Pathogenesis, diagnosis, dietary management, and prevention of gastrointestinal disorders in the paediatric population

This review was conducted using the international database PubMed. From this website, we have searched for articles in English using the following keywords: (1) special diet; (2) gastrointestinal disorders; (3) diet treatment and gastroesophageal reflux disease; (4) diet treatment and cystic fibrosis; (5) diet and IBD; (6) diet and short-bowel syndrome; and (7) diet and eosinophilic esophagitis. We have chosen mainly studies based on child cohorts, and we have extracted evidence from the studies of the last ten years (Fig. 1). We have used the article’s abstracts to decide if the articles were of interest to the topic. We also have reviewed the references of the selected articles and read those that might interest the current topic.

Fig. 1figure 1

Flow chart of the literature research

Diet management in food allergy

FA is a common disorder among children; its incidence is estimated at around 8%. FA is an adverse immune response to food proteins, and results in gastrointestinal and extra-intestinal symptoms, affecting the skin, with erythematous rashes, pruritus, urticaria, and angioedema; upper or lower airways; cardiovascular and nervous systems. There is also the possibility of generalized reactions when there is a severe immune response to some allergens. The diagnosis of FA is based on the clinical history and laboratory findings, such as in vivo (skin prick test) and in vitro (allergen-specific serum immunoglobulin (Ig)E) tests, and elimination diet. The gold standard for diagnosis is the oral food challenge [2, 3].

FA is classified into non-IgE-mediated disease and IgE-mediated disease, but there are also mixed forms, with clinical manifestations which could be heterogeneous, involving different organs like skin, gut or airways. Food protein-induced enterocolitis syndrome, food protein-induced enteropaty, food protein-induced proctocolitis, and food protein-induced hemosiderosis must also be included in the differential diagnosis [4, 5].

Non-IgE-mediated FAs are caused by an immune response involving other components apart from IgE antibodies. The reactions do not appear immediately after the ingestion of the food and commonly involve the skin and gastrointestinal tract, causing also enterocolitis syndrome and rectocolitis [4,5,6,7].

Two adjacent IgE molecules, binding to the food protein, lead to the degranulation of the mast cell and basophil with a consequent release of preformed mediator within minutes of exposure. This type of reaction is immediate and generally occurs within 2 h after the ingestionIt can consist of acute urticaria, angioedema, vomiting, and wheezing. There is the possibility for late manifestations, with described reactions one week after milk ingestion. The presence of specific serum IgE can support the immune sensitization in IgE-mediated allergy, and the specific IgE levels seem to predict the severity of the manifestations [4, 5].

Among a large range of immunogenic foods, eight foods only provoke 90% of IgE-mediated food-allergic reactions: cow’s milk, egg, soy, wheat, shellfish, fish, peanuts, and tree nuts (Table 1) [8]. Cow's milk proteins allergy (CMA) is the most common cause of FA in the paediatric population, especially under the age of 3 years [9, 10], with a prevalence of 2–3% [11]. CMA is the consequence of ingesting cow’s milk proteins, which are particularly immunogenic in susceptible children. The clinical patient’s history provides the elements to suppose a diagnosis. The major allergenic proteins in cow’s milk are casein proteins: αs1-, αs2-, β- and κ-casein; and whey proteins: α-lactalbumin and β-lactoglobulin [11].

Table 1 The eight types of foods causing 90% of IgE-mediated food-allergy reactionsCMA diagnosis and management

Diagnosis of CMA is based on the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines [12]. Accordingly, patients with suspected symptoms should undergo an elimination diet for 2–4 weeks; then, if there is a clinical improvement, the diagnosis must be confirmed by a standardised oral food challenge test (Fig. 2). Treatment consists of cow’s milk and derivate elimination diet. After a confirmed diagnosis, exclusive breastfeeding for 4–6 months is the first choice to treat these children. As a second-line treatment option, the elimination of cow milk and milk derivate from the mother’s diet is suggested [13]. Breast milk has demonstrated beneficial effects on immune modulation, promoting the systemic release of IL-10, which plays a central role in the down-regulation of inflammation, and it has been associated with reduced disease severity of CMA-related atopic dermatitis in children [14]. However, there is no conclusive evidence on the protective role of breastfeeding on the onset of specific FAs [15].

