Selected Studies on Digestive Enzymes influencing Neurological Conditions
last updated 8.25.05
Harvard Clinic Scientist Finds Gut and Autism Link
Dr. Timothy Buie, a pediatric gastroenterologist from Harvard/Mass General Hospital has performed over 400 gastrointestinal endoscopies with biopsies, as well as evaluation of digestive enzyme function in children diagnosed with autism and finding a connection. The results of his testing are similar to the observations made by Dr. Andrew Wakefield regarding the presence of chronic inflammation of the intestinal tract, although the incidence was noted to be less frequent in his group.
Dr. Buie announced his findings last Saturday at the Oasis 2001 Conference for Autism in Portland, Oregon, the day before the announcement of Wakefield's forced departure from Royal Free in the UK.
The biopsy results indicated the presence of chronic inflammation of the digestive tract including esophagitis, gastritis and enterocolitis along with the presence of Iymphoid nodular hyperplasia in 15 of 89 children. Additionally the results of the enzyme testing of Dr. Buie’s patients paralleled that of Dr. Karoly Horvath and colleagues at the University of Maryland School of Medicine. Dr. Buie found that the autistic children he examined showed disaccbaride/glucoamylase enzyme levels below normal. Some 55% of these children had lactase deficiencies (which breaks down lactose in milk) as well as deficiencies of the enzyme sucrase (responsible for digestion of table sugar).
The findings also lend support to anecdotal reports of improvement of some autistic children on wheat and dairy (gluten, casein) free diets. Buie says that Harvard wants to do research into the use of protein enzyme supplements, which aid in the digestion of wheat and milk products for treatment.
Buie echoed the opinion of other a growing number of clinical researchers and practitioners treating autistic patients, "these children are ill, in distress and pain, and not just mentally, neurologically dysfunctional."
Gastrointestinal Abnormalities in Children with Autistic Disorder
Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT. J Pediatr 1999 Nov;135(5):559-63.
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, USA. PMID: 10547242 [PubMed - indexed for MEDLINE]
OBJECTIVES: Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms. STUDY DESIGN: Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension. RESULTS: Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth's cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function. Seventy-five percent of the autistic children (27/36) had an increased pancreatico-biliary fluid output after intravenous secretin administration. Nineteen of the 21 patients with diarrhea had significantly higher fluid output than those without diarrhea. CONCLUSIONS: Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients. The observed increase in pancreatico-biliary secretion after secretin infusion suggests an upregulation of secretin receptors in the pancreas and liver. Further studies are required to determine the possible association between the brain and gastrointestinal dysfunctions in children with autistic disorder.
Opioid peptides and dipeptidyl peptidase in autism.
Hunter LC, O'Hare A, Herron WJ, Fisher LA, Jones GE.
Dev Med Child Neurol 2003 Feb;45(2):121-8. YAbA Ltd, Logan Building, Roslin Biocentre, Midlothian, UK. PMID: 12578238 [PubMed - in process]
It has been hypothesized that autism results from an 'opioid peptide excess'. The aims of this study were to (1) confirm the presence of opioid peptides in the urine of children with autism and (2) determine whether dipeptidyl peptidase IV (DPPIV/CD26) is defective in children with autism. Opioid peptides were not detected in either the urine of children with autism (10 children; nine males, one female; age range 2 years 6 months to 10 years 1 month) or their siblings (10 children; seven males, three females; age range 2 years 3 months to 12 years 7 months) using liquid chromatography-ultraviolet-mass spectrometric analysis (LC-UV-MS). Plasma from 11 normally developing adults (25 years 5 months to 55 years 5 months) was also tested. The amount and activity of DPPIV in the plasma were quantified by an ELISA and DPPIV enzyme assay respectively; DPPIV was not found to be defective. The percentage of mononuclear cells expressing DPPIV (as CD26) was determined by flow cytometry. Children with autism had a significantly lower percentage of cells expressing CD3 and CD26, suggesting that they had lower T-cell numbers than their siblings.
In conclusion, this study failed to replicate the findings of others and questions the validity of the opioid peptide excess theory for the cause of autism.
Gastrointestinal Dysfunction and Autism
Repligen site - Gastrointestinal Dysfunction and Autism
A number of investigators have reported that a significant percentage of autistic children present with gastrointestinal symptoms including diarrhea, constipation, abdominal pain, reflux, gaseousness, and/or foul smelling stools. The fraction of autistic children that show one or more of these symptoms has not been well documented but a recently reported survey suggests it exceeds 50% (Gastroenterology, 1999, v116, abstract G2433). Furthermore, elevated intestinal permeability measured by the lactulose/mannitol test was observed in 43% of autistic children not presenting with clinical gastrointestinal symptoms (D'Eufemia et. al., 1996, Acta Paediatrica, v85, p1076). Additional evidence of abnormal intestinal permeability is the observation of peptiduria in autistic children (Reichelt, K.L., Dev. Brain Dysfunction, 1994, v4, pp. 71-85).
Wakefield et. al. have characterized an inflammatory/immune response in the colon and ileum of autistic children which has been termed “autistic enterocolitis”. An initial report characterized an lymphoid nodular hyperplasia and intestinal inflammation in 12 autistic children (Lancet 1998, v351, p637). These preliminary observations have now been extended to 60 children and additional documentation of the inflammatory enterocolitis through endoscopic and histologic measures have been made (Wakefield, A.J. et. al., submitted; Furlano, A. et. al., submitted).
