Dr. Reichelt has been researching the impact of gluten intolerance on certain individuals with developmental delays. Much of the following is from the CELIAC@SJUVM.STJOHNS.EDU mailing list. It is copyright Michael Jones, Jim Lyles, Lisa Lewis, Evan Hunt, 1994-6 - All rights reserved worldwide.

Subject: Intolerance to food proteins

There are several different types of intolerance. Coeliac disease is one where certain peptides from gliadin and gluten are toxic to the gut mucosa due to lack of break down. Usually these people have certain Major histocompatability genes or surface molecules on cells that bind peptides. They show IgA often IgG antibodies to gluten and gliadin as well as endomycium antibodies. (ref to peptides Wieser et al (1984) lebensmittelundersuch. Forsh. 79:3371-1176), Cornell (1988) Clin Chim Acta 176:279-229.)

It is especially important to stay on diet confirmed by biopsy because of certain malignant lymphomas that may develop especially in symptom free coeliac disease (not all get diarrhroea), as well as certain types of epilepsy (Gobbi et al (1992) The Lancet 340:439-443). IgA and endomycium bodies together may make biopsies superfluous, but as of today, biopsies are probably necessary.

The other type of intolerance is due to psychoactive peptides formed in the gut such as exorphins (Opioids formed in the gut). Especially important are casein, gliadin and gluten. Also intact proteins are taken up from the gut postprandially [after meals] Husby et al (1985) Scand J Immunol 22:83-92. Although little (2-5 nanomles per ml blood) insufficient break-down may end in peptide build up over time with psychoactive effects. More than the expected number of psychotic patients have specific IgA antibodies increase but not endomycium antibodies. There are 15 opioid sequences in one molecule of gluten as found by Prof Yoshikawa, Japan. It is easy to see that this may develop into a problem if the breakdown is insufficient of inhibited.

Cheers
Tiny

Subject: Diet and mental disease

Christie Lundy asked:

>I would be interested on more information and/or references
>concerning psychoactive peptides formed in the gut. I remember
>studies done in the 70's that indicated patients diagnosed
>with schizophrenia as having a high incidence of celiac sprue and
>responding (at least in part) to a gluten and milk-free diet, but later
>studies failed to reproduce the same results. The recently
>posted message from Dr. Reichelt seems to indicate that current studies
>are making a connection between some forms of food intolerance
>and some forms of psychiatric disorders. I have read that Western
>Ireland has a high incidence of both celiac sprue and schizophrenia.
>Specifically, I would be like to know how the exorphins are formed
>and leave the gut. Wouldn't the liver act in a defensive manner
>destroying the exorphins before they would be able to act on other
>organisms such as the brain? Also, how is the brain effected by
>exorphins? Are current theories suggesting that a build-up of
>exorphins is responsible for the psychosis of some patients?

Due to epidemiology Prof Dohan, Philadelphia proposed that there was a clearcut connection of gluten to schizophrenia (Dohan et al (1984) Biol Psychiat 19:385-399; Dohan (1983) Biol psychiat 18:561-564). See also Lorenz K (1990) Adv in Cereal Sci and Technol X:435-469. The effect of diet takes a long time because the kidneys are very well adapted to preserve peptides and proteins. We found that it took 28 weeks of strict diet to normalize the urinary excretion of peptides in a double blind study of diet followed with urine analysis and rating scales (Reichelt et al (1990) J Orthomol Med 5:223-239). Most experiments on diet have been far too short in time, but even then all admit to individuals being much improved on diet although not statistically for the group (Rice JR et al (1978) Amer J psychiat 135:1417-1148; Storms LH et al (1982) Arch Gen Psychiat 39:323-327; NB: Vlissides DN et al (1986) Brit J Psychiat 148:441-452)

The low number partaking in the experiments have been criticized (King DS (1985) Biol Psychiat 20:785-787.). Clearcut effect of diet in schizophrenia was found by a) Dohan and Grasberger (1973) Am J Psychiat 130:685-686: Singh and Kay (1976) Science 191:401-402; Cade R et al (1990) Psychiatry: A world perspective 3:494-500 (he uses our urine screening too).

In autistic children we have very good results as documented with STRICT diet (Knivsberg SA-M et al (1990) Brain Dysfunct 3:315-327 and also Reichelt Klet al (1991) Brain Dysfunct 4:308-319). In the last publication evidence for the identification of bovine casomorphin 1-8 immunoreactive peptides was reported, and opioids are formed from food proteins in the gut. Also extremely important is the fact that everybody takes up bioactive peptides and also trace amounts of protein from the gut (Gardner MLG (1994) in Physiology of the gastrointestinal tract (Johnson LR : edit) Rave Press, NY pp 1795-1820), That this is so can be seen from the fact that we all have IgG antgibodies to food proteins. Because there are 15 opioid sequences in one molecule of gluten (Fukudome and Yoshokawa (1991) Febs lett 296:107-111) even trace amount so protein uptake can be catastsrophic if not properly broken down.

In general we also find increased IgA antibody levels in schizophrenics (Reichelt et al in press) and usually peptide increased in the urine. The problem is usually that diet is tried as a last resort, and because there are strong indications that opioids inhibit the normal maturation of the CNS (Zagon and Mclaughlin (1987) Brain Res 412:66-72) it is no wonder that we often are too late or that it takes time to change the course of the disease. NMR studies are quite clear that trophic changes do take place. The opioids do get in the CNS as in Post partum psychosis, which is a dramatic and symptom rich psychosis (Lindstr|m et al 1984) Amer J Psychiat 141:1059-1066)

Diet is however, not easy and may be experiences as a socially isolating procedure. It must also be strict. Finally the opioids make it difficult to quit the food in question as in all addictive states. More details can be obtained by writing me directly. Cheers
TINY

Subject: Diet

The only certainly established peptide problem so far is gliadin, gluten and casein. However, people can be allergic (IgE mediated) to almost anything. Opioids may also be formed from hemoglobin (hemoceptins) so I guess it is better not to consume blood products.

For autistic children and schizophrenics it is best to stick with gluten, gliadin and casein, because that is what we have studied. After all we all need proteins of some sort to develop normally and it is important to warn against overenthusiastic slashing of this and that in an arbitrary way. Growth is a good variable to monitor adequate nutrition.

There should always be a postive identifiable reason for removing any item from the diet and preferably some scientific evidence. Children all the way up to puberty are quite adaptable in their CNS and two year olds definitely so.

Kalle Reichelt has just returned from an extended trip and in reviewing the earlier posts to this conference on proteins, peptides, gut permeability, autism and schizophrenia, has the following comments to offer:

Subject: Gluten, autism and schizophrenia

A: Experiments double blind with gluten and schizophrenia: Most have been on far too small series and for very short time. We found in a double blind study that the peptide patterns took at least 28 weeks to normalize Reichelt et al (1990) J Orthomolec. med 5:223-239.)

Also two positive studies have been reported 1) Singh MM and Kay SR (1976) Science 191:401-402.2) Dohan FC and Grasberger JC (1973) Amer J Psychiat 130:685-686. Several negative statistically evaluated reports (on small series) generally however, describe individuals that respond favourably. They were for short periods of time though and on chronic or semichronic patients. In these patients we know that there are morphological changes in the CNS. The references are: Potkin SG et al (1981) Am J Psychiat 138:1208-1211. Storms LH et al (1982) Arch gen Psychiat 9:323-327. Vlissides DN et al (1986) Brit J psychiat 148:441-452. Rice JR et al (1978) Am J Psychiat 135:1147-1148. All of these have been criticized for lack of statistical power (King DS (1985) Biol Psychiat 20:785-787.)

Double blind on autistic children is very hard to do. Howver,we have run the urines blind and applied the strategy of two independent persons to carry out functional tests and evaluation. The results cannot possibly be placebo because they last for 4 years and those that quit diet show REGRESSION. In spite of ordaining longer time to complete the tests the children off diet could not complete tests easily finished when on diet. References: Knivsberg A-M et al (1990) Brain Dysfunction 3:315-327. Reichelt KL et al (1990) J Appl Nutrition 42:1-11. Reichelt KL et al (1994) Dev Brain Dysfunct. 7:71-85.

Epidemiology: I would like to draw your attention to two papers that are extremely well done: Lorenz K and Lee VA (1977) The nutritional and physiological impact of cereal products in human nutrition. CRC Critical Reviews in Food Sci and Nutrition 9:383-457. Lorenz K (1990) Cereals and Schizophrenia. Adv in Cereal Sci and Technol X: 435-469.