Fig. 2figure 2

CMA diagnosis and treatment algorithm

When breastfeeding should be not available or contraindicated, special milk formulas are considered the diet substitute for infant nutrition. The special formulas with reduced allergenicity are: extensively hydrolysed formula (eHF), containing oligopeptides with a molecular weight < 3000 Da; partially hydrolysed formula (pHF); amino acid formula (AAF), containing only free amino acids; soy formula (SF); rice hydrolyzed formula (RHF); and other mammalian milk (sheep, goat, camel). The recommended formula is eHF [9]. AAF is recommended only for infants with IgE-mediated CMA at high risk for anaphylactic reactions [16]. Soy formula is not recommended for infants under 6 months of age, as it can induce sensitization to soy proteins [17]. Soy formula can be considered in CMA when eHF are not tolerated, although the possibility of cross-reactivity cannot be excluded [18].

Diet can directly influence organs' growth but could also act as an epigenetic modulator at different levels of immune system function in children suffering from CMA [19,20,21,22,23,24]. Indeed, a significantly lower incidence of respiratory-associated adverse events and diarrhoea has been found in infants fed with formula with added bovine milk fat globule membrane and bovine lactoferrin [20]. The eHF supplemented with the probiotic Lactobacillus Rhamnosus GG (LGG) seems to reduce the incidence of allergic manifestations and promote the development of oral tolerance in children with IgE-mediated CMA [21]. Moreover, a cohort study on 365 children showed that eHF supplementedwith the probiotic LGG reported the best effect in reducing the incidence of allergic manifestations and improving the immune tolerance acquisition rate compared with the other formulas [24].

Due to their effects on neurodevelopment and immune response, there is also a growing interest in the role of long-chain polyunsaturated fatty acids (LCPUFA) added in milk formulas. The n-3 LCPUFA supplementation during pregnancy has shown a reduced risk of egg sensitization in the first year of life and a reduced risk of developing atopic eczema [22]. Milk formulas with added LCPUFA could influence the risk of developing allergies in children [23]. More recently, in their systematic review and meta-analysis, authors reported that LGG may promote oral tolerance in children suffering from CMA (moderate-quality evidence), as well as facilitating recovery from intestinal symptoms [25]. After 6 months of elimination diet, a revaluation of the child is indicated to consider the possibility of cow’s milk reintroduction. Cow’s milk reintroduction starts with baked milk products and after with fresh cow’s milk (Fig. 1) [12, 16].

Food introduction time and immunotherapy

Previously, postponing the introduction of allergenic foods to prevent food allergies was suggested. Currently, a new approach has emerged to reduce the incidence of FA. Indeed, the Learning Early About Peanut (LEAP) trial has shown the importance of the early introduction of allergens. In children at high risk for allergy, the early introduction of peanuts in the first year of life prevented the development of peanut allergy [26]. Furthermore, maternal peanuts consumption during breastfeeding combined with the early introduction of peanuts in children’s diet before the first year of age has been associated with the lowest incidence of peanuts allergy [27]. Considerable caution was also adopted in the timing of egg introduction timing, because of its allergenicity. Nevertheless, it has emerged that the egg introduction between the fourth and sixth months of age has been associated with a reduced risk of egg allergy [28].

Allergy to one type of tree nut was often treated with diet avoidance of all tree nuts. However, it has been found that the rate of clinical co-allergy was lower than that of co-sensitisation and not extended to all tree nuts, thus the diet choices could be less selective [29].

