Opioid peptides and gastrointestinal symptoms in autism spectrum disorders

Cristiane P. Lázaro Milena P. Pondé Luiz E.A. Rodrigues About the authors

Abstract

Autism spectrum disorders (ASDs) are characterized by deficits in the individual’s ability to socialize, communicate, and use the imagination, in addition to stereotyped behaviors. These disorders have a heterogenous phenotype, both in relation to symptoms and regarding severity. Organic problems related to the gastrointestinal tract are often associated with ASD, including dysbiosis, inflammatory bowel disease, exocrine pancreatic insufficiency, celiac disease, indigestion, malabsorption, food intolerance, and food allergies, leading to vitamin deficiencies and malnutrition. In an attempt to explain the pathophysiology involved in autism, a theory founded on opioid excess has been the focus of various investigations, since it partially explains the symptomatology of the disorder. Another hypothesis has been put forward whereby the probable triggers of ASDs would be related to the presence of bacteria in the bowel, oxidative stress, and intestinal permeability. The present update reviews these hypotheses.

Autistic disorder; probability theory; opioids; intestinal bacteria; oxidative stress; bowel permeability


Introduction

Autism spectrum disorder (ASD) is characterized by stereotyped behavior and a deficiency in the individual’s ability to socialize, communicate, and use imagination.11. Brentani H, Paula CS, Bordini D, Rolim D, Sato F, Portolese J, et al. Autism spectrum disorders: an overview on diagnosis and treatment. Rev Bras Psiquiatr. 2013;35:S62-72. Although the disorder is associated with neural development, its true causes remain to be clarified. Recent evidence supports the hypothesis of a complex and highly heterogenous genetic etiology, and points to a combined effect between the environment and various different genes.22. Codina-Solè M, Rodríguez-Santiago B, Homs A, Santoyo J, Rigau M, Aznar-Laín G, et al. Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders. Mol Autism. 2015;6:21. As a consequence, phenotypes in ASD appear to be manifold.

Many autistic individuals suffer from gastrointestinal problems33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. such as abnormalities of the bowel mucosa, dysfunctions associated with selective permeability, and significant differences in composition of the gut microbiota.44. Czaja-Bulsa G. Non coeliac gluten sensitivity - A new disease with gluten intolerance. Clin Nutr. 2015;34:189-94. Individuals with ASD also exhibit an imbalance in immune response.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. Since the gastrointestinal tract has direct connections with the immune system, alterations in the gastrointestinal tract may generate alterations in the immune system.

In an attempt to explain the pathophysiology involved in autism, Panksepp et al.55. Panksepp J, Najam N, Soares F. Morphine reduces social cohesion in rats. Pharmacol Biochem Behav. 1979;11:131-4. conducted a pioneering experimental study with rats and reported a decrease in social cohesion with an increase in opioid peptides in the organism. Recent studies investigated the role of opioid peptides and intestinal permeability,66. Souza NC, Mendonca JN, Portari GV, Jordao Junior AA, Marchini JS, Chiarello PG. Intestinal permeability and nutritional status in developmental disorders. Altern Ther Health Med. 2012;18:19-24. as well as alterations in the expression of certain genes.77. Cieślińska A, Sienkiewicz-Szłapka E, Wasilewska J, Fiedorowicz E, Chwała B, Moszyńska-Dumara M, et al. Influence of candidate polymorphisms on the dipeptidyl peptidase IV and μ-opioid receptor genes expression in aspect of the β-casomorphin-7 modulation functions in autism. Peptides. 2015;65:6-11. Heberling et al.22. Codina-Solè M, Rodríguez-Santiago B, Homs A, Santoyo J, Rigau M, Aznar-Laín G, et al. Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders. Mol Autism. 2015;6:21. suggested that certain gut bacteria, oxidative stress and changes in intestinal permeability could be involved in the etiology of ASD.

Factors related to nutrition, such as gluten and casein intolerance, are under investigation, as they are associated with various gastrointestinal symptoms. Thus, interventions have been implemented in which gluten and casein are excluded from the diet and probiotics and multivitamins are included.44. Czaja-Bulsa G. Non coeliac gluten sensitivity - A new disease with gluten intolerance. Clin Nutr. 2015;34:189-94. This update article discusses current hypotheses that associate the etiology of autism with alterations in opioid metabolism and with gastrointestinal tract symptoms.