Gut permeability: Because peptides (Gardner MLG(83) Biochem Soc Trans 11:810-812. and this year a review, and also intact proteins are taken up in normal persons (eg Husby S et al (1985) Scand J Immunol 22:83-92); there is no need for increased uptake. All we need is decreased breakdown, something which regularly causes peptiduria and peptidaemia (Wright EC et al (1979) J Inherit metab Disease 2:1-3; BlauN et al (1980) J Inherit metab Dis 11 (suppl 2) 240-242.; Lunde H et al (1982) J neurochem 38:238-246; Abassi Z et al (1992) metabolism 41:683-685; Watanabe Y et al (1993) Res Comm. Chem Pathol Pharmacol 81:323-350.)

Because peptides generally are good peptidase inhibitors (La Bella FL et al (1985) Peptides 6:645-660) it is easy to see that vicious circles can get going. This process may even start before birth because intact antigens have been found in mothers milk too (Axelsson I et al (1986) Acta Paed Scand 75:702-707; Troncone R et al (1987) Acta paed Scand 76:453-456; Kilshaw and Cant 81984) Int Arch Allergy Appl Immunol 75:8-15 and Stuart CA et al (1984) Clin Allergy 14:533-535).

Finally I would like to draw your attention to the fact that the coeliac inducing peptide isolated from gliadin (Wieser H et al (1984) Z Lebensmittel Unters Forsch 179:371-376 contains the gliadinomorphin sequence Y-P-Q-P-Q-P-F. Also the gluten molecule contains up to 15 opioid sequnces brilliantly elucidated by Prof DR Yoshikawa (Fukudome SI and Yoshikawa M (1991) FEBS Letters 296:107-111) and such opioids are formed in the gut.

Some references on gut leakage and schizophrenia will be forwarded later. However, Dr Sci MLG Gardner, School of Biomediacl Sci. Univ of Bradford, Bradford BD 7 1DP, United Kingdom is extremely knowledgeable on this matter.

Seasonal greeting to all. Cheers

Tiny.

Subject: Autism and coeliac disease.

1: Already Prof Asperger in Austria noticed that many (not all) coeliac children showed psychiatric problems (Asperger H (1961) Die Psychopathologie des Coeliakikranken Kindes. Ann. Paediat.197:146-151). A similar relationship of malabsorption to autism was also indicated in the USA (Coleman M ed: Autistic syndromes. North Holland Press, Amsterdam 1976.) See also Goodwin MS et al (1971) J Autism Child Schizophrenia 1:48-62.

Coeliac disease may go undetected until lyphoma is discovered. It is relevant that one of the dominant symptoms is depression (carried out in Sweden) (eg Hallert C et al (1982) Scand J gastroenterol 17:25-28.)

2: Because we have a) isolated bovine casomorphin 1-8 immunoreactive peptides from the urine and dialysis fluid of schizophrenics and autistics (eg Reichelt KL et al (1991) Brain Dysfunction 4:308-319) and also find an increased frequency of IgA antibodies higher than the upper normal limit (Reichelt et al (1994) Dev Brain Dysfunction 7:71-85; Reichelt and Landmark (1994) Biol Psychiat In press), there is reason to believe that opioids from the diet are important. The mucosa is normal in these cases as are endomycium antibodies.

3: The structure of gliadinomorphin is Y-P-Q-P-Q-P-F and is found inside Wieser s peptide causing coeliac disease. The structure of casomorphin (bovine) is very similar: Y-P-F-P-G-P-I. We have recently found evidence for gliadinomorphin too (in prep).

4: Opioids may very well be important to the development of autism because they modulate trophically CNS development (Zagon and McLaughlin (1987) Brain Res 412:68-72; Zagon and McLaughlin (1989) Brain Res 490:14-25). Also the psychophysiological work of Panksepp is extremely important and relevant to this problem (eg Panksepp L et al (1980) neurosci Biobehav Rev 4:473-487). The pruning of synapses which is essential to normal development is likewise disturbed by opioids.

5. Certain epilepsies and CNS damage of various kinds can be related to factors derived from gluten in spite of normal vitamin levels .See for instance Gobbi G et al (1992) The Lancet 340:439-443; Paul KD et al (1985) Z Klin Med 40:707-709; Cooke WT et al (1966) Brain 89:683-722; Ward ME et al (1985) Neurology 35:1199-1201; Kinney HC et al (1982) J neurol Sci 5:9-22; Finelli PF et al (1980) Neurology 30:245-249).

6. The important genetic studies done by Sir M Rutter and his crew indicates that at least two (2) genetic defects must be present. (Le Cotour A (1988) Aspects of Autism. Edit:L Wing, gaskell, The nat Aut Soc pp 38-52). It is therefore probable that either two peptidase defects (Reichelt et al (1994) Dev brain Dysfunct 7:71-85) or a peptidase defect combined with sulphation defect as suggested by Prof Dr R Waring could be the root cause.(Waring and Reichelt; in press). After all defective transulphation would cause defects in aminoglycans lining the gut wall and therefore increase transmucosal transport or diffusion as shown in certain dieased states (Murch SH et al (1993) The Lancet 341:711-714). Certainly gut uptake of various compounds should be performed as soon as possible in these diseases.

7: Dr Sci MLG Gardner, Univ of Bradford School of Biomed Sci is an authority on the gut and various uptake mechanisms. His fax no is - 0274 309 742 England.

8.: In post-partum psychosis, which is one of the most vivid psychotic conditions known, the Swedes have shown that human casomorphin is the mediator and accumulates in blood, spinal fluid and urine. (Lindstrom L et al (1984) Am J Psychiat 141:1059-1066.) Human casomorphin is present as a family of peptides and has the structure Y-P-F-V-E-P-I-P and exists as 1-8,1-7,1-6 etc. It has long been known that stopping milk production fast (before receptor changes take place) eleviates the psychotic condition .

9: There is going to be a very technical and basic meeting on the relationship of gluten to disease especially epilepsy in San Marino (a small independent country inside Italy) April 10-12 1985. The registration is in the hands of: San marino Conference c/o Ufficio Attivita promozionali Instituto Sicurezza Sociale, Via la Toscana -Cailungo 47031 Republica San Marino.

Cheers

Tiny

Subject: Intestinal permeability in schizophrenia

The data on this are conflicting and have been studies using different techniques.

1: Wood NC et al (1987) Brit J Psychiat 150:853-856 used the cellobiose/mannitol test and found increased permeability in chronic schizophrenics in 11 out of 32 patients.

2: Lambert MT et al (1989) Brit J Psychiat 155,619-622.: used Chromium labelled EDTA and found no difference in 12 schizophrenic patients, 12 patients in remission and normals.

3. We do however, all take up trace amounts of intact protein after a meal (see eg. Husby S et al (1985) Scand J Immunol 22:83-92) so that a decreased breakdown of fragments of these proteins could easily lead to accumulation. One molecule of gluten contains 15 opioid sequences (Fukudome and Yoshikawa (1991) FEBS Letters 296:107-111) and even 2.5 nanomoles of protein per ml blood could therefore cause an "avalanche" of peptides being formed. The more so because peptidase defects regularly cause peptiduria (Watanabe Y et al (1993) Res Comm Chem Pathol Pharmacol 81:323-350; Abassi Z et al (1992) metabolism 41:683-685; Blau N et al (1980) J Inherit metab Dis 11 (Suppl 2) 240-242). Peptidura is of course a sign of hyperpeptidaemia. We do not really need increased uptake to get into trouble although that would accelerate the process and if sufficiently large it could overwhelm even normal breakdown capacity. That there is gut to blood to mother milk transport of intact food proteins is illustrated by papers where intact antigens were found in mothers milk (Axellson I et al (1986) Acta paed Scand 75:702-707; Kilshaw PJ and Cant AJ (1984) Int Arch Allergy Appl Immunol 75:8-15; Troncone R et al (1987) Acta paed Scand 76:453-456; Stuart CA et al (1984) Clin Allergy 14:533-535)

4. We all have IgG antibodies to food proteins indicating uptake of immunologically active proteins in trace quantities. In schizophrenia IgG antibody increases against gluten have been reported (Dohan FC et al (1972) Biol Psychiat 5:127-131; Hekkens W Th et al (1980) in Biochemistry of schizophrenia and Addiction (edit: Hemmings G) Lancaster, MTP press; Rix KJB et al (1985) PSYCHOL MED 15:347-354). Increased IgE antibodies to food proteins were also found in schizophrenics (Sugerman AA et al (1982) Annal Allergy 48:166-171). Ashkenazi A et al (1979) Amer J psychiat 136:1306-1309: found that leukocytes reacted to a fraction of gluten in a fashion intermediate between coeliac disease and normal controls.

