Epidemiology of Paediatric Italian Food Allergy: Results of the EPIFA study.

Background: Updated epidemiologic data are important for defining effective public health strategies for pediatric food allergy (FA). Objective: The Epidemiology of Paediatric Italian Food Allergy (EPIFA) study was designed to investigate the epidemiology of pediatric FA in one of the most heavily populated Italian regions. Methods: A retrospective cohort study was performed in collaboration with family pediatricians aimed at investigating the epidemiology of Italian pediatric FA during 2009 to 2021. Family pediatricians in the Campania region were invited to use the Google Forms platform for online compilation of data forms. Data forms were reviewed by experienced pediatric allergists at the coordinating center. Results: A total population of 105,151 subjects (aged 0-14 years) was screened during the study period. Data from 752 FA patients were evaluated. A progressive increase in FA incidence and prevalence was observed from 2009 to 2021, with a relative increase up to 34% and 113.6%, respectively, at the end of study period. The relative increase in FA prevalence was higher in the 0-3-year-old age group in the same study period (+120.8%). The most frequent allergens were cow's milk, hen's egg, and nuts. Conclusion: The results of the EPIFA study showed an increase in pediatric FA incidence and prevalence from 2009 to 2021 in Italy. These results underline the necessity of new effective strategies for preventing and managing these conditions.

Growth pattern of paediatric patients affected by cow milk protein allergy fed with rice hydrolyzed formula.

OBJECTIVES: Formulas made from hydrolyzed rice proteins (HRPF) are well-tolerated plant-based alternatives to cow's milk protein (CMP)-based formulas for the dietary management of paediatric patients with CMP allergy (CMPA). Growth in patients with CMPA fed with HRPF has been evaluated in several studies with conflicting results. The aim was to evaluate the growth pattern of children with CMPA over a 12-month follow-up period. METHODS: Prospective cohort study evaluating growth patterns in challenge proven CMPA paediatric patients receiving HRPF for 12 months. Outcomes were anthropometry (body weight, body length, head circumference), adherence to the study formula and occurrence of adverse events (AEs). RESULTS: Sixty-six children were included and completed the 12-month study. At baseline, all CMPA patients were weaned. For the entire CMPA pediatric patients' cohort, from baseline to the end of the study period, the growth pattern resulted within the normal range of World Health Organization (WHO) growth references. The formula was well tolerated. Adherence was optimal and no AEs related to HRPF use were reported. CONCLUSIONS: HRPF is well tolerated and can help support healthy growth and development in infants and young children with CMPA. These type of formula can be given with complementary foods in the dietary management of CMPA.

How dietary advanced glycation end products could facilitate the occurrence of food allergy.

BACKGROUND: Food allergy (FA) is one of the most common chronic conditions in children with an increasing prevalence facilitated by the exposure to environmental factors in predisposed individuals. It has been hypothesized that the increased consumption of ultra-processed foods, containing high levels of dietary advanced glycation end products (AGEs), could facilitate the occurrence of FA. OBJECTIVE: We sought to provide preclinical and clinical evidence on the potential role of AGEs in facilitating the occurrence of FA. METHODS: Human enterocytes, human small intestine organ culture, and PBMCs from children at risk for allergy were used to investigate the direct effect of AGEs on gut barrier, inflammation, TH2 cytokine response, and mitochondrial function. Intake of the 3 most common glycation products in Western diet foods, Nε-(carboxymethyl) lysine, Nε-(1-carboxyethyl) lysin, and Nδ-(5-hydro-5- methyl-4-imidazolone-2-yl)-ornithine (MG-H1), and the accumulation of AGEs in the skin were comparatively investigated in children with FA and in age-matched healthy controls. RESULTS: Human enterocytes exposed to AGEs showed alteration in gut barrier, AGE receptor expression, reactive oxygen species production, and autophagy, with increased transepithelial passage of food antigens. Small intestine organ cultures exposed to AGEs showed an increase of CD25+ cells and proliferating crypt enterocytes. PBMCs exposed to AGEs showed alteration in proliferation rate, AGE receptor activation, release of inflammatory and TH2 cytokines, and mitochondrial metabolism. Significant higher dietary AGE intake and skin accumulation were observed children with FA (n = 42) compared with age-matched healthy controls (n = 66). CONCLUSIONS: These data, supporting a potential role for dietary AGEs in facilitating the occurrence of FA, suggest the importance of limiting exposure to AGEs children as a potential preventive strategy against this common condition.

Increased dietary intake of ultraprocessed foods and mitochondrial metabolism alterations in pediatric obesity.

