Autism is a life-long developmental disorder affecting as many as 1 in 500 children. The causes for this profound disorder are largely unknown. Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology, reported to extend from the esophagus to the colon, is described here along with other studies pointing to a connection between diet and the severity of symptoms expressed in autism. The evidence that there is impaired intestinal permeability in autism is reviewed, and various theories are discussed by which a leaky gut could develop. Lastly, some possible ways in which impaired gastrointestinal function might influence brain function are discussed.
RapinI. Current concepts: autism. N Engl J Medicine337: 97104, 1997.
2.
DeykinEY, McMahonN. The incidence of seizures among children with autistic syndromes. Am J Psychiatry136: 13101312, 1979.
3.
American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th ed.Washington DC, 1994.
4.
TuchmanRF, RapinI. Regression in pervasive developmental disorders: seizures and epileptiform electroencephalogram correlates. Pediatrics4: 560566, 1997.
5.
HoshidoY, KanekoM, YashimaY, UmashiroH, VolmarFR, CohenDJ. Clinical features of autistic children with setback in their infancy. Japan J Psychiatry Neurol41: 237246, 1987.
6.
BaileyA, LeCouteurA, GottesmanI, BoltonP, SimonoffE, YudaE, RutterM. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med25: 6377, 1995.
7.
TrottierG, SrivastavaL, WalkerCD. Etiology of infantile autism: a review of recent advances in genetic neurobiological research. J Psychiatry Neurosci24: 103115, 1999.
8.
GreenbergDA, HodgeSE, SowinskiJ, NicollD. Excess of twins among affected sibling pairs with autism: implications for the etiology of autism. Am J Hum Genet69: 10621067, 2001.
9.
DalesL, HammerSJ, SmithNJ. Time trends in autism and MMR immunization coverage in California. J Am Med Assoc285: 11831185, 2001.
10.
KayeJA. Mumps, measles and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. Br Med J322: 460463, 2001.
11.
TaylorB, MillerE, FarringtonCP, PetropoulosMC, Favot-MayaudI, LiJ, WrightPA. Autism and measles mumps and rubella vaccine: no epidemiological evidence for a causal association. Lancet353: 20262029, 1999.
12.
GillbergC, WingL. Autism: not an extremely rare disease. Acta Physiol Scand99: 399406, 1999.
13.
WingL, PotterD. The epidemiology of autistic spectrum disorders: is the prevalence rising?Mental Retardation Dev Disabilities Res Rev8: 151161, 2002.
WakefieldAJ, AnthonyA, MurchSH, ThomsonM, MontgomerySM, DaviesS, O'learyJJ, BerelowitzM, Walker-SmithJA. Enterocolitis in children with developmental disorders. Am J Gastroenterol95: 22852295, 2000.
16.
SabraA, BellantiJA, ColonAR. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet352: 234235, 1998.
17.
HorvathK, PapadimitriouJC, RabsztynA, DrachenbergC, TildonJT. Gastrointestinal abnormalities in children with autistic disorder. J Pediat135: 559563, 1999.
18.
BlackC, KayeJA, JickH. Relation of childhood gastrointestinal disorders to autism: nested case-control study using data from the UK General Practice Research Database. Br Med J325: 419421, 2002.
19.
GoodwinMS, CowenMA, GoodwinTC. Malabsorption and cerebral dysfunction: a multivariate and comparative study of autistic children. J Autism Child Schizophrenia1: 4862, 1971.
ShattockP, KennedyA, RowellF, BerneyTP. Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunct3: 328345, 1990.
28.
ReicheltKL, KnivsbergAM, LindG, NodlandM. Probable etiology and possible treatment of childhood autism. Brain Dysfunct4: 308319, 1991.
HodgesS, AshmoreSP, PatalHL, TannerMS. Cellobiose: mannitol differential permeability in small bowel disease. Arch Dis Child64: 853854, 1989.
33.
HamiltonI, HillA, BoseB, BoucherIAD, ForsythJS. Small intestinal permeability in pediatric clinical practice. J Pediatr Gastroenterol Nutr6: 697701, 1987.
34.
D' EufemiaP, CelliM, FinocchiaroR, PacificoL, ViozziL, ZaccagniniM, CardiE, GiardiniO. Abnormal intestinal permeability in children with autism. Acta Paediat85: 10761079, 1996.
35.
KerneisS, BogdanovaA, KraehenbuhlJ-P, PringaultE. Conversion of Peyer's patch lymphocytes of human enterocytes into M cells that transport bacteria. Science277: 949952, 1997.
36.
ReicheltKL, EkreinJ, ScottH. Gluten, milk proteins and autism: dietary intervention effects on behavior and peptide secretion. J Appl Nutr42: 111, 1990.
37.
ZioudrouC, StreatyRA, KleeWA. Opioid peptides derived from food proteins. The exorphins. J Biol Chem254: 24462449, 1979.
38.
ChangKJ, SuYF, BrentDA, ChangJK. Isolation of a specific μ-opiate receptor peptide, morphiceptin, from an enzymatic digest of milk protein. J Biol Chem260: 97069712, 1985.
39.
LindstromLH, NybergF, TereniusL, BauerK, BesevG, GunneLM, LyrenasS, Willdeck-LundG, LindbergB. CSF and plasma β-casomorphin-like opioid peptides in post-partum psychosis. Am J Psych41: 10591066, 1984.
40.
DohanFC. Hypothesis: genes and neuroactive peptides from food as cause of schizophrenia. Adv Biochim Psychopharmacol22: 535548, 1980.
41.
HemmingsWA. The entry into the brain of large molecules derived from dietary protein. Proc Roy Soc London Ser B200: 175192, 1978.
42.
SunZ, CadeJR, FreglyMJ, PrivetteRM. β-Casomorphin induces Fos-like immunoreactivity in discrete brain regions relevant to schizophrenia and autism. Autism3: 6783, 1999.
43.
ReicheltKL, LandmarkJ. Specific IgA antibody increases in schizophrenia. Biol Psych37: 410413, 1995.
44.
DohanFC. More on celiac disease as a model for schizophrenia. Biol Psych18: 561564, 1983.
45.
DohanFC, GrasbergerJC. Relapsed schizophrenics: earlier discharge from hospital after cereal-free, milk-free diet. Am J Psych130: 685688, 1973.
46.
ReicheltKL, SagedalE, LandmarkJ, SangvikBT, EggenO, ScottH. The effect of gluten-free diet on urinary peptide excretion and clinical state in schizophrenia. J Ontomol Med5: 223239, 1990.
47.
SinghMM, KaySR. Wheat gluten as a pathogenic factor in schizophrenia. Science191: 401402, 1976.
48.
FiocchiC. Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions. Am J Physiol273(Gastrointest Liver Physiol 36): G769G775, 1997.
49.
MurchSH, MacDonaldTT, Walker-SmithJA, LevinM, LionettiP, KleinNJ. Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet341: 711741, 1993.
50.
FudenbergHH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy9: 1317, 1996.
51.
AlbertiA, PirroneP, EliaM, WaringRH, RomanoC. Sulphation deficit in “low functioning” autistic children: a pilot study. Bioi Psych46: 420424, 1999.
52.
GuptaS. Immunology and immunologic treatment of autism. Proceedings of the National Autism Assn; 1996; Chicago: 455460.
53.
BeekenWL, BuschHJ, SylwesterDL. Intestinal protein loss in Crohn's disease. Gastroenterology62: 207215, 1972.
54.
FurlanoRI, AndrewA, DayR, BrownA, GarveyL, ThomsonMA, DaviesSE, BerelowitzM, ForbesA, WakefieldAJ, Walker-SmithJA, MurchSH. Colonic CD8 and γδ T-cell infiltration with epithelial damage in children with autism. J Pediat138: 366372, 2001.
55.
HarrisonM, KilbyA, Walker-SmithJA, FranceNE, WoodCB. Cow's milk protein tolerance: a possible association with gastroenteritis. Br Med J19: 15011504, 1976.
56.
HeymannM, GrassetE, DucrocR, DesjeuxJF. Antigen absorption by the jejunal epithelium of children with cow's milk allergy. Pediatr Res241: 197202, 1988.
57.
UnnoN, MenconiMJ, SmithM, FinkMP. Nitric oxide mediates interferon-γ-induced hyperpermeability in cultured human intestinal epithelial monolayers. Crit Care Med23: 11701176, 1995.
58.
SandersSE, MadaraJL, McGuirkDK, GelmanDS, GolmanSP. Assessment of inflammatory events in epithelial permeability: a rapid screening method using fluorescein dextrans. Gastroenterology106: 15141523, 1995.
59.
MadaraJL, StaffordJ. Interferon-γ directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Invest83: 724727, 1989.
HeymannM, DesjeuxJF. Cytokine-induced alteration of the epithelial barrier to food antigens in disease. Ann NY Acad Sci915: 304311, 2000.
62.
KawashimaH, MoriT, KashiwagiY, TakekumaK, HoshikaA, WakefieldA. Detection and sequences of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci45: 723729, 2000.