The opioid excess theory

Panksepp et al.55. Panksepp J, Najam N, Soares F. Morphine reduces social cohesion in rats. Pharmacol Biochem Behav. 1979;11:131-4. found that an excess of casomorphin, an opioid-like peptide fragment of milk casein, induced social isolation and apathy in animals. Panksepp88. Panksepp J. A neurochemical theory of autism. Trends Neurosci. 1979;2:174-7. then proposed the opioid excess theory to explain the pathogenesis of ASD and advocated that opioid peptides released from gluten and casein could pass through the mucosa and cross the blood-brain barrier, reaching the central nervous system (CNS) and affecting brain function.

Food-derived bioactive peptides are protein fragments originating from enzymatic hydrolysis and proteolysis induced by microorganisms.99. Muro Urista C, Alvarez Fernandez R, Riera Rodriguez R, Arana Cuenca A, Tellez Jurado A. Review: Production and functionality of active peptides from milk. Food Sci Technol Int. 2011;17:293-317. They consist of oligopeptides (three to 20 amino acids) with distinct functions and conformations.1010. Wada Y, Lonnerdal B. Bioactive peptides derived from human milk proteins--mechanisms of action. J Nutr Biochem. 2014;25:503-14. Some bioactive peptides act directly on the gastrointestinal lumen, while others act on peripheral organs following absorption in the bowel, playing a role in reducing arterial blood pressure, modulating immune cells, and regulating nervous functions.1111. Chakrabarti S, Jahandideh F, Wu J. Food-derived bioactive peptides on inflammation and oxidative stress. Biomed Res Int. 2014;2014;608979. Factors involved in the absorption of these peptides include the inhibition of peptidases1212. Sanchez de Medina F, Romero-Calvo I, Mascaraque C, Martinez-Augustin O. Intestinal inflammation and mucosal barrier function. Inflamm Bowel Dis. 2014;20:2394-404. and the permeability of the intestinal barrier.1313. de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010;51:418-24. Nevertheless, the opioid excess theory has been criticized due to the fact that no abnormal concentrations of opioid peptides had ever been detected in the plasma or in the CNS of individuals with ASD.1414. Cass H, Gringras P, March J, McKendrick I, O'Hare AE, Owen L, et al. Absence of urinary opioid peptides in children with autism. Arch Dis Child. 2008;93:745-50.

Randomized controlled studies have been conducted to evaluate the efficacy of excluding gluten and casein from the diet of individuals with ASD.1515. Whiteley P, Haracopos D, Knivsberg AM, Reichelt KL, Parlar S, Jacobsen J, et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010;13:87-100.,1616. Knivsberg AM, Reichelt KL, Hoien T, Nodland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci. 2002;5:251-61. Some results suggested positive effects on behavior and development; however, other studies failed to find any improvement in the intervention group.1717. Johnson CR, Handen BL, Zimmer M, Sacco K, Turner K. Effects of gluten free/casein free diet in young children with autism: a pilot study. J Dev Phys Disabil. 2011;23:213-25.,1818. Seung H, Rogalski Y, Shankar M, Elder JH. The gluten- and casein-free diet and autism: Communication outcomes from a preliminary double-blind clinical trial. J Med Speech Lang Pathol. 2007;15:337-45. Meta-analyses55. Panksepp J, Najam N, Soares F. Morphine reduces social cohesion in rats. Pharmacol Biochem Behav. 1979;11:131-4.,1919. Mulloy A, Lang R, O’Reilly M, Sigafoos J, Lancioni G, Rispoli M. Addendum to gluten-free and casein-free diets in treatment of autism spectrum disorders: a systematic review. Res Autism Spectr Disord. 2011;5:86-8. recommended caution with respect to adopting this diet because of limited scientific evidence on its use. Furthermore, the dietary restrictions imposed may lead to more social rejection and stigmatization, as well as to deficits in these individuals’ socialization and integration.

Hypothesis on the association among gut bacteria, oxidative stress, and intestinal permeability

The microbiota of the human gastrointestinal tract plays a central role both in health and in the generation of disease.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. Anaerobic bacteria account for the production of acetic and propionic acid, in addition to short-chain fatty acids, particularly butyric acid, which supplies energy to the intestinal epithelial cells and consequently strengthens the immune system. The principal bacteria producing short-chain fatty acids are Bacteroides, Lactobacillus, and Bifidobacterium, which induce the production of anti-inflammatory cytokines, unlike Clostridium, which stimulates the proinflammatory cytokines. Bacteria of the Clostridium genus, such as C. difficile and C. perfringens, are major producers of toxins.2020. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16:444-53.

