,MFGM increased fecal short-chain fatty acids(SCFAs)levels,which elevated G protein-coupled receptor(GPR)43 and GPR109A expressions.The increased expressions of GPR43 and GPR109A induced CD103+dendritic cells accumulation and promoted Tregs differentiation in mesenteric lymph node to a certain extent.In summary,MFGM alleviated CMA in a BLG-induced allergic mice model through enhancing intestinal barrier and promoting Tregs differentiation,which may be correlated with SCFAs-mediated activation of GPRs.These findings suggest that MFGM may be useful as a promising functional ingredient against CMA.

Maternal obesity exacerbates the responsiveness of offspring BALB/c mice to cow's milk protein-induced food allergy

Food allergy has become a significant public health problem affecting a large number of people worldwide.Maternal obesity causes inflammation and alters the immune system of offspring,which may exacerbate their food allergy.The aim of this study was to determine whether offspring mice born to obese mothers would have more serve reactions to cow's milk protein-induced food allergy,and further investigate the underlying mechanisms.Female offspring BALB/c mice of mothers with normal and high-fat diets were sensitized withβ-lactoglobulin(BLG),respectively.Maternal obesity increased the serum immunoglobulin E and mouse mast cell protease levels,though did not have significant influence on anaphylactic symptom score,core temperature and diarrhea rate of offspring mice after BLG sensitization.Furthermore,maternal obesity led to a lower level of occludin mRNA expression in BLG-sensitized mice.The mice born to obese mothers exhibited increased mRNA expression levels of GATA-3,interleukin(IL)-4 and IL-10 in jejunum after BLG sensitization,indicating maternal obesity intensified Th2-type biased immune responses.In conclusion,maternal obesity exerted exacerbating effects on the responsiveness of their offspring to cow's milk protein sensitization.

Very early onset perinatal constipation:Can it be cow’s milk protein allergy?

Delayed passage of meconium or constipation during the perinatal period is traditionally regarded as a signal to initiate further work up to evaluate for serious diagnoses such as Hirschsprung’s disease(HD),meconium ileus due to Cystic Fibrosis,etc.The diagnosis of HD particularly warrants invasive testing to confirm the diagnosis,such as anorectal manometry or rectal suction biopsy.What if there was another etiology of perinatal constipation,that is far lesser known?Cow’s milk protein allergy(CMPA)is often diagnosed in infants within the first few weeks of life,however,there are studies that show that the CMPA allergen can be passed from mother to an infant in-utero,therefore allowing symptoms to show as early as day one of life.The presentation is more atypical,with perinatal constipation rather than with bloody stools,diarrhea,and vomiting.The diagnosis and management would be avoidance of cow's milk protein within the diet,with results and symptom improvement in patients immediately.Therefore,we discuss whether an alternative pathway to address perinatal constipation should be further discussed and implemented to potentially avoid invasive techniques in patients.This entails first ruling out CMPA with safe,noninvasive techniques with diet modification,and if unsuccessful,then moving forward with further diagnostic modalities.

Efficient reduction ofβ-lactoglobulin allergenicity in milk using Clostridium tyrobutyricum Z816

Milk allergy is one of the most common food allergies,affecting 6%of young children,andβ-lactoglobulin(β-LG)is the main milk allergen.Clostridium tyrobutyricum Z816 was selected for the degradation ofβ-LG,which was successfully reduced by about 90%using permeabilized bacteria under the optimized conditions.The hydrolyzed peptides were identified by liquid chromatography-tandem mass spectrometry(LC-MS/MS)and analyzed by molecular modeling,which indicated that C.tyrobutyricum Z816 could effectively degrade the antigenic epitopes ofβ-LG.Finally,the concentration and digestibility ofβ-LG in actual samples was quantified using enzyme-linked immunosorbent assay(ELISA)and gastrointestinal digestion simulation experiments.The results showed more than 92%ofβ-LG in actual samples was hydrolyzed,and the gastric and total digestibility of whey protein isolate(WPI)was improved by 85.96%and 64.51%,respectively.Therefore,C.tyrobutyricum Z816 offers an effective method to degradeβ-LG and reduce the occurrence of milk allergies,which has great significance for the development of hypoallergenic dairy products.

