Autistic syndromes and diet : a reasonable connection
Author:
Dr Karl Reichelt - University of Oslo, Norway
Dr Karl Reichelt, long-time professor at the University of Oslo, Norway, is a world authority on
gluten and casein intolerance in autism. He has published many papers, including research
showing evidence of abnormal peptides in the urine of people with autism. In 2004, he was
visiting professor at the University of Newcastle, Australia
Abstract:
By KL Reichelt
Institute of Paediatric Research, University of Oslo, Rikshospitalet /Radiumhospitalet, N -0027
Oslo,Norway
Karlr@ulrik.uio.no
The casein- and glute- free dietary intervention in autism is based on peptide increases and
opioid activity, some of which are exogenous. Furthermore, opioids can explain many of the
symptoms discovered, and dietary intervention has been found to be effective by several groups.
The physiology involved in the demand for diet makes sense. Phenylketonuria is a reasonable
model, where reducing the load of phenylalanine or pre-lesion of deficient enzyme prevents the
genetic defect from becoming manifest. Many of the symptoms found in autism can be explained
by the effects of the peptides. The diet has been proven safe when supplements such as calcium
and vitamins and cod liver oil are taken.
Full Paper:
Biology
Since a genetic disposition to autism has been established with very high heritability (Bailey et
al., 1995; Lathe 2006) in the autistic syndromes, there must be chemical changes. However, the
probable large increase in rates of autism over recent years indicates environmental factors, too.
This is not surprising, because a genetic disposition must often be exposed to environmental
/endocrine inputs or overload to become manifest.
A clearly genetic disorder like phenylketonuria can be treated by decreasing the metabolic load
presented by phenylalanine. Also, the polymorphic nature of most enzymes makes it possible to
increase low activity enzymes by cofactor supplementation(Ames et al., 2002).
Increase in opioids in autism was measured as opioid binding activity increase (Gillberg et al.,
1985) or antibody binding activity (Le Boyer et al., 1994). More specific demonstrations of
exorphins in urine from autistic children have been described (Reichelt et al., 1990; Cade et al.,
2000; Shanahan et al., 2000) as part of a more general peptide increase ( Shattock et al., 1990;
Cade et al., 2000; Reichelt and Knivsberg, 2003 ).
High-functioning patients with autism and Asperger's syndrome do not always show peptide
increase, which is not surprising because urine overflow of peptides depends on peptide
levels high enough to bypass reuptake mechanisms in the kidneys.(Sponheim et al., 2006).
That the urinary peptides are active in the central nervous system affecting behaviour and
morphology has been extensively published (Hole et al., 1979; Drysdale et al., 1982; Idet et al.,
1982; Sun et al., 1999; Sun and Cade 1999)
In recent years, release of inflammatory cytokines by casein and gliadin has been found
( Jyonuchi et al., 2005; Ashwood et al., 2004), causing pan-enteric inflammation, and therefore
increasing the uptake from the gut. Increased gut permeability has been found in autism
(D’Eufemia et al., 1996). A general inflammatory activation has also been reported (
Croonenberghs et al., 2002).
How is this possible?
The normal gut takes up peptides (Chabance et al., 1998: Gardner 1994) and peptide uptake is
increased by preventing breakdown by peptidases, even without increased permeability (Mahe et
al., 1989). Normally, intact proteins are also taken up( Paganelli and Levinsky, 1980; Kilshaw and
Cant, 1984; Husby et al., 1984; Axelsson et al., 1986; Troncone et al., 1987;) and inflammation of
the gut wall, as seen in cpeliac disease, is expected to increase both peptide uptake and urine
excretion (Reichelt et al., 1998). Protein uptake expressed as increased IgA antibodies against
food proteins in serum is also increased in coeliac disease and is also found in autistic children
(Reichelt et al., 1990 and 1991; Lucarelli et al., 1995; Cade et al., 2000) In fact, intact
proteins from the food can be found in mothers' milk (Axelsson et al., 1986; Kilshaw and Cant
,1984; Stuart et al., 1984; Troncone et al., 1987 )
Rett syndrome, as part of CPDD (childhood onset pervasive developmental disorder) also shows
peptide increases in more than 80 % of cases (Solaas et al., 1999) as well as IgA antibody
increases (Reichelt and Skjeldal, 2006).
The exorphins are furthermore taken up through the blood-brain barrier (Ermisch et al., 1983;
Nyberg et al., 1989) and these have behavioural and trophic effects (Reichelt and Knivsberg
,2003)
The gut to brain relationship has been considerably strengthened by the effect of food in chronic
bowel inflammation (Geissler et al., 1995; Hart et al., 1998). In these papers, food intake resulted
in white matter perivascular oedmea seen on NMR (almost hives-like). EEG changes in ADHD
(hyperkinetic) kids with food intolerance has likewise been found on exposure to mostly casein
and gluten(Uhlig et al., 1997). Also, in coeliac disease, long-standing EEG changes in children
could be induced by provocation caused exposure to gluten/gliadin (Paul et al., 1985).
Behavioural and neurological effects of untreated celiac disease (Pynnönen et al 2002;
Hadjivassiliou et al 1998; Paul et al 1985; Gobbi et al 1992; Hallert et al 1982; Chapmann et
al 1978 ).
These effects range from epilepsies to severe mental symptoms and developmental delays, and
cerebellar lesions. Likewise, irritable bowel syndrome or inflammation can cause psychiatric
disorders such as depression (Svedlund et al., 1985; Masandet al., 1995; Pynnünen et al., 2005;
Hauget al., 2002) This is also the case for animal models (Welch et al., 2005), where brain
areas involved in the autistic state are influenced by chronic gut irritation. It may reasonably be
concluded that what happens in the gut affects the brain(Murch 2005)
Dietary evidence
Because of the dietary origin of some of the peptides, dietary intervention has been tried (Reichelt
et al., 1990, Reichelt et al., 1991, Lucarelli et al., 1995, Knivsberg et al., 1995, Whiteley et al.,
1999, Cade et al., 2000; Kniker et al., 2002, Knivsberg et al., 2002). The intervention by diet in
small series has p values on the promille level of significance after one year, and decrease in
peptides confirms the dietary origin of this peptide increase. The diet must be strict, as one
molecule of glutenin has 16 opioid residues. Especially older autistic children tend actively to
seek gluten/casein-containing foods from almost any source (addiction).
An Internet survey of a large number of autistic children on the diet (Klavness and Bigam, 2002)
demonstrates that the individual improvements ranged from very fast to excruciatingly slow rates,
and a trend for younger children to respond faster.
A 2002 paired and randomly assigned controlled, single blind paper (Knivsberg et al., 2002) has
received a Cochrane rating. A relationship f gluten to behavioural problems has been described
earlier (Daynes 1956)
Based on the laws of mass action (Guldberg and Waage), supplying cofactors (trace minerals
and vitamins) in excess of usual intake but below toxic levels can force polymorphically
insufficient enzymes to higher activity (Ames et al., 2002). This has been demonstrated for
phenylketonuria.
Other elements which ought to be critical
Learning programmes: Man is a learning 'animal' and therefore correcting the physiology must be
followed by a planned training programme. ABA or instrumental learning initiated by Lovaas
in Los Angeles has, by using repetition and reward systematically as well as little input signalling,
shown improvements (Sallows and Graupner, 2005). It makes sense that combining biomedical
treatment with a systematic training would be a useful type of intervention.
Nutritional inputs: Omega 3 and 6 unsaturated fatty acids easily obtained through cod liver
oil produce more flexible membranes and permit greater flexibility of membrane-bound proteins
like receptors, increasing their efficiency (Heron et al., 1980). Vitamins and trace minerals with or
without chelation, depending on heavy metal contamination (Nataf et al., 2006) would likewise
have a reasonable place and could increase desired enzyme activities (Ames et al., 2002).
Hypothesis: Is that there is a genetic disposition in several loci.?
Enzyme polymorphism ranging from inactive to slightly active
With low-activity variants of enzymes by exposure to various factors such as mercury, gut
inflammation leads to increased peptide /protein uptake because of decreased peptide
breakdown. Pan-enteric gut inflammatory states (Ashwood et al., 2004 ) would further increase
uptake and also increase gut irritation, because digestive enzymes would be hypofunctional due
to the inflammation. Damage to the blood-brain barrier could, even with normal peptide levels,
produce behavioural effects by gaining access to the central nervous system. The peptide effects
may be direct, such as those seen for opioids, or indirect by peptide inhibition of peptide
breakdown (La Bella et al.,1985). Depending on the constitution, different sub-syndromes are
seen, just as a dammed river can form many different shapes of lake upriver from the dam.
Can the peptides explain some of the symptoms of autism?
Social Isolation/indifference
Opioids inhibit social bonding (Panksepp et al., 1978) and abrogate the separation distress calls
of new-born animals (Panksepp et al.,1984). Because oxytocin (formed by peptidases like
convertase) apparently has a social bonding effect (Kirsch et al., 2005), it may be low in autism. A
combined effect would indeed be deadly to social bonding.
Slow habituation
The palmar conductance measured in autistic children shows exaggerated response to auditory
stimulation and poor habituation (Bernal and Miller, 1971). Increased sensory arousal and
insufficient reactive inhibtion (lack of habituation) would cause avoidance of new inputs
and produce a preference for the status quo and rituals (Mednick et al., 1974). A peptide
candidate for this is the serotonin uptake stimulator, pyroglu-trp-glyNH2 (Pedersen et al., 1999). It
is well established that low serotonin in the synaptic cleft causes sensory - especially auditiory hypersensitivity, poor habituation and sleep problems, as seen in carcinoid tumours where
tryptophan is sequestered into the carinoid tumour, thus reducing the precursor available for
the brain.
Language problems
Social indifference would, by itself, cause language problems, but with poor habituation, the
necessary cortical inhibition of one word to the next to enable sentence formation would not be
expected to be present. As one treated autistic girl explained: 'All the words came tumbling mixed
up like Irish stew.'
Sleep problems
Many, not all, CPDD children show a peculiar sleep disturbance. They go to sleep and, after a
short while, wake up apparently completely rested. Decreased serotonin in the synaptic cleft, as
seen in carcinoid tumours, causes a similar sleep pattern. The peptide Pyroglu-trp-glyNH2 was
found to be increased in many autistic children and increases serotonin uptake into platelets and
synaptosomes (Pedersen et al., 1999) and could explain such a state.
Decreased pain sensitivity
Analgaesia would be explained by the increase in opioids, as would the fluctuating analgaesia by
exorphins from the digestion (Hole et al., 1978; Cade et al 2000).
Trophic changes in the brain
Opiods affect brain maturation as growth factors (Hauser et al., 1989) and Fos antigen is induced
in key nuclei of the brain (Sun et al., 1999), as would be expected in autism and schizophrenia.
Such nuclei as nucleus accumbens and amygdala etc showed highly significant statistical
changes.
In the first five years, a tendency to macrocrania and excess brain growth had been found in
children with autism (Courchesne et al., 2004) and growth factors (Nelson et al., 2002) which
would be expected from inhibition of breakdown by accumulating peptides (La Bella et al., 1985).
For details, see Reichelt and Knivsberg 2003.
Increased rate of epilepsy with age is found in autism (Deykin and MacMahon 1979). In coeliac
disease, increased rates of epilepsy have been reported (Chapman et al., 1978; Gobbi et al.,
1992). Opioids have a biphasic (hormetic dose) response and, at certain concentrations, are
quite epileptogenic in the limbic brain (Siggins et al., 1986). We have seen substantial decrease
in seizures in autistic children while on diet, which fits this background.
Conclusion
Since some of the peptides found to be increased are of dietary origin, and can explain the
symptoms of CPDD, this should be a fruitful lead to follow (Murch 2005). The many reported
positive effects of diet likewise reinforce this view. However, as with most syndromes, other
subgroups than those already known are likely to surface. Fragile X and tuberous sclerosis, which
can cause autistic syndromes, do not show peptide increase.
References
Ames BN et al.,(2002) High-dose vitamin therapy stimulates variant enzymes with decreased
coenzyme binding affinity (increased Km) ; relevance to genetic disease and polymorphism. Am J
Clin Nutr. 75: 616-658
Ashwood P et al., (2004) Spontaneous mucosal lymphocyte cytokine profiles in children with
autism and gastrointestinal symptoms: Mucosal immune activation and reduced counter
regulatory interleukin –10. J Clin Immunol 24: 664-673
Axelsson I et al., ( 1986) Bovine beta-lactoglbulinin human milk. Acta Paediatr Scand 75: 702-707
Bailey A et al., ( 1995) Autism as a strongly genetic disorder: Evidence from a British twin study.
Psychol Med 25: 63-77
Bernal ME and Miller WH (1971) Electrodermal and cardiac responses of schizophrenic children
to sensory stimuli. Psychophysiol. 7: 155-165
Cade R et al., (2000) Autism and schizophrenia : Intestinal disorders. Nutr. Neuroscience 2: 5772
Chabance B et al., (1998) Casein peptide release and passage to the blood in humans during
digestion of milk and yogurt. Biochimie 80: 155-165
Chapman RGW et al., (1978) Increased prevalence of epilepsy in coeliac disease. Brit Med J 22
july : 250-251
Courchesne E et al., ( 2004) The autistic brain: birth through adulthood. Current Opin. Neurol.