Finally we have (Reichelt Kl and Landmark J (1994) Biol psychiat: in press) found IgA antibody increases in schizophrenics diagnosed after DSM III and sex and age matched controls. These IgA antibodies were mainly against gliadin, gluten, lactoglobulin and casein.

Unfortunately it is extremely difficult to finance research into diet and psychoses. Neuropharmacology has become very dominant for obvious reasons . The dismal state of the patients and their social integration in many cases clearly makes more research an urgent matter Cheers

TINY

Dr. Kalle Reichelt, a Norweigan researcher,has cited several articles as evidence that dietary proteins in general, and gluten/gliadin specifically, can be transfered to a breast-fed baby:

The following is from a post written by Reichelt to another internet discussion group:

>...food proteins can be demonstrated in mothers milk (3-6) as intact
> proteins. This could easily therefore take place also during pregnancy.

>3: Kilshaw PJ and Cant AJ (1984) The passage of maternal dietary
> protein into human breast milk. Int Arch Allergy and Appl
>Immunol 75: 8-15.

>4: Axelsson I, Jacobsson I, Lindberg T, and Benediktsson B (1986)
> Bovine lactoglobulin in human milk .Acta Paed Scand 75: 702-707.

>5: Stuart CA, Twiselton R, Nicholas M and Hide DW (1984) Passage
> of cow s milk protein in breast milk .Clin Allergy 14:533-535.

> 6:Troncone R, Scarcella A, Donatiello A, Cannataro P, Tarabusco A and
> Auricchio S (1987) passage of gliadin into human breast milk .
> Acta paed Scand 76: 453-456.

>From Dr. Reichelt in reply to my post yesterday, in which I wondered whether the amounts of gluten in mother's milk is significant:

Subject: Trace amount of protein in milk.

Hi.
It should be stressed that the amount are small. However, the point is that even trace amounts can be important because if the proteins are not properly broken down peptides will accumulate. After all the uptake of proteins from the gut into blood has also been demonstrated: Husby et al (1985) passage of undegraded dietary antigen into the blood of healthy adults. Scand j Immunol 22: 83-92.

Other references in brief : Bloch KJ et al (1979) gastroenterology 77:1039-1044. Thomas et al (1974) Immunology 27:631-639. Walker WA et al (1974) gastroenterol 67: 531-550.

Because gluten contains at least 15 opioid sequences per molecule (Fukudodme S-I and Yoshikawa M (1991) Opioid peptides derived from wheat gluten: Their isolation and characterization. FEBS Letters 296:107-111.) It is therefore clear that one molecule could theoretically give 15 opioids. This means that trace amount of peptide could quickly become very important. Cheers
Tiny

Subject: Diet and mental disease.

Ratatat wrote in reply to the letter above (by the same subject):

>I read somewhere the the French Revolution was blamed on temporary mass
>schizophrenia brought on by the gluten in the bread that the peasants ate
>- some sort of fungus that had grown in it due to poor storage.

Hi.
The big threat to grain eaters in Europe used to be alkaloids from certain fungal toxins in grains collectively known as ergot alkaloids and ergotamines. They cause epidemics of peripheral gangrene of the limbs. I do not have any data on schizophrenia in this context, although ergot alkaloids have been used to treat migraines and enhance delivery in obstetrics. In much of the balkans they also have fungal toxins that cause kidney and liver problems. (This is found in most countries where modern antifungal spraying is not economically feasible). Also in periods of starvation (esp war) Lathyrism caused by neurotoxin from chickling peas is well known.

However, there is a precedent for excitotoxic amino acid like compounds from food causing Central nervous disease in certain pacific islands such as Guam with vastly increased incidence. The Chamorros of the marianas and micronesia ate the seed of a false sago plant Cycas Circinnalis, from which the compound beta-N Oxalamio-L -alanine could be isolated. This causes amyotrophic lateral scelerosis, parkinsonism and Alzheimer -type dementia with considerable frequency (1,2)

References:
1: Lewin R (1987) Environmental hypothesis for brain diseases strengthened by new data. Science 237:483-484.
2: Spencer PS et al (1987) Guam amyotrophic lateral Sclerosis
-Parkinsonism
-Dementia linked to a plant excitant neurotoxin.Science 237:517-522.

All the best. Cheers

Tiny.

Subject: ADDHA.

Hi.
Just a few references to diet and hyperactivity syndrome.
1: Egger J et al (1985) Controlled oligoantigenic treatment of the hyperkinetic syndrome. The Lancet. March 9th :540-544.
2: Kaplan SJ et al (1989) Dietary replacement in preschool-aged hyperactive boys. Pediatrics 83:7-17.
3: Egger J et al (1992) Controlled trial of hyposensitisation with food-induced hyperkinetic syndrome. The Lancet 339:1150-1153.
4: Carter CM et al (1993) Effects of a few food diet in attention deficit disorder. Arch Dis Child 69:564-568.
5: Marshall (1989) Attention deficit disorder and allergy: A neurochemical model of the relationship between illnesses. Psychol Bulletin 106: 434-446. Furthermore high intake of low roughage (purified) carbohydrates cause rapid increases in blood sugar followed by rapid insulin increase and subsequent steep fall. This is prevented by high fiber additions concomitant with carbohydrate intake. It is possible to have an overshoot with postprandial hypoglycemia. This is more common in habitually violent offenders in Finland. Virkkunen M (1982)) Reactive hypoglycemia tendency among habitually violent offenders. Neuropsychopharmacol 8:35-40.

Finally we have found peptide increases (possibly phosphorylated/glycosylated?) in Hyperkinesia. (Hole K et al (1988) Attention deficit disorders: A study of peptide-containing urinary complexes. J develop behav Pediatrics. 9:205-212.).

It should also be noted that concentrated glucose can increase the paracellular uptake in the gut. That is also more protein and peptides can be taken up.

Ref: Pappenheimer JR and Madara JL (1993) Role of active transport in regulation of junctional permeability and paracellular absorption of nutrients by intestinal epithelia. in Istonic transport in leaky Epithelia (Alfred benzen Symposium) Munksgaard, Copenhagen: pp 221-232.

Hope this may be of some use to at least some parents.

