Research



Elaine's Article in Medical Veritas Journal, Nov. 2004
Gut Pathogens and ASD
GI Symptoms of ASD
Brain/Gut Connection


Elaine's Article in Medical Veritas Journal, Nov. 2004

This manuscript was published in the November 2004 issue of Medical Veritas and is presented here by permission.
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Gut Pathogens and ASD

Jyonouchi's Paper
Neuropsychobiology. 2002;46(2):76-84.

Elaine Gottschall's Comments on Jyonouchi's Paper

The abstract of Jyonouchi's paper says Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavorial symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. THIS MAY PREDISPOSE ASD CHILDREN TO SENSITIVIES TO COMMON DIETARY PROTEINS LEADING TO GI INFLAMMATION AND AGGRAVATION OF SOME BEHAVIORAL SYMPTOMS.
The authors demonstrate conclusively that there is an abnormal immune response to cow's milk protein and wheat protein (gliadin) and soy in ASD. What is interesting is that the diet model is NOT THE SAME AS THE OPIOID MODEL BUT IS BASED ON A VARIABLE IMMUNE RESPONSE IN WHICH NOT EVERY CHILD WILL SHOW SENSITIVITY TO EVERY FOOD.
But the punch line is: The authors suggest that the root cause of the food protein sensitivity may be an underlying sensitivity to endotoxin or lipopolysaccharides (LPS) which comes from the surfaces of gram negative bacteria in the gut.

This summarized means that this response to the bacterial endotoxin (LPS) PREDISPOSE THESE CHILDREN TO SENSITIZATION TO DIETARY PROTEINS. This is consistent with a model of abnormal gut flora development that promotes immune response to gut bacteria. This means that ASD kids may develop a kind of autoimmunie response to their own gut flora.

Neuropsychobiology. 2002;46(2):76-84

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12378124&dopt=Abstract

Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder.

Jyonouchi H, Sun S, Itokazu N.

Department of Pediatrics, University of Minnesota, Minneapolis, Minn, USA.

OBJECTIVES: Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms. METHODS: We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses. RESULTS: ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs.

ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs. CONCLUSION: Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria. Copyright 2002 S. Karger AG, Basel

PMID: 12378124 [PubMed - indexed for MEDLINE]

The Bolte Paper

Med Hypotheses. 1998 Aug;51(2):133-44.

Elaine Gottschall's Comments on Bolte's Paper
The point is made that this bacterium produces a potent neurotoxin and goes on to say that the vagus nerve is capable of transporting tetanus neurotoxin and provides a route of ascent from the intestinal tract to the central nervous system. ......Once in the brain the tetanus neurotoxin disrupts the release of neurotransmitters by the proteolytic cleavage of synaptobrevin, a synaptic vesicle membrane protein. This inhibitian of neurotransmitter release would explain a wide variety of behavioral deficits apparent in autism. And it goes on to say that some children with autism have also shown significant reduction in sterotyped behaviors when treated with antimocrobials effective against intestinal clostridia.

Med Hypotheses. 1998 Aug;51(2):133-44.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9881820&dopt=Abstract

Autism and Clostridium tetani.
Bolte ER.

Autism is a severe developmental disability believed to have multiple etiologies. This paper outlines the possibility of a subacute, chronic tetanus infection of the intestinal tract as the underlying cause for symptoms of autism observed in some individuals. A significant percentage of individuals with autism have a history of extensive antibiotic use. Oral antibiotics significantly disrupt protective intestinal microbiota, creating a favorable environment for colonization by opportunistic pathogens. Clostridium tetani is an ubiquitous anaerobic bacillus that produces a potent neurotoxin. Intestinal colonization by C. tetani, and subsequent neurotoxin release, have been demonstrated in laboratory animals which were fed vegetative cells. The vagus nerve is capable of transporting tetanus neurotoxin (TeNT) and provides a route of ascent from the intestinal tract to the CNS. This route bypasses TeNT's normal preferential binding sites in the spinal cord, and therefore the symptoms of a typical tetanus infection are not evident. Once in the brain, TeNT disrupts the release of neurotransmitters by the proteolytic cleavage of synaptobrevin, a synaptic vesicle membrane protein. This inhibition of neurotransmitter release would explain a wide variety of behavioral deficits apparent in autism. Lab animals injected in the brain with TeNT have exhibited many of these behaviors. Some children with autism have also shown a significant reduction in stereotyped behaviors when treated with antimicrobials effective against intestinal clostridia. When viewed as sequelae to a subacute, chronic tetanus infection, many of the puzzling abnormalities of autism have a logical basis. A review of atypical tetanus cases, and strategies to test the validity of this paper's hypothesis, are included.

