Impact of pediatric gastrointestinal disorders on learning and cognitive development in schoolchildren

Celiac disease (CD) and its connection to LD

CD is a serious disease of autoimmune etiology, which affects genetically predisposed individuals after eating gluten (e.g., wheat). Pathophysiologically, it leads to small intestinal damage, and specifically villous atrophy, which results in malabsorption of nutrients such as folate and iron. Beyond its well-documented GI pathogenicity, CD is also acknowledged for its potential impact on cognitive functions and behavior, including LD. The prevalence of CD is approximately 1:100 for the general population. An even higher incidence is reported in individuals with NDDs such as ASD and ADHD [15,16].

Untreated CD has been associated in the literature with cognitive complaints, often described as “brain fog”. The latter includes difficulties in memory, concentration and executive functioning[17]. Titel et al reported that cognitive impairment, in a large cohort of diabetic children (type 1) with accompanying CD, improved significantly after establishment of a strict gluten-free diet (GFD). This suggests a potential association between gluten exposure and neurocognitive dysfunction[16]. From a pathophysiological perspective, chronic systemic inflammation, nutrient deficiencies (particularly iron, folate, and vitamin B12), and gut-brain axis impairment have been previously proposed as possible contributors to LD in CD patients[16].

Moreover, a higher prevalence of ADHD in individuals with CD has been reported compared to the general population. In particular, a meta-analysis found a significant association between CD and ADHD, with a pooled odds ratio of 1.39 [14], indicating that CD patients are more likely to exhibit attentional deficits[18]. Further relevant research suggests that adherence to a GFD may improve ADHD symptoms, (mostly inattention), thus suggesting a possible linkage between gluten exposure and cognitive and behavioral impairments[18].

The association between CD and ASD remains undetermined. Whereas some studies have reported a higher prevalence of CD among children with ASD, others have found no difference compared to the general population [19]. GI symptoms, (including those of CD), are common in ASD, and food sensitivities may exacerbate behavioral symptoms. However, routine screening for CD in the ASD setting is not generally recommended, apart from standard clinical indications and guidelines [19].

Overall, CD may adversely impact cognitive function and learning potential, especially if left untreated. The associations between CD, ADHD and ASD highlight the importance of considering gluten-related immune mechanisms in pediatric patients with neuropsychiatric manifestations. Given the potential for cognitive improvement on a GFD, early diagnosis and dietary management may enact a key role in mitigating LD, and therefore enhancing overall cognitive performance in affected individuals.

Irritable bowel syndrome (IBS) and other functional GI disorders: Impact on LD

IBS is a very common GI disease under the umbrella term of functional GI disorders (FGIDs). The hallmark of these disorders is the absence of structural damage. Their clinical manifestations extend beyond the GI tract, even impacting psychosocial process. As a clinical syndrome, IBS appears with cardinal symptoms recurrent abdominal discomfort or pain, bloating, and altered bowel habits. It is often linked to neuropsychiatric conditions, including ADHD and ASD. Emerging evidence suggests that individuals with IBS or other FGIDs may exhibit higher rates of cognitive difficulties, including deficits in attention, executive functioning and working memory[20].

An association has also been reported between ADHD-FGIDs, most notably IBS, functional dyspepsia and chronic constipation. In a large cohort study, young adults (17-35 years old) with ADHD showed a higher IBS prevalence than non-ADHD individuals (odds ratio 1.67, 95% confidence interval 1.56-1.80; P<0.001)[20]. Within the same cohort, the coexistence of FGIDs was associated with more frequent medical visits, reflecting the magnitude of the GI burden. It should be noted that the abovementioned findings indicate association rather than causation, and probably indicate overlapping neurobiological and gut-brain axis mechanisms [20].