In the intestinal microbiota of individuals with ASD, the amount of bifidobacteria is reduced and there is abnormal growth of Clostridium species.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. Finegold et al.2020. Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16:444-53. identified Desulfovibrio as the prevalent organism in the intestinal flora of these individuals and found that it modifies the bacterial ecosystem, reducing the presence of important species such as Bifidobacterium longum and B. pseudolongum, which produce hydrogen sulfate, a gas that is toxic to humans.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70.

Sulfur metabolism

The oxidation of thiol (sulfhydryl) groups may play a central role in the development of ASD.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. Meta-analyses suggest that there are deficiencies in the transmethylation/transsulfuration metabolism2121. Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina B, et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med. 2012;52:2128-41. associated with the sulfur amino acids methionine and cysteine.

The essential amino acid methionine must be available in the diet to enable cysteine synthesis to occur. Deficiencies in metabolic pathways will compromise the excretion of heavy metals, because cysteine is a limiting factor in the production of reduced glutathione, a natural antioxidant in the body.2222. Lázaro CP, Pondé MP, Rodrigues LE. Some biochemical implications in autism spectrum disorder. Braz J Med Hum Health. 2014;2:151-8. In fact, various metabolic precursors involved in the synthesis of reduced glutathione are decreased in the plasma of individuals with ASD, suggesting that synthesis of this antioxidant may be compromised.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70.,2222. Lázaro CP, Pondé MP, Rodrigues LE. Some biochemical implications in autism spectrum disorder. Braz J Med Hum Health. 2014;2:151-8. As a consequence of this metabolic inhibition, autistic individuals may be more sensitive to the toxic effects of heavy metals. Evidence of this was found in urine and blood samples from people with ASD. Compared to those of controls, blood samples from the individuals with ASD showed greater amounts of lead in the red blood cells, while their urine samples showed higher tin, tungsten, and lead levels.2323. Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, et al. Toxicological status of children with autism vs. neurotypical children and the association with autism severity. Biol Trace Elem Res. 2013;151:171-80.

Transmethylation is also involved in the regeneration and conversion of methionine into S-adenosylmethionine, which is the most important enzymatic co-factor in the transfer of methyl groups for the biosynthesis of DNA, RNA, proteins, phospholipids, creatinine, and neurotransmitters.2222. Lázaro CP, Pondé MP, Rodrigues LE. Some biochemical implications in autism spectrum disorder. Braz J Med Hum Health. 2014;2:151-8.

Intestinal permeability

The proper function of the intestinal mucosal barrier guarantees that the bowel counteracts the entry of microorganisms and molecules, thus preserving its ability to absorb nutrients.1212. Sanchez de Medina F, Romero-Calvo I, Mascaraque C, Martinez-Augustin O. Intestinal inflammation and mucosal barrier function. Inflamm Bowel Dis. 2014;20:2394-404. The secretion of mucins, immunoglobulin A, and antimicrobial peptides strengthens the mucosal barrier in the outer mucus layer, while internally, the immune cells provide this protection.1212. Sanchez de Medina F, Romero-Calvo I, Mascaraque C, Martinez-Augustin O. Intestinal inflammation and mucosal barrier function. Inflamm Bowel Dis. 2014;20:2394-404. The mucosal barrier has physical, biochemical, and immune characteristics that allow it to secure the flow of substances through the paracellular pathway, which is associated with transportation through the intercellular space.2424. Krug SM, Schulzke JD, Fromm M. Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol. 2014;36:166-76.

Intestinal permeability to small water-soluble molecules is determined by the tight junctions, which open and close constantly in response to stimuli such as diet, humoral or neuronal signaling, and through inflammatory mediators.2525. Turner JR, Buschmann MM, Romero-Calvo I, Sailer A, Shen L. The role of molecular remodeling in differential regulation of tight junction permeability. Semin Cell Dev Biol. 2014;36:204-12. Although the tight junctions are represented by a complex of more than 50 proteins, there is evidence that the family of claudins (transmembrane proteins) and zonulin2626. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258:25-33. are involved in the regulation of selective permeability, including size, electric resistance, and preference for ionic charge.2727. De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013;8:e76993. The delicate nature of this balance is interrupted in pathologic states. It has been reported that zonulin expression increases in autoimmune conditions and is associated with dysfunction of tight junctions. Physiologically, however, exposure of the bowel to bacteria and to gluten triggers zonulin release.2626. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258:25-33. Some studies suggest that the function of the epithelial barrier is damaged in ASD,1313. de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010;51:418-24. while others have reported that individuals with ASD are prone to gluten allergy1717. Johnson CR, Handen BL, Zimmer M, Sacco K, Turner K. Effects of gluten free/casein free diet in young children with autism: a pilot study. J Dev Phys Disabil. 2011;23:213-25.; therefore, it would be reasonable to presume that zonulin could be involved in this process.2626. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258:25-33.

