The research at the ImmunoNutritionLab is focused on modern nutritional interventions with a pivotal role in improving the health status of both current and future generations.

A Translational Approach

The ImmunonutritionLab is at the forefront of biomedical innovation thanks not only to its basic research activity, but also to the development and testing of new protocols.

The ImmunonutritionLab integrates basic and clinical research through a translational approach: laboratory findings are quickly translating into clinical therapies and procedures (bench to bedside).

Its commitment to the improvement of clinical practice is proven by numerous ongoing clinical trials and by many new study proposals submitted from Industries. These activities have steadily grown during the years thanks to the support provided by the patients’ fidelity and Industries estimation.

The ImmunonutritionLab  activities are in partnership with the “Gastro Intestinal Allergy Nutrition Team” (GIANTs of Naples).


Clinical Studies

The BAPO trial is a randomized, quadruple-blind, placebo controlled, clinical trial on obese pediatric patients of both sex, aged 7-16 years. Subjects are randomly assigned to one of the two 6-month intervention groups: standard care for pediatric obesity + butyrate or placebo. The primary outcome is a BMI z-score reduction ≥ 0.25, the secondary outcomes are the effects on glucose and lipid profile, waist circumference, mir221- expression, serum hormones/adipokines, eating behaviors and gut microbiota composition. [ link]
Non-IgE mediated food allergies are characterized by gastrointestinal symptoms (diarrhea, vomiting, bloody stool, persistent distress/colic, regurgitation and constipation) and Cow’s Milk is the most frequent involved food. There are no validated tests for the diagnosis of non-IgE Cow’s Milk allergy (CMA), apart from the oral food challenge. The V1605-201/APTITUDE study aims to evaluate the sensitivity and specificity of a standardized Atopy patch test DBV1605 in the diagnosis of non-IgE mediated CMA. [ link]
Long chain polyunsaturated fatty acids (PUFAs) play a role in allergic diseases. Observations link n-3 PUFA docosahexaenoic acid (DHA) to allergy prevention. Preliminary results reported association between food allergy and dysbalanced PUFAs metabolism. The study aims to explore the influence of crucial enzymatic activities in PUFAs metabolism, delta-5, (FADS1) and delta-6 (FADS2) desaturase, gene polymorphisms on n-6 and n-3 serum levels in children with IgE-mediated cow milk allergy (CMA).
The PREMEDI (MEditerranean DIet during PREgnancy) study is a primary prevention randomized clinical trial aiming to evaluate the effects of Mediterranean diet (MD) during pregnancy on epigenetic mechanisms that regulate the expression of the genes involved in the pathogenesis of obesity and allergy in the offspring. It also aims to evaluate the effects of MD on structure and function of maternal and neonatal gut microbiota, maternal weight gain and complications, fetal complications, neonatal outcomes, child growth, and allergic manifestations. [ link]
Several evidences in the literature suggest a change in the epidemiological scenario of food allergies (FA) in the last decade, with an increase in the prevalence, persistence and severity of clinical manifestations. Recent data on the epidemiology of FA in the Italian pediatric age in the last decade are currently scarce. The EPIFA study aims to update the epidemiological data to facilitate the definition of prevention and intervention strategies for the correct management of these conditions.
MATOMS is an observational, transversal, comparative study to evaluate comparatively the metagenomics and metabolomics characteristics of gut microbiome of children/adolescents of both sex, aged between 10-16 years with obesity, obesity complicated by metabolic syndrome and healthy controls matched for age and sex. [ link]
Autism Spectrum Disorders (ASD) is a severe neurological condition characterized by severe stereotypical behaviors and deficits in social interaction. Preliminary data suggest that particular elimination diets and/or modifications of the intestinal microbiota can determine a positive effect on the symptoms of ASD. Observational study in which we evaluate eating habits, adverse food reactions and the effects of the elimination diet on ASD symptoms and we characterize the composition and function (production of short-chain fatty acids, SCFA) of the intestinal microbiota in children with ASD and in healthy children. [ link]

