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1. Intolerance to food proteins 2. Diet and mental disease 3. Diet 4. Gluten, autism and schizophrenia 5. Autism and coeliac disease. ======================================================================== Dr. Kalle Reichelt Pediatric Research Institute N-0027 Oslo, Norway Tel: +47 22 86 90 45 Fax: +47 22 86 91 17 E-mail: Kalle Reichelt, (K.L.Reichelt@rh.uio.no) Dr. Reichelt has been researching the impact of gluten intolerance on certain individuals with developmental delays. Most of the following is from the CELIAC@LISTSERV.ICORS.ORG mailing list. Extracted postings are available in other files on Dr Reichelt. The naming convention is: REICH94 (1994 postings) This file REICH95 (1995 postings) REICHU (Updates to the current years postings) Copyright Michael Jones, Bill Elkus, Jim Lyles, and Lisa Lewis 1995 - All rights reserved worldwide. ======================================================================== Subject: Intolerance to food proteins Date: 8 Nov 1994 9:01 AM 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 Date: 21 Nov 1994 8:29 AM 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 Date: 22 Nov 1994 15:00:55 +0100 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 Date: 27 Dec 1994 9:39 AM 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. Date: 28 Dec 1994 9:25 AM 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
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