Autism spectrum disorder (ASD) is a term that encompasses neuro developmental disorders characterized by behavioural, communication, and social deficits. In addition to this triad of impairments, changes related to cellular processes including gut permeability, neuro anatomical alterations and neuro-inflammation have also been identified in individuals with ASD. Patients with ASD also demonstrate altered proportions of bacteria in the gut. Since the gut microbiome has a significant impact on many physiological processes including those beyond the gut, dysbiosis observed in ASD has been the subject of recent research investigating its implications in the aforementioned pathways. This review will explore the specific cellular processes drawn from this research. The specific dysbiosis observed in ASD will be defined and linkages will be drawn to relate bacterial processes to the aberrant cell processes in ASD. Microbiota-related treatments will also be outlined based on the current understanding of the dysbiosis-ASD relationship. Finally, the evidence reviewed here will outline areas of ambiguity and provide a foundation for further research into specific pathways.

Keywords: autism spectrum disorder, gut permeability, dysbiosis, neuro-inflammation

ASD, autism spectrum disorder; DSM5, diagnostic and statistical manual; PDDs, pervasive developmental disorders; CNS, central nervous system

Autism Spectrum Disorder (ASD) is a range of neuro developmental disorders that demonstrate the triad of impairments: difficulties in social and emotional understanding, difficulties in communication, and repetitive, stereotyped behaviours and/or interests.¹ As a diagnostic term, ASD has in the fifth edition of the Diagnostic and Statistical Manual (DSM5) replaced what DSM-IV classified as Pervasive Developmental Disorders (PDDs), a group of disorders that encompassed five defined disorders: Asperger's disorder, Autistic disorder, Rett’s Disorder, Childhood Degenerative Disorder, and Pervasive Developmental Disorder Not Otherwise Specified.¹ Each of the PDDs display different behavioural, motor, or intellectual abnormalities but are nonetheless centered around the triad of impairments. Current understanding attributes ASD to the influence of both genetic and environmental factors, where genetic predisposition is highly affected by external variables, such as epigenetics.²

ASD manifests itself as a wide range of symptoms. Patients with ASD not only display the classic triad of impairments, but may also present psychological abnormalities such as attention deficits, sensory hyper- and/or hypo-sensitivities, and behaviours that may be aggressive or self-harming in nature.^3,4 Patients with ASD may have a higher prevalence of seizures, insomnia, and ear infections.³ Notably, an increased prevalence of GI symptoms such as constipation, diarrhoea, bloating, abdominal pain, reflux, vomiting, and flatulence are also characteristic of ASD.⁵

The pathophysiological factors that have been associated with ASD symptoms include structural brain differences, chronic neuro-inflammation, oxidative stress, mitochondrial dysfunction, and gut permeability.^6–13 Many studies have demonstrated that brain regions associated with functions that are impaired in ASD have altered activation, reduced or altered connectivity, and distinct integration between different brain areas.^14,15 Additionally, several biomarkers and endo-phenotypes have been associated with ASD such as biomarkers for oxidative damage, blood cytokine levels, and metabolites of mitochondrial functions.^16,17 However, it is important to note that the external validity of many studies is limited by small sample sizes, reproducibility challenges and the heterogeneity of genetic pathways to ASD.

Studies show that over 70% of ASD patient currently experience or have a history of gastrointestinal (GI) complications, suggesting a link between ASD and gut abnormalities.¹⁸ Patients with ASD often have altered microbial compositions, such as increased Clostridium (p=0.0393), Desulfovibrio (p=0.011), and Bacteroides (p=0.044), as well as decreased Bifidobacteria (p=0.050).^19,20 The colonization of Clostridium due to decreased Bifidobacteria has been associated with higher risks of GI complaints, suggesting that gut dysbiosis is a link between human ASD and comorbid gut abnormalities.²¹ There are several means by which gut dysbiosis can influence central nervous system (CNS) activity, raising the hypothetical possibility of neuro developmental pathogenesis through alterations in normal brain-gut signaling.²² The pathogenic microbiota may increase immune-mediated inflammation, compete for binding sites on enteric walls with commensal bacteria, or regulate pathways via production metabolites.²³ One of the main mechanisms that we will examine is how bacterial products may enter systemic circulation and pass through the blood-brain barrier to alter neurobiology. Specifically, we will be discussing how heightened gut permeability and neuro immune dysregulation may be implicated in the etiology of ASD, as well as the viability of probiotic treatment.