Autistic Spectrum Disorder (ASD) is a complex group of behavioral disorders characterized by defects in social interaction and communication associated with repetitive behaviors. Alterations in nutritional status, eating habits and adverse reactions to food appear to be common in children with ASD. Randomized prospective study whose main objective is the evaluation of the impact of a nutritional intervention on the reduction of food selectivity and as secondary the evaluation of the improvement of eating habits, adherence to the Mediterranean Diet, auxological parameters and quality of life of parents. [ link]

Non-IgE mediated gastrointestinal food allergy is an evolving web of clinical conditions characterized by subacute and/or chronic symptoms and include food protein-induced: enterocolitis syndrome (FPIES), enteropathy (FPE), allergic proctocolitis (FPIAP), and motility disorders (FPIMD). Despite the epidemiological relevance, pathogenesis, best diagnostic and therapeutic approach, and natural history of these disorders are still poorly characterized. The NIGEFA project is focused on the study of the pathogenesis and natural history of non-IgE mediated gastrointestinal food allergy in the pediatric age. [ link]
The MATFA study is designed to explore the influence of gut microbiome in pediatric allergy with “Shotgun Metagenomics” approach. We comparatively aimed to define metagenomics and metabolomics features in children affected by food allergy or respiratory allergies and in healthy controls for the development of new strategies for the prevention and treatment of allergy. [ link]

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder that results in areas of dry, itchy skin. AD is typified by defective skin barrier function with activation of abnormal immunological and inflammatory pathways upon exposure to ubiquitous environmental allergens. Specific probiotics have been shown to normalize intestinal permeability, to counteract intestinal immune dysfunction and to normalize gut dysbiosis. The aim of this randomized, double-blind, placebo-controlled study is to evaluate the efficacy of the most studied probiotic in the pediatric allergy field – L.rhamnosus GG – in children affected by atopic dermatitis. [ link]

The PSC-DS DG BABY 18 is a randomized, double-blind, placebo controlled clinical trial to evaluate the efficacy and safety of L. casei DG® (L. paracasei CNCM I-1572) in the treatment of infantile colic. The secondary outcomes are the reduction of the average daily crying time, the persistence of infantile colic, the reduction in the number of regurgitation episodes, evaluation of the fecal consistency and frequency, evaluation of the number of infectious.

Atopic dermatitis (AD) is a multifactorial, chronic inflammatory skin disorder that results in areas of dry, itchy skin. AD is typified by defective skin barrier function with activation of abnormal immunological and inflammatory pathways upon exposure to ubiquitous environmental allergens. Specific probiotics have been shown to normalize intestinal permeability, to counteract intestinal immune dysfunction and to normalize gut dysbiosis. The aim of this randomized, double-blind, placebo-controlled study is to evaluate the efficacy of the most studied probiotic in the pediatric allergy field – L.rhamnosus GG – in children affected by atopic dermatitis. [ link]

Epigenetic mechanisms could drive the disease course of cow’s milk allergy (CMA) and formula choice could modulate these mechanisms. Our group demonstrated a significant difference in DNA methylation of T helper (Th)1/Th2 cytokine and of FoxP3 genes, concomitantly an up-regulation of microRNAs involved in Th1/Treg response, in children who acquired immune tolerance after treatment with extensively hydrolyzed casein formula containing the probiotic L.rhamnosus GG compared to soy formula. EPICMA II aims to evaluate the effect of other different formulas available for the dietary treatment of CMA on epigenetic mechanisms in CMA children. [ link]

The treatment of FA is based on a rigorous elimination diet and on the correct management of acute allergic reactions. The daily management of a correct elimination diet and a possible allergic reaction, entail a significant burden and high levels of anxiety and stress in mothers of children with FA, resulting in an impact on Quality of Life (QoL). The objectives of the study are to validate the Italian version of two specific questionnaires for food allergies and to explore the potential differences in the QoL of mothers of children with FA followed by a multidisciplinary team. [ link]

Unhealthy lifestyle habits during the childhood could negatively impact the health status during infancy and the later stages of life. The School represents the major Institution to implement actions aim at promoting healthy lifestyles habits. The Joint School-Health Project of the Neapolitan Child aimed at assessing the impact of a health education programme to improve lifestyle habits during the childhood. To evaluate the effects of this educational programme, the dietary habits, the sleep hours, the hours spent in sedentary behaviors (tv, smartphone) and the hours of physical activity will be evaluate at the baseline and at the end of the educational programme. [ link]

