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Background Amino acid-based formula (AAF) is a relevant dietary strategy for paediatric patients affected by cow’s milk allergy (CMA). The present study was designed to evaluate the hypoallergenicity of a new AAF in children with immunoglobulin (Ig)E-mediated CMA. Methods According to the criteria provided by the American Academy of Pediatrics Subcommittee on Nutrition and Allergic Diseases, we designed a prospective trial in CMA children (aged 1–36 months) aimed to demonstrate the hypoallergenicity of the new AAF in 90% of subjects with 95% confidence during the double-blind, placebo-controlled challenge (DBPCFC). A skin prick test (SPT) with the new AAF was also performed. Results Twenty-nine children [all Caucasian, 55.2% male, mean age (±SD) 16.9 ± 5.7 months] were enrolled. The SPT and the DBPCFC with the new AAF were negative in all study subjects. Conclusions The study results support the hypoallergenicity of the new AAF. This formula could be considered an additional dietary option for non-breastfed children affected by CMA. Trial registration The trial was registered in the ClinicalTrials.gov Protocol Registration System (ID number: NCT03909113).

The complex microbial community of the gut microbiome plays a fundamental role in driving development and function of the human immune system. This phenomenon is named the gut microbiome-immune system axis. When operating optimally, this axis influences both innate and adaptive immunity, which orchestrates the maintenance of crucial elements of host-microorganisms symbiosis, in a dialogue that modulates responses in the most beneficial way. Growing evidence reveals some environmental factors which can positively and negatively modulate the gut microbiome-immune system axis with consequences on the body health status. Several conditions which increasingly affect the pediatric age, such as allergies, autoimmune and inflammatory disorders, arise from a failure of the gut microbiome-immune system axis. Prenatal or postnatal modulation of this axis through some interventional strategies (including diet, probiotics and postbiotics), may lead to a positive gene-environment interaction with improvement of immune-modulatory effects and final positive effect on human health. In particular probiotics and postbiotics exerting pleiotropic regulatory actions on the gut-microbiome-immune system axis provide an innovative preventive and therapeutic strategy for many pediatric conditions.

Cow's milk allergy (CMA) is one of the most common food allergies and one of the main causes of food-induced anaphylaxis in the pediatric age. Moreover, up to 45% of CMA children develop other atopic manifestations later in life, a phenomenon commonly named atopic march. Thus, CMA imposes a significant cost to health care systems as well as to families, and has emerged as one of the most expensive allergic diseases. The immunonutrition strategy builds its foundation on the ability of selected dietary factors to modulate immune system development and function. Recent studies highlighted the potential of immunonutrition in the management of CMA. This review is focused on the mechanisms and long-term clinical outcomes of the immunonutrition approach in children with CMA. Introduction Much has changed during the recent decades regarding prevalence, persistence, and severity of clinical features and socio-economic burden of food allergy (FA) that currently affects up to 10% of children living in Western countries (1). Based on the immune mechanisms, FA may be classified as IgE-mediated, non-IgE-mediated, or a combination of both pathways (2). In addition, children presenting with FA in early life are at increased risk of developing other allergic manifestations later in life, such as allergic asthma and rhinitis, a phenomenon commonly named atopic march (AM) (3). With an estimated prevalence of up to 3%, cow's milk allergy (CMA) is one of the most common FA and one of the main causes of food-induced anaphylaxis in the pediatric age (4). This condition imposes a significant cost to health care systems as well as to families, and has emerged as one of the most expensive allergic diseases (4). Furthermore, early life CMA could be the first step of AM, which affects up to 45% of CMA children, also after the acquisition of immune tolerance to cow's milk proteins (CMP) (5–8). Both CMA and AM derive from a negative interaction between genetic and environmental factors (3) resulting in alteration in the gut microbiome (GM) and in immune system dysfunction. These modulatory effects are at least in part mediated by epigenetic mechanisms, and are now emerging as potential targets of intervention to facilitate the immune tolerance acquisition and to limit the occurrence of AM in CMA patients (5, 9–11). The traditional dietary management of CMA has greatly changed in the last few years, moving from a passive approach based on the strict elimination diet of CMP-containing foods, to a proactive one, able to change the CMA course (12). The discovery of the pivotal role of selected dietary factors in influencing immune system development and function has introduced the immunonutrition concept. The application of the immunonutrition approach in the management of CMA is paving the way to “active diet therapy,” an integrated dietary strategy able to facilitate the acquisition of immune tolerance and to prevent the occurrence of AM (5, 9, 13–15). The modern dietary management in CMA pediatric patients is focused on three targets: • Dietary education (allergen avoidance and healthy diet) • Ensure adequate intake of macro and micro-nutrients (stimulation of optimal body growth and development) • Active diet therapy (stimulation of immune tolerance and protection against AM occurrence). The immunonutrition approach could be promoted for all three of these targets. This review is focused on the objectives and long-term clinical outcomes of the immunonutrition approach in children affected by CMA