ASD is comorbid with many gastrointestinal complications involving increased gut permeability.^24–27 The physical integrity of the luminal barrier is often assessed through the sugar permeability test, which involves simultaneous oral delivery of the saccharides lactulose and mannitol, followed by measuring the urinary lactulose:mannitol ratio.^28,29 Unlike mannitol, lactulose is too bulky to traverse the luminal mucosa via aqueous pores of the intestinal epithelium.^30,31 For serum lactulose molecules to arise, lactulose must travel in between epithelial cells at areas of cell extrusion.^30,32 Through the sugar permeability test, D’Eufemia et al.,²⁴ reported a significantly elevated urinary lactulose: mannitol ratio in 43% of patients with ASD.²⁴ Increased serum lactulose suggests the presence of leaky tight junctions linking together adjacent intestinal epithelial cells.^24,32,33 This destabilization of the luminal epithelium allows entry of certain food antigens that induce ASD-related antigenic responses³⁴ and neurological dysfunction.³⁵ The propagation of the immune response further damages the mucosa through zonulin-mediated positive feedback.^36,37

Zonulin modulates intercellular tight junctions involved in transportation of macromolecules from the lumen into intestinal tissue.^36–38 It is therefore necessary to the regulation of immune responses and tolerance.^36,39 Both intestinal and extra-intestinal inflammatory disorders can arise when the zonulin pathway is deregulated in genetically susceptible individuals.^36,40

Food-derived opioid-like peptides can be referred to as exorphins due to their structural and functional similarities with endorphin, a type of opioid hormone.^41,42 Prolonged opiate exposure in animal models is shown to yield behavioural symptoms comparable to those in children with ASD, namely, repetitive actions and social disengagement.⁴³ Noting the implications of diet on schizophrenia, studies speculated that a faulty intestinal barrier allows neuro active food derivatives or exorphins to travel into the blood and later the cerebrospinal fluid where they then directly interact with cells of the central nervous system.^44,45 Although there is conflicting evidence concerning whether endogenous endorphins are elevated in autism. In addition to entry of incompletely digested foods, increased gut permeability has also allowed the increased levels of serum pathogenic compounds arising from gut dysbiosis.^46,47 Specifically, we will be examining propionic acid, a short-chain fatty acid produced during bacterial fermentation, as well as the release of lipopolysaccharides from the membrane of gram-negative bacteria. Through blood circulation, these compounds are able to travel from the gut lumen to the CNS where they interfere with cellular respiration, microglia regulation, and other pathways that may be related to the neurobiology of ASD.^48,49

Experiments on mice have shown that infections leading to maternal immune abnormalities during pregnancy can lead to symptoms equivalent to those seen in ASD, providing further evidence that some environmental factors altering maternal and fetal immune systems may lead to fetal predisposition to ASD.^50,51 Applying the findings from observational studies on human ASD, an ASD murine model was constructed through maternal immune activation, where pregnant mice were injected with immune-activating polyinosinic:polycytidylic acid (poly I:C) to produce offspring that served as phenotypic models of ASD.^52–54 Offspring of MIA mice exhibit ASD-like pathologies and symptoms, such as defects in intestinal integrity, alterations in the microbiome composition, intestinal cytokine levels and metabolome profiles analogous to that subsets in the human ASD population.^54,55 Symptomatic similarities between human ASD and MIA offspring suggest that the MIA offspring serve as reliable models of ASD. Most of ASD-associated behavioural and metabolic symptoms in these mice were ameliorated through oral treatment of Bacteroides fragilis, a bacterial species shown effective against colitis.⁵² MIA-induced microbiome had mild elevations in Clostridia and Bacteroides populations.⁵⁵ In the same study researchers noted that although there was insignificant difference in the relative abundance of Clostridia (p=0.8340) and Bacteroidia (p=0.9943) between MIA offspring and controls, the microbial species that experienced slightly greater proliferation within the MIA offspring than within the controls belonged to one of the two classes. The altered microbiome in ASD model mice aligns with studies reporting elevated Clostridium levels in the fecal matter of ASD individuals.^56–58 The exception to the increase in certain Bacteroides (12.02±1.62% control, 13.48±0.75% MIA) and Clostridium (1.00±0.25% control, 1.58±0.34% MIA) species was B. fragilis, which was notably decreased in MIA offspring.⁵² Supplementation of B. fragilis back into the intestinal environment of MIA offspring modified the microbiome composition such that it was comparable to that of the controls.⁵² There was however no significant effect on the overall gut microbial abundance or diversity (microbiome density p=0.2980, species diversity p=0.5440) upon B. fragilis treatment.⁵²