In addition, Horvath et. al. have carried out histologic examinations of 36 autistic children with gastrointestinal symptoms. In this study 69% had grade I or II reflux esophagitis, 42% had chronic gastritis and 67% had chronic duodenitis (Horvath, K., et. al., Journal of Pediatrics, 1999, 135: 559-63).
Thus there is a growing body of evidence that a unique pattern of gastrointestinal dysfunction exists in a large fraction of children diagnosed with autism.
DPP IV Actions on Gluten, Casein, and Soy
Synergistic Action of an X-Prolyl Dipeptidyl Aminopeptidase and a Non-Specific Aminopeptidase in Protein Hydrolysis.
Byun T, Kofod L, Blinkovsky A. June 13, 2001 J Agric Food Chem 2001 Apr;49(4):2061-3.
Novozymes Biotech, Incorporated, 1445 Drew Avenue, Davis, California 95616.
Non-specific monoaminopeptidase (AP; E.C. 3.4.11) and X-prolyl dipeptidyl aminopeptidase (X-PDAP; E.C. 18.104.22.168), both from Aspergillus oryzae, demonstrate strong synergism in hydrolyzing proline-containing peptides. Incubation of AP alone with the peptide Ala-Pro-Gly-Asp-Arg-Ile-Tyr-Val-His-Pro-Phe does not generate free amino acids. However, when AP and X-PDAP are added in combination, complete and immediate hydrolysis of all peptide bonds, other than X-Pro bonds, is observed. In the enzymatic hydrolysis of casein, soy, and gluten, degree of hydrolysis (DH) values of 54, 54, and 47% were achieved, respectively, when subtilisin (E.C. 22.214.171.124) was supplemented with AP. Addition of a third enzyme, X-PDAP, resulted in significantly higher DH values of 69, 72, and 64%, respectively, establishing the utility of this synergism in protein hydrolysis.
This study indicates a synergistic effect between DPP IV when it is present in combination with another non-specific aminopeptidase and another protease. This blend can hydrolyze approximately 65% - 70% of the peptide bonds in gluten, casein, and soy protein.
7-Month Peptizyde and Zyme Prime Summary Report
260 people using enzymes from reported over a 7 month period on an independent forum. Results were tracked and summarized in a 30 page document. The overwhelming majority of respondents saw noticeable improvements with enzymes. This study was done in 2001. Since that time, many other enzyme products have been developed and tested with similar results. An executive summary is follows:
- Of 260 total respondents (100%) using these products for at least 3 weeks, 235 (90%) reported positive results, 14 (6%) reported negative results, and 11 (4%) reported inconclusive results. Significant improvements were seen in eye contact, language, humor, foods tolerated, foods accepted, sleep, weight gain or loss, digestion, stools/bowels, overall appearance, transitioning, socialization, awareness, problem solving, short-term memory, flexibility in routine, range of interests, sound and light tolerance, sensory integration, spontaneous affection, and energy level among others.
- Significant decreases were seen in aggression, hyperness, anxiety, self-stimming, self-injurious behavior, pain, and headaches among others.
- Most positive results were apparent within the first 3 weeks. Most people say any side effects or adjustment effects which start with enzyme use stop within 3 weeks.
- The majority of respondents (about 85%) were either 100% GFCF or partial GFCF with enzymes. More gluten/casein foods were added as people stayed with enzymes over time. More foods were added in general with both products over time.
- After 7 months on enzymes, there have been no reports of any regression after success is seen past the 3-week adjustment period, including in those eating gluten/casein liberally.
- People saw significant improvements whether they are on or not on a restrictive diet.
- Improvements continued over time with continued enzyme use. The longer on enzymes, the more foods people tend to re-introduce and the more positive results are seen.
- Most people return to eating most foods, although not all people can eat all foods, with these enzymes. Some guidelines are noted in this summary in Part 2.
- Timing is key to getting consistently positive results.
- Many people see the Happy Child Effect, which refers to the general, overall positive disposition of the child once they start taking enzymes regularly. The child becomes noticeably more pleasant, easy going, cooperative, and helpful.
- People having difficulties or concerns when starting enzymes were far more likely to achieve positive results when they posted their concerns on the enzymesandautism board for assistance. This is attributed to getting more education and information on using enzymes which helped them make any needed adjustments.
- Some people were able to significantly reduce their costs on food, supplements, and other therapies by using enzymes. This correlated to length of time on enzymes and to what extent they remained on a restrictive diet.
- Most parents found using enzymes to be far more convenient and flexible than a restrictive diet. This greatly reduced stress, increased happiness and quality of life for the entire family.
- A few people have seen no results either way; however, a few people have improved to the extent they no longer fit the criteria for their previous diagnosis.
- Enzymes have been used for years to safely assist in food intolerances/allergies, leaky gut, yeast and immune system support among others.
Most respondents posted that enzymes were an important part of their child’s improvement but not to the extent that all other therapies or medications were no longer needed, although at times a restrictive diet could be eliminated and other supplements greatly reduced. Most say that adding these enzymes were definitely beneficial and made most other therapies more productive. They say the addition of enzymes allow them to streamline their overall plan to a more efficient, easier, convenient, cheaper, effective and simpler treatment. These result were uncontrolled and parent-judged