Cheers
Tiny

Subject: Schizophrenia and diet

On 20 Jun 1995, Stephen Ronan (sbr@world.std.com) wrote:
Re: Schizophrenia

>Gayle Kennedy wrote:
>>[...]
>> confusion and irrational anger, I keep wondering if the celiac diet would
>> be of any use to persons with schizophrenic symptoms....
>
>As far as I know the first person to suggest a possible link between
>schizophrenia (or a subset thereof) and gluten consumption was Dr. F.
>Curtis Dohan. Dohan graduated from medical school of the University of
>Pennsylvania in 1932. He was chief of the endocrine section of the William
>Pepper Laboratory at Penn from 1947 to 1966 and served on the medical
>faculty until 1975. About twenty-five years after first presenting his
>hypothesis, Dohan died in November 1991.
>
>"'The day before he died, we got a paper from a scientist in Norway,
>_Evidence and Arguments for Schizophrenia as a Dietary Disease_ and it was
>the last thing I read to him' said his wife Marie. That night, she got as
>far as Page 5. He died the following morning." (Philadelphia Inquirer, Nov
>14, 1991).
>
>I presume the Norwegian scientist was Dr. Kalle Reichelt...
>(Dr. Reichelt, incidentally, has given permission for his postings to be
>freely redistributed.) We are fortunate that he is pursuing his research
>regarding gluten, since NIMH has largely neglected this approach ever
>since conducting a rather minor intramural study of 8 patients about 15
>years ago (Potkin et al).
>
>The gluten apparently implicated in a subset of schizophrenia is protein
>found in the cereal grains wheat, rye, barley and oats.
>
>When some other people eat this gluten, the little, finger-like villi (that
>stick up from the inner walls of the small intestine, and wave around, and
>absorb food) get severely flattened and damaged and therefore cannot
>absorb food normally. It is not well understood how exactly the gluten
>causes the damage.
>
>People with that particular type of reaction to gluten are diagnosed as
>having something called celiac syndrome. A malabsorption of food with
>symptoms of diarrhea and fatty stools, and failure to thrive and grow at
>normal rates are often the symptoms first noticed in children with celiac
>syndrome. Fairly often doctors miss the diagnosis. When successfully
>diagnosed, people with celiac syndrome are advised to eliminate all gluten
>and dairy from their diets and when they do so, it is usually the case
>that the villi in their small intestine recover and their digestion
>normalizes.
>
>In the 1960's, F. Curtis Dohan MD came to believe that in regions where
>gluten consumption is common, the rate not only of celiac syndrome but
>also schizophrenia is substantially higher than in places where gluten
>consumption is absent (e.g., where people rely on sweet potato, rice or
>millet rather than wheat, rye, barley or oats).
>
>Subsequent research, including experiments by others involving biopsies,
>led Dohan to conclude that people diagnosed as schizophrenic did _not_
>typically have the same reaction to gluten as people with celiac syndrome.
>They did not have the same type of damage to the villi of the small
>intestine. He thought that the genetic basis might be related but
>different. He eventually came to believe that a gluten-sensitive subset of
>schizophrenics were processing gluten and the casein in dairy foods in a
>way that exposed their brains to certain very potent psychoactive
>substances that are now known to exist in those foods.
>
>In his initial published clinical trial, at a V.A. hospital, Dohan tried
>removing gluten and dairy from the diets of people diagnosed as
>schizophrenic while they were on a locked admitting ward. They went back
>on a regular gluten-containing diet once they moved to the open wards. Of
>those on the gluten-free diet on the locked ward, 80% were on that ward
>and the gluten-free diet for 10 days or less.
>
>Other people diagnosed as schizophrenic who went through the same wards
>were kept on a high-gluten diet while on the locked ward instead of a
>gluten- and dairy-free diet.
>
>The people at the V.A. hospital who were on the gluten-free diet while on
>the locked ward were discharged almost twice as quickly as those who were
>on the high-gluten diet. "The average time until discharge for the
>discharged CFMF [cereal-free, milk-free] patients (77 days) was 55 percent
>of that of the discharged HC [high cereal] patients (139 days)."
>
>The abstract of Dohan's article about this research read as follows (Am J
>Psychiatry 130:6 June 1973):
>
>"Routinely treated schizophrenics, who on admission were randomly assigned
>to a diet free of cereal grains and milk while on the locked ward, were
>discharged from the hospital about twice as rapidly as control patients
>assigned to a high-cereal diet. Wheat gluten secretly added to the
>cereal-free diet abolished this effect..."
>
>Dohan's study involved about 110 subjects, roughly half of whom were on
>the CFMF diet for at least a short while. As I recall (and I'm not
>positive), Dohan himself was not 'blind' to who was getting each diet,
>though facility staff were.
>
>Subsequently, Singh and Kay conducted a study that was reported in Science
>in January, 1976. Their article's abstract stated: "Schizophrenics
>maintained on a cereal grain-free and milk-free diet and receiving optimal
>treatment with neuroleptics showed an interruption or reversal of their
>therapeutic progress during a period of 'blind' wheat gluten challenge.
>The exacerbation of the disease process was not due to variations in
>neuroleptic doses. After termination of the gluten challenge, the course
>of improvement was reinstated. The observed effects seemed to be due to a
>primary schizophrenia-promoting effect of wheat gluten."
>
>In the Singh/Kay study, "Three of the patients were diagnosed as paranoid,
>four as catatonic, and seven as hebephrenic schizophrenics." [BTW, my
>impression has been that that people whose symptoms include very high
>levels of muscular tension (catatonia) and a giddy silliness (once known
>as hebephrenia) have tended to be most likely of all to improve via
>gluten-free diets. Then again, that info may be of limited value since the
>medicines typically used these days interrupt or preclude much catatonic
>symptomatology and the "hebephrenic" diagnosis disappeared.]
>
>As reported in the American Journal of Psychiatry 135: 1417-1418, 1978,
>Rice et al. began a study with 21 patients diagnosed as schizophrenic (5
>schizo-affective, 11 paranoid, and 5 chronic undifferentiated type). Five
>patients dropped out. The 16 patients who completed the study had a mean
>of 9 years of hospitalization and a mean age of 38.
>
>Potkin et al. (see below) cited the Rice study as involving: "16
>chronic schizophrenic patients treated with neuroleptics who were on a
>normal diet and challenged with gluten and subsequently were on a
>gluten-free, milk-free diet. In this study, 1 patient, who had been
>hospitalized for 14 years, became more agitated, uncooperative, and
>paranoid with the gluten load. This patient and another patient, who had
>been hospitalized for 13 years, substantially improved on the gluten-free
>diet. The latter patient improved to the degree that she could be
>discharged to the care of her family." No similar gains from a gluten-free
>diet were found among others in the study.
>
>In Am. J. Psychiatry 138:9, September 1981 Potkin et al. reported on their
>own experiment, which involved 8 patients "3 were subcategorized as
>being paranoid and 5 as chronic undifferentiated" (pg. 1209). These people
>were provided a relatively high-gluten diet for a month or two and a
>gluten- and dairy-free diet for two or three months, with their condition
>in the final two weeks of each of these periods compared. No significant
>difference in symptoms during the two diets was found.
>
>NIMH lost interest. Hope you haven't and don't...
>
>Steve Ronan

Hi.
I would like to draw your attention to a wee paper from us (1) on diet and schizophrenia, where we followed completely blind 10 semichronic (not the best starting point) male schizophrenics for 1 year. We could conclude:

a) That both urinary peptide excretion and rating scales (Comprehensive Psychopathological rating scale and Whitaker Index of schizophrenic thinking) as well as clinical state improved slowly on diet, with regression in those off. This was a crossover study.

b) It is not unreasonable that changes will be slow because the kidneys are efficient peptide, amino acid and protein preserving organs.

c) The trophic changes in brain in schizophrenia established macroscopically and microscopically in a great many publications the last 10 years, would take time to correct if at all possible. Probably not completely being maturational defects to some extent (2). There is also the problem of an optimal timing for maturation of nerve cells as demonstrated in the visual cortex. This means that experiments on chronic cases is a poor way to test the hypothesis. Fairly fresh cases would be ideal.

We have recently been able to demonstrate the presence of at least 5 (five) peptides with opioid activity in urines and dialysis fluid from schizophrenics that react to antibodies against bovine casomorphin 1-8. One of these cochromatographs and has the same amino acid composition as bovine casomorphin 1-8. (Reichelt submitted; as in autists (3)). The very fulminant psychosis seen in post-partum psychosis seems to be mediated by human casomorphin (4) and demonstrates that such peptides do have access to the Central nervous system (CNS).

Furthermore IgA antibodies against gliadin, beta-lactoglobulin and casein are increased in male schizophrenics (5) indicating a connection. NB: The biopsies were normal so that this is not coeliac disease, but a state with increased transmucosal protein/peptide transport. After all uptake in small amounts of intact protein and peptides is well documented (see earlier communications)

WE think therefore that it is important to be gluten/gliadin free and milk protein free if diet is to be used. The more so because gliadinomorphin and casomorphin are very similar and gliadinomorphin is part of the coeliac disease peptide B3142(6)
Gliadinomorphin : Y-P-Q-P-Q-P-F
Casomorphin(b) Y-P-F-P-G-P-I etc.

There are a series of gluten derived opioids too. This is one of the reasons why we remove both protein sources in autistic syndromes too (2,7,8) with again long term but clearly measurable effects and regression in all who quit diet.

The paper that was read to Dohan has been changed to: Can schizophrenia be reasonably explained by Dohan's hypothesis on genetic interaction with a dietary peptide overload? It is hard to get this published because it goes against the present trends. However, I think it extremely important so I keep trying (I am of course rather partial to the hypothesis which makes it difficult).

I find it remarkable that given the complete lack of aetiology directed treatment that a proper clinical trial should be so difficult to establish. After all also an American has published data along these lines (9) using our old urine screening assay. Our new technique based on Shattocks groups work in the UK but changed a little (Reichelt in prep) is of course available to anyone who is interested. It is fast and with fewer false positives. They are also welcome here to learn by doing. Finally it should be stressed that opioids do have maturation inhibitory effects in rat brain (10), which would fit Crows(2) data quite nicely.