Regarding fish allergy, the most common protein that can cause allergy in children is parvalbumin, whose chemical structure changes based on the fish’s species. These differences explain the evidence that a child with a fish allergy might be allergic to some types of fish but not to others [30].

The most promising therapeutic option to induce food tolerance in FA is Food allergen immunotherapy (FA-AIT). It consists of the administration of the culprit allergen, through different routes, in children with a documented FA, at gradually increasing doses with 2-to-4 weeks intervals, followed by a maintenance phase [31, 32]. FA-AIT aims at obtaining the desensitization towards a specific food and developing the immune tolerance to this food protein. FA-AIT has been proven to reduce the risk of potentially life-threatening allergic reactions in the event of accidental ingestion. Oral immunotherapy (OIT) showed an encouraging clinical efficacy with estimated desensitization rate at around 90%, despite adverse events linked to the allergen intake have been documented. Thus, to limit the incidence of these severe adverse reactions, it has been recently suggested OIT administration in with anti-IgE antibodies [33]. Epicutaneous immunotherapy (EPIT) is also possible, and it consists of applying a patch containing a food allergen on the children’s skin. However, OIT seems more effective than EPIT in treating peanut allergy [34]. The European Academy of Allergy and Clinical Immunology (EAACI) has published clinical guidelines on AIT for IgE-mediated FAs, recommending OIT for persistent cow’s milk, hen’s egg and peanut allergies in children from 4 -5 years of age [35].

Currently, food avoidance remains the first-line treatment strategy for treating FA, and the early introduction of food seems to be a promising prevention strategy in developing immune tolerance. New immunotherapy strategies will change the management of FAs.

Diet treatment in cystic fibrosis

CF is an autosomal recessive disease caused by genetic mutations that interest the CF transmembrane conductance regulator (CFTR) gene. The incidence of CF is around one in 3500 white births in Europe [36]. It is a multisystem disorder that not only affects the lung but it may also involve other organs, like the gastrointestinal tract, with a significant impact on the patient’s nutritional status, mainly secondary to pancreatic insufficiency with consequent malabsorption and risk of malnutrition. Nutrition management is a fundamental element in CF therapy, and a high-fat diet is the basis of this treatment. The updated guidelines on nutrition management of patients with CF also recommend with a high-grade of evidence nutrition education and behavioural counselling for families of infants with CF [37].

Table 2 shows the energy need of CF patients compared to healthy people and the timing of monitoring according to the patient’s age (Table 2).

Table 2 Nutritional status needs and monitoring in CF

In children with CF, the high-fat diet combined with microspheric pancreatic enzyme replacement therapy improved outcomes and life expectancy [38]. Accordingly, due to the link between nutritional status and clinical outcome in these patients, children with a lower body mass index (BMI) had an increased incidence of severe lung disease compared to those with a normal BMI. An increased BMI that involves only the fat tissue can also be associated with a worse disease prognosis [39]. The use of age-appropriate BMI-related thresholds is recommended to decide when nutrition interventions are necessary [37].

The relationship between a good nutritional status and a better lung function has been well-established for some years [40]. Infants with CF should receive human milk like healthy infants, since the ones who were breastfed had a better lung function and fewer infections than children who were not breastfed [41]. A standard infant formula could be provided when human milk is unavailable. Infants newly diagnosed with CF fed with a protein hydrolysate formula showed the same energy intake, growth velocity and nutritional status compared with those fed with conventional formula [42]. A retrospective cohort study of preterm CF infants’ growth in the first 2 years of life evidenced that late preterm infants with CF were at higher risk of being below the 10th percentile for weight-for-length at 2 years of age compared with term infants with CF, showing this subgroup of patients need for nutritional attention [43]. Table 3 reports clinical trials investigating different nutritional management in CF (Table 3).