Heberling et al.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. suggested that the pathogenesis of ASD was associated with the relationship between three factors: oxidative stress with a subsequent metabolic sulfur deficiency, an abnormal growth of gut bacteria, and an increase in intestinal permeability. The metabolic sulfur deficiencies associated with an imbalance in the composition of gut bacteria, principally with a proliferation of Clostridium and/or Desulfovibrio, together with a reduction in bifidobacteria,33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. would explain the association between the first two factors. In addition, the metabolic sulfur deficiency would be self-perpetuating, with decreased total and reduced glutathione levels resulting from the decline in bifidobacteria.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70. A dysfunctional intestinal mucosa would, in turn, facilitate the absorption of toxins, bacterial products, lymphocytes, proinflammatory cytokines, and neurotransmitters, which would reach the bloodstream, cross the blood-brain barrier, and cause neuroinflammation.33. Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70.

Although the interactions of the brain, bowel, and microbiome are multifactorial and not yet completely clarified, the vagal system functions as a communication channel between the microbiota and the brain.2727. De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013;8:e76993. In view of the aforementioned scientific evidence, it is suggested that the microbiome may play an important role in the CNS, both in promoting health and in the genesis and maintenance of pathologic states. There are direct and indirect interactions between the gut-brain axis and microbiome, which may be associated with a new concept of integrative physiology in which associations occur between the neural, immune, and endocrine systems, as well as with nutrients and immune markers of the CNS and gastrointestinal tract.2828. Grenham S, Clarke G, Cryan JF, Dinan TG. Brain-gut-microbe communication in health and disease. Front Physiol. 2011;2:94.

The mechanisms used by pathogens to influence host behavior have been known for decades; however, evidence is growing for direct, noninvasive interactions with the neurophysiological system. The ability of microorganisms to produce and recognize neurochemical compounds structurally similar to those produced by the host’s nervous system explains how they are able to affect behavior through a non-infectious and, possibly, non-immune-mediated pathway.2929. Lyte M. Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog. 2013;9:e1003726. Looking at the microbiome from the standpoint of microbial endocrinology, specific pathways are involved in which microorganisms affect behavior, permitting a new approach for the treatment of mental illnesses by modulating the microbiome-gut-brain axis.3030. Wood JD. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology. 2004;127:635-57. Studies conducted to investigate these effects have shown that cytokines and inflammatory mediators have known neuronal targets, both in the CNS and in the enteric nervous system (Meissner’s plexus and Auerbach’s plexus).3030. Wood JD. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology. 2004;127:635-57. The fact that bacteria produce neuroendocrine hormones also suggests that the interaction of the microbiome may go well beyond the bacterial neuroendocrine interactions that occur in infectious diseases.

Conclusion

Current literature does not support the opioid excess theory, since abnormal opioid peptide levels have never been found in the CNS of individuals with ASD. Nevertheless, oxidative stress in individuals with ASD may be a consequence of metabolic sulfur deficiency, abnormal gut bacteria growth, and increased intestinal permeability, thus suggesting a possible correlation between gastrointestinal abnormalities and symptoms of ASD. These data suggest that it may be possible to improve autism-related symptoms by modulating the microbiome-gut-brain axis in individuals with a specific phenotype. Although the evidence to support opioid-free diets (gluten-free, casein-free) is limited and weak, dietary restrictions should only be introduced after gastrointestinal symptoms have appeared or intolerance or allergy to these foods has been diagnosed.