Lactobacillus GG (LGG) is able to exert long lasting effects in children with atopic disorders. Nutramigen LGG accelerates tolerance acquisition in infants with cow’s milk allergy. The mechanisms of these effects are still largely undefined. The effect of LGG could be related at least in part by the immunoregulatory role played by LGG. This probiotic can balance the generation of cytokines possibly involved in IgE- or non-IgE-mediated cow’s milk allergy Interleulkin (IL)-4, IL-5, IL-10, IFN-γ , TGF-β, and TNF-Υ), which can contribute to modulation of inflammatory processes. The investigators have demonstrated that children with IgE-mediated CMA produce significantly higher level of IL-4 and IL-13 in response to cow’s milk protein, and that tolerance is associated with a marked reduction of IL-13 production and a concomitant increased frequency of IFN-γ releasing cells. Epigenetics studies the heritable (and potentially reversible) changes of the genome inherited from one cell generation to the next which alter gene expression but do not involve changes in primary DNA sequences, highlighting the complexity of the inter-relationship between genetics and nutrition. There are three distinct, but closely interacting, epigenetic mechanisms (histone acetylation, DNA methylation, and non-coding microRNAs) that are responsible for modifying the expression of critical genes associated with physiologic and pathologic processes. The profile of epigenetic modifications associated with Th lineage commitment, coupled with the sensitivity of the early developmental period, has led to speculation that factors that disrupt these pathways may increase the risk of allergic diseases. Specifically, effects on DNA methylation and endogenous histone deacetylase inhibitors acting on specific pathways (Th1 and T regulatory cell differentiation) may favour Th2-associated allergic differentiation. MicroRNAs are another structural components of an epigenetic mechanism of post-transcriptional regulation of messenger RNA translation. It has been recently identified a specific Th2-associated microRNA (miR-21) that is critical for the regulation of Th cell polarization. It has been previously demonstrated an inverse DNA methylation pattern of cytokines involved in Th2 response (IL-4, IL-5) compared with cytokines involved in Th1 response (IL-10, INF- y) in children with CMA acquiring oral tolerance, with the most pronounced effects in those treated with Nutramigen LGG. [ link]

Food allergy is a common chronic condition in childhood. Recent studies have suggested that the natural history of food allergy has changed during the last two decades, with an increased prevalence, severity of clinical manifestations, and risk of persistence into later ages. The increased food allergy prevalence in children has an important economic impact, with significant direct costs for the healthcare system and even larger costs for the families of food-allergic patients. In addition, children with food allergies are at increased risk to develop other allergic manifestations later in life. According to a recent study, children with a food allergy are 2 to 4 times more likely to develop other atopic manifestations such as asthma (4.0 times), atopic eczema (2.4 times), and respiratory allergies (3.6 times), compared to children without a food allergy. Cow’s milk allergy is among the most common food allergy in early childhood, with an estimated prevalence of 2% to 3%. It has been previously showed that in children with cow milk allergy, an extensively hydrolysed casein formula supplemented with the probiotic Lactobacillus rhamnosus GG induced higher tolerance rates compared to extensively hydrolysed casein formula without Lactobacillus rhamnosus GG and other formulas. These findings were consistent with those of a 1-year follow-up study performed in the US that showed better outcomes using an extensively hydrolysed casein formula+Lactobacillus rhamnosus GG vs. an extensively hydrolysed casein formula or amino acid-based formula for the first-line dietary management of cow milk allergy. In addition it has been recently demonstrated that extensively hydrolysed casein formula + Lactobacillus rhamnosus GG reduces the incidence of other atopic manifestations and hastens the development of oral tolerance in children with IgE-mediated cow milk allergy. The present randomized controlled trial (RCT) was designed to test whether different dietary interventions could influence the occurrence of other atopic manifestations in children with IgE-mediated cow milk allergy. [ link]