References:
1: Reichelt KL et al (1990) The effect of a gluten free diet on glycoprotein associated urinary peptide excretion in schizophrenia J Ort Mrd 5: 223-239.
2: Crow T(1994) Aetiology of schizophrenia. Current Opin.Psychiat7: 39-42
3: Reichelt Kl et al (1991) The probable etiology and possible treatment of childhood autism. Brain Dysfunct. 4:308-319.
4: Lindstr|m LH et al (1984) CSF and plasma beta-casomorphin-like opioid peptides in post-partum psychosis. Amer.j psychiat. 141:1059-1066.
5: Reichelt Kl and Landmark J (1995) Specific IgA antibody increases in schizophrenia. J Biol Psychiat37:410-413.
6. Wieser H et al (1984) Amino-acid sequence of the coleiac active peptide B 3142. Z Lebensmittel Untersuch Forsch 79:3371-3376.
7: Knivsberg A-M et al (1990) Dietary intervention in autistic syndromes. Brain Dysfun. 3:315-327.
8: Knivbserg A-M et al (1995) Autistic syndromes and diet. A four year follow-up study of 15 subjects. Scand J Educat. Res: In press (accepted)
9: Cade R et al (1990) The effects of dialysis and diet in schizophrenia Psychiatry: A World prespective 3:494-500.
10: Zagon IS and Mclaughlin PJ (1987) Endogenous opioid systems regulate cell proliferation in the developing rat brain. Brain Res 412:68-72

Subject: Gluten, casein and behaviour

Jason Kennerly asked:

> - can gluten intolerance cause a forboding feeling that there is a
>'conspiracy' working against you or causes you support, obsessiveness, or
>lack of insight? Can it cause feelings of persecution, the sense that
>things somehow pertain to you or your close friends and reletives? Can it
>make someone display symptons of paranoid-type schizophrenia?

Hi.
It is of course very difficult to make follow the effect of gliadin, gluten and casein derived peptides and their specific effects on the brain. However, the fact that opioids from exogenous proteins can be isolated from patients (1,Reichelt et al submitted), and that other peptides found in urine and dialysis fluid from patients (2,3) also causes behavioural changes in animal models, makes it possible that paranoid ideation and persecutory feeling could well be human correlates of the behaviour changes noted in animals (2,3). We cannot do such experiments on humans although they have been carried out before the advent of ethical committees. Thus prof R Heath in New Orleans injected a serum prep on volunteering prisoners called tarexein. They definitely demonstrated schizoid behaviour. (I have seen the videos myself).

We have effect on schizophrenics on diet (blind) (4) which agrees with some publications (5,6) but not with others. I think the negative experiments were run for too short an interval. A dietary casein and gluten free diet would need 1/2 to one year to be certain. In autistic children we do also find a clearcut effect of diet run over 4 years (1). However, if it is correct that you drink tons of coffee, this could in itself be the cause. This is because caffeine act as a CNS stimulatory agent causing higher arousal which again makes you more introverted. If the doses are very large borderline conditions may develop and the world by seeming strange causes paranoid ideation to explain the changed perception of the world. See Prof Eysencks many paperbacks on psychology. Amphetamine has the same effect (bad trips) in introverted persons. In Hyperkinetic children where the attention related CNS centres show lower activation, they go from extreme extroversion and become normalized. Treating epileptic children with the drugs available often causes a iatrogenic hyperactivity (ADD) syndrome because of increased CNS inhibition. This is a clinical problem which is difficult but unavoidable.

References:
1:Reichelt Kl et al (1991) Brain Dysfunct. 4:308-319.
2:Hole K et al (1979) Neuroscience 4:1883-1893.
3:Drysdale A et al (1982) Neuroscience 7:1567-1574
4:Reichelt KL et al (1990) J Ortomol Med 5:223-239
5:Singh MM and Kay (1976) Science 191:401-402.
6:Vlissides DN et al (1986) Brit J psychiat 148:447-452 (some cases, not all)
Right now I do not have time for more references, but we can get back to that later.
All the best. Cheers

TINY

Subject: ear infections, allergy, autism & gluten

Jack Challem, Editor of The Nutrition Reporter (TM) newsletter, wrote:

>I'm sure you'll hear a lot of opinions. But I'll point to you to a
>specific journal citation that confirmed what people have been saying for
>years. The fundamental cause of ear infections is allergy, which causes fluid
>retention in the ear, which creates a great breeding ground for bacteria. The
>most common allergens for small children are milk and wheat.

>Nsouli TM, "Role of food allergy in serious otitis media," Annals of Allergy,
>September 1994;73:215-219.

This is quite interesting because the IgA antibodies formed in the gut are transported to all mucous membranes in the body and may react with appropriate antigens. Because intact antigens are taken up into the blood postprandially (1) and we have also demonstrated increased levels of IgA antibodies to gluten, gliadin and casein in some autistic patients (2,3); I can easily see a possible connection, where all mucosal membranes are irritated by the circulating antigen reacting with deposited IgA antibodies.

References:
1: Husby S et al (1985) Scand J Immunol 22:83-92.
2: Reichelt Kl et al (1990) J Applied Nutr. 42:1-11
3: Reichelt KL et al (1994) Develop Brain Dysfunct. 7:71-85

Subject: Behaviour and gluten

Hi

Classic works on autistic symptoms in coeliac disease have been published (1) and also depression (2). But of course not in all (is there ever something that applies to all?)

It is extremely relevant that we find very high IgA antibodies against food proteins in Downs syndrome (3). The effect of food proteins are also manifest from our data on diet and autism (4).

Furthermore a series of neurological conditions have been related to gluten intolerance. Thus spinocerebellar degeneration, neurological symptoms, cerebellar syndromes and degeneration of the CNS have all been implicated (5-8). Gluten provocation in young children with coeliac disease can cause long lasting EEG (Electroencephalographic) changes in spite of normal vitamin levels (9). In adults gluten intolerance, occipital calcifications and a parietal epilepsy have been found (10).

Finally it is important that proteins which contain many eg. exorphin sequences such as gluten where there are 15 per molecule (11), even trace amounts may cause problems when the break down is decreased or intestinal uptake increased swamping even normal digestive capacity. Animal model of extreme relevance because monoamine changes are similar to those described in human coeliac patients by Hallert (2) is that carried out in Canada by Thibeault (12). Cats usually do not eat gluten.

References:
1: Asperger H (1961) Die Psychopathologie des Coeliakiekranken Kindes. Ann Paediatr. 197:146-151.
2: Hallert C et al (1982) psychic disturbances in adult coeliac disease III.reduced central monoamine metabolism and signs of depression. Scand J Gastroenterol. 17:25-28.
3: Reichelt Kl et al (1994) Increased levels of antibodies to food proteins in Downs syndrome. Acta Paediat Japon. 36:489-492.
4: Reichelt Kl et al (1994) Nature and consequences of hyperpeptiduria amd bovine casomorphin found in autistic syndromes. Develop brain Dysfunct. 7:71-85.
5: Ward ME et al (1985) Celiac Disease and Spinocerebellar Degeneration with Normal Vitamin E status. Neurology 35:1199-1201.
6: Cooke WT et al (1966) Neurological disorders associated with adult coeliac disease. Brain 89:683-722.
7: Finelli PF et al (1980) Adult coeliac disease presenting as cerebellar syndrome. neurology 30:245-249.
8: Kinney HC et al (1982) Degeneration of the central nervous system associated with coeliac disease. J Neurol Sci 5:9-22.
9: Paul KD et al (1985) EEG-Befunde bei Zoeliakikrnaken Kinderen in Abh{ngigheit der Ern{hrung. Z Klin med 40:707-709.
10: Gobbi G et al (1992) Coeliac disease, epilepsy and cerebral calcifications. Lancet 340:439-443.
11: Fukudome Si and Yoshikawa M (1991) Opioid peptides derived from wheat gluten: their isolation and characterization. FEBS Lett 296:107-111.
12: Thibault L et al (1988) Changes in serum amino acids content and dopamine-beta-hydroxylase and brain neurotransmitter interaction in cats fed casein with and without gluten. J Clin Biochem Nutr. 4:209-221.
13: Zagon IS and McLaughlin PJ (1987) Endogenous opioid systems regulate mcell proliferation in the developing rat brain. Brain res 412:68-72

Conclusion: Because gluten can cause neurological problems it is not strange at all that it may also give behavioural problems. The opposite would be improbable.

We believe (4) that the mediators of these problems are peptides and specifically exorphins that do have inhibition of nerve development as one of their effects (13).

