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RESEARCH




The Science of Autistic Spectrum Disorder


Behaviour and health are intimately linked. Everyone is aware of how physical ill health affects mood and energy levels and how a chronic physical condition can affect personality and outlook. The same is true for children. Not only are children beginning to experience health problems never seen before in childhood such as ulcerative colitis and obesity but many children are starting life suffering from varying degrees of learning and behavioural issues. One such issue is autistic spectrum disorder (ASD) generally considered to be a rare condition when Kanner published his original paper on the subject in 1943. At that time, incidence of autism was 2-4 per 10,000 children but had risen in the 1990s to 60 per 10,000 (1)

WHAT IS AUTISM?
Autism is now known to be a spectrum of conditions ranging from Asperger’s Syndrome through to the Classical type outlined by Kanner. It is a complex developmental disorder which can be noticeable when the child is a few months old but is commonly identified at 3-4 years old when aberrant behaviour is more apparent and easier to observe. It is characterised by a triad of impairments in the areas of communication, socialisation and imagination. It often manifests as rigidity of behaviour, impaired communication with particular issues with socially appropriate use of language, and may overlap with other developmental or psychiatric conditions such as obsessive-compulsive disorder or developmental dyspraxia.

There is no definitive biochemical or genetic testing available to confirm diagnosis therefore this is a subjective process of observing behaviour. Jim Gurney, epidemiologist notes that ‘one person’s autism is not another person’s autism’. Crucially we have little idea of social norms for some of the complex aspects of behaviour in order to make a judgment about what is normal vs. abnormal. Furthermore Autism is a medical (psychiatric) diagnosis being made in relation to what is really a cognitive disorder and very idiosyncratic in its actual characterisation in a given individual. One central aspect of the condition that may link together its many manifestations proposed by Ute Frith is a lack of ‘theory of (another’s) mind’ which means people with autism are unable to conceptualise the thoughts/feelings of others. They also suffer from diminished ‘executive function’ which reduces the ability to plan future actions and ‘weak central coherence’ which gives rise to an inability to extract meaning from events and experiences without being side-tracked by excessive detail (2). For further information on the ‘Theory of Mind’ and other aspects of autism, readers are referred to the excellent book ‘Autism: Explaining the Enigma’ by Ute Frith.

AETIOLOGICAL CONSIDERATIONS
Controversy arose over the issue of the MMR vaccine inflating gastrointestinal inflammation in ASD sufferers and has been the subject of much discussion and speculation. Recent Japanese research has concluded that the vaccine is ‘most unlikely to be a main cause of ASD’ as the incidence of ASD rose significantly even in unvaccinated children (3). It may be that the time frame for development of autistic symptoms simply coincides with the childhood vaccination schedule (4). However, digestive disturbance may be a crucial feature of autism, as we shall see.

THE IMPORTANCE OF DIGESTION
A common contributing factor to ASD is often the failure to establish healthy gut flora in early life. Many children suffer from dysbiosis due to antibiotics given at a young age and may have developed imbalance colonies of gut bacteria due to caesarean delivery and/or formula feeding. Long term dysbiosis can cause inflammation in the gut lining and increased gut permeability.

Recent clinical trials have highlighted the prevalence of gastrointestinal symptoms including inflammation and dysfunction in autistic children. Mild to moderate inflammation was found in both upper and lower intestinal tract in conjunction with decreased liver sulfation and pathologic intestinal permeability reported in many children (5). Infection with Clostridium was found in some children, mainly species not found in controls, and the Cetobacterium somerae was present in the stool in some cases. Significant dysbiosis is also a widespread problem (6,7). Constipation and diarrhoea is also extremely common in ADHD (Attention Deficit Hyperactivity disorder, closely related to ADS) sufferers (8). Interestingly, one group of autistic children with higher gut incidence of Clostridium histolyticum, a know toxin producer, had siblings with similar levels of gut C. histolyticum but no autistic symptoms (9). A small study examined whether ADHD children evidenced gastric symptoms as well as the recognised lymphocytic colitis and small bowel enteropathy common in these children – it was found that the children had a gastritis marked by high CD8+ cells, which is distinct from Crohn’s where CD4+ cells dominate in the subepithelial basement membrane and surface epithelium (10). Subacute chronic tetanus infection can be another potent gut and neurotoxin. C. tetani releases neurotoxin which can be transported from the intestinal tract to the brain via the vagus nerve. Normally the bacterium would bind to sites located in the spinal cord but can bypass these sites and reach the brain without normal tetanus symptoms occurring. In the brain, tetanus neurotoxin (TeNT) cleaves synaptobrevin, a synaptic vesicle membrane protein, and can inhibit neurotransmitter release which could explain changes in behaviour. Treatment with antimicrobials effective against intestinal Clostridia has led to improvement in some children’s behaviour (11).

FOOD INTOLERANCE
Sensitivity to gluten and casein food proteins have been identified as an important factor in the behaviour of autistic children. A recent Cochrane report demonstrated that, despite a paucity of robustly designed studies, one excellent trial demonstrated unequivocal benefits of excluding gluten and casein on the symptoms of ASD (12)

In order to restore health to the child’s gastrointestinal system, probiotics combined with glutamine supplementation maybe useful.

THE ROLE OF PROBIOTICS
Lactobacillus acidophilus is the most widely studied of all probiotics and is known to stimulate immunity increasing levels of interleukin-1 alpha and TNF-alpha (13) and also promote non-specific immunity and protect against infective diarrhoea and inflammatory bowel disease (14, 15).

L. crispatus is noted as a predominant hydrogen peroxide producing species and seems to inhibit pathogenic E.coli from adhering to basement membrane via competition with laminin (collagen) molecules for binding sites. The crispatus species also appears capable of preventing colonisation of damaged intestinal tissues by pathogens (16, 17).

L. crispatus is known to ferment lactose to short chain fatty acids including acetate and propionate, providing dual benefits of improved lactose digestion and providing short chain fatty acids for colonic mucosal energy metabolism, useful in the case of damaged or permeable intestinal membrane (18). Like L. rhamnosus, the crispatus species is capable of peptidase enzyme synthesis (19) and this property of both aids digestion of dietary casein and gluten, two food proteins often linked with worsening behaviour in autism.

The species Lactobacillus rhamnosus species is noted to have the following potentially useful properties:

  • Enhancement of systemic cellular immune response and induction of higher levels of immunoprotective antibody slgA important in those suffering from gastrointestinal infection (20)
  • Shortening the duration of diarrhoea causing rotavirus common in children 6-24 months old and promoting enterocyte production (increasing in the number of cells in the villi) (21)
  • Down-regulation of immunoinflammatory response in milk hypersensitive patients and synthesis of peptidase enzyme which aids digestion of dietary protein from casein (19)

Both Bifidobacterium bifidum and Bifidobacterium lactis have been shown to enhance gut immunity and reduce the incidence of gut infections in children by preventing the build up of intestinal endotoxin and preventing adherence of E. coli (22, 23). B.bifidum can also protect the gut lining from lipid peroxidation due to notable antioxidant capacity (24).

THE ROLE OF GLUTAMINE
Glutamine is essential for maintenance of healthy gut epithelial tissue and used as oxidative fuel by the intestinal cells enabling repair of the intestinal epithelium and prevention of the translocation (passage) of undesirable toxins and metabolites to the lymph nodes, liver and spleen (25). When gastrointestinal inflammation is present, immune cells in the blood stream concentrate under the tight junctions of the gut epithelium and cause the junction to open momentarily allowing gut lumen pathogens access to systemic circulation. The immature intestine is extremely sensitive to inflammatory agents, much more so than the adult gut, and intake of glutamine has been shown to modulate inflammation (26) and reduce frequency of infection (27). In autistic children, plasma glutamine levels are often reduced and amino acid metabolism dysfunctional, leading Rolf et al to denote the decrease in platelet amino acids as ‘a biochemical marker related to infantile autism’ (28,29). Not only are glutamine and phenylalanine levels reduced, but levels of glycine can be raised affecting the uptake of amino acids at the blood brain barrier and causing CNS disturbance. It is possible such a dysregulation in amino acid levels disturbs inhibitory neurotransmission function resulting in increased excitability probably more so in ADHD suffers (Attention deficit/hyperactivity disorder) than autistics (30). Children with autism were also found to have low levels of the glutamine dependent enzyme glutathione which could give rise to free radical accumulation and damage to the brain which is a feature of many other neurodegenerative conditions such as Alzheimer’s and Parkinsons. Nitric oxide accumulation could be particularly relevant to the pathophysiology of autism (31,32). Deficiency of glutamine can also add to immunosuppression due to increase in proinflammatory processes (33).

