Tolerogenic effect elicited by protein fraction derived from different formulas for dietary treatment of cow's milk allergy in human cells

Several formulas are available for the dietary treatment of cow's milk allergy (CMA). Clinical data suggest potential different effect on immune tolerance elicited by these formulas. We aimed to comparatively evaluate the tolerogenic effect elicited by the protein fraction of different formulas available for the dietary treatment of CMA. Five formulas were compared: extensively hydrolyzed whey formula (EHWF), extensively hydrolyzed casein formula (EHCF), hydrolyzed rice formula (HRF), soy formula (SF), and amino acid-based formula (AAF). Formulas were reconstituted in water according to manufacturer's instructions and subjected to an in vitro infant gut simulated digestion using a sequential gastric and duodenal static model. Protein fraction was then purified and used for the experiments on non-immune and immune components of tolerance network in human enterocytes and in peripheral mononuclear blood cells (PBMCs). We assessed epithelial layer permeability and tight junction proteins (occludin and zonula occludens 1, ZO-1), mucin 5AC (Muc5AC), IL-33 and thymic stromal lymphopoietin (TSLP) in human enterocytes. In addition, Th1/Th2 cytokines response and T regulatory cells (Tregs) activation were investigated in PBMCs from IgE-mediated CMA infants. EHCF-derived protein fraction positively modulated the expression of gut barrier components (Muc5AC, occludin and ZO-1) in human enterocytes, while SF was able to stimulate only the expression of occludin. EHWF and HRF protein fractions elicited a significant increase in TSLP production, while IL-33 release was significantly increased by HRF and SF protein fractions in human enterocytes. Only EHCF-derived protein fraction elicited an increase in the production of the tolerogenic cytokines (IL-10, IFN-γ) and in the number of activated CD4+FoxP3+Tregs, through NFAT, AP1 and NF-kB1 pathway. The effect paralleled with an up-regulation of FOXP3 demethylation rate. Protein fraction from all study formulas was unable to induce Th2 cytokines production. The results suggest a different regulatory action on tolerogenic mechanisms elicited by protein fraction from different formulas commonly used for CMA management. EHCF-derived protein fraction was able to elicit tolerogenic effect through at least in part an epigenetic modulation of FOXP3 gene. These results could explain the different clinical effects observed using EHCF on immune tolerance acquisition in CMA patients and on allergy prevention in children at risk for atopy (see Graphical abstract in Figure 1)

Lactose Intolerance: Common Misunderstandings

Lactose intolerance primarily refers to a syndrome having different symptoms upon the consumption of foods containing lactose. It is one of the most common form of food intolerance and occurs when lactase activity is reduced in the brush border of the small bowel mucosa. Individuals may be lactose intolerant to varying degrees, depending on the severity of these symptoms. When lactose is not digested, it can be fermented by gut microbiota leading to symptoms of lactose intolerance that include abdominal pain, bloating, flatulence, and diarrhea with a considerable intraindividual and interindividual variability in the severity of clinical manifestations. These gastrointestinal symptoms could be similar to cow's milk allergy and could be wrongly labeled as symptoms of "milk allergy." There are important differences between lactose intolerance and cow's milk allergy; therefore, a better knowledge of these differences could limit misunderstandings in the diagnostic approach and in the management of these conditions

Gut Microbiota as a Target for Food Allergy

Purpose of review: The purpose of this review is to present an overview on the potential role of gut microbiota as target of intervention against food allergy. Recent findings: Many studies suggest a key pathogenetic role for gut microbiota modifications (dysbiosis) in food allergy development. Several factors responsible for dysbiosis have been associated with the occurrence of food allergy, such as caesarean delivery, lack of breast milk, drugs use (mainly antibiotics and gastric acidity inhibitors), antiseptic agents use, and low fibers/hight fat diet. No specific bacterial taxa have been consistently associated with food allergy, but evidence suggests that gut dysbiosis occurs even before food allergy signs and symptoms presentation. Data from animal and human studies highlight the ability of particular bacterial taxa to ferment dietary fibers for the production of short chain fatty acids that affect host immunity and help to explain their health-promoting role. Summary: Modulation of gut microbiota composition and/or function represents a promising strategy for treatment and prevention of food allergy in childhood. Key Words: butyrate, dysbiosis, oral tolerance, probiotics, short chain fatty acids Abbreviations: BLG, beta-lactoglobulin, CMA, cow’s milk allergy, EHCF, extensively hydrolyzed casein formula, FA, food allergy, HDAC, histone deacetylase, LGG, Lactobacillus rhamnosus GG, PBMCs, peripheral blood mononuclear cells, SCFAs, short chain fatty ac

The epigenetic effects of butyrate: potential therapeutic implications for clinical practice

