The possibility and probability of a gut-to-brain connection in autism
Department of Pediatric Research, Rikshospitalet Medical Centre, University of Oslo, Oslo, NorwayA. M. Knivsberg, PhD
The Reading Centre, University of Stavanger, Stavanger, Norway
BACKGROUND: We have shown that urine peptide increase is found in autism, and that some of these peptides have a dietary origin. To be explanatory for the disease process, a dietary effect on the brain must be shown to be possible and probable.
METHODS: Diagnosis was based on DSM-III and DSM-IV criteria. We ran first morning urine samples equivalent to 250 nm creatinine on high-performance liquid chromatography (HPLC) reversed phase C18 columns using trifluoroacetic acid acetonitrile gradients. The elution patterns were registered using 215 nm absorption for largely peptide bonds, 280 nm for aromatic groups, and 325 nm for indolyl components. We refered to a series of published ability tests, including Raven’s Progressive Matrices and the Illinois Test of Psycholinguistic Ability, which were administered before and after dietary intervention. The literature was also reviewed to find evidence of a gut-to-brain connection.
RESULTS: In autistic syndromes, we can show marked increases in UV 215-absorbing material eluting after hippuric acid that are mostly peptides. We also show highly significant decreases after introducing a gluten- and casein-free diet with a duration of more than 1 year. We refer to previously published studies showing improvement in children on this diet who were followed for 4 years and a pairwise matched, randomly assigned study with highly significant changes. The literature shows abundant data pointing to the importance of a gut-to-brain connection.
CONCLUSIONS: An effect of diet on excreted compounds and behavior has been found. A gut-to-brain axis is both possible and probable.
KEYWORDS: autism, peptides, proteins, uptake, diet
ANNALS OF CLINICAL PSYCHIATRY 2009;21(4):205–211
Autism has a solid genetic disposition.1,2 This necessarily entails chemical changes. However, genetic disorders that become evident over time probably depend on environmentally supplied compounds that lead to accumulation of metabolites that are proximal to the genetic deviation and decrease distal to the lesion. This is like a dam in a river, which causes differently shaped lakes to be formed, depending on topography, and secondary pathways (overflow) to open when full. In humans, our constitution is the “topography,” so that one genetic defect may lead to different phenotypes. Toxicologic inhibition of, or lack of, cofactors for enzymes in the same pathway may lead to similar results and may mimic or reinforce a purely genetic state of affairs.
The FIGURE represents a metabolic chain in which E1, E2, etc, are different enzymes and p is a negative feedback inhibitor on the rate-limiting enzyme, E1. With insufficiency of enzyme following D indicated by a vertical block, D will increase; since feedback is prevented by a decrease in e, f, g, and especially p, the system can easily run wild. Removing input a will reduce D, and supplying cofactors to the enzyme following D may increase its efficiency.3 Cofactors are usually derived from vitamins, trace minerals, and—if membrane bound—by increasing conformational flexibility by a more fluid membrane (unsaturated fatty acids). An excellent example of the simplistic outline shown above is phenylketonuria (Föllings disease), in which an inability to metabolize the amino acid phenylalanine (F) causes accumulation of this amino acid and opening of secondary pathways. Reducing the input of F prevents severe mental retardation.
FIGURE Consequences of an enzyme insufficiency to a metabolic chain
Conditions that must be fulfilled
To be credible, the idea that dietary peptides and/or proteins influence the behavior and development of autistic children, the following conditions appear necessary:
It must be physiologically possible and probable.
There must be demonstrable chemical changes that support this view.
It must be shown with reasonable probability that removing the offending source of the accumulated compounds is effective and possible, in order to decrease the input.
The pathophysiology of the disease ought to be plausibly explained.
Supportive evidence from other disorders that may have similar pathophysiology should exist.
1. Physiologically possible—and probable
If low molecular weight peptides from food proteins are the mediators of the autistic state, peptides should be formed in the gut or systemically from uptake of precursors. Peptides are formed in the gut in animals4 and humans.5 If proteins are taken up and the breakdown is insufficient, peptides will accumulate. Intact uptake of protein and peptides is found in animals and humans,5,6 and peptides taken up from the gut can be found in urine.6 Decreased breakdown of peptides in the intestinal mucosa increases the uptake of specific peptides in animals.7,8 Exorphins are especially peptidase resistant because of their structure.
Several investigations have shown uptake of intact protein and enzymes in humans9 and animals.10 This uptake can be measured as increased IgA antibodies to such proteins.11 That proteins are taken up in normal persons is strongly supported by the presence of proteins in the breast milk of mothers who ingested these proteins.12-15 Also botulinum toxin, a protease, is taken up, passes the blood–nervous system barrier, and cuts one peptide bond in SNAP-25 protein in the synapses, with fatal results.16 The prion, a protein introduced through diet, retains its tridimensional structure, acting like a chaperone toward an endogenous protein, which causes misfolding and spongiform encephalitis. This example may illustrate why active enzymes can also pass into the bloodstream.
Inflammation of the mucosa reduces the activity of lytic enzymes such as those seen in celiac disease, resulting in increased uptake of protein and peptides.17 In autism, inflammatory cytokines are apparently released by milk proteins and gluten/gliadin.18 Several groups have reported panenteritis in autism, which would result in increased uptake from the gut due to mucosal damage and loss of membrane-attached enzymes.19,21 Inflammatory cytokines can alter the epithelial barrier to food antigens in disease.22
Exorphins are able to penetrate the blood-brain barrier in animals23 and humans.24 The results of peripheral (IV) application of casomorphin 1-7 on behavior in rats25 as well as in inducing immediate early antigen Fos26 blocked by naloxone, reinforce this view. Gluten exorphin B5 also causes hyperprolactemia in rats27 after peripheral administration. The behavioral effects in rats were the same as those obtained by intracranioventricular injections,28 and the opioids were found to cause inhibition of dopamine uptake and dopaminergic hyperactivity.28,29
Because the basic mechanisms are in place, we may therefore conclude that peptides and proteins are taken up from the gut and can produce bioactive peptides. Also, because the blood-brain barrier is peptide permeable, CNS effects are to be expected.
2. Demonstrable chemical changes
Increased secretion of peptides in urine has been found in patients with autism and schizophrenia.30-34 TABLE 1 shows the total amount of UV 215-absorbing material eluted after hippuric acid on high-performance liquid chromatography (HPLC) reversed-phase columns; 215 nm absorption is taken as a measure of peptide-like bonds (UV 280 nm absorption is measured simultaneously for aromatic groups). The difference from controls is strongly significant. In TABLE 1, the P values were obtained by comparing each country with controls in the same age range. Urine equivalent to 250 nm creati-nine from the first morning urine was run on HPLC C18 reversed-phase columns in a trifluoroacetic acid (TFA, 10 mM) acetonitrile gradient.34 Two-tailed, unpaired t test with Welch correction was used. The very large SDs (standard deviations) are mainly due to some excessively high levels in patients with regressive autism.
In addition, IgA antibodies increased against gluten, gliadin, and casein but not lactoglobulin, lactalbumin, and ovalbumin.30,32,35 This means that, without celiac disease, uptake of protein or its epitopes across the mucosa is increased.
Many studies show intestinal and mucosal damage in autistic children.19,20,36,37 This could explain the increased gut permeability shown.38 Exposing children on celiac diet treatment to gliadin/gluten during provocation caused long-lasting EEG changes.39 Nuclear magnetic resonance (NMR) spectroscopy of the brain after intake of food in chronic ileitis in humans shows perivascular edema in the white substance shortly after food intake.40,41
Increased urine peptide levels reflect decreased breakdown due to solely genetic, genetic and toxicologic, or solely toxicologic reasons. When the normal breakdown is deficient, peptides are regularly found in the urine of animals42-44 and humans.45 If the peptide level is below the reuptake capacity of the kidney tubules, near-normal peptide levels in the urine may be expected, as seen in 80% of high-functioning autistic children.46
Total level of UV 215 nm–absorbing material eluted after hippuric acid—a comparison of different countries vs controls
||560 to 773
||343 to 453
||500 to 667
||416 to 711
||317 to 537
||277 to 302
3. Effect of diet
Since the exorphins are derived from casein, gliadin, and gluten, and IgA antibodies against these proteins are statistically increased in children with autism, a reasonable course was to try to remove these proteins. This is similar to removing phenylalanine in phenylketonuria (Föllings disease). Most interventions carried out for a sufficient period of time (months to 1 year) register positive effects.30,32,47,51 The open study47 was followed for 4 years49 to counteract placebo effects (TABLE 2). A paired, single-blind, randomly assigned study confirmed the earlier data (TABLE 3).51 Over the Internet, a great number of before and after registrations have been done52 and show an amazing variation in the rate of recovery. Data from the Autism Institute in San Diego, California, point to the same.53 Negative reports are from trials conducted for very short time periods, with extremely varying age and no control of compliance. After puberty, the response to diet is very mixed.54 It is possible that enzyme supplementation may replace diet in the future.55 Many case reports have also been positive.56
Since vitamins and trace minerals are cofactors for many enzymes, it makes sense that they may influence the direction of reactions by mass action and also conformational change of the Km for substrates.3 However, very high levels of vitamin treatment and trace minerals over long periods of time are without published peer-reviewed data, except for B6 and magnesium.57 Other effects may also be present, such as the mercury-chelating effect of vitamin C,58 resulting in improvement of autistic symptoms.