Downs syndrome and gut permeability

Hi.
Many Downs syndrome children have very high levels of IgA and also IgG antibodies to food proteins (1,2) even if most of these do not have endomycium antibodies and a normal gut lining. We have interpreted this as indicating increased gut permeability but in most cases not a coeliac condition. There is an inverse relationship between the size of the children and the level of these antibodies (1). Apparently also Downs syndrome with autism is more frequent than expected (3). I have four children with this combined state so far.
It also is very relevant that Shattock found peptide increases in the urine of such patients (4).
We also find substantial peptide increases in coeliacs (Reichelt et al submitted) and thus confirming data published on increases in hydrolysis released amino acids in the urine of coeliacs. (5)

References:
1: Kanavin \ et al (1988) Immunological studies of patients with Downs syndrome. Acta Med Scand 224: 474-477.
2: Reichelt KL et al (1994) Increased levels of antibodies to food proteins in Down syndrome. Acta paediat Japon. 36: 489-492.
3: Howlin P et al (1995) The recognition of autism in children with Down syndrome - implications for intervention and some speculations about pathology. develop Med and Child neurol. 37: 398-414.
4: Shattock P et al (1990) Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunct 3: 328-346.
5: Klosse JA et al (1971) An automated chromatographic system for the combined analysis of urinary peptides and amino acids. Clin Chim Acta 42: 409-422.

Subject: dietary proteins in mothers milk

Hi.
It has been clearly established that bioactive and significant amounts of protein and peptides are taken up from the gut (1,2).
It is therefore not suprising that the same proteins can be measured in mothers milk (3-6). This has been done by immunological technique and also demonstration that the proteins are not fragments of the precursors by electrophoresis on acrylamide gels. Gliadin proteins see ref 6.
That this mechanism may have serious consequences is illustrated by the many papers relating peptide fragments of milk proteins and the induction of antibodies that destroy the beta-cells (insulin producing cells) and cause diabetes mellitus (7-9). Certain epilepsy is also related to gluten (10).

References:
1: Gardner MLG (1994) Absorption of intact proteins and peptides. in Physiol of gastrointestinal Tract 3rd edit (edit: LR Johnson) Raven press, NY pp1795-1820.
2: Gardner MLG and Stffens K-J (eds)(1995) Absorption of orally adminsitered enzymes. Springer Verlag, Berlin, Heidelberg.
3: AxelssonI et al (1986) Bovine bveta-lactoglobulin in human milk. Acta Paed Scand 75: 702-707.
4: Kilshaw PJ and Cant AJ (1984) The passage of maternal dietary protein into human breast milk. Int Arch Allergy and Appl Immunol 75:8-15.
5: Stuart Ca et al (1984) Passage of cow's milk protein in breast milk. Clin Allergy 14: 533-535.
6: Troncone R et al (1987) Passge of gliadin intio human breast milk. Acta paediat Scand. 76: 453-456.
7: Karjalainen J et al (1992) Bovine albumin peptide as possible trigger of insulin-dependent diabetes mellitus. New Eng J Med 327: 302-307.
8: Martin JM et al (1991) Milk protein in the etiology of insulin-dependent diabetes mellitus (IDDM) Ann Med 23: 447-452.
9: Virtanen SM et al (1994) Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children. Diabteologica 37: 381-387.
10: Gobbi G et al (1992) Coeliac disease, epilepsy and cerebral calcifications. The Lancet 340: 439-443.

Subject: Copious stools.

Hi.
I would like to draw your attention to a paper which highlights exactly autism and large stools. Shattock P (1988) Autism: possible clues to the underlying pathology.-2. A parent's view. in Aspects of Autism: Biological Research (edit: Wing L) Gaskell/The national autistic society (ISBN 0-902241 25 7) pp 11-18.
Intensive diet and combined with training as described by Prof I Lovaas, Los Angeles can still train patients to compensate for lost opportunity.

Subject: Soy intolerance

Toril Myrtveit wrote:
>I just went to a week-end cooking course (for g/c-free foods), where I
>learned that most people with casein intolerance didn't tolerate soy either.
>(no soy-milk, no soy-margarine, no soy sauce,...) This was all new to me.
>Supposedly, the soy-intolerance is due to the caseinates being similar in
>soy and cow-milk. Sounds wacko to me, and there was no medical experts
>there to explain why this should be so.

Hi.
The evidence for this is very dubious. Sometimes when children are allergic (IgE mediated) to milk their antibodies may cross react with soy bean proteins. Exorphins have not been found from soy-proteins. The only bioactive peptides found so far are antioxidant peptides from Soybean beta-Conglycinin (1), and an immunomodulating peptide (2).
All proteins do give rise to peptides during uptake from the gut, and if not broken down or otherwise increased they may inhibit the break down of other dietary and also endogenous peptides. The reason for this has been extensively discussed (3), and is due to peptides generally being good peptidase inhibitors.
Therefore increasing the intake of peptidases (not proteinases) in enterosoluble capsules like those from papaya would be a good idea. Preliminary data look promising.

References:
1: Chen H.M et al (1995) Structural analysis of antioxidative peptides from Soybean Beta-Conglycinin. j Agricult and Food Chem 43: 574-578.
2: Yamauchi F and Suetsuna K (1993) Immunological effects of dietary peptide derived from soybean protein. J Nutr Biochem 4: 450-457.
3: LaBella FL et al (1985) Administration of peptides inhibit the degradation of enodgenous peptides. The dilemma of distinguishing direct from indirect effects. Peptides 6: 645-660.

Subject: Concentrated carbohydrates and Hyperkinesia

Hi.
Heated discussions reflect our lack of knowledge. The less we know the more heated things get in general. We all know very little. However it is wise to listen to the parents, and very many of these see a connection between concentrated carbohydrate intake like sweets and unruly states.
How is this possible:
1: Ingestion of large amounts or concentrated amounts of sweets induces a rapid rise in blood glucose which again causes a fast rise in insulin which then causes a rapid decrease which may give hypoglycemia postprandially in sensitive persons (1). Hypoglycemia is known to cause behavioural problems and temper tantrums in children. All this can be prevented by ingesting concentrated fiber with the sweets which by absorption to the fibers causes a gentler glucose increase etc.
2: The intestinal permeability can be increased through the paracellular route by hyperosmotic solutions (2-4) such as concentrated sweets etc would be. This would increase protein and peptide uptake reviewed (5). So you see there are definitely possibilities related to concentrated carbohydrate intake especially if hyperosmotic.
3: Be sceptical of anyone who pooh-pooh. They are very often wrong (6).

References:
1: Virkkunen M (1982) Reactive hypoglycemia tendency among habitually violent offenders. Neuropsychopharmacol 8:35-40.
2: Travis S and Menzies I (1992) Intestinal permeability: functional assessment and significance. Clinical Sci 82:471-488.
3: Madera JL (1989) Loosening of tight junctions, lessons from the intestine. J Clin Invest 83:1089-1094.
4: Madara JL and Pappenheimer JR (1987) Physiological regulation of transepithelial impedance in the intestinal mucosa of rat and hamsters. J membr Biol. 100: 149-164.
5: Gardner MLG (1994) Absorption of intact proteins and peptides. in Physiol of the gastrointestinal tract. (Ed: LR Johnson). 3rd edit. pp 1795-1820, Raven Press, NY.
6: Christensen L and Redig C (1993) Effect of meal composition on mood. behavioural neuroscience 107:346-353.

All the best. Sorry we know so little Cheers

TINY

Subject: 4 year follow up

Seasonal greetings.
The reprint of the paper Autistic Syndromes and diet: a follow-up study by Knivsberg A-M et al (1995) Scand J Educational Res 39:223-236 can be obtained from Sp Ped A-M Knivsberg, Centre for Reading Reserach, PO Box 2504 Ullandshaug, N-4004 Stavanger, Norway. She is on the Stop Autism Now list too.

All the best Cheers

TINY

Subject: Food and mental problems

What most people ignore is that both peptides and trace amounts but biologically significant amounts of proteins are taken up across the gut mucosa(1,2). Because one molecule of gluten contains at least 15 opioid sequences it is quite clear that this could cause a problem. Increased peptide excretion is found in the urine of coeliacs before treatment (3) (Reichelt et al in prep).
That this is so is confirmed by a series of papers that demonstrate intact food proteins in mothers milk(4-7).
A Canadian group has confirmed that gluten does change a brain enzyme and monoamine levels (8) in cats. They are not gluten eating animals.
There is increasing evidence that components from food do indeed cause serious psychiatric(9-12) and neurological(13-16) disease. Even rheumatoid arthritis as such may have a link to food proteins(17) and it well established that stress (which such a disease is to a very large extent) increases gut permeability. Nobody denies the possibility of reactive depression, but there is little reason why this could not be made worse by dietary factors. Because antibodies are indeed induced by peptides it may even be so that dietary peptides by mimicry to endogenous cell surface peptide sequences, may be responsible for many autoimmune diseases(18).