Likewise, IBS has been reported at higher rates in pediatric populations with coexisting ASD, and has been associated with increased behavioral challenges and sensory sensitivities. ASD schoolchildren who experience recurrent GI symptoms, including chronic constipation and abdominal pain, are at greater risk for heightened stress responses, disrupted sleep and increased irritability, all of which may adversely affect their capacity to focus and engage in learning environments[21]. Additionally, anxiety disorders frequently coexist in children with IBS, further contributing to cognitive difficulties and school performance.

Recent clinical observations have described an overlap between FGIDs in children and anxiety-driven behaviors focused on bodily sensations and food ingestion, thus suggesting a close crosstalk between GI semiology and psychopathology [22,23].

A rather distressing manifestation is emetophobia (from the Greek word for “fear of vomiting”). Emetophobia in certain affected children may result in significant food avoidance, social withdrawal and reduced school performance. These symptoms are primarily anxiety-driven, rather than weight- or body-image-related. Such avoidance behaviors may lead to school absenteeism [24,25].

Therefore, the documented connection among FGIDs, LD and psychiatric comorbidities warrants a multidisciplinary approach to management. Addressing IBS in children with NDDs through dietary intervention, stress management policies and microbiome-targeted interventions may not only improve GI symptoms, but also support educational functioning. Nevertheless, it has to be stressed that the available evidence for direct effects on LD per se currently remains limited [15].

Future research should focus on elucidating mechanisms by which gut dysbiosis influences cognitive performance and psychiatric symptoms, paving the way for targeted therapeutic strategies.

Inflammatory bowel disease (IBD) and LD

IBD, whose principal forms are Crohn’s disease and ulcerative colitis, is a chronic inflammatory, immune-mediated disease of the GI tract with relapsing character. The cardinal symptoms in children include abdominal pain, diarrhea, rectal bleeding and weight loss, or even failure to thrive. Beyond its well-documented impact on digestion and immunity, emerging evidence suggests that IBD also affects cognitive function and learning abilities in children [26]. Disruptions in gut homeostasis, commonly seen in IBD, have been implicated in cognitive dysfunction, emotional disturbances and neuropsychiatric comorbidities, including depression, anxiety and ADHD [6].

Children and adolescents with IBD frequently experience academic difficulties due to a combination of disease activity, treatment side-effects and psychosocial factors. Studies have shown that children with IBD have reduced school attendance, concentration difficulties and lower academic performance compared to their healthy peers[26]. This may stem from both direct biological mechanisms, (e.g., chronic inflammation, malnutrition) and indirect factors (e.g., fatigue, pain, frequent hospital visits). A population-based study from Canada demonstrated that children with IBD had lower rates of school attendance and a greater risk of cognitive fatigue and executive dysfunction[26]. In Israel, children diagnosed with IBD were found to miss significantly more school days compared to their healthy peers, with absenteeism most pronounced among those with Crohn’s disease (average of 24 days), followed by ulcerative colitis (21 days) and healthy controls (5.1 days) [26]. Furthermore, it has been suggested that the cascade of cytokine production within IBD may to contribute to brain processes. In particularly, tumor necrosis factor (TNF)-α, has been associated with neuroinflammation, with a potential negative impact on memory, attention and processing functions[6]. Pediatric IBD patients are more prone to emotional distress, anxiety and depressive disorders, all of which contribute synergistically to a deterioration of school performance[15].

Nutritional deficiencies are a major concern in IBD, and can significantly impact brain development and learning function. Iron, vitamin B12, folate and vitamin D deficiencies, commonly observed in IBD patients (both pediatric and adults), have been associated with impaired memory, attention deficits and executive dysfunction[26]. Pathogenetically, these deficiencies are a result of malabsorption of key nutrients due to intestinal inflammation, and surgical resections in severe cases, and may result in neurodevelopmental delays, particularly in schoolchildren with an early onset. Exclusive enteral nutrition is a core dietary intervention, often used as a first-line therapy in pediatric Crohn’s disease, that has proved promising in reducing inflammation, while providing essential nutrients that support brain development. Nevertheless, persistent malnutrition in pediatric IBD, and consequently failure to thrive, are well-acknowledged factors for lower IQ scores and academic underachievement in schoolchildren with an aggressive disease course[26].