17: 489-496
Croonenberghs J et al., (2002) Activation of the inflammatory
response system in autism spectrum disorders. J Pediatr 148:605-610
Daynes F (1956) Bread and tears-naughtiness, depression and fits due to wheat sensitivity. Proc
Royal Soc of Med. 48: 391-394
D’Eufemia P et al., (1996) Abnormal intestinal permeability in children with autism. Acta Paediatr
85: 1076-1079
Deykin EY and MacMahon N (1978) The incidence of seizures among children with autism, Am J
Psychiat. 136: 1310-1312
Drysdale A et al., (1982) A peptide containing fraction of plasma of schizophrenic patients which
binds to opiate receptors and induces hyperactivity in rats. Neuroscience 7: 1567-1574
Ermisch A et al., (1983) On blood-brain barrier to peptides (3 H)beta-casomorphine –5 ujpake by
eighteen brain regions in vivo. J Neurochem. 41:1229-1233.
Gardner MLG Absorption of intact proteins and peptides in physiology of the gastropintestinal
tract. Edit: Johnson LR. 3 edit. Raven press NY ,pp 1795-1820.
Geissler A et al., ( 1995) Focall white matter lesions of patients with inflammatory bowel disease.
Lancet 345: 897-898
Gilllberg C et al., ( 1985). Endorphin activity in childhood psychosis spinal fluid in 24 cases. Arch
Gen Psychiat 42: 780-783
Gobbi G et al., (1992) Coeliac disease, epilepsy and cerebral calcifications. Lancet 340: 439443
Hadjivassilliou M et al., (1998)Clinical, radiological, neuro-physiological and neuropathological
characteristics of gluten ataxia. Lancet 352: 1582-1585
Hallert K et al., (1982) Psychic disturbances in adult coeliac disease III. Reduced central
monoamine metabolism and signs of depression. Scand J Gastroenerol 17: 25-28
Hart PE et al., ( 1998) Brain white matter lesions in inflammatory bowel disease. Lancet 351:
1558.
Haug TT et al., (2002) Are anxiety and depression related to gastrointestinal symptoms in the
general population? Scand J Gastroenterol 32:294-298
Hauser KR et al., (1989) Endogenous opioid systems and the regulation of dendritic growth and
spina formation J Comp Neurobiol. 281: 13-22
Heron DS et al., (1980) Lipid fluidity markedly modulates the binding of serotonin to mouse brain
membranes. P.N.A.S. (US) 77: 7463-7467
Hole K et al., (1979) A peptide containing fraction from schizophrenia which stimulates opiate
receptors and inhibits dopamine uptake. Neuroscience 4: 1139-1147
Husby S et al., (1984) Passage of un-degraded dietary antigen into the blood of healthy adults.
Scand J Immunol 22: 83-92
Idet M et al., (1982) Elevated opioid activity in sera of chronic schizophrenics. Acta Physiol Hung
60: 121-127
Jyonouchi H et al., (2005) Evaluation of an association between gastrointestinal symptoms and
cytokine production against common dietary proteins in childen with autism spectrum disorders. J
Pediatr 146: 605-610
Kilshaw FJ and Cant AJ (1984) The passage of maternal dietary protein into human breast milk.
Int Arch. Allergy Appl Immunol. 75: 8-15
Kirsch P et al.,(2005) Oxytocin modulates neural circuitry for social co-operation and fear in
humans. J Neuroscience 25: 11489-11497
Klaveness J and Bigam J (2002) The GFCF kids diet survey, in Building Bridges (Ed. The Autism
Research Unit, Sunderland Univ), pp77-84
Kniker T et al.,(2001) The possible role of intolerance to milk/dairy and wheat/gluten foods in
older children and adults with autism spectrum disorder, in 2001: An Autism Odyssey, Edit The
Autism Research Unit, Sunderland Univ pp 183-191
Knivsberg A-M et al., (1995) Autistic syndromes and diet: A follow-up study. Scand J Educat.
Res. 39:223-236
Knivsberg A-M et al., (2002) A randomized, controlled study of dietary intervention in autistic
syndromes. Nurtr. Neuroscience 5: 251-261
La Bella F.L, et al., (1985) Administration of peptides inhibit the degradation of endogenous
peptides. The dilemma of distinguishing direct from indirect effects. Peptides 6: 645-660.
Lathe R (2006) Autism, Brain and Environment, Jessica Kingsley Publ, London, pp37-48
Le Boyer M et al., (1994) Difference between plasma N and C-terminally directed betaendorphin immunoreactivity in infantile autism. Am J Psychiat 151: 1797-1801
Lucarelli S, et al., (1995) Food allergy and infantile autism. Panminerva Medica 37: 137-141
Mahe S et al., (1989) Absorption of intact morphiceptin by diisopropylfluorophosphate-treated
rabit ileum. Peptides 10: 45-52
Masand PS et al., (1995) Major depression and irritable bowel syndrome: is there a relationship?