The total time for each patient on a diet free of gluten and casein is 2 years. UV 215 units were as described in TABLE 1. Wilcoxon matched-pairs signed rank test 2-tailed was used. Pairing was effective. The decrease in peptide levels was found despite abundant intake of meat and fish (TABLE 4), further supporting the view that the peptide compounds do come from casein and gluten. Similar changes were found in the open study. No changes other than diet were made in the experimental group, which was given a gluten- and casein-free diet for 1 year. Mann-Whitney U test 2-tailed was used. (For details and tests used, see the original paper.51)
Measured behavioral changes from the first open test—followed for 4 years to reduce placebo effects47,49
||Initial score ± SD
||1-year change ± SD
||4-year change ± SD
||6.8 ± 2.8
||+8.6 ± 2.8
||+8.6 ± 3.2
||25.7 ± 5.5
||+2.7 ± 2.5
||+6.1 ± 2.8
||8.5 ± 3.3
||-6.1 ± 2.7
||5.3 ± 2.2
||-5.3 ± 1.22
Single blind pair-wise randomly assigned autistic children and the 1-year effect of gluten- and casein-free diet compared to autistic children without this intervention51
Diet to control, significance, P value
Within-group significance, P value
|Total score for autistic symptoms
||12.5 ± 2.2
||5.6 ± 2.4
||11.5 ± 3.9
||11.2 ± 5.0
|Subscore for social isolation, aloofness
||7.6 ± 1.7
||3.0 ± 1.4
||7.1 ± 2.8
||6.2 ± 2.9
|Subscore for communicative skills, social contact
||3.9 ± 0.9
||6.2 ± 1.1
||4.3 ± 1.3
||4.5 ± 1.6
|Subscore for strange and unusual behavior
||4.9 ± 1.5
||2.6 ± 1.7
||4.5 ± 1.6
||4.8 ± 2.6
Peptide levels before and after dietary intervention in the same patients
||Autism peak before
||Autism peak after
4. Explaining the pathophysiology
We ought to be able to explain many physiological aspects of autism:
increased brain size in the first 2 years of life and later reductions in volume and development59
lack of social empathy and typical aloofness
stereotopies and rituals
emotional, uncontrolled outbursts
genetic disposition and recent increases in the number of children with autism.
Increase in peptides would lead to a general peptidase inhibition.60 This would mean that growth factor breakdown would also be decreased, and an increase has been found.61 In later stages, the opioid as such inhibits maturation in animal models,62,63 and a complex nuclear magnetic resonance picture emerges, with decreases and increases in different structures.64 Of great interest are brain changes caused by inflammatory bowel disease (IBD) in areas most affected in autism.65
Panksepp66 showed that opioids induced social aloofness in animal models and especially abrogated social distress calls induced by removing the mother. The lack of socially meaningful relationships is also very pronounced in human opium/heroin addicts. Opioids and casomorphins have been shown to induce epileptic seizures, especially those of the temporal cortex.67 Epilepsy is common in autistic children,68 and contrary to controls, increases with age. Fluctuating analgesia has been registered in autism and would be expected in opioids that have a dietary origin.
That genetics and environment interact is not news, and if exposed to increased mercury (Hg) load that acts as an enzyme poison and measured as bioactive Hg,69 a dietary overload may well explain the increased frequency of autism in recent years. Also, in Norway, we have found an increase in functional Hg in autistic children (in preparation). In Norway, the increase in daily consumption of casein can be seen in TABLE 5. The considerable increase in milk-derived compounds has also been found in the United States, the land of ice cream, milk shakes, etc.
Change in milk products consumed in norway, causing increased dietary loading
|Milk, million L
|White cheese, tons
|Brown cheese, tons
|Melted cheese, tons
|Conserved milk products, L
Other evidence in support of a gut-brain connection
Interestingly, celiac disease seems to predispose to depression,70 and autistic traits are found in children with celiac disease.71 Chronic gastrointestinal problems are connected to a lifetime prevalence of depression.72-75 Finally, exposing children with ADHD and intolerance to certain foods76 showed magnetic EEG changes when exposed to the same foods.77
A series of articles have documented CNS damage with increased gliadin uptake, including peripheral neuropathy and cerebellar ataxia,78 and epilepsy.79 These findings have been extensively discussed.34
The evidence for a gut-to-brain connection is considerable. Physiology and the experimental facts show that this is not only plausible but probable.34,80 Medical diagnoses, which are largely based on symptoms only, usually are quite heterogenous. Disorders like fragile X, tuberous sclerosis, and Klüver-Bucy syndrome do not show peptide increases, and there are some unexplained cases as well. Measurable behavioral changes have been obtained in children with autism when gluten and casein are removed.
DISCLOSURES: Dr. Reichelt has received grant/research support from the Autism Research Institute, San Diego, CA, and is an unpaid consultant to Biomedical Laboratory in Oslo, Norway. Dr. Knivsberg reports no financial relationship with any company whose products are menioned in this article or with manufacturers of competing products.
ACKNOWLEDGEMENTS: We thank Dr. B. Rimland for supporting our work financially and with his great inspiration and friendship.
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CORRESPONDENCE: K. L. Reichelt, MD, PhD, Department of Pediatric Research, Rikshospitalet, N0027, Oslo, Norway E-MAIL: email@example.com, Karl.L.Reichelt@rr-research.no
Annals of Clinical Psychiatry ©2009 American Academy of Clinical Psychiatrists