Butyrate is a short chain fatty acid derived from the microbial fermentation of dietary fibers in the colon. In the last decade, multiple beneficial effects of butyrate at intestinal and extraintestinal level have been demonstrated. The mechanisms of action of butyrate are different and many of these involve an epigenetic regulation of gene expression through the inhibition of histone deacetylase. There is a growing interest in butyrate because its impact on epigenetic mechanisms will lead to more specific and efficacious therapeutic strategies for the prevention and treatment of different diseases ranging from genetic/metabolic conditions to neurological degenerative disorders. This review is focused on recent data regarding the epigenetic effects of butyrate with potential clinical implications in human medicine

Food allergies: Novel mechanisms and therapeutic perspectives

Childhood food allergy (FA) rates have rapidly increased with significant direct medical costs for the health care system and even larger costs for the families with a food-allergic child. The possible causes of food allergy become the target of intense scrutiny in recent years. Increasing evidence underline the importance in early life of gut microbiome in the development of allergic diseases. There are a range of factors in the modern environment that may be associated with changes to both the gut microbiome and risk of FA, such as mode of delivery, antibiotic exposure, infant feeding practices, farming environment, and country of origin. Knowledge of the relationship between early life gut microbiome and allergic diseases may facilitate development of novel preventive and treatment strategies. Based on our current knowledge, there are no currently available approved therapies for food allergy. More studies are needed to evaluate the safety and efficacy of allergen-specific and allergen-nonspecific approaches, as well as combination approaches

Acute disseminated encephalomyelitis presenting as fever of unknown origin: case report

BACKGROUND: Fever of unknown origin (FUO) can be defined as a body temperature higher than 38.3°C on several occasions over more than 3 weeks, the diagnosis of which remains uncertain after 1 week of evaluation. Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system with a wide range of clinical manifestations. The highest incidence of ADEM is observed during childhood and it usually occurs following a viral or bacterial infection or, more rarely, following a vaccination, or without a preceding cause. CASE PRESENTATION: Here, we describe an atypical case of ADEM that initially manifested as several weeks of FUO in a fifteen years old boy. CONCLUSIONS: This case report suggests a new possible syndromic association between ADEM and FUO, which should be considered in the clinical examination of patients with FUO, especially in the presence of also modest neurologic or neuropsychiatric symptoms

Acute Disseminated Encephalomyelitis Presenting as Fever of Unknown Origin: Case Report

Background: Fever of unknown origin (FUO) can be defined as a body temperature higher than 38.3°C on several occasions over more than 3 weeks, the diagnosis of which remains uncertain after 1 week of evaluation. Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system (CNS) with a wide range of clinical manifestations. The highest incidence of ADEM is observed during childhood and it usually occurs following a viral or bacterial infection or, more rarely, following a vaccination, or without a preceding cause. Case presentation: Here, we describe an atypical case of ADEM that initially manifested as several weeks of FUO in a 15 years old boy. Conclusions: This case report suggests a new possible syndromic association between ADEM and FUO, which should be considered in the clinical examination of patients with FUO, especially in the presence of also modest neurologic or neuropsychiatric symptoms.&nbsp

Congenital Diarrheal Disorders: An Updated Diagnostic Approach

Congenital diarrheal disorders (CDDs) are a group of inherited enteropathies with a typical onset early in the life. Infants with these disorders have frequently chronic diarrhea of sufficient severity to require parenteral nutrition. For most CDDs the disease-gene is known and molecular analysis may contribute to an unequivocal diagnosis. We review CDDs on the basis of the genetic defect, focusing on the significant contribution of molecular analysis in the complex, multistep diagnostic work-up

Randomized controlled trial on the influence of dietary intervention on epigenetic mechanisms in children with cow's milk allergy: the EPICMA study

Epigenetic mechanisms could drive the disease course of cow's milk allergy (CMA) and formula choice could modulate these pathways. We compared the effect of two different dietary approaches on epigenetic mechanisms in CMA children. Randomized controlled trial on IgE-mediated CMA children receiving a 12-month treatment with extensively hydrolyzed casein formula containing the probiotic L.rhamnosus GG (EHCF + LGG) or with soy formula (SF). At the baseline, after 6 and 12 months of treatment FoxP3 methylation rate and its expression in CD4+ T cells were assessed. At same study points IL-4, IL-5, IL-10, and IFN-γ methylation rate, expression and serum concentration, miRNAs expression were also investigated. 20 children (10/group) were evaluated. Baseline demographic, clinical and epigenetic features were similar in the two study groups. At 6 and 12 months, EHCF + LGG group showed a significant increase in FoxP3 demethylation rate compared to SF group. At the same study points, EHCF + LGG group presented a higher increase in IL-4 and IL-5 and a higher reduction in IL-10 and IFN-γ DNA methylation rate compared to SF group. A different modulation of miR-155, -146a, -128 and -193a expression was observed in EHCF + LGG vs. SF. Dietary intervention could exert a different epigenetic modulation on the immune system in CMA children