Dietary polyphenols reduced the allergenicity ofβ-lactoglobulin via non-covalent interactions:a study on the structure-allergenicity relationship

Studies showed that complexation of polyphenols with milk allergens reduced their immunogenic potential.However,the relationship between structures of polyphenols and their hypoallergenic effects on milk allergens in association with physiological and conformational changes of the complexes remain unclear.In this study,polyphenols from eight botanical sources were extracted to prepare non-covalent complexes withβ-lactoglobulin(β-LG),a major allergen in milk.The dominant phenolic compounds bound toβ-LG with a diminished allergenicity were identified to investigate their respective role on the structural and allergenic properties ofβ-LG.Extracts from Vaccinium fruits and black soybeans were found to have great inhibitory effects on the IgE-and IgG-binding abilities ofβ-LG.Among the fourteen structure-related phenolic compounds,flavonoids and tannins with larger MWs and multi-hydroxyl substituents,notably rutin,EGCG,and ellagitannins were more potent to elicit changes on the conformational structures ofβ-LG to decrease the allergenicity of complexedβ-LG.Correlation analysis further demonstrated that a destabilized secondary structure and protein depolymerization caused by polyphenol-binding were closely related to the allergenicity property of formed complexes.This study provides insights into the understanding of structure-allergenicity relationship ofβ-LG-polyphenol interactions and would benefit the development of polyphenol-fortified matrices with hypoallergenic potential.

Cow’s milk-induced gastrointestinal disorders:From infancy to adulthood

Milk is related to many gastrointestinal disorders from the cradle to the grave due to the many milk ingredients that can trigger gastrointestinal discomfort and disorders.Cow’s milk protein allergy(CMPA)is the most common food allergy,especially in infancy and childhood,which may persist into adulthood.There are three main types of CMPA;immunoglobulin E(IgE)-mediated CMPA,non-IgEmediated CMPA,and mixed type.CMPA appears before the first birthday in almost all cases.Symptoms may start even during the neonatal period and can be severe enough to simulate neonatal sepsis.CMPA(often non-IgE mediated)can present with symptoms of gastroesophageal reflux,eosinophilic esophagitis,hemorrhagic gastritis,food protein-induced protein-losing enteropathy,and food protein-induced enterocolitis syndrome.Most CMPAs are benign and outgrown during childhood.CMPA is not as common in adults as in children,but when present,it is usually severe with a protracted course.Lactose intolerance is a prevalent condition characterized by the development of many symptoms related to the consumption of foods containing lactose.Lactose intolerance has four typical types:Developmental,congenital,primary,and secondary.Lactose intolerance and CMPA may be the underlying pathophysiologic mechanisms for many functional gastrointestinal disorders in children and adults.They are also common in inflammatory bowel diseases.Milk consumption may have preventive or promoter effects on cancer development.Milk may also become a source of microbial infection in humans,causing a wide array of diseases,and may help increase the prevalence of antimicrobial resistance.This editorial summarizes the common milk-related disorders and their symptoms from childhood to adulthood.

Cytological evaluation by Caco-2 and KU812 of non-allergenic peptides from simulated digestion of infant formula in vitro

Milk allergy is a common allergic reaction found in infants and young children,most of them appear tolerance after growing up.In this study,infant formula was digested by simulated in vitro digestion method.The potential non-allergenic peptides were further screened from undigested products by exclusion of the known epitopes fromβ-lactoglobulin(BLG)andα-lactalbumin(ALA).These potential non-allergenic peptides were synthesized and their transferability were determined by Caco-2 cell monolayer model.Finally,the potential allergenicity were evaluated by KU812 cell degranulation model.The results showed that 7 peptides were screened as non-allergenic sequences,among which were 3 from ALA and 4 from BLG.The Caco-2 cell model showed that all the synthetic peptides were absorbed and transported well.However,only peptide BLG_(107-118)showed potential allegencity by KU812 model.In conclusion,6 peptides,including ALA_(29-51),ALA_(80-90),ALA_(94-103),BLG_(1-20),BLG_(24-50),and BLG_(123-139)were evaluated as hypoallergenic peptides,which could be used for candidates of peptides inducing immune tolerance for persons with milk allergy.