Administration of B. fragilis also normalized colonic elevation of IL-6 in MIA offspring.⁵⁹ IL-6 is critical cytokine involved in MIA pathways linked to abnormal fetal brain development and predisposition of offspring to neuro developmental pathologies.^60,61 MIA offspring also exhibited decreased prepulse inhibition at lower decibels, which is reflective of behaviour defects.⁵² Poor startle response, a common trait among autistic patients, is indicative of impaired sensorimotor gating.^62,63 Behaviour assays also showed deficits in duration and frequency of vocalization, sociability, and demonstration of repetitive behaviour, which are often considered diagnostic symptoms of ASD.⁵² However, B. fragilis-treated MIA offspring experienced improved behavioural, communicative and sensorimotor responses despite retaining deficits in sociability and exploratory propensity.⁵² Similarly, risperidone, an antipsychotic that is used in the management of irritability and aggression in ASD, was unable to correct social disengagement in both ASD individuals and genetic murine model for ASD.^64–67 From these results, it is hypothesized that social behaviour is governed by a complex set of neuronal circuitry,⁵² which may not entirely overlap with pathways modulated by B. fragilis or antipsychotics.

Metabolomic assessments show that MIA has substantial impact on 8% of serum metabolites.⁵⁹ Relative to controls, MIA offspring are found to have a 46-fold increase in 4-ethylphenylsulphate (4EPS) and a moderate increase in indolepyruvate.⁵² The striking elevation in 4EPS led to secondary experiments that showed how increasing 4EPS is sufficient in bringing about ASD-related behavioural abnormalities in previously naïve mice.⁵² It is also speculated that 4EPS production is exclusively regulated by commensal microbiota since germ-free mice only display trace amounts of serum 4EPS.⁵² These results demonstrate how gut microbes may lead to ASD-related behaviour through dysregulation of systemic metabolites levels. Interestingly, 4EPS and indolepyruvate also possess structural equivalents to human metabolites p-cresol and indolyl-3-acryloylglycine (IAG).⁵² Although there are conflicting reports regarding whether the increase in IAG levels between ASD groups and controls is statistically significant p-cresol is postulated to be a urinary biomarker for ASD.^68–71 Not unlike other MIA-induced symptoms, atypical metabolic profiles were normalized by B. fragilis supplementation.⁵² Overall, the findings suggest that probiotic supplementation can be a viable treatment for symptoms of through rectifying gut dysbiosis.

Many studies have proposed links between the etiology of ASD symptoms and gut dysbiosis. Given the high prevalence of increased gut permeability in ASD patients, it is a hypothesized that poor luminal integrity is an avenue by which bacterial compounds access the central nervous system impair neuronal function. Changes in gut microbiota may result in response to oxidative stress, but also further propagate it. Chronic neuroinflammation, which characterized by neuroglial activation and altered profiles of cytokines, chemokines, and growth factors, is also observed in individuals with ASD. The association between gut flora and neuro developmental disorders is further supported by a maternal immune activation study where phenotypic models of ASD displayed decreased colonies of B. fragilis. Interestingly, many ASD symptoms were normalized in MIA offspring upon recovery of B. fragilis levels through oral administration. These findings demonstrate that alterations in the gut microbiome can contribute to the development of ASD-associated symptoms.