References:
1: Gardner MLG (1994) Physiology of the gastrointestinal tract. Edit: LR Johnson. Raven press 3rd edit. pp 1795-1820.
2: Husby S et al (1985) Scand J Immunol 22:83-92.
3: Klosse JA et al (1972) Clin Chim Acta 42:409-422.
4: Kilshaw PJ and Cant AJ (1984) Inter. Arch Allergy Appl Immunol 75:8-15.
5: Axelsson I et al (1986) Acta paed Scand 75:702-707.
6: Stuart CA et al (1984) Clin Allergy 14:533-535.
7: Troncone R et al (1987) Acta paed Scand 76:453-456.
8: Thibault L et al (1988) J Clin Biochem Nutr. 4:209-221.
9: Hallert C et al (1982) Psychic disturbances in adult coeliac disease III.Reduced central monoamine metabolism and signs of depression. Scand J Gastroenterol 17:25-28.
10: Singh MM and Kay SR (1976) Wheat gluten as a pthogenic factor in schizophrenia. Science 191:401-402.
11: Dohan FC and Grasberger JC (1973) relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet. Amer J Psychiat 130:685-686.
12: Reichelt KL et al (1990) The effect of gluten free diet on glycoprotein attached urinary peptidee excretion and behaviour in schizophrenics. J Orthomol Med 5:223-239.
13: Gobbi G et al (1992) Coeliac disease, epilepsy and cerebral califications. The Lancet 340:439-443.
14: Paul K-D et al (1985) EEG-Befunde Zoeliakikranken Kindern in Abh{ngigkkeit von der Ern{hrung. Z Klin Med 40:707-709.
15: Kahn A et al (1987) Difficulty of initiating sleep associated with cow's milk allergy in infants. Sleep 10:116-121.
16: Hadjivassiliou M et al (1996) Does cryptic gluten sensitivity play a part in neurological illness? The Lancet 347:369-371.
17: Kjeldsen-Kragh J et al (1991) Controlled trial of fasting and one-year vegetarian diet in rheumatoid arthritis. The Lancet 338:899-902.
18: Karjalainen J et al (1992) Bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. New Eng J Med 327:302-307.

Subject: Autoimmune states.

I would like to draw your attention to a series of papers that link lactalbumin in milk, early exposure to this protein, the formation of antibodies and subsequent autoimmunity as a possible cause of diabetes mellitus (insulin needy diabetes) (1-4). Because peptides are the actual epitopes or immunolgically critical signals cut out from foreign proteins and presented to immunecompetent cells for antibody formation(5); it is easy to envision molecular mimicry with cross reactivity towards endogenous proteins etc. In the case of diabetes it is thought that the antibody formed against a peptide from lactalbumin cross reacts with an acute phase protein induced by, e.g. infections, on the surface of the beta-cells in the pancreas. This causes their destruction. There is an increase in autoimmune diseases in celiacs.(6)

1: Martin JM et al (1991) Milk proteins in the etiology of Insulin-dependent diabetes mellitus. Annal of med 23:447-452.

2: Karjalainen J et al 81992) Bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. New Eng j Med 327: 302-307

3: Dahl-J|rgensen K.et al (1991) Relationship between cow's milk consumption and incidence of IDDM in childhood. Diabetes care 14: 1081-1083.

4: Shanahan F et al (1982) Coeliac disease and Diabetes mellitus: A study of 24 patients with HLA typing. Quarterly J Med (New series) LI, Nom 203: 329-335.

5: Janeway CA (1993) How the Immune system recognizes invaders. Scientific American 269: 40-47.

6: Cooper BT et al (1978) Coeliac disease and immunological disorders, Brit med J 1: 537-539.

Subject: More On Autism-Gluten relationship

On 3/20/96, Karyn S. Friedman said on the Celiac List:

>Autism IS INDEED related to the malprocessing of certain proteins -
>primarily gluten and casein - into inappropriate neurotransmitters.

>Newest research indicates that [celiac and autism] are in fact distinct, since
>kids with autism only rarely show positive on the antibody test. The
>correlation is that there is some gut permeability and malabsorption, and
>that a strict GF diet must be maintained.

It is true that endomycium tests is not very frequently positive. It is not true for IgA against gliadin, gluten and casein however. In (1), we found in 44 DSM III diagnosed autistic children IgA antibodies increased over and above the normal upper limit in 12 out of 44 children, 8 with IgA against gluten and 6 against gliadin; 4 (four) against lactoglobulin and 8 (eight) against casein. This means an increased uptake from the gut but not coeliac disease. (Some had antiboides against several proteins in one and the same patient.)

Reference:
1: Reichelt Kl et al (1991) Probable etiology and possible tretament of childhood autism. Brain Dysfunct. 4:308-319.

Subject: Food allergy vs. intolerance, soy and autism.

>This article was sent in reply to a question about whether the problem
>with casein and gluten in autism is an "allergy" or an "intolerance". He
>was also asked whether soy protein is also typically a problem in autism.

1: It is not allergy but intolerance which is the problem. That is peptides formed from taken up proteins and peptides taken directly from the gut are the root of the problem.
Therefore only some of the children with autism show IgA antibodies. Smaller peptides, which sometimes dominate, do not cause antibody formation. However, peptides with different chain length can still have the same effect. Typically beta endorphin is 32 or 26 amino acids long and is an opioid, while shorter fragments like enkephalin (5 amino acids) etc have similar effects.

2: Soy proteins sometimes cross react with antibodies against casein. So far opioids have not been found from soy protein. However, if increased levels of peptides and proteins generally are taken up, also peptides without specific action can still inhibit the break down of other peptides such as endogenous peptides (1).
That is innocuous peptides from soy protein can inhibit the break down of say endogenous opioids. Opioids (exorphins) are part of the problem and some other peptides with bioactivities directly and indirectly.

3: It sometimes takes a long time to see an effect of diet (as in celiac disease at times) and the diet must be strict. One molecule of gluten contains 15 opioid sequences. There are other causes of autism besides peptides, although maybe as much as 80% are peptide mediated.
We therefore examine the urinary peptides and the antibodies before starting diet. It is also essential that your local MD should be in charge because of the many other possibilities. Avoiding malnutrition is important too.

4: Several immunomodulating peptides are formed from casein (2) and therefore removal of casein will change the immune responses of the body. However, I think many of these are transient. Immunocompetent lymphocytes are thus modulated by opioids (3). It is quite frequent thus that also in celiac disease not only is gluten removed, but also milk and then gently reintroduced at a later date. Reequilibration takes time.

5: Occasionally too much structural damage has been done to the CNS so that we are too late: This is not strange because opioids are inhibitory to Central nervous development (4). However, before puberty it should always ameliorate the disease. Nice aunts and grandmothers often pity the children and let them have "just a little" and therefore cancel out the strenuous efforts of the parents. This in not uncommon.

References:
1: La Bella et al (1985) Peptides 6: 645-660.
2: Migliore-samour D and Jollet P (1988) Experientia 44: 88-93.
3: Morgan EL et al (1990) J neuroimmunol 28: 209-217.
4: Zagon IS and Mclaughlin PJ (1987) Brain Res 412: 68-72.

To clarify paragraph 4: of the previous he wrote:

Subject: intolerance and allergy
Date: 9 Apr 1996 09:04:04 +0200

hi.
My note pertained to celiac disease. Because the gluten does damage to the gut lining it increases the uptake of many other compounds and reduces eg peptidases in the gut lining so that peptides will be taken up in increasing quantities.
Therefore if only gluten/gliadin is the main problem one may at a later day tolerate milk proteins because of closure of the gut. Careful introduction is to safeguard against redamage and increase the level of digestive enzymes involved. These are formed by substrate induction or new protein synthesis. That takes time.

Subject: Down.

Because most of the Down children have IgA and often IgG antibodies way above the upper normal limit but usually without endomycium positive test: this is not coeliac disease but a sign of vastly increased gut permeability to protein uptake.

That intact protein uptake is a reality also normally, is illustrated by botulinum toxin which kills us and a series of papers showing uptake of intact proteins (1,2). Even bioactive enzymes (as is botulinum toxin) is taken up in bioactive form (3-5). This uptake is further confirmed by the secretion of such proteins in mothers milk (6-9). This is why we all have some IgG antibodies to the usual food proteins.