Eosinophilic esophagitis (EoE) is a chronic antigen-mediated inflammatory disease of the esophagus that affects both children and adults. The incidence and prevalence of EoE is rapidly increasing in Western countries with an estimated incidence of 6.6 per 100,000 person-years (95% CI, 3-11.7) in children and 7.7 per 100,000 person-years (95% CI, 1.8-17.8) in adults. Clinically, it is characterized by various symptoms related to esophageal dysfunction, including vomiting, regurgitation, feeding difficulties, epigastric heartburn, dysphagia, or food bolus impaction, and may cause growth retardation. Diagnosis is made on the basis of clinical symptoms and histological evidence of eosinophilic infiltration of the esophagus (at least 15 eosinophils/high power microscope field (eos /hpf), excluding other etiologies of esophageal eosinophilia (gastroesophageal reflux disease, infectious esophagitis, achalasia, celiac disease and Crohn’s disease, connective tissue disorders, gra ft versus host disease, drug hypersensitivity and hypereosinophilic syndromes). EoE is primarily characterized by a T helper 2 type inflammation, but the pathogenesis and the immunopathological mechanisms underlying the pathology are not yet fully understood. Recent evidence suggests that in genetically predisposed individuals, interaction with environmental factors (e.g., dietary lifestyle) may play a role in activating several inflammatory pathways and cause EoE. Ultra-processed foods (UPFs) are food and beverage products resulting from industrial formulations, ready for consumption, typically obtained with five or more ingredients from different manufacturing processes (cooking methods, addition of additives such as stabilizers or preservatives). During the last decade, the consumption of the latter has increased significantly among the pediatric population to represent 30% of the daily caloric intake of an average child in Europe and America. Recent evidences show that UPFs favor the onset of chronic non-communicable diseases through the activation of different inflammatory pathways. The components mostly represented in UPFs are the advanced glycation end products (AGEs), a heterogeneous group of highly oxidizing compounds that are formed through non-enzymatic reactions (Maillard reaction) between reduced sugars and free amino groups of proteins, lipids, or nucleic acids. Evidence demonstrates that dietary AGEs are absorbed and contribute significantly to the total concentration of AGEs in the body. AGEs induce oxidative stress and inflammation, leading to structural and functional protein alterations, cellular apoptosis and multi-tissue/organ damage. These mechanisms are mediated at least in part by interactions with their cell-surface receptor for advanced glycation end-products (RAGE). The AGEs-RAGE interaction modulates the immune response. AGEs are able to activate le mast cells, to stimulate the release of histamine and to induce a chronic inflammatory state that promotes a T helper 2 type response.

In last decades, a change in dietary habits has been observed in industrialized countries characterized by a drastic increase in the consumption of ultra-processed foods (UPF, Ultra-Processed Foods). As defined by the NOVA classification, UPFs are industrial formulations of food substances added with colourings, flavourings, emulsifiers, thickeners and other additives. Among the main compounds of UPFs are the advanced glycation end-products (AGEs). Increasing evidence suggests an association between dietary exposure to AGEs and the development of chronic non-communicable diseases, such as obesity and allergies, in the general population, through increased oxidative stress and inflammation. Preliminary evidence suggests that a maternal diet rich in AGEs during pregnancy and lactation could negatively influence the composition of breast milk and have a negative impact on the infants health. However, data regarding the presence of derivatives of UPFs in breast milk are not available. The UFIM (Ultraprocessed Foods In Breast Milk) study aims at evaluate the presence of UPFs-derivatives compounds in breast milk. [ link]

Food Allergy (FA) is one of the most expensive allergic disorders in the pediatric age, and affecting up to 10% of children worldwide, it is recognized as a global health problem. The Oral Food Challenge (OFC) is the gold standard for FA diagnosis, but it is time-consuming, expensive, and potentially dangerous, as it can determine severe anaphylaxis. In addition, causing long-lasting impact on patient anxiety and mental health due to the physical duress and health risks involved with its application, OFC strategy is little applied in clinical practice with consequent diagnostic errors and delays. The goal of the Naples Pediatric Food Allergy (NAPFA) score is to develop a new clinical score including the main anamnestic, and clinical features for the easy identification of pediatric FA in primary care setting. [ link]