Children with IBD, as well as adolescents, exhibit a higher prevalence of psychiatric disorders, including ADHD, depression and anxiety, compared to the general population [6]. Results from large-scale registries and cohort studies have identified a bidirectional relationship between IBD and neuropsychiatric pathologies, suggesting that chronic inflammation and dysbiosis influence the CNS. In addition, genome-wide genetic association results have revealed common susceptibility loci between IBD and psychiatric diagnoses, particularly major depressive disorder and ADHD [6].

A relevant review of pediatric IBD reported that children with relapse were characterized by statistically significant higher rates of depression and anxiety compared to their counterparts in remission[27]. Notably, psychiatric comorbidities, and mainly depression and anxiety disorders, are more prevalent among IBD patients than the general population, and can materially compromise learning and school performance. A review article by Salducan et al summarized the current evidence regarding pediatric IBD patients, and concluded that schoolchildren are at an increased risk of associated anxiety, depression, panic disorder, phobias and dysthymias, a fact that may negatively affect the cognitive and educational outcomes of such children [28].

In summary, children with IBD are reported in the literature to have more frequent school absences and academic problems that extend beyond pure GI symptoms, primarily due to fatigue, depression and anxiety [29]. These psychological factors may contribute to LD. Therefore, clinical alertness, and early multidisciplinary intervention for comprehensive care that addresses both physical and mental health aspects of IBD are required [30].

Gastroesophageal reflux disease (GERD) and its impact on LD

GERD can indirectly, but significantly, influence the learning abilities of schoolchildren. The most chronic GERD symptoms include persistent heartburn and regurgitation, which not infrequently result in discomfort and retrosternal pain. This semiology is known to distract schoolchildren and adolescents from academic tasks, leading to reduced concentration, attention and classroom engagement, especially once symptoms are recurrent and refractory and are accompanied by prolonged school activities. Persistent discomfort may equally contribute to increased school absences, which may also compromise children’s school performance [31,32].

Moreover, GERD has been indirectly associated in the literature with diverse NDDs. According to Dutt et al, children with cerebral palsy exhibit a high prevalence of sleep disturbances, and GERD is acknowledged as a silent and underdiagnosed contributing factor for sleep disruption in such a pediatric population [33]. Evidence has revealed that early-onset neurological impairment and abnormal electroencephalography results are significant risk factors for severe GERD in children [34]. Sleep disturbances represent an additional and clinically relevant concern, since GERD symptoms frequently disrupt sleep patterns, leading to daytime fatigue and diminished cognitive function. Adequate sleep is crucial for memory consolidation and learning; therefore, interrupted or fragmented sleep due to nocturnal reflux can impair a child’s ability to process, retain and retrieve new information. Daytime somnolence and irritability may further aggravate attention difficulties and classroom behavior.

Several pediatric studies further support an indirect association between GERD and impaired school functioning through symptom burden, sleep disruption and reduced quality of life. In a Turkish pediatric quality-of-life study (n=93), children and adolescents with GERD reported significantly lower scores in school-related functioning domains, including concentration, energy levels and classroom participation, compared with healthy peers, with greater symptom severity correlating with increased functional impairment [32].

In a Japanese pediatric cohort of 336 children aged 4-12 years, Sakaguchi et al (2014) [31] found that GERD symptoms were significantly associated with sleep disturbances and behavioral problems, including attention deficits. Such symptoms are also linked to increased school absenteeism and classroom disengagement.

Pediatric quality-of-life studies have consistently shown a negative correlation between GERD symptom severity and school functioning. For example, Acierno et al (2010) developed a GERD-specific quality-of-life tool and found that children (n=19) with moderate-to-severe symptoms reported difficulties with concentration and classroom engagement [35].