An examination of all the evidence presented in this review shows a probable link between gut dysbiosis and ASD, however, the nature of this link should be explored in more depth. Further research is required to better establish the specific changes in individuals with ASD that are related to gut permeability and neuro-inflammation, as well as the mechanisms underlying the interplay between these changes and microbiota. The relationship between gut dysbiosis and ASD is a field where there are currently a greater number of questions than answers: there is a need for studies with larger sample sizes and better methods for testing gut dysbiosis in individuals. As treatments targeting gut dysbiosis and microbiota-associated pathways are being explored as an avenue ASD treatment, this field still provides a worthwhile basis for further exploration.

None.

The author declares no conflict of interest.

1. Kenneth S. Neuro developmental Disorders. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013:5.
2. Ruggeri B, Sarkans U, Schumann G, et al. Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology. 2014;231(6):1201–1216.
3. Barbaresi W, Katusic S, Voigt R. Autism. Archives of Pediatrics & Adolescent Medicine. 2006;160(11):1167.
4. Miles J. Autism spectrum disorders–A genetics review. Genet Med. 2011;13(4):278–294.
5. McElhanon B, McCracken C, Karpen S, et al. Gastrointestinal symptoms in autism spectrum disorder: a meta–analysis. Pediatrics. 2014;133(5):872–883.
6. Zeidán Chuliá F, Salmina A, Malinovskaya N, et al. The glial perspective of autism spectrum disorders. Neurosci Biobehav Rev. 2014;38:160–172.
7. Kraneveld A, De Theije C, van Heesch F, et al. The neuro–immune axis: prospect for novel treatments for mental disorders. Basic Clin Pharmacol Toxicol. 2014;114(1):128–136.
8. Frustaci A, Neri M, Cesario A, et al. Oxidative stress–related biomarkers in autism: Systematic review and meta–analyses. Free Radic Biol and Med. 2012;52(10):2128–2141.
9. Rose S, Frye R, Slattery J, et al. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well–matched case control cohort. PLoS One. 2014;9(1):e85436.
10. Shpyleva S, Ivanovsky S, De Conti A, et al. Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T+tf/J mouse model of autism and similarities with human post mortem cerebellum. PLoS One. 2014;9(11):e113712.
11. Rossignol D, Frye R. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta–analysis. Mol Psychiatry. 2012;17(3):290–314.
12. Heberling C, Dhurjati P, 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(3):264–270.
13. De Magistris L, Familiari V, Pascotto A, 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(4):418–424.
14. Philip RCM, Dauvermann MR, Whalley HC, et al. A systematic review and meta–analysis of the fMRI investigation of autism spectrum disorders. Neurosci Biobehav Rev. 2012;36(2):901–942.
15. Nickl Jockschat T, Habel U, Maria Michel T, et al. Brain structure anomalies in autism spectrum disorder–a meta–analysis of VBM studies using anatomic likelihood estimation. Hum Brain Mapp. 2012;33(6):1470–1489.
16. Ruggeri B, Sarkans U, Schumann G, et al. Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology. 2013;231(6):1201–1216.
17. Wang L, Conlon M, Christophersen C, et al. Gastrointestinal microbiota and metabolite biomarkers in children with autism spectrum disorders. Biomark Med. 2014;8(3):331–344.
18. Van De Sande M, van Buul V, Brouns F. Autism and nutrition: the role of the gut–brain axis. Nutr Res Rev. 2014;27(2):199–214.
19. Finegold SM, Molitoris D, Song Y, et al. Gastrointestinal microflora studies in late–onset autism. Clin Infect Dis. 2002;35(Suppl 1):S6–S16.
20. Finegold S, Dowd S, Gontcharova V, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444–453.