The childhood obesity prevalence has increased dramatically in the last decades, affecting more than 340 million children worldwide. This condition is the major risk factor for a set of metabolic abnormalities, also known as metabolic syndrome, a condition that reduce life expectancy by 5-20 years. Changes in the global food system, and the increased consumption of ultra-processed foods (UPFs), may have contributed to the increase in the prevalence of childhood obesity and related morbidities. The mechanisms by which UPFs might promote obesity and metabolic syndrome could be multiple and not completely identified. The Ultra-processed Food in Obesity (UFO) Project has been designed to investigate the potential associations between UPFs intake and MetS in pediatric subjects. [ link]

‘Tackling Malnutrition’ is focused on developing nutritional strategies targeting the most vulnerable categories of the national population (i.e., families in the condition of financial hardship, people affected by pathologies, or older people), thus ensuring adequate nutrition and limiting the onset of malnutrition situations that would end up reducing resilience and aggravating conditions of frailty. We are a partnership for the Sustainable Development of Food and Nutrition, funded under the Italian National Recovery and Resilience Plan (NRRP).

Breast milk is considered the gold standard for infant nutrition due to its ability to provide adequate nutrition and a high amount of protective factors for the baby’s health. According to the guidelines of the World Health Organization (WHO), exclusive feeding with breast milk should be conducted until the end of 6 months of life and should be continued in the following months with the simultaneous introduction of complementary foods. Several scientific evidence demonstrates that breastfeeding is associated with positive health outcomes, both during infancy and in later life. Given the protective role of breast milk for health, studying its content is of fundamental importance to have an integrated vision of the biological effects of its components on the health of the child, and of the factors that are able to modulate its composition. The “Building a Deeper Knowledge on Breast Milk Composition” (BuKoBc) project was designed to study the content of human milk in its entirety and at different times during the feeding and during the day, also in relation to environmental factors capable of modulating its composition. The results of this study may provide data on optimal reference ranges for nutrient intake in breastfed infants and may provide guidance in defining optimal nutrient intake for infants who cannot be breastfed. Furthermore, the in-depth study of the environmental factors capable of influencing the composition of breast milk will allow the development of nutritional intervention strategies for the breastfeeding mother in order to positively modulate the composition of her milk.

The latest data from the World Health Organization (WHO) shows that malnutrition in all of its forms affects over 2.5 billion people globally. This condition is constantly increasing and affects the entire population, from childhood to the elderly. Malnutrition in all its forms negatively impacts the quality of life of patients affected and increases the risk of morbidity and mortality, as well as healthcare costs. Considering the complexity and multifactorial nature of malnutrition, the integration of multiomics data obtained from analyses with high-throughput technologies such as epigenomics, metagenomics, metabolomics, could benefit the prediction and evaluation of prognosis and/or response to specific treatments; this could pave the way for personalized precision medicine interventions for patients suffering from malnutrition. The “Science Against Malnutrition Project” (SAM) aims at characterize malnutrition through the identification of specific biomarkers of the condition with the goal of developing innovative prevention and treatment programs.

Pediatric Food allergy (FA) is an increasing health problem worldwide with significant socioeconomic costs for the families and health care system. Genetic and epigenetic mechanisms involved in FA occurrence are not fully understood, which hampers the development of effective diagnostic, preventive and therapeutic strategies. Several genes could play a role in pediatric FA. Gene expression can be modulated by different epigenetic mechanisms regulated by several environmental factors. These epigenetic mechanisms could have a role on FA occurrence and disease course. We will focus on genetic and epigenetic mechanisms involved in FA with the aim of identifying innovative biomarkers and targets for limiting the disease burden and reducing the socio-economic costa for the families and the health care system.


Preclinical studies

Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in gut microbiome, leading to reduced butyrate production have been reported in patients with SARS-CoV-2 infection. We investigated the protective action of this compound against SARS-CoV-2 infection in human small intestine and enterocytes, focusing on the relevant aspects of the infection.