Table 3 Clinical trials of nutrition interventions on children with CF

GERD is a common comorbidity among patients with CF with a high prevalence also in young patients, and it is linked to an increased number of infectious pulmonary exacerbations. A higher prevalence of extra-oesophageal symptoms generally characterizes GERD in CF patients. GERD may affect respiratory function, suggesting that early detection of the disorder and a targeted treatment based on proton pump inhibitors (PPIs) could improve the clinical outcome of these patients [46, 47].

Malnutrition prevention in CF

Malnutrition is more common in CF children with a documented exocrine pancreatic insufficiency. Pancreatic enzyme replacement therapy (PERT) is considered the main treatment in the event of impaired exocrine pancreatic function [38, 48, 49].

Despite the importance of an appropriate dietary management, some children and adolescents with CF show a low adherence to the dietary recommendations and may end up suffering from malnutrition, which can compromise the immune system and lung function, as well as increasing the risk of respiratory infections [50]. A child with CF needs 10–15% more energy intake than a healthy child; accordingly, the nutritional management of CF patients includes a high-calorie/high-fat diet, added to PERT, and vitamin and mineral replacement. The high-fat diet has improved the nutritional status prolonging survival. The high-caloric diet includes a high-fat intake, which represents 35%–40% of the daily energy requirements, and it is necessary to cover the high-calorie demand of these patients, even throughout the promotion of the use of high-calorie fat additives to foods and beverages [51]. ESPEN guidelines recommend adjusting energy intake to avoid obesity, considering the energy intake adapted by age, and performing regular clinical re-evaluations of patients taking oral nutritional supplements to determine whether the patient should continue taking them [37].

The adherence to a low glycaemic index, high fat, high-calorie diet can improve glycaemic indices in children and adolescents with CF compared to the high fat, high-calorie diet [44]. When an oral supplementation with pressurized whey proteins is chosen, there is an increase in intracellular glutathione levels, improving the inflammatory status of patients with CF [52]. A randomized controlled trial (RCT) conducted on CF children with pancreatic insufficiency showed an improvement in fat absorption and a better growth after treatment with a novel oral structured lipid supplement [45]. ESPEN guidelines strongly recommend a nutrition intervention that comprises a full review of nutrition status and PERT, suggesting investigating any underlying medical conditions that could compromise health status. A polymeric enteral tube feeding could be considered only when oral interventions have failed to obtain an acceptable rate of growth and nutritional status [37].

In summary, managing patients with CF need a multidisciplinary approach, since diet and nutrition intake significantly impact the disease course and susceptibility to severe infections. Before the new frontier of the promising channel modulators, nutritional therapy, based on a high calorie/high-fat diet and PERT in combination with regular follow-up, has changed the natural history of CF patients, and, to date, it continues to represent the primary option to improve survival and quality of life (QoL) in CF.

Nutrition and diet in inflammatory bowel disease

Ulcerative colitis (UC) and Crohn’s disease (CD) are the most common IBD. UC is a chronic disease featured by diffuse rectal and colic mucosa inflammation, which involves the rectum in 95% of cases. It can be extended continuously to more proximal parts of the large intestine. The classic clinical symptom of UC is bloody diarrhoea, and the clinical presentation is characterized by periods of remission and exacerbation [53]. CD is a chronic inflammatory gut disease involving all gastrointestinal tracts. It generally interests the ileocolic tract with a complete colon wall layers inflammation, which is not continuously extended differently from UC. The most common symptoms of CD are abdominal pain, diarrhea and weight loss [54]. Diagnosis of IBD is mainly histological [55]. During the last years, the incidence of IBD has increased, suggesting the possible pathogenic role of environmental factors. Among these, the influence of diet has been revaluated.

The so-called "Western diet” and some dietary constituents, like fat, seem to have a proinflammatory effect that may promote the onset of IBD in genetically susceptible individuals [56]. Conversely, a prospective study has shown that a long-term intake of dietary fibres, particularly fibres from fruit, was protective against the risk of development of CD [57]. A decreased risk of developing IBD was observed with a diet rich in fruit and vegetables and n-3 fatty acids, which is therefore recommended in these patients [

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