21. De Theije C, Wu J, da Silva S, et al. Pathways underlying the gut–to–brain connection in autism spectrum disorders as future targets for disease management. Eur J Pharmacol. 2011;668(Suppl 1):S70–S80.
22. Borre Y, O Keeffe G, Clarke G, et al. Microbiota and neuro developmental windows: implications for brain disorders. Trends Mol Med. 2014;20(9):509–518.
23. Foster JA, McVey Neufeld KA. Gut–brain axis: how the microbiome influences anxiety and depression. Trends in Neurosciences. 2013;36(5):305–312.
24. D Eufemia P, Celli M, Finocchiaro R, et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996;85(9):1076–1079.
25. Boukthir S, Matoussi N, Belhadj A, et al. [Abnormal intestinal permeability in children with autism]. Tunis Med. 2010;88(9):685–686.
26. De Magistris L, Familiari V, Pascotto A, 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(4):418–424.
27. Ibrahim SH, Voigt RG, Katusic SK, et al. Incidence of gastrointestinal symptoms in children with autism: a population–based study. Pediatrics. 2009;124(2):680–686.
28. Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology. 1995;108(5):1566–1581.
29. Hodges S, Ashmore SP, Patel HR, et al. Cellobiose: mannitol differential permeability in small bowel disease. Arch Dis Child. 1989;64(6):853–855.
30. Travis S, Menzies I. Intestinal permeability: functional assessment and significance. Clin Sci (Lond). 1992;82(5):471–488.
31. Johnston SD, Smye M, Watson RG, et al. Lactulose–mannitol intestinal permeability test: a useful screening test for adult coeliac disease. Ann Clin Biochem. 2000;37(Pt 4):512–519.
32. Barboza Junior MS, Silva TM, Guerrant RL, et al. Measurement of intestinal permeability using mannitol and lactulose in children with diarrheal diseases. Braz J Med Biol Res. 1999;32(12):1499–1504.
33. Hamilton I, Hill A, Bose B, et al. Small intestinal permeability in pediatric clinical practice. J Pediatr Gastroenterol Nutr. 1987;6(5):697–701.
34. Zioudrou C, Streaty RA, Klee WA. Opioid peptides derived from food proteins. The exorphins. J Biol Chem. 1979;254(7):2446–2449.
35. Paul S, Kennedy A, Rowell F, et al. Role of neuro peptides in autism and their relationships with classical neurotransmitters. Brain Dysfunct. 1970;3(5–6):328–345.
36. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011;91(1):151–175.
37. Drago S, El Asmar R, Di Pierro M, et al. Gliadin, zonulin and gut permeability: effects on celiac and non–celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41(4):408–419.
38. Fasano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol. 2012;10(10):1096–1100.
39. Fasano A. Physiological, pathological, and therapeutic implications of zonulin–mediated intestinal barrier modulation. Am J Pathol. 2008;173(5):1243–1252.
40. Visser J, Rozing J, Sapone A, et al. Tight junctions, intestinal permeability, and autoimmunity celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci. 2009;1165:195–205.
41. Koch G, Wiedemann K, Teschemacher H. Opioid activities of human beta–casomorphins. Naunyn Schmiedebergs Arch Pharmacol. 1985;331(4):351–354.
42. Lindström LH, Nyberg F, Terenius L, et al. CSF and plasma beta–casomorphin–like opioid peptides in postpartum psychosis. Am J Psychiatry. 1984;141(9):1059–1066.
43. Panksepp J. A neurochemical theory of autism. Trends in Neurosciences. 1979;2:174–177.
44. Dohan FC. Hypothesis: genes and neuroactive peptides from food as cause of schizophrenia. Adv Biochem Psychopharmacol. 1980;22:535–548.
45. Hemmings WA. The entry into the brain of large molecules derived from dietary protein. Proc R Soc Lond B Biol Sci. 1978;200(1139):175–192.
46. Nankova BB, Agarwal R, MacFabe DF, et al. Enteric bacterial metabolites propionic and butyric acid modulate gene expression, including CREB dependent catecholaminergic neurotransmission, in PC12 cells possible relevance to autism spectrum disorders. PLoS ONE. 2014;9(8):103740.