Consensus statement on the epidemiology,diagnosis,prevention,and management of cow's milk protein allergy in the Middle East:a modified Delphi-based study

Background This study aimed to develop an expert consensus regarding the epidemiology,diagnosis,and management of cow’s milk protein allergy(CMPA)in the Middle East.Methods A three-step modified Delphi method was utilized to develop the consensus.Fifteen specialized pediatricians participated in the development of this consensus.Each statement was considered a consensus if it achieved an agreement level of>80%.Results The experts agreed that the double-blind placebo-controlled oral challenge test(OCT)should be performed for 2-A weeks using an amino acid formula(AAF)in formula-fed infants or children with suspected CMPA.Formula-fed infants with confirmed CMPA should be offered a therapeutic formula.The panel stated that an extensively hydrolyzed formula(eHF)is indicated in the absence of red flag signs.At the same time,the AAF is offered for infants with red flag signs,such as severe anaphylactic reactions.The panel agreed that infants on an eHF with resolved symptoms within 2-4 weeks should continue the eHF with particular attention to the growth and nutritional status.On the other hand,an AAF should be considered for infants with persistent symptoms;the AAF should be continued if the symptoms resolve within 2-4 weeks,with particular attention to the growth and nutritional status.In cases with no symptomatic improvements after the introduction of an AAF.other measures should be followed.The panel developed a management algorithm,which achieved an agreement level of 90.9%.Conclusion This consensus document combined the best available evidence and clinical experience to optimize the management of CMPA in the Middle East.

Current status of fecal calprotectin as a diagnostic or monitoring biomarker for cow's milk protein allergy in children:a scoping review

Background There are few approved biomarkers for diagnosis and monitoring of cow's milk protein allergy(CMPA),thus the oral food challenge remains to be the golden diagnostic standard.A potential biomarker is fecal calprotectin,a cytosolic protein,elevating in the presence of intestinal mucosal inflammation.We aimed to undertake a scoping review of the evi-dence pertaining to the current status of fecal calprotectin used for diagnosis and monitoring CMPA in children,and tried to indicate the aspects needed to be concerned in the future investigations and researches.Methods A scoping review was performed using the literature searched from PUBMED,EMBASE,and Web of Science Databases until July 2019 on the studies about the application of fecal calprotectin as a biomarker of CMPA in children.Studies were examined according to the inclusion and exclusion criteria.Data were extracted,and a narrative synthesis was conducted to summarize and analyze.Results Thirteen studies with different study design embracing 1238 children were included.The age range was from infants to adolescents.Most children with CMPA presented gastrointestinal symptoms,among which hematochezia was most com-mon.Amount of data suggested that infants with CMPA represented elevated levels of fecal calprotectin,particularly with distinct significance in non-IgE-mediated CMPA groups.Decreases of fecal calprotectin after elimination diet were demon-strated in enrolled studies.However,no matter in the CMPA positive or negative groups,the changes of fecal calprotectin before or after challenge showed no significance.Contradictory results were generated from studies on the role of fecal calprotectin in predicting allergic disease.Conclusions Available evidence is not sufficient to confirm the utilization of fecal calprotectin both in diagnosis and moni-toring of CMPA and predicting for allergic disease.More clinical and bench researches with elaborate design should be conducted and the exact cut-off values of fecal calprotectin in different groups remain to be determined.