The increased intake of ultraprocessed foods (UPFs) in the pediatric age paralleled with the risen prevalence of childhood obesity. The Ultraprocessed Foods in Obesity (UFO) Project aimed at investigating the potential mechanisms for the effects of UPFs in facilitating pediatric obesity, focusing on the direct role of advanced glycation end-products (AGEs) on mitochondrial function, the key regulator of obesity pathophysiology. We comparatively investigated the daily dietary intake of UPFs, energy, nutrients, dietary AGEs [Nε -(carboxymethyl)lysine (CML), Nε -(1-carboxyethyl)lysine (CEL), and Nδ -(5-hydro-5- methyl-4-imidazolon-2-yl)-ornithine (MG-H1)] in 53 obese patients and in 100 healthy controls visiting the Tertiary Center for Pediatric Nutrition of the Department of Translational Medical Science at the University of Naples "Federico II". AGEs skin accumulation and mitochondrial function in peripheral blood mononuclear cells (PBMCs) were also assessed. A higher intake of UPFs and AGEs, energy, protein, fat, and saturated fatty acids was observed in obese patients. Obese children presented significantly higher skin AGEs accumulation and alterations in mitochondrial metabolism. PBMCs from healthy controls exposed to AGEs showed the same mitochondrial alterations observed in patients. These findings support the UPFs role in pediatric obesity, and the need for dietary strategies limiting UPFs exposure for obesity prevention and treatment.

Nutritional Strategies for the Prevention and Management of Cow's Milk Allergy in the Pediatric Age.

Cow's milk allergy (CMA) is one of the most common pediatric food allergies. The prevalence and severity of CMA have increased dramatically in the last decades, under the pressure of environmental factors in genetically predisposed individuals. Among the environmental influences, nutritional factors play a crucial role. Diet is the most modifiable factor, representing a potential target for the prevention and treatment of CMA. In this review, we report the most scientific-based nutritional strategies for preventing and managing pediatric CMA. In addition, we propose the most complete supplement of compounds able to prevent nutrient deficiencies in CMA pediatric patients and to positively influence the disease course.

The step-down approach in children with cow's milk allergy: Results of a randomized controlled trial.

BACKGROUND: The Step-Down Approach for Cow's Milk Allergy (SDACMA) trial evaluated the tolerability and the rate of immune tolerance acquisition in CMA children starting dietary treatment with amino acid-based formula (AAF) and then switching to EHCF containing the probiotic Lacticaseibacillus rhamnosus GG (EHCF + LGG). METHODS: Randomized controlled trial involving IgE-mediated CMA children receiving AAF from at least 4 weeks. EHCF + LGG tolerance was evaluated by the results of double-blind placebo-controlled food challenge (DBPCFC). Subjects tolerating EHCF + LGG were randomly allocated to remain on AAF, or to switch to EHCF + LGG. Immune tolerance acquisition to cow's milk proteins was evaluated with DBPCFC after 12 months of treatment. Allergy screening tests and body growth were also monitored. RESULTS: Sixty IgE-mediated CMA children were enrolled. The proportion of children treated with AAF who resulted tolerant to the first exposure of EHCF + LGG was 0.98 (exact 95% CI 0.91-0.99). The rate of the immune tolerance acquisition to cow milk proteins after 12 months treatment was higher in the EHCF + LGG (0.48, 95% exact CI 0.29-0.67, n/N = 14/29) than in the AAF group (0.03, 95% exact CI 0.001-0.17, n/N = 1/30). There was an absolute benefit increase (ABI) of tolerance rate equal to 0.45 (95% CI 0.23-0.63, Newcombe method 10) for EHCF + LGG versus AAF, corresponding to a NNT of 2 (2-4, Bender's method). A normal body growth pattern was observed in the two study groups. CONCLUSION: In IgE-mediated CMA children the step-down from AAF to EHCF + LGG is well tolerated and could facilitate the immune tolerance acquisition.

Therapeutic Effects of Butyrate on Pediatric Obesity: A Randomized Clinical Trial.

