Dietary peptides as cause of disease

(Denne teksten henvender seg først og fremst til fagfolk og foreligger kun på engelsk) 

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 as a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition, suggestive of an autoimmune lesion. There is strong evidence that there is impaired intestinal permeability in autism.

The involvement of dietary peptides in ASD and ADHD is the based on the following points:

- Diet derived peptides are involved in the development symptoms in at least a fraction of these patients. 
- Gastrointestinal problems are frequent in this patient group and may involve intolerance to opioid peptides from milk or gluten and  disturbances of the gut flora, with overgrowth of clostridial species. 
- Inflammatory intestinal pathology has been reported in children with regressive autism cosisting of a pan-enteric mucosal immunopathology is distinct from other inflammatory bowel diseases. 
- Vojdani et al (2004) have shown that a significant percentage of autism patients had elevations in antibodies against gliadin and cerebellar peptides simultaneously, indicating that a subgroup of patients with autism produce antibodies against Purkinje cells and gliadin peptides, which may be responsible for some of the neurological symptoms in autism.

During the last decade there has been seen an increase in autism and ADHD. Recent figures indicate that 0.5 % of the population suffers from autism and as much as 5 % have ADHD.  This means that about 30-40 million people have one of these diagnosis in Europe and the United States.


Dietary peptides 

Proteins in the food, digested by enzymes acting in the stomach and small intestine, give rise to a large number of peptides. A considerable fraction of such digested peptides are taken up in the upper part of the small intestine and may reach the blood stream and other tissues of the body (Gardner ML, 1994).

The majority of the peptides produced in this digestive process have no bioactivity and are not harmful to humans. However, some of  the peptides produced have be shown to have biologic effects. The “opioid excess” theory suggests that excess dietary peptides with opioid (morphin like) activity occur in elevated levels in autistic individuals, and may reach the brain and affect neurotransmitters and thereby causing certain symptoms. This has been linked to a suboptimal peptidase activity in the gut, leading to reduced breakdown of peptides (Reichelt).

In inflammatory states of the gut, the permeability is increased, and larger amounts of intact peptides and proteins reach the blood stream. This seems to be the case in autism, celiac disease, inflammatory bowel disease, rheumatoid artritis, and possibly more, where antigenic peptides reach suceptible tissues and drive a pathological process.

Recent observations indicate that gluten derived as well as milk derived peptides may trigger an autoimmune process in autistic children. This seems to involve protein mimicry (?) and seem to invoke production of antibodies to various peptidases, thus further reducing the breakdown the opioid peptides (Vojdani et al 2004). Finally, it is generally held that immunological reactions to proteins and peptides plays an important role in human allergic diseases. The goal for our probiotic product is to eliminate harmful peptides in individuals reacting adversly to such peptides.


Dietary interventions and use of probiotics in autism

Both clinical studies, and a large number of parent reports, show that dietary restrictition of gluten and casein may lead to considerable improvement in the ASD and ADHD children. This supports the role of such dietary peptides in autism spectrum disorders. Furthermore, there is accumulating evidence for a disturbance of the microbial flora in autistic individuals, with an overgrowth of clostridial species. Such disturbances may be corrected by giving probiotic bacteria that can eliminate pathogenic peptides and normalise the gut flora.

Our newly invented probiotic product offers a possible solution both to increase the breakdown of unwanted peptides and to normalise the gastrointestinal flora.


Biochemistry of gluten and casein derived exorphins

Exorphins is a class of biologically active short peptides that are produced enzymatically from gluten or casein proteins in the gut during digestion. These peptides, which are 4-8 amino acids long, have opioid activity and are relatively specific for d-receptors. Some representative gluten exorphins have the following amino acid sequence:

Exorphin A5: Gly-Tyr-Tyr-Pro-Thr 
Exorphin B5: Tyr-Gly-Gly-Trp-Leu 
Exorphin C:  Tyr-Pro-Ile-Ser-Leu 
Gliadorphin: Tyr-Pro-Gln-Pro-Gln-Pro-Phe

During the last decade it has also been demonstrated that peptide sequences derived from incomplete catabolism of milk proteins have opioid activity. Caseins degrade to peptides with 3-20 amino acids, some of which have opioid activity and are termed casomorphins. Representative examples of the amino acid sequence of some casomorphins:

b-casomorphin 1-7: Tyr-Pro-Phe-Pro-Gly-Pro-Ile 
b-casomorphin 1-5: Tyr-Pro-Phe-Pro-Gly 
b-casomorphin 1-4 amide: Tyr-Pro-Phe-Pro-NH2

Furthermore, Wakefield has recently found a relation between ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in a group of children. Reichelt  have demonstrated increased peptide excretion in autistic individals as well as in schizophrenia and celiac disease. Accordingly, the findings of gluten derived exorphins in the urine of patients with schizophrenia, autism and mood disorders suggest a causal relation, further supported by dietary experiments.

Intact peptides can be absorbed from the small bowel, transported by the blood and reach the brain. In normal individuals peptides are rapidly broken down in the blood, and only small amounts of peptides are found in the urine. However, hyperpeptiduria, i.e. increased concentration of peptides in the urine, is regularly found in autism, schizophrenia and major depressive disorders.

Other gut-derived substances may also be involved in the development of such diseases. Paul Shattocks group at Sunderland has found that indolyl-acryloylglycin (IAG) is present in elevated levels the urine of autistic children. Friedman has demonstrated  the presence of the nonhuman peptide dermorphin in urines of autistic children. This is a peptide that contain a D-amino acid in position 3 and which is rather resistant to enzymatic hydrolysis.



Marti T, Molberg O, Li Q, Gray GM, Khosla C, Sollid LM, Pharmacol Exp Ther. 2004 sep 9; [Epub ahead of print PropylEndopeptidase Mediated Destructio of T Cell Epitopes in Whole Gluten - Chemical and Immunological Characterization.

Bull G, Shattock P, Whiteley P, Anderson R, Groundwater PW, Lough JW, Lees G.Indolyl-3-acryloylglycine (IAG) is a putative diagnostic urinary marker for autism spectrum disorders. Med Sci Monit. 2003 Oct;9(10): CR422-5.

Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N, Cooper EL. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, Murch SH. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry. 2002;7(4):375-82, 334.

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