LewinJ, DhillonAP, SimR, PounderRE, WakefieldAJ. Confirmation of persistent measles virus infection of intestinal tissue by immunogold electron microscopy. Gut36: 564569, 1995.
65.
MiyamotoH, TanakaT, KitamotoN, FukudaY, ShimoyamaT. Detection of immunoreactive antigen, with a monoclonal antibody to measles virus, in tissues from a patient with Crohn's disease. J Gastroenterol30: 2833, 1995.
66.
IizukaM, NakagoniO, ChibaM, UedaS, MasamuneO. Absence of measles virus in Crohn's disease. Lancet345: 199, 1995.
67.
PabstHF, SpadyDW, CarsonMM, StelfoxHT, BeelerJA, KrezolekMP. Kinetics of immunologic responses after primary MMR vaccination. Vaccine15: 1014, 1997.
TaylorB, MillerE, LingamR, AndrewsN, SimmonsA, StoweJ. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. Br Med J324: 393396, 2002.
70.
FombonneE, ChakrabartiS. No evidence for a new variant of MMR-induced autism. Pediatrics108:E58, 2001.
71.
EdwardesM, BaltzanM. MMR immunization and autism. J Am Med Assoc285: 28522853, 2001.
72.
BernardS, EnayatiA, RedwoodL, RogerH, BinstockT. Autism: a novel form of mercury poisoning. Med Hypotheses56: 462471, 2001.
73.
BohmeM, DienerM, MestresP, RummelW. Direct and indirect actions of HgCl2 and methyl mercury chloride on permeability and chloride secretion across the rat colonic mucosa. Toxicol Appl Pharmacol114: 285294, 1992.
74.
WatzlB, AbrahamseSL, Treptow-van LishautS, NeudeckerC, HanschGM, RechkemmerG, Pool-ZobelBL. Enhancement of ovalbumin-induced antibody production and mucosal mast cell response by mercury. Food Chem Toxicol37: 627637, 1999.
75.
NelsonKB, GretherJK, CroenLA, DambrosiaJM, DickensBF, JelliffeLL, HansenRL, PhillipsTM. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol49: 597606, 2001.
76.
WarrenRP, OdellJD, WarrenWL, BurgerRA, MaciulisA, DanielsWW, TorresRA. Brief report: immunoglobulin A deficiency in a subset of autistic subjects. J Autism Dev Disord27: 187192, 1997.
77.
JohnsonLR. Gastrointestinal physiology: Digestion and absorption. In: JohnsonLR, Ed. Essential Medical Physiology, 2nd ed.Philadelphia, PA: Lippincott-Raven, 1998.
78.
LundinP, WestromBR, PantzarN, KarlssonBW. Bidirectional small intestinal permeability changes to different-sized molecules after HCl-induced injury in the rat. Dig Dis Sci42: 677683, 1997.
79.
HorvathK, StefanatosG, SokolskiKN, WachtelR, NaborsL, TildonJT. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys9: 915, 1998.
80.
SandlerAD, SuttonKA, DeWeeseJ, GirardiMA, SheppardV, BodfishJW. Lack of benefit of a single dose of synthetic human secretin in the treatment of autism and pervasive developmental disorder. N Engl J of Med341: 18011806, 1999.
81.
ChezMG, BuchananCP, BaganBT, HammerMS, McCarthyKS, OvrutskayaI, NowinskiCV, CohenZS. Secretin and autism: a two-part clinical investigation. J Autism Dev Disorders30: 8794, 2000.
82.
Dunn-GeierJ, HoHH, AuerspergE, DoyleD, EavesL, MatsubaC, OrrbineE, PhamB, WhitingS. Effects of secretin in children with autism: a randomized controlled trial. Dev Med Child Neurol42: 796802, 2000.
83.
LightdaleJR, HayerC, DuerA, Lind-WhiteC, JenkinsS, SiegelB, ElliotGR, HeymanMB. Effects of intravenous secretin on language and behavior of children with autism and gastrointestinal symptoms: a single-blinded, open-label pilot study. Pediatrics108:E90, 2001.
84.
RobertsW, WeaverL, BrianJ, BrysonS, EmelianovaS, GriffithsA, MacKinnonB, YimC, WolpinJ, KorenG. Repeated doses of porcine secretin in the treatment of autism: a randomized, placebo-controlled trial. Pediatrics107:E71, 2001.
85.
GillbergC, ColemanM. The biology of the autistic syndromes. 3rd ed. In: HartHM, Ed. Clinics in Developmental Medicine No. 153/4. London: MacKeith Press, 2000.