Results from two randomized-controlled trials suggested that a specific postbiotic product, deriving from the fermentation of cow’s milk with the probiotic L.paracasei CBA L74 (FM-CBAL74), is able to prevent infectious diseases in young children. Through direct interaction with human enterocytes, FM-CBAL74 elicited a positive regulation of several defense mechanisms, including the modulation of gut barrier, the stimulation of adaptative (secretory immunoglobulin A, sIgA), and of innate immunity (human alpha-defensins 1–3; human beta-defensin 2; cathelicidin LL-37). The acknowledgment of which specific FM-CBAL74 bioactive components, deriving from the fermentation of cow’s milk with the probiotic, could be responsible for the observed protective actions represents a crucial aspect. For this reason, we evaluated the effects of cell surface polysaccharides or other bioactive components from FM-CBAL74 on non-immune and immune defense mechanisms against infections in human enterocytes.

Current hypotheses and models of food allergy (FA) do not adequately explain the dramatic increase observed in the last years. It has been hypothesized that advanced glycation endproducts (AGEs), present at high level in junk food (sugars, roasted/barbecued meat), could be involved in FA pathogenesis. The aim of our project is to evaluate the subcutaneous AGEs levels and the correlation with dietary habit in children with challenge-proven FA, children with respiratory allergy and age and sex-matched healthy controls. Pathogenetic mechanisms elicited by AGEs were also investigated in a cellular model of human enterocytes and in peripheral blood mononuclear cells from children at risk for atopy. [ link]

Rotavirus (RV) is the leading cause of severe childhood acute gastroenteritis (AGE). Each year, RV is responsible for about 25 million clinic visits, two million hospital admissions, and 180 000–450 000 deaths in children under 5 years of age globally. Clinical evidences suggest the potential of the postbiotic approach based on cow milk fermentation with the probiotic L. paracasei CBAL74 (FM-CBAL74) in preventing pediatric infectious diseases. The aim of this study is to evaluate the preventive action elicited by FM-CBAL74 against Rotavirus-induced AGE in a well-established in vitro model of human enterocytes. [ link]

Fermented foods have been proposed in limiting SARS-CoV-2 infection. Emerging evidence suggest the efficacy of cow’s milk fermented with the probiotic L.paracasei CBAL74 (FM-CBAL74) in preventing infectious diseases. We evaluated the protective action of FM-CBAL74 against SARS-CoV-2 infection in human enterocytes, analyzing the crucial aspects of the infection.
L.rhamnosus GG (LGG) is one of the most widely used probiotic strains. Various health effects are well documented including stimulation of immune responses that prevent allergic conditions. LGG bacterial components that were yet identified as important factors governing host interactions include adhesive pili or fimbriae, lipoteichoic acid molecules, major secreted proteins and galactose-rich exopolysaccharides, as well as specific DNA motifs. We investigated the immunomodulatory effects of these components in vitro model of human enterocytes and in peripheral blood mononuclear cells.

Eosinophilic Esophagitis (EoE) is dramatically increased in the last two decades. The pathogenesis of EoE is incompletely understood but involves genetic, environmental, and host immune system factors. One increasingly recognized and potentially pathogenic component of ultra-processed foods is a group of posttranslational modifications known as advanced glycation endproducts (AGEs).  We aimed to investigate the effects of AGEs in esophagus organ culture from children on inflammatory and immune response.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a drastic impact on pediatric health. The multifactorial pathogenesis of AD is still somewhat of an enigma. The gut microbiome might play a crucial role in the development of AD by regulating immune system maturation through cross-talk between the microbiome and the host, especially in early life. Recent evidence showed that the short chain fatty acid butyrate prevents skin inflammation in sensitized mice. We investigated the protective effect of butyrate on oxidative stress, differentiation and wound-healing of the skin using the normal human epidermal keratinocytes (NHEK cells).

Several formulas are available for the dietary treatment of cow’s milk allergy (CMA). Formulas available for CMA treatment differ mainly regarding the protein fraction features, such as source (cow’s milk, soy, or rice), degree and procedure of hydrolysis. Clinical data suggest potential different effect on immune tolerance elicited by these formulas. The aim of this study is to comparatively evaluate the tolerogenic effect elicited by the protein fraction of different formulas available for the dietary treatment of CMA. [ link]