References

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  • 2
    Codina-Solè M, Rodríguez-Santiago B, Homs A, Santoyo J, Rigau M, Aznar-Laín G, et al. Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders. Mol Autism. 2015;6:21.
  • 3
    Heberling CA, Dhurjati PS, Sasser M. Hypothesis for a systems connectivity model of Autism Spectrum Disorder pathogenesis: links to gut bacteria, oxidative stress, and intestinal permeability. Med Hypotheses. 2013;80:264-70.
  • 4
    Czaja-Bulsa G. Non coeliac gluten sensitivity - A new disease with gluten intolerance. Clin Nutr. 2015;34:189-94.
  • 5
    Panksepp J, Najam N, Soares F. Morphine reduces social cohesion in rats. Pharmacol Biochem Behav. 1979;11:131-4.
  • 6
    Souza NC, Mendonca JN, Portari GV, Jordao Junior AA, Marchini JS, Chiarello PG. Intestinal permeability and nutritional status in developmental disorders. Altern Ther Health Med. 2012;18:19-24.
  • 7
    Cieślińska A, Sienkiewicz-Szłapka E, Wasilewska J, Fiedorowicz E, Chwała B, Moszyńska-Dumara M, et al. Influence of candidate polymorphisms on the dipeptidyl peptidase IV and μ-opioid receptor genes expression in aspect of the β-casomorphin-7 modulation functions in autism. Peptides. 2015;65:6-11.
  • 8
    Panksepp J. A neurochemical theory of autism. Trends Neurosci. 1979;2:174-7.
  • 9
    Muro Urista C, Alvarez Fernandez R, Riera Rodriguez R, Arana Cuenca A, Tellez Jurado A. Review: Production and functionality of active peptides from milk. Food Sci Technol Int. 2011;17:293-317.
  • 10
    Wada Y, Lonnerdal B. Bioactive peptides derived from human milk proteins--mechanisms of action. J Nutr Biochem. 2014;25:503-14.
  • 11
    Chakrabarti S, Jahandideh F, Wu J. Food-derived bioactive peptides on inflammation and oxidative stress. Biomed Res Int. 2014;2014;608979.
  • 12
    Sanchez de Medina F, Romero-Calvo I, Mascaraque C, Martinez-Augustin O. Intestinal inflammation and mucosal barrier function. Inflamm Bowel Dis. 2014;20:2394-404.
  • 13
    de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010;51:418-24.
  • 14
    Cass H, Gringras P, March J, McKendrick I, O'Hare AE, Owen L, et al. Absence of urinary opioid peptides in children with autism. Arch Dis Child. 2008;93:745-50.
  • 15
    Whiteley P, Haracopos D, Knivsberg AM, Reichelt KL, Parlar S, Jacobsen J, et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010;13:87-100.
  • 16
    Knivsberg AM, Reichelt KL, Hoien T, Nodland M. A randomised, controlled study of dietary intervention in autistic syndromes. Nutr Neurosci. 2002;5:251-61.
  • 17
    Johnson CR, Handen BL, Zimmer M, Sacco K, Turner K. Effects of gluten free/casein free diet in young children with autism: a pilot study. J Dev Phys Disabil. 2011;23:213-25.
  • 18
    Seung H, Rogalski Y, Shankar M, Elder JH. The gluten- and casein-free diet and autism: Communication outcomes from a preliminary double-blind clinical trial. J Med Speech Lang Pathol. 2007;15:337-45.
  • 19
    Mulloy A, Lang R, O’Reilly M, Sigafoos J, Lancioni G, Rispoli M. Addendum to gluten-free and casein-free diets in treatment of autism spectrum disorders: a systematic review. Res Autism Spectr Disord. 2011;5:86-8.
  • 20
    Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE, Wolcott RD, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16:444-53.
  • 21
    Frustaci A, Neri M, Cesario A, Adams JB, Domenici E, Dalla Bernardina B, et al. Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic Biol Med. 2012;52:2128-41.
  • 22
    Lázaro CP, Pondé MP, Rodrigues LE. Some biochemical implications in autism spectrum disorder. Braz J Med Hum Health. 2014;2:151-8.
  • 23
    Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, et al. Toxicological status of children with autism vs. neurotypical children and the association with autism severity. Biol Trace Elem Res. 2013;151:171-80.
  • 24
    Krug SM, Schulzke JD, Fromm M. Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol. 2014;36:166-76.
  • 25
    Turner JR, Buschmann MM, Romero-Calvo I, Sailer A, Shen L. The role of molecular remodeling in differential regulation of tight junction permeability. Semin Cell Dev Biol. 2014;36:204-12.
  • 26
    Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012;1258:25-33.
  • 27
    De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo A, Serrazzanetti DI, et al. Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013;8:e76993.
  • 28
    Grenham S, Clarke G, Cryan JF, Dinan TG. Brain-gut-microbe communication in health and disease. Front Physiol. 2011;2:94.
  • 29
    Lyte M. Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog. 2013;9:e1003726.
  • 30
    Wood JD. Enteric neuroimmunophysiology and pathophysiology. Gastroenterology. 2004;127:635-57.

Publication Dates

  • Publication in this collection
    14 June 2016
  • Date of issue
    Jul-Sep 2016

History

  • Received
    17 July 2015
  • Accepted
    24 Jan 2016
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