PMID: 9881820 [PubMed - indexed for MEDLINE]
The Warren and Singh Paper
Mol Chem Neuropathol. 1996 May-Aug;28(1-3):77-81.
This webpage owner's comments on Warren and Singh's Paper
This one is amazing because even the genetics tells us that pathogens are the key to the problem of ASD.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8871944&dopt=Abstract
1: Mol Chem Neuropathol. 1996 May-Aug;28(1-3):77-81.

Immunogenetic studies in autism and related disorders.

Warren RP, Singh VK, Averett RE, Odell JD, Maciulis A, Burger RA, Daniels WW, Warren WL.
Utah State University, Logan 84322, USA.

The major histocompatibility complex comprises a number of genes that control the function and regulation of the immune system. One of these genes, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. We previously reported that a deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) had an increased frequently in autism. In this study we attempted to confirm the increased incidence of the C4B null allele in autism and investigated the presence of a C4B null allele in two other childhood disorders, attention-deficit hyperactivity disorder and dyslexia (reading disability). In addition, we explored the relationship of autism to the DR beta 1 gene, a gene located close to the C4B in autism. We confirmed the finding of an increased frequency of the C4B null allele in autism and found that the related disorders also had an increased frequency of this null allele. In addition, two alleles of the DR beta 1 gene also had significantly increased representation in the autistic subjects.

PMID: 8871944 [PubMed - indexed for MEDLINE]

Other Research Articles about ASD and Pathogens
Med Hypotheses. 2001 Dec;57(6):714-7.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11918432&dopt=Abstract

Anterior insular cortex: linking intestinal pathology and brain function in autism-spectrum subgroups.

Binstock T.
Institute for Molecular Introspections, Estes Park, Colorado 80517, USA. aspergerian@yahoo.com

Autism includes deficits in communications skills and is associated with intestinal pathology. Numerous parents and some physicians report that an autistic child's attention and language improve in response to treatments which eliminate certain dietary antigens and/or which improve intestinal health. For at least some autism-spectrum children, the link between intestinal pathology, attention, and language may derive from shared neuroanatomic pathways within the anterior insular cortex (aIC); from a neurotrophic virus such as herpes simplex (HSV) migrating within afferents to the insular cortex; and/or from synaptic exhaustion in the aIC as induced by chronically inappropriate neuronal activity in the enteric nervous system and/or its vagal efferents.

PMID: 11918432 [PubMed - indexed for MEDLINE]


Clin Infect Dis. 2002 Sep 1;35(Suppl 1):S6-S16

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12173102&dopt=Abstract

Gastrointestinal microflora studies in late-onset autism.

Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen ML, Bolte E, McTeague M, Sandler R, Wexler H, Marlowe EM, Collins MD, Lawson PA, Summanen P, Baysallar M, Tomzynski TJ, Read E, Johnson E, Rolfe R, Nasir P, Shah H, Haake DA, Manning P, Kaul A.

Infectious Diseases Section, Veterans Affairs Medical Center, West Los Angeles, CA, USA. sidfinegol@aol.com

Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. Fecal flora of children with regressive autism was compared with that of control children, and clostridial counts were higher. The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. Children with autism had 9 species of Clostridium not found in controls, whereas controls yielded only 3 species not found in children with autism. In all, there were 25 different clostridial species found. In gastric and duodenal specimens, the most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.

PMID: 12173102 [PubMed - indexed for MEDLINE]


J Child Neurol. 2000 Jul;15(7):429-35. Related Articles,

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10921511

Comment in: J Child Neurol. 2001 May;16(5):387.

Short-term benefit from oral vancomycin treatment of regressive-onset autism.

Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen ML, Nelson MN, Wexler HM.

Section of Pediatric Gastroenterology and Nutrition, Rush Children's
Hospital, Rush Medical College, Chicago, IL 60612, USA.
rushstudy@aol.com

In most cases symptoms of autism begin in early infancy. However, a subset of children appears to develop normally until a clear deterioration is observed. Many parents of children with "regressive"-onset autism have noted antecedent antibiotic exposure followed by chronic diarrhea. We speculated that, in a subgroup of children, disruption of indigenous gut flora might promote colonization by one or more neurotoxin-producing bacteria, contributing, at least in part, to their autistic symptomatology. To help test this hypothesis, 11 children with regressive-onset autism were recruited for an intervention trial using a minimally absorbed oral antibiotic. Entry criteria included antecedent broad-spectrum antimicrobial exposure followed by chronic persistent diarrhea, deterioration of previously acquired skills, and then autistic features. Short-term improvement was noted using multