Gluten sensitivity and childhood disorders of learning, behavior and development
While celiac disease often goes undiagnosed, failure to recognize the non-celiac manifestations of gluten sensitivity is widespread. The neurological effects can contribute to disorders of learning, behavior and neurodevelopment even in the absence of intestinal symptoms. The authors of a study published in the Journal of Attention Disorders observe:
"Several studies report a possible association of celiac disease (CD) with psychiatric and psychological disturbances, such as ADHD."
They examined 132 subjects affected by CD for ADHD symptoms by behavioral scale before and 6 months after a gluten-free diet was started, and found that:
"The overall score improved significantly as well as most of the ADHD-like symptomatology specific features (Bonferroni-corrected, paired-sample t tests)."
They state in their conclusion:
"The data indicate that ADHD-like symptomatology is markedly overrepresented among untreated CD patients and that a gluten-free diet may improve symptoms significantly within a short period of time. The results of this study also suggest that CD should be included in the list of diseases associated with ADHD-like symptomatology."
Remember, as the authors of a paper published by GeneReviews state:
"Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than nonclassic celiac disease, characterized by absence of gastrointestinal symptoms."
The report on a study published in the journal Psychosomatics begins with the observation:
"A high prevalence of depressive symptoms, hypothetically related to serotonergic dysfunction, has been reported among adults with celiac disease. The authors used semistructured psychiatric interviews and symptom measurement scales to study mental disorders in 29 adolescents with celiac disease and 29 matched comparison subjects.
The also observe in review of the existing evidence:
"Patients with celiac disease may suffer from neurological symptoms, such as peripheral neuropathy, ataxia, intellectual deterioration, brain atrophy, and epilepsy...In addition to neurological manifestations, a significantly higher prevalence of depressive symptoms (30–69%) and depressive disorders (42%) has been reported in adult celiac disease patients, compared to medical and normal comparison subjects...Improvement in depressive disorders has been described in some celiac disease patients after they started a gluten-free diet."
What did their findings show specifically in regard to adolescents?
"We found that celiac disease was associated with higher lifetime prevalences of major depressive disorder and disruptive behavior disorder in adolescents...at least in some of these patients major depression and disruptive behavior disorder were related to celiac disease and alleviated by treatment of celiac disease with a gluten-free diet."
The clinical implications of the data are summarized in their conclusion:
"Celiac disease is associated with increased prevalence of depressive and disruptive behavior disorders in adolescents, particularly in the phase before diet treatment. In some cases psychiatric symptoms appear to improve after the patient starts a gluten-free diet. The possibility of undiagnosed celiac disease should be taken into account in the differential diagnosis of these disorders, since the diet treatment is essential."
Interestingly, in light of the reports that follow, they also make this observation:
"The risk of psychological disorders is substantially higher in children with a chronic disease and, for unknown reasons, particularly in patients with inflammatory bowel disease."
What are the mechanisms by which gluten sensitivity can contribute to neurodevelopmental disorders? A study published in the Journal of Clinical Immunology examines gut mucosal immunopathology in relation to regressive autism:
"Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features..."
The authors undertook a detailed analysis of mucosal infiltrate with flow cytometry (inspected the cellular components of gut lining secretions) and intestinal biopsies, and...
"...found a prominent mucosal eosinophil [allergen-reactive white blood cell] infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet... The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases."
Antibodies to neuronal tissues, signaling molecules and key enzymes can also play a role in neurological disorders associated with gluten sensitivity. The authors of a paper published in the journal Acta Neurologica Scandinavica state:
"The high prevalence of gluten sensitivity in patients with stiff-person syndrome (SPS) lead us to investigate the relationship between gluten sensitivity and GAD-antibody-associated diseases."
GAD is glutamic acid decarboxylase, aka glutamate decarboxylase. Most clinicians reading this are aware that GAD is a target for autoantibodies in type 1 diabetes, but may not recall that it is required to convert glutamate into GABA, our most abundant inhibitory (calming) neurotransmitter. Functional deficiencies of GABA can manifest as anxiety, restlessness, disorganized attention, inner excitability and tension with difficulty relaxing, feeling overwhelmed, worry, etc. The authors used ELISA assays for anti-GAD and for serological markers of gluten sensitivity in patients recruited from clinics based at the Royal Hallamshire hospital, Sheffield, UK. Those with gluten sensitivity were followed up after the introduction of a gluten-free diet. Their data painted a compelling picture:
"Six of seven (86%) patients with SPS were positive for anti-GAD...This compared with 9/90 (11%) patients with idiopathic sporadic ataxia...16/40 (40%) patients with gluten ataxia...and 6/10 patients with type 1 diabetes only...The titre of anti-GAD reduced following the introduction of a gluten-free diet in patients with SPS who had serological evidence of gluten sensitivity. The same was observed in patients with gluten ataxia and anti-GAD antibodies. This was also associated with clinical improvement."
Parents of patients and the practitioners caring for them should bear their conclusion in mind:
"These findings suggest a link between gluten sensitivity and GAD antibody-associated diseases."
Interestingly, impairment in the ability to digest gliadin (from gluten), a problem which has a genetic basis, can contribute to affective disorders. The authors of a paper published in Behavioral and Brain Functions offer evidence from an investigation of the urine of depressed patients for relevant undigested peptides:
"We find overlapping patterns of peptide peaks in severe depression, but with considerable individuality. Mass spectrometry shows that some of these peptides are probably of dietary origin, because their sequences are found only in certain dietary proteins. Opioids from casein and gliadin are typical examples."
Their conclusion is part of the rationale for offering specific digestive enzymes (peptidases) to patients with gluten sensitivity:
"Peptide increase in urine is found when break down is deficient, and the data presented agree with reports on peptidase deficiencies in depression."
Another mechanism by which gluten can promote autoimmune disorders with neurological, behavioral and neurodevelopmental consequences is by causing abnormal permeability ('leakiness') of the intestinal mucosal barrier. This causes the gut-associated immune tissue to be abnormally exposed to the intestinal contents. The authors of a paper published recently in the Annals of the New York Academy of Sciences examine the link between intestinal permeability and autoimmune disease:
"Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity."
In delineating the process by which exposure to antigen in the gut triggers a genetic susceptibility, they note:
"In all cases, increased permeability precedes disease and causes an abnormality in antigen delivery that triggers immune events, eventually leading to a multiorgan process and autoimmunity."
Moreover...
"Alterations in the intestinal balance between beneficial and potentially harmful bacteria have also been associated with allergy, type 1 diabetes and inflammatory bowel diseases..."
These factors come to a point that disrupts the tight junctions (TJ) of the intestinal barrier by perturbing the production of zonulin, an agent involved in loss of barrier function and autoimmune disease:
"The zonulin upregulation during the acute phase of CD was confirmed by measuring zonulin concentration...Compared to healthy controls, CD subjects showed significantly higher zonulin serum concentrations during the acute phase of the disease that decreased following a gluten-free diet...Similar results were obtained from T1D subjects...Our group has generated evidence that gliadin induces increased intestinal permeability by releasing preformed zonulin...When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability."
They summarize their findings with this important statement:
"Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to dysfunction of intercellular TJ all seem to be key components in the pathogenesis of autoimmune diseases. Both in CD and T1D gliadin may play a role in causing loss of intestinal barrier function and/or inducing the autoimmune response in genetically predisposed individuals...Since TJ dysfunction allows this interaction, new therapeutic strategies aimed at re-establishing the intestinal barrier function offer innovative, unexplored approaches for the treatment of these devastating diseases."
Further confirmation of the damage gliadin does to the intestinal epithelial barrier is offered in a paper published in the Scandinavian Journal of Gastroenterology:
"We investigated whether gliadin has any immediate effect on zonulin release and signaling."
They exposed human intestinal tissue to gliadin and evaluated zonulin release and barrier permeability by PCR (polymerase chain reaction) and immunofluorescence microscopy. They too documented similar effects:
"When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability..."
However, they found that non-celiac patients also exhibited an increased zonulin release that, while not the magnitude of the celiac patients, caused intestinal permeability:
"...biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability..."
This would be an argument in favor of everyone adopting a gluten-free diet. The authors' conclusion is striking:
"Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules."
The authors of a study published in the journal Gastroenterology add to the body of knowledge by identifying the mechanism by which gluten increases zonulin release and intestinal permeability:
"Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability...We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment."
They demonstrated that the chemokine receptor CXCR3 binds gliadin by examining CXCR3 protein and gene expression in intestinal epithelial cell lines and biopsy specimens, and gliadin-CXCR3 interaction by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. On a positive note, the observed that...
"Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability...[however] Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet."
What about evidence that following a gluten-free diet helps with behavioral disorders of children and adolescents? The authors of a study published in BMC (BioMed Central) Psychiatry state:
"Coeliac disease in adolescents has been associated with an increased prevalence of depressive and disruptive behavioural disorders, particularly in the phase before diet treatment. We studied the possible effects of a gluten-free diet on psychiatric symptoms, on hormonal status (prolactin, thyroidal function) and on large neutral amino acid serum concentrations in adolescents with coeliac disease commencing a gluten-free diet."
Moreover...
"Coeliac disease is an under-diagnosed autoimmune type of gastrointestinal disorder... Non-specific symptoms such as fatigue and dyspepsia are common, but the disease may also be clinically silent....Undetected or neglected, coeliac disease is associated with serious complications...depressive and disruptive behavioural disorders are highly common also among adolescents, particularly in the phase before diet treatment...Recently 73% of patients with untreated coeliac disease – but only 7% of patients adhering to a gluten-free diet – were reported to have cerebral blood flow abnormalities similar to those among patients with depressive disorders."
They assessed adolescents aged 12 to 16 years with several symptom scales and followed them at intervals after starting a gluten-free diet. What did their data show?
"Adolescent coeliac disease patients with depression had significantly lower pre-diet tryptophan/ competing amino-acid (CAA) ratios and free tryptophan concentrations, and significantly higher biopsy morning prolactin levels compared to those without depression. A significant decrease in psychiatric symptoms was found at 3 months on a gluten-free diet compared to patients' baseline condition, coinciding with significantly decreased coeliac disease activity and prolactin levels and with a significant increase in serum concentrations of CAAs."
Parents and clinicians should consider their conclusions:
"...since diet treatment may alleviate psychiatric symptoms, and earlier diagnosis may have beneficial effects on psychological and even on neurobiological vulnerability to depression, the possibility of psychiatric complications of coeliac disease needs to be taken into account in differential diagnosis of depressive and behavioural disorders."
A paper published in the journal Nutritional Neuroscience suggests similar indications for some children with autism spectrum disorders:
"There is increasing interest in the use of gluten- and casein-free diets for children with autism spectrum disorders (ASDs). We report results from a two-stage, 24-month, randomised, controlled trial incorporating an adaptive 'catch-up' design and interim analysis."
They randomly assigned 72 Danish children to two diets and examined them for inattention and hyperactivity at baseline, 8 and 12 months. At that point there data showed that...
"...there was a significant improvement to mean diet group scores (time*treatment interaction) on sub-domains of ADOS, GARS and ADHD-IV measures. Surpassing of predefined statistical thresholds as evidence of improvement in group A at 12 months sanctioned the re-assignment of group B participants to active dietary treatment."
The authors state in their conclusion:
"Our results suggest that dietary intervention may positively affect developmental outcome for some children diagnosed with ASD."
What is the practical bottom line for parents and practitioners? There is mounting scientific evidence that the possibility of gluten sensitivity should not be overlooked when investigating the contributing causes to childhood disorders of learning, behavior and neurodevelopment. Given that celiac disease can be 'silent', and that we are particularly concerned with the non-celiac neurological manifestations of gluten sensitivity, testing for the genetic susceptibility in addition to anti-gliadin antibodies is a clinically prudent course of action.