Importance: The pediatric obesity disease burden imposes the necessity of new effective strategies. Objective: To determine whether oral butyrate supplementation as an adjunct to standard care is effective in the treatment of pediatric obesity. Design, Setting, and Participants: A randomized, quadruple-blind, placebo-controlled trial was performed from November 1, 2020, to December 31, 2021, at the Tertiary Center for Pediatric Nutrition, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy. Participants included children aged 5 to 17 years with body mass index (BMI) greater than the 95th percentile. Interventions: Standard care for pediatric obesity supplemented with oral sodium butyrate, 20 mg/kg body weight per day, or placebo for 6 months was administered. Main Outcomes and Measures: The main outcome was the decrease of at least 0.25 BMI SD scores at 6 months. The secondary outcomes were changes in waist circumference; fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, ghrelin, microRNA-221, and interleukin-6 levels; homeostatic model assessment of insulin resistance (HOMA-IR); dietary and lifestyle habits; and gut microbiome structure. Intention-to-treat analysis was conducted. Results: Fifty-four children with obesity (31 girls [57%], mean [SD] age, 11 [2.91] years) were randomized into the butyrate and placebo groups; 4 were lost to follow-up after receiving the intervention in the butyrate group and 2 in the placebo group. At intention-to-treat analysis (n = 54), children treated with butyrate had a higher rate of BMI decrease greater than or equal to 0.25 SD scores at 6 months (96% vs 56%, absolute benefit increase, 40%; 95% CI, 21% to 61%; P < .01). At per-protocol analysis (n = 48), the butyrate group showed the following changes as compared with the placebo group: waist circumference, -5.07 cm (95% CI, -7.68 to -2.46 cm; P < .001); insulin level, -5.41 µU/mL (95% CI, -10.49 to -0.34 µU/mL; P = .03); HOMA-IR, -1.14 (95% CI, -2.13 to -0.15; P = .02); ghrelin level, -47.89 µg/mL (95% CI, -91.80 to -3.98 µg/mL; P < .001); microRNA221 relative expression, -2.17 (95% CI, -3.35 to -0.99; P < .001); and IL-6 level, -4.81 pg/mL (95% CI, -7.74 to -1.88 pg/mL; P < .001). Similar patterns of adherence to standard care were observed in the 2 groups. Baseline gut microbiome signatures predictable of the therapeutic response were identified. Adverse effects included transient mild nausea and headache reported by 2 patients during the first month of butyrate intervention. Conclusions and Relevance: Oral butyrate supplementation may be effective in the treatment of pediatric obesity. Trial Registration: ClinicalTrials.gov Identifier: NCT04620057.

The potential role of preventive and therapeutic immunonutrition strategies for pediatric food allergy: A mini-review.

Food allergy (FA) represents one of the main chronic conditions of the pediatric population. The gut microbiome (GM)-immune system axis is a milestone in affecting FA susceptibility. The dynamic and bidirectional crosstalk between the GM and immune system starts early in life, and it is deeply modulated during the first 1,000 days of life. Nutritional factors during this crucial period mainly influence the proper GM-immune system development and function across the lifespan, with potential beneficial or detrimental effects on health status. Immunonutrition strategies, applied from conception, could represent an innovative target for prevention and treatment of pediatric FA. Here we described the potential role of preventive and therapeutic immunonutrition strategies for pediatric FA, highlighting putative future perspectives in this field.

Effects of the Mediterranean Diet during pregnancy on the onset of allergy in at risk children: A study protocol of a multi-center, randomized- controlled, parallel groups, prospective trial (the PREMEDI study).

Introduction: Maternal diet during pregnancy has been linked to offspring allergy risk and it could represent a potential target for allergy prevention. The Mediterranean Diet (MD) is considered one of the healthiest dietary models. Randomized-controlled trials on the effect of MD in preventing pediatric allergic diseases are still needed. Methods and analysis: The Mediterranean Diet during Pregnancy study (PREMEDI) will be a 9-month multi-center, randomized-controlled, parallel groups, prospective trial. Healthy women (20-35 years) at their first trimester of pregnancy at risk for atopy baby, will be randomly allocated to Group 1 (standard obstetrical and gynecological follow-up and nutritional counseling to promote MD) or Group 2 (standard obstetrical and gynecological follow-up alone). 138 mother-child pair per group will be needed to detect a reduction in cumulative incidence of ≥1 allergic disease at 24 months of age. The primary study aim will be the evaluation of the occurrence of allergic disorders in the first 24 months of life. The secondary aims will be the evaluation of maternal weight gain, pregnancy/perinatal complications, growth indices and occurrence of other chronic disorders, mother-child pair adherence to MD and gut microbiome features, breastfeeding duration and breast milk composition, epigenetic modulation of genes involved in immune system, and metabolic pathways in the offspring. Ethics and dissemination: The study protocol has been approved by the Ethics Committee of the University of Naples Federico II (number 283/21) and it will be conducted in accordance with the Helsinki Declaration (Fortaleza revision, 2013), the Good Clinical Practice Standards (CPMP/ICH/135/95), the Italian Decree-Law 196/2003 regarding personal data and the European regulations on this subject. The study has been registered in the Clinical Trials Protocol Registration System. Clinical trial registration: [http://clinicaltrials.gov], identifier [NCT05119868].