THE BENEFITS OF GLUTAMINE

  • Improved Intestinal Barrier Function (34)
  • Improved glucose homeostasis (35)
  • Prevents apoptosis in gut epithelial cells (36)
  • Protects against injury and inflammation (37)
  • Modulates systemic immunity (38)
  • Promotes intracellular glutathione and DNA renewal (39)

If barrier function is lost, inflammation results in leakage of water and ions into the lumen producing diarrhoea. Often sufferers of Inflammatory Bowel Disease have 50-80% less tight junction integrity than controls so supplementation of glutamine is highly indicated in children with gastrointestinal inflammation and ASD symptoms. Since lactobacillus bacteria are also noted for their ability to decrease intestinal permeability, the combination of Lactic Acid Bacteria and glutamine is an ideal complement (40,41).

CONCLUSIONS
Whilst nutritional factors may not be a direct cause of autism, they may play a role in exacerbating the symptoms of the condition. The nutrition practitioner’s role is to investigate whether underlying food intolerances, gut dysbiosis or nutritional deficiencies may be contributing to mood, behaviour or learning. Naturopathically-orientated practitioners are, of course, likely to focus their treatments on improving digestion as a fundamental therapeutic area. In addition to this digestive support, further progress may be made by using multivitamin/mineral (especially B6 and zinc) and fatty acid supplementation (particularly fish oil).

References
1. Wing and Potter. The Epidemiologh of Autistic Spectrum Disorders: Is the prevalence Rising? Mental Retard Dev Disabil Res Ref 2002;8(3):151-61
2. Happé F, Firth U (2006). “The weak coherence account: detail-focused cognitive style in autism spectrum disorders”. J Autism Dev Disord 36 (1):5-25
3. Honda H, Shimzu Y, Rutter M. No Effect of MMR Withdrawal on the Incidence of Autism: a Total Population Study. J Cild Psychol Psychiatry 2005 Jun; 46 (6) 572-9)
4. Brudnak, MA; Application of Genomeceuticals to the molecular and immunological aspects of autism. Med hyptheses 2001 Aug;57(2):186-91
5. Horvarth et al. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep 2002 Jun;4(3):251-8
6. Finegold et al. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis 2002 Sep 1;35 (Suppl 1): S6-S16
7. Erickson et al. Gastroinstestinal Factors in Autistic Disorder: A Critical Review.
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9. Parracho et al. Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol 2005 Oct; 54 (pt 10):987-91
10. Torrente et al. Focal-enhanced gastritis in regressive autism with features distinct from Crohn’s and Helicobacter pylori gastritis. Am J Gastroenterol 2004 Apr; 99(4): 598-605
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17. Horie et al. Inhibition of the adherence of Escherichia. Colistrains to basement membrane by lactobacillus crispatusexpressing an S-layer. J Applied Microbiol 2002 March;92(3):396
18. van der Wielen et al. Effect of administration of Lactobacillus crispatus, Clostridium lactatifermentans and dietary lactose on the development of the normal microflora and volatile fatty acids in the caeca of broiler chicks. Br Poult Sci 2002 Sep;43(4):545-50
19. Pelto et al. Probiotic bacteria down-regulate the milk-induced inflammatory response in milk-hypersensitive subjects but have an immunostimulatory effect in health subjects
20. Ying-H et al. Systemic Immunity – Enhancing Effects in Healthy Subjects Following Dietary Consumption of the Lactic Acid Bacterium Lactobacillus rhamnosus HN001 J Am Coll Nutr 2001 20; no 2, 149-156
21. Banasaz et al. Increased Enterocyte Production in Gnotobiotic Rats Mono-Associated with Lactobacillus rhamnosus GG. Applied and Environmental Microbiol. June 2002 p3031-3034 vol 68, no 6.
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29. Rolf et al. Serotonin and amino acid content in platelets of autistic children. Acta Psychiatr Scand 1993 May;87(5):312-6
30. Zaval et al. Imbalance of plasma amino aids in patients with autism and subjects with attention deficit/hyperactivity disorder
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34. Lima et al. Intestinal barrier function and weight gain in malnourished children taking glutamine supplemented enteral formula. J Pediatr Gastroenterol Nutr 2005 Jan;40(1):24-5
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36. Evans et al. Glutamine inhibits cytokine-induced apoptosis inhuman colonic epithelial cells via the pyrimidine pathway. Am J Physiol Gastrointest Liver Physiol 2005 Sep;289(3): G388-96 Epub 2005 May 5
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38. Yeh et al. Dietary glutamine supplementation modulates Th1/Th2 cytokine and interleukin-6 expressions in septic mice. Cytokine 2005 Sep7;31(5):329-34
39. Wasa et al. Glutamine stimulates amino acid transport during ischemia-reperfusion in human intestinal cells. J Surg Res 2005 Jan;123(1):75-81
40. Schmitz et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 1999;116:301-09
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Also see: The Truth about Supplements and The Essentiality of Fats




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