47. Jyonouchi H, Sun S, Itokazu N. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder. Neuropsychobiology. 2002;46(2):76–84.
48. Frye RE, Melnyk S, MacFabe DF. Unique acyl carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry. 2013;3(1):220.
49. Rodriguez JI, Kern JK. Evidence of microglial activation in autism and its possible role in brain under connectivity. Neuron Glia Biol. 2011;7(2–4):205–213.
50. Fatemi S, Reutiman T, Folsom T, et al. Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: Implications for genesis of neurodevelopmental disorders. Schizophrenia Research. 2008;99(1–3):56–70.
51. Shi L, Fatemi SH, Sidwell RW, et al. Maternal influenza infection causes marked behavioural and pharmacological changes in the offspring. J Neurosci. 2003;23(1):297–302.
52. Hsiao EY, McBride SW, Hsien S, et al. The microbiota modulates gut physiology and behavioural abnormalities associated with autism. Cell. 2013;155(7):1451–1463.
53. Malkova NV, Yu CZ, Hsiao EY, et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012;26(4):607–616.
54. DeFelice ML, Ruchelli ED, Markowitz JE, et al. Intestinal cytokines in children with pervasive developmental disorders. Am J Gastroenterol. 2003;98(8):1777–1782.
55. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453(7195):620–625.
56. Song Y, Liu C, Finegold S. Real Time PCR quantitation of clostridia in feces of autistic children. Appl Environ Microb. 2004;70(11):6459–6465.
57. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA. 2010;107(27):12204–12209.
58. Finegold SM, Downes J, Summanen PH. Microbiology of regressive autism. Anaerobe. 2012;18(2):260.
59. Wang L, Angley MT, Gerber JP, et al. Is urinary indolyl–3–acryloylglycine a biomarker for autism with gastrointestinal symptoms? Biomarkers. 2009;14(8):596–603.
60. Lintas C, Sacco R, Persico AM. Genome wide expression studies in autism spectrum disorder, Rett syndrome, and Down syndrome. Neurobiol Dis. 2012;45(1):57–68.
61. Careaga M, Van de Water J, Ashwood P. Immune dysfunction in autism: a pathway to treatment. Neurotherapeutics. 2010;7(3):283–292.
62. Perry W, Minassian A, Lopez B, et al. Sensorimotor gating deficits in adults with autism. Biol Psychiatry. 2007;61(4):482–486.
63. Mandelbaum DE, Stevens M, Rosenberg E, et al. Sensorimotor performance in school age children with autism, developmental language disorder, or low IQ. Dev Med Child Neurol. 2006;48(1):33–39.
64. Canitano R, Scandurra V. Risperidone in the treatment of behavioral disorders associated with autism in children and adolescents. Neuropsychiatr Dis Treat. 2008;4(4):723–730.
65. Nagaraj R, Singhi P, Malhi P. Risperidone in children with autism: randomized, placebo controlled, double blind study. J Child Neurol. 2006;21(6):450–455.
66. McDougle CJ, Scahill L, Aman MG, et al. Risperidone for the core symptom domains of autism: results from the study by the autism network of the research units on pediatric psychopharmacology. Am J Psychiatry. 2005;162(6):1142–1148.
67. Peñagarikano O, Abrahams BS, Herman EI, et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism related deficits. Cell. 2011;147(1):235–246.
68. Bull G, Shattock P, Whiteley P, et al. Indolyl–3–acryloylglycine (IAG) is a putative diagnostic urinary marker for autism spectrum disorders. Med Sci Monit. 2003;9(10):422–425.
69. Wright B, Brzozowski AM, Calvert E, et al. Is the presence of urinary indolyl–3–acryloylglycine associated with autism spectrum disorder? Dev Med Child Neurol. 2005;47(3):190–192.
70. Persico AM, Napolioni V. Urinary p cresol in autism spectrum disorder. Neurotoxicol Teratol. 2013;36:82–90.
71. Altieri L, Neri C, Sacco R, et al. Urinary p–cresol is elevated in small children with severe autism spectrum disorder. Biomarkers. 2011;16(3):252–260.