Body growth assessment in children with IgE-mediated cow's milk protein allergy fed with a new amino acid-based formula.

Background: Amino acid-based formula (AAF) is a relevant dietary option for non-breastfed children. The present study was designed to evaluate the body growth pattern in cow's milk protein allergy (CMPA) children treated for 6 months with a new AAF. Methods: This was an open-label, single arm study evaluating body growth pattern in immunoglobulin E (IgE)-mediated CMPA infants receiving a new AAF for 6 months. The outcomes were anthropometry (weight, length, head circumference), adherence to the study formula and occurrence of adverse events (AEs). Results: Fifteen children [all Caucasian and born at term; 53.3% born with spontaneous delivery; 80% male; 80% with familial allergy risk; mean age (±SD) 3 ± 2.5 months at IgE-mediated CMPA diagnosis; mean age (±SD) 16.7 ± 5.9 months at enrolment, mean total serum IgE (±SD) 298.2 ± 200.4 kU/L] were included and completed the 6-month study. Data from fifteen age- and sex-matched healthy controls were also adopted as comparison. At baseline, all CMPA patients were weaned and were receiving the new AAF. All 15 patients completed the 6-month study period. For the entire CMPA pediatric patients' cohort, from baseline to the end of the study period, the body growth pattern resulted within the normal range of World Health Organization (WHO) growth references and resulted similar to healthy controls anthropometric values. The formula was well tolerated. The adherence was optimal and no AEs related to AAF use were reported. Conclusions: The new AAF ensured normal growth in subjects affected by IgE-mediated CMPA. This formula constitutes another suitable safe option for the management of pediatric patients affected by CMPA.

Therapeutic effects elicited by the probiotic Lacticaseibacillus rhamnosus GG in children with atopic dermatitis. The results of the ProPAD trial.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting up to 20% of the pediatric population associated with alteration of skin and gut microbiome. Probiotics have been proposed for AD treatment. The ProPAD study aimed to investigate the therapeutic effects of the probiotic Lacticaseibacillus rhamnosus GG (LGG) in children with AD. METHODS: In total, 100 AD patients aged 6-36 months were enrolled in a randomized, double-blind, controlled trial to receive placebo (Group A) or LGG (1 x 1010 CFU/daily) (Group B) for 12 weeks. The primary outcome was the evaluation of the efficacy of LGG supplementation on AD severity comparing the Scoring Atopic Dermatitis (SCORAD) index at baseline (T0) and at 12-week (T12). A reduction of ≥8.7 points on the SCORAD index was considered as minimum clinically important difference (MCID). The secondary outcomes were the SCORAD index evaluation at 4-week (T16) after the end of LGG treatment, number of days without rescue medications, changes in Infant Dermatitis Quality Of Life questionnaire (IDQOL), gut microbiome structure and function, and skin microbiome structure. RESULTS: The rate of subjects achieving MCID at T12 and at T16 was higher in Group B (p < .05), and remained higher at T16 (p < .05)The number of days without rescue medications was higher in Group B. IDQOL improved at T12 in the Group B (p < .05). A beneficial modulation of gut and skin microbiome was observed only in Group B patients. CONCLUSIONS: The probiotic LGG could be useful as adjunctive therapy in pediatric AD. The beneficial effects on disease severity and quality of life paralleled with a beneficial modulation of gut and skin microbiome.

Potential Clinical Applications of the Postbiotic Butyrate in Human Skin Diseases.

Human skin is the largest organ and the most external interface between the environment and the body. Vast communities of viruses, bacteria, archaea, fungi, and mites, collectively named the skin microbiome (SM), cover the skin surface and connected structures. Skin-resident microorganisms contribute to the establishment of cutaneous homeostasis and can modulate host inflammatory responses. Imbalances in the SM structure and function (dysbiosis) are associated with several skin conditions. Therefore, novel target for the skincare field could be represented by strategies, which restore or preserve the SM natural/individual balance. Several of the beneficial effects exerted by the SM are aroused by the microbial metabolite butyrate. Since butyrate exerts a pivotal role in preserving skin health, it could be used as a postbiotic strategy for preventing or treating skin diseases. Herein, we describe and share perspectives of the potential clinical applications of therapeutic strategies using the postbiotic butyrate against human skin diseases.

OnabotulinumtoxinA Modulates Visual Cortical Excitability in Chronic Migraine: Effects of 12-Week Treatment.