However, it is also clear that the complete Down syndrome is more often found with coeliac disease too (10). (Biopsy and endomycium +).

I think the personally that the MHC genetics only tells us something about increased affinity for certain epitopes increasing the chance of antibody formation (11). Thus the real problem may rather be in epitope presentation from food proteins. this remains to be elucidated of course.

References:
1: Husby S et al (1985) passage of undegraded dietary antigen into the blood of healthy adults. Scand J Immunol 22: 83-92.
2: Paganelli R and Levinsky, RJ (1980) Solid phase radioimmunoassay for detection of circulating food protein antigen in human serum. J Immunol methods 37: 333-340.
3: Schoutsen N and DeJong JN (1984) Xanthine oxidase in rabbit plasma afterapplication of a bovine milk preparation to small intestine. Arch int Physiol et de biochim 92: 379-384.
4: Oster KA et al (1974) Immune response to bovine xanthine oxidase in atherosclerotic patients. Amer lab. 6: 41-47.
5: Gardner MLG and Steffens K-J. (1995) Absorption of orally administered enzymes. Springer Verlag, Berlin.
6: Kilshaw PJ and Cant AJ (1984) The passage of maternal dietary protein into human breast milk. Int Arch Allergy Appl Immunol 75: 8-15.
7: Troncone R et al (1987) Passage of gliadin into human milk. Acta paed Scand 76: 453-456.
8: Axelsson I et al (1986) Bovine betalactoglobulin in human milk. Acta paed Scand 75: 702-707.
9: Stuart CA et al (1984) passage of cow's milk protein in breast milk. Clin Allergy 14: 533-535.
10: Hilhorst MI et al (1993) Down Syndrome and coeliac disease: five new cases with a review of the literature. Eur J pediatr 152: 884-887.
11: Harrison LC (1995) Antigen-specific therapy for autoimmune disease:prospects for prevention of insulin-dependent diabetes. Molecular med 1: 722-727.

Subject: Reintroduction of milk.

Hello.
This is a serious business.

A: The amount of peptides that must accumulate before symptoms reappear varies. What this means is that some react fast and some only slowly after weeks and months on reexposure. This probably depends on 1: the level of peptide and protein uptake from the gut and 2: the defects in break down capacity (peptidases). Even in coeliac disease reintroduction of gluten sometimes causes instantaneous symptoms, but at times up to months may pass before reappearance of symptoms, because we have found bovine casomorphins(1) in the urine as have P Shattock and Prof Cade in the USA; it is not possible to give a simple answer.

B: The passage through the blood-brain barrier is another critical factor. Depending on the size of the accumulated peptides and their structure (eg pyroglu -peptides) the brain exposure will vary(2).

C: In general: If the disorder appeared after a normal period of development (late onset) I suspect gluten and gliadin to be the dominant problem. If present from the neonatal period onwards: probably milk protein. However, mother secretes food proteins in trace amounts so this is not clear.

Conclusion: I would be extremely reluctant to reintroduce milk proteins. (You may substitute soy proteins etc). The more they want it the less they should have it. After all opioids have a powerful maturation inhibitory effect on the CNS(3-4). This pertains not only to proliferation but also maturation which involves extensive pruning. The last big pruning event is puberty. So definitely not before puberty is over. If introduced: in very small doses and gradually increasing. Observe closely over months.

References:
1: Reichelt Kl et al (1991) probable etiology and possible treatment of Childhood autism. Brain Dysfunct 4: 308-319.
2: Seim AR and Reichelt KL (1995) An Enzyme/brain-barrier Theory of Psychiatric Pathogenesis: Unifying Observations on Phenylketonuria, Autism, Schizophrenia and Postpartum psychosis. Medical Hypothesis 45: 498-502.
3: Zagon IS and McLaughlin PJ (1987) Endogenous opioid systems regulate cell proliferation in the developing rat brain. Brain Res 412: 68-72.
4: Zagon IS and McLaughlin PJ (1991) identification of opioid peptides regulating proliferation of neurones and glia in the developing nervous system. Brain Res 542:318-332.

Sorry to be such a kill joy. But the disorder is pretty disastrous as such.
All the best Cheers

TINY

Subject: c/f and g/f diets.

Removal of casein and gluten removal effects are very individual, and I suspect (do not know) if there are treshold effects.
There are four probable variables: 1: Uptake of proteins and peptides from the gut; 2: Rate of break down; 3: Transport through the blood-brain barrier. 4: The receptor sensitivity on target neurones and cells. Peptides are in general very good peptidase (break down enzyme) inhibitors(1) and this means that as peptides accumulate increasing nonspecific peptidase inhibition may cause a vicious circle.

In general in biology increased stimulation of receptors reduces their numbers and also sensitivity. Decreasing their stimulation tends to increase the receptor numbers and sensitivity. Therefore on a strict diet the sensitivity towards forbidden items may increase. However, because we also have endogenous opioids which are physiological and varies with degrees of stress, pleasure etc etc it is almost impossible to foretell in any given individual how his (hers) receptor profile will change.

Ref 1: Labella et al (1985) Administration of peptides inhibit the degradation of endogenous peptides. The dilemma of distinguishing direct from indirect effects, Peptides 6: 645-660.

Subject: Pruning

It is difficult to believe that data are "junk science" when a: several different groups find the same, b: we and others have isolated bovine casomorphin from urines and dialysis fluid of autistic patients and c: about 1/4 of these children have IgA antibodies against gliadin, gluten and or casein higher than the upper normal limit but without coeliac disease. Furthermore we do not claim that this pertains to all but to some, probably many.
It is especially peculiar that psychiatrists who so far have a rather terrible track record should be so antagonistic. Not only were mothers supposed to cause autism in children even though they might have several normal sibs, but they have at various stages been enthusiastic adherents to insulin shocks, excessive and not properly used electroschock, lobotomies, excessive use of neuroleptics with tardive dyskinesias, psychodrama, therapeutic society, group therapy and individual psychotherapy even without demonstrable effects but expensive. Junk science? After all every molecule in our body is at sometime directly or indirectly formed from nutrients. Problems related to this uptake can therefore have widespread effects.
B. Opioids and the brain: Most of the experimental work has been carried out by McLaughlin's group (1-3) and effects have also been found for the cerebellum (4).
It is well established that the brain undergoes two main pruning periods one from about 2 years of age and up and the other at puberty (5-7), and especially related to schizophrenia (7). Maturational changes and autism and the cerebellum have been discussed extensively (8). Direct effects of opioids on pruning has been reported in a preliminary publication (9). It is excellent that persons should be sceptical. Indeed it is in general so that negative criticism is much more valuable than acceptance. This is because we must then do better work, examine our data again and the paradigms. This is always useful, but please discuss the data and do not base your opinion on authorities or experts (they are often not that much up to date at all).

References:
1: Zagon IS and McLaughlin PJ (1984) Naltrexone modulates body and brain development in rats: A role for endogenous opioid systems in growth. Life Sci 35: 2057-2064.
2: Zagon IS and Mclaughlin PJ (1987) Endogenous opioid systems regulate cell proliferation in the developing rat brain. Brain Res 412: 68-72.
3: Hauser KT et al (1989) Endogenous opioid systems and the regulation of dendritic growth and spine formation. J Comp neurology 281: 13-22.
4: Zagon IS and McLaughlin PJ (1991) identification of opioid peptides regulating proliferation of neurons and glia in the developing nervous system. Brain Res 542: 318-323.
5: Huttenlocher PR (1984) Synapse elimination and plasticity in developing human cerebral cortex. Am J ment Defic. 88: 488-496
6: Goldman-Rakic PS et al (1983) The neurobiology of cognitive development. in Handbook of Child psychology:Biology and Infancy development. P Mussen: edit. NY, Wiley.pp 281-344.
7: Feinberg I (1982/1983) Schizophrenia: Caused by a fault in programmed synaptic elimination during adolescence? J psychiat Res 17: 319-334.
8: Courchesne E et al (1994) Neural activity-dependent brain changes in development: Implications for psychopathology. Development. & Psychopathol 6: 697-722.
9: Tenconi B et al (1991) Prenatal exposure to opiates alters reactive pruning and regeneration of serotoninergic neurons. Brain Dysfunct 4: 49-50.

If all this is too much I think the paper by Courchesne 1994 is very worth reading and integrates a lot of neurobiology

There is also a page with info on avoiding dairy. See The No Milk Page