The joint clinical practice guidelines of the North American and European Societies for Pediatric Gastroenterology emphasize that sleep disturbance and daytime fatigue are common extra-esophageal manifestations of GERD in children, and may contribute to impaired daytime cognitive performance and reduced school engagement [36]. Furthermore, studies examining children with chronic medical conditions, including GI disorders, demonstrate greater school absenteeism, reduced academic engagement and difficulties in sustained attention, underscoring the educational impact of the chronic symptom burden, even in the absence of direct cognitive pathology [14].

Addressing GERD in schoolchildren is therefore essential to mitigate its potential impact on learning and cognitive performance. Effective management may include lifestyle modifications, pharmacological treatments and, in selected cases, surgical interventions. Timely symptom control may improve comfort, sleep quality and functional school participation, thereby supporting overall cognitive functioning and educational outcomes [37].

Food sensitivities and dietary deficiencies in neuropsychiatric disorders

Food sensitivities and dietary deficiencies are well-acknowledged causes that significantly influence cognitive performance and school functioning in children, particularly those with NDDs. Neuropsychiatric disorders, such as ADHD and ASD, display selective eating patterns, leading to inadequate intake of essential nutrients. This nutritional imbalance can deteriorate cognitive and hence academic performance. In this respect, Liu et al reviewed the current evidence regarding the neurological and epigenetic impact of nutritional deficiencies on psychopathology, and deduced that deficiencies in iron and essential fatty acids have been linked to impaired neurological development, adversely affecting learning and cognition [38].

Moreover, certain food sensitivities may directly interfere with behavioral and learning processes. In particularly, schoolchildren with developmental disorders are more likely to have self-reported allergies, such as (cow) milk and egg allergies, which can contribute to developmental delays. Addressing these dietary issues through healthcare and nutrition providers with early interventions is important to support the cognitive and academic development of schoolchildren with LD [39].

Sensory sensitivities are common in schoolchildren with ASD, and they may contribute to avoidant/restrictive food intake disorder (ARFID), a diagnosis that also has the hallmark of extreme food selectivity and nutritional deficiencies, occasionally severe, including vitamin A and B12 deficiencies, which are crucial for brain development and vision. A recent review article by Schimansky et al reported cases of nutritional blindness in children with ARFID. The prevalence is even greater in schoolchildren with ASD, and a late diagnosis may render the blindness irreversible. This fact highlights the significance of early diagnosis and a multidisciplinary management approach [40].

The paramount role of balanced nutrition in brain development exceeds macronutrient intake. Grajek et al, in a review article, summarized the relevant evidence, and reported that high fat and sugar diets negatively affect brain function, increasing the risk of neuropsychiatric disorders. Contrariwise, plant-based diets, healthy fats of vegetable origin, and lean proteins, have been associated with improved mental health outcomes. Notably, randomized dietary intervention trials, including landmark ones like SMILES and HELFIMED, demonstrated that improving overall diet quality through Mediterranean-style dietary patterns can positively influence neurocognitive outcomes [41].

Moreover, further studies from pediatric populations suggest that specific additives, mainly artificial food colorings and preservatives, can worsen hyperactivity and inattention symptoms, which may negatively influence academic performance and focus [42,43]. Notably, in a relevant British double-blinded, placebo-controlled crossover trial involving 153 preschoolers (3-year-olds) and 144 school-aged children (8-9 years), consumption of artificial food colorings and the preservative sodium benzoate were associated with increased hyperactivity, as measured by behavioral ratings and attention tests. The aforementioned reports strengthen a possible link between dietary additives and adverse behavioral effects in children from the general population [43]. Furthermore, restricted elimination diets targeting, common allergens like gluten and dairy, have been shown to improve behavioral symptoms in distinct subgroups of children diagnosed with ADHD and specific LD, implying that systemic inflammation triggered by food intolerance may directly have an impact on cognitive and behavioral functions [44,45].