Chronic migraine is a burdensome disease presenting with episodic pain and several symptoms that may persist even among headache attacks. Multisensory integration is modified in migraine, as assessed by the level of the perception of sound-induced flash illusions, a simple paradigm reflecting changes in cortical excitability which reveals to be altered in migraineurs. OnabotulinumtoxinA is an effective preventive therapy for chronic migraineurs, reducing peripheral and central sensitization, and may influence cortical excitability. Patients affected by chronic migraine who started onabotulinumtoxinA preventive therapy were included. Clinical effects (headache diaries and migraine related questionnaires) were assessed at the beginning of the therapy and after 12 weeks. Contextually, patients underwent the evaluation of multisensory perception by means of the sound-induced flash illusions. OnabotulinumtoxinA showed effectiveness both in migraine prevention and in reducing headache burden. Even one session of therapy was able to restore, at least partially, multisensory processing, as shown by patients' susceptibility to the sound-induced flash illusion. OnabotulinumtoxinA could influence migraineurs cortical excitability concurrently to the beneficial effects in headache prevention.

Evidence on the Preventive Effects of the Postbiotic Derived from Cow's Milk Fermentation with Lacticaseibacillus paracasei CBA L74 against Pediatric Gastrointestinal Infections.

Postbiotics are commonly defined as preparations of inanimate probiotics and/or their cellular components and/or their metabolites/end products that confer health benefits on the host. They have been suggested as a promising strategy to limit infectious diseases. Emerging evidence support the efficacy of the postbiotic derived from cow's milk fermentation with the probiotic Lacticaseibacillus paracasei CBAL74 (FM-CBAL74) in preventing pediatric infectious diseases. We aimed at reviewing the evidence available.

Phenylalanine Butyramide Is a New Cosmetic Ingredient with Soothing and Anti-Reddening Potential.

Human skin is colonized by diverse commensal microbes, making up the skin microbiota (SM), contributing to skin integrity and homeostasis. Many of the beneficial effects aroused by the SM are exerted by microbial metabolites such as short-chain fatty acids (SCFAs), including butyric acid. The SCFAs can be used in cosmetic formulations against skin diseases to protect SM by preserving and/or restoring their natural balance. Unpleasant sensorial properties and unfavorable physico-chemical properties of butyrate strongly limit its cosmetic use. In contrast, some butyrate derivatives, including phenylalanine butyramide (C13H18N2O2, FBA), a solid form of butyric acid, are odorless while retaining the pharmacokinetic properties and safety profile of butyric acid. This study assessed the FBA's permeation across the skin and its soothing and anti-reddening potential to estimate its cosmetic application. The dosage method used to estimate FBA's levels was validated to be sure of analytical results. The FBA diffusion tests were estimated in vitro using a Franz-type vertical diffusion cell. The soothing action was evaluated in vivo by Colorimeter CL400, measuring the erythema index. The results suggest that the FBA represents an innovative way to exploit the benefits of butyric acid in the cosmetic fields since it cannot reach the bloodstream, is odorless, and has a significative soothing action (decrease the erythema index -15.7% after 30', and -17.8% after 60').

Tolerability of a new amino acid-based formula for children with IgE-mediated cow's milk allergy.

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 role of probiotics and postbiotics in modulating the gut microbiome-immune system axis in the pediatric age.

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.

The Protective Role of Butyrate against Obesity and Obesity-Related Diseases.

Worldwide obesity is a public health concern that has reached pandemic levels. Obesity is the major predisposing factor to comorbidities, including type 2 diabetes, cardiovascular diseases, dyslipidemia, and non-alcoholic fatty liver disease. The common forms of obesity are multifactorial and derive from a complex interplay of environmental changes and the individual genetic predisposition. Increasing evidence suggest a pivotal role played by alterations of gut microbiota (GM) that could represent the causative link between environmental factors and onset of obesity. The beneficial effects of GM are mainly mediated by the secretion of various metabolites. Short-chain fatty acids (SCFAs) acetate, propionate and butyrate are small organic metabolites produced by fermentation of dietary fibers and resistant starch with vast beneficial effects in energy metabolism, intestinal homeostasis and immune responses regulation. An aberrant production of SCFAs has emerged in obesity and metabolic diseases. Among SCFAs, butyrate emerged because it might have a potential in alleviating obesity and related comorbidities. Here we reviewed the preclinical and clinical data that contribute to explain the role of butyrate in this context, highlighting its crucial contribute in the diet-GM-host health axis.

Immunonutrition for Pediatric Patients With Cow's Milk Allergy: How Early Interventions Could Impact Long-Term Outcomes.

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.