J Clin Psychiat. 56: 363-367
Mednick SA et al., (1974) Genetics, Environment and Psychpathology, North Holland
Press,Amsterdam.
Murch S (2005) Diet, Immunity ,and autistic spectrum disorders, J of Pediatr 146: 592-584
Nataf R et al., (2006) Porphyrinuria in childhood autistic disorders: Implications for environmental
toxicity. Toxicol and Appl Pharmacol 214: 99-108
Nelson KB et al., (2001) Neuropeptides and neurotrophins in neonatal blood of children with
autism and mental retardation. Ann Neurol 49:547-606
Nyberg F et al., (1989) Immunoreactive bea-casomorphin-8 in cerebrospinal fluid from pregnant
and lactating women: Corrrelation with plasma level. J Clin. Endocrinol Metab. 68: 283-289
Paganelli R and Levinsky RJ (1980) Solid phase radioimmunoassay of circulating food proein
antigen in human serum. J Immunol Method. 37: 333-340
Panksepp J et al., (1978)casomorphins reduce separation distress in chicken. Peptides 5:829831
Panksepp et al., (1980) Edndogenous opioids and social behaviour. Neurosci Biobehav. Rev.
4:473-487.
Paul KD et al., (1985) EEG.befunde in Zoeliakikranken Kindern in Abhängigheit von der
Ernährung. Zeitschr. für Klin Med. 40:707-709
Pedersen OS et al., (1999) Serotonin uptake stimulating peptide found in plasma of normal
individuals and in urines of autistic children. J Peptide Res 53: 641-646
Pynnünen PA et al (2002) Untreated coeliac disease and development of mental disorders in
children and adolescents. Psychosomatics 43: 331-334
Pynnünen P.A. et al., (2005) Gluten-free diet may alleviate depression and behavioural
symptoms in adolescents with coeliac disease: a prospective follow-up, care series study. BMC
Psychiatry 5: 14.-25
Reichelt KL et al., (1990) Gluten, milk proteins and autism: dietary intervention in autistic
syndromes. J Appl Nutr. 42:1-11.
Reichelt KL et al., (1991) Probable aetiology and possible treatment of childhood autism. Brain
Dysfunct 4: 308-319
Reichelt WH et al., (1998) Peptide excretion in coeliac disease. J Pediatr Gastroenterol. and Nutr.
26:305-309
Reichelt KL and Knivsberg A-M (2003) Can the pathophysiology of autism be explained by the
nature of the discovered urine peptides? Nutrit Neurosci 6: 19-28
Reichelt KL and Skjeldal O (2006) IgA antibodies in Rett syndrome. Autism 10: 189-197
Sallows GO and Graupner TD (2005) Intensive behavioural treatment for children with autism:
Four-year outcome and predictors. Am J Mental Retard. 110: 417-438
Shanahan MR et al., (2000) Peptide diagnostic markers for human disorders. Eur Patent Appl
EP0 969 015 A2 pp 1-44
Shattock P, et al., (1990) Role of neuropeptides in autism and their relationships with classical
neurotransmitters. Brain Dysfunction 3: 315-327.
Siggins GR et al., (1986) Opioid peptides and epileptogenesis in the limbic system: cellular
mechanisms. Advances in Neurology, 44: 501-512
Solaas KM et al., (2002) Urinary peptides in Rett syndrome. Autism 6: 315-329
Sponheim, E. et al., (2006) Peptidmønstre i urin hos barn med mildere former for autisme. TNLF
126: 1475-1477.
Stuart CA et al., (1984) Passage of cow’s milk protein in breast milk. Clin Allerg. 14: 533-535
Sun Z and Cade RJ (1999) A peptide found in schizophrenia and autism causes behavioural
changes in rats. Autism 3:85-95
Sun C et al., (1999) Beta-casomorphin induces FOS –like immunoreactivity in discrete brain
regions relevant to schizophrenia and autism. Autism 3: 67-83
Svedlund J et al., (1985) Upper gastrointestinal and mental symptoms in the irritable bowel
syndrome. Scand J Gastro-enterol 20: 595-601
Troncone R et al., (1987) Passage of gliadin into human breast milk. Acta Paediatr. Scand 76:
453-456
Uhlig T et al., (1997) Topographic mapping of brain electrical activity in children with food-induced
attention deficit hyperkinetic disorder. Eur J Pediatr 156: 557-561
Welch MG et al., (2005) Brain effects of chronic IBD in areas abnormal in autism and treatment
by single neuropeptides secretinn and oxytocin. J Mol. Neurosci. 25: 259-273