Taken together, both food sensitivities and dietary deficiencies are crucial in the management of schoolchildren with LD. A multidisciplinary approach involving healthcare providers, nutritionists, educators and families is advised in order to develop and implement effective dietary interventions aiming at the possible improvement of behavioral, cognitive and overall performance.

The role of gut microbiota dysbiosis in LD

The crosstalk between gut microbiota and the CNS has attracted global interest in the last decades. In particular, to what extent the (non)commensal intestinal flora shapes neurodevelopment and impacts on the LD of schoolchildren is a cutting-edge interdisciplinary topic. Gut microbiota dysbiosis, defined simply as an imbalance in the microbial community within the GI tract, has been repeatedly hypothesized in various NDDs, potentially influencing cognitive functions and academic performance [13]. It should be noted, however, that most available evidence is observational and does not suffice to prove causality between microbiota alterations and LD.

These associations are thought to be mediated through the aforementioned microbiota-gut-brain axis [20]. Suggested interconnected pathways include the following. First, the immune pathway, whereby gut microbiota modulate immune signaling through cytokine production; dysbiosis may promote systemic and neuroinflammation, processes implicated in NDDs and cognitive dysfunction [13]. Second, the neuronal pathway involves signaling through the autonomous enteric nervous system (mainly vagus nerve), allowing microbial metabolites to influence brain activity and behavior. Third, the endocrine and metabolic pathway includes microbiota-driven regulation of neuroactive compounds, such as serotonin and dopamine, which are directly involved in attention, mood regulation and learning processes. Specific gut microbial taxa are also involved in tryptophan metabolism and dopamine precursor availability, modulating neuroendocrine and CNS function [13].

GI symptoms frequently coexist in children with ASD and ADHD, and are often accompanied by gut microbiota alterations, but this overlapping probably reflects shared biological and psychosocial vulnerabilities, rather than a unidirectional causal pathway.

Several biologically plausible mechanisms have been proposed for how dysbiosis may contribute to LD. Neuroinflammation represents a key pathway, as microbial imbalance may increase gut permeability, allowing translocation of inflammatory mediators such as lipopolysaccharides (LPS) into the systemic circulation. These factors can compromise blood-brain barrier (BBB) integrity and promote neuroinflammatory cascades affecting cognition [46]. Additionally, altered microbial synthesis of neurotransmitters and reduced production of short-chain fatty acids—important modulators of synaptic plasticity—may further hamper learning-related neural processes [13].

Recognition of the role of gut microbiota in neurodevelopment and neuroplasticity opens potential avenues for supportive and preventive strategies, rather than established therapeutic interventions. Current evidence does not support routine probiotic or prebiotic supplementation to improve learning outcomes in schoolchildren. Instead, the literature emphasizes the importance of an overall healthy lifestyle—such as balanced nutrition that supports microbiome diversity, regular physical activity and avoidance of sedentary behavior—which may contribute to gut and brain health [13]. Microbiome-targeted interventions in this context remain experimental and should be interpreted cautiously in selected populations and cases.

Early-life nutrition and maternal dietary patterns play a critical role in shaping gut microbiota development and immune programming, with potential long-term implications for neurodevelopment and cognitive function. The establishment of the gut microbiome begins during pregnancy, and continues dynamically through early infancy and childhood, influenced by maternal diet and early nutritional exposures, which interact with gut-brain signaling pathways related to cognition and behavior [47]. Adherence of mothers in gestation to healthy dietary habits—particularly Mediterranean-style diets rich in dietary fiber, polyphenols and unsaturated fats (e.g., omega-3)—has been repeatedly linked to more favorable gut microbiota profiles and to better neurodevelopmental and immunological maturation of the newborn [48].

Although direct evidence linking early-life nutritional exposures to later LD remains rather limited, these factors represent biologically plausible contributors to cognitive and learning processes via microbiome-mediated mechanisms. Therefore, current evidence is largely associative, and prospective pediatric studies are warranted to clarify causality and determine whether early nutritional interventions result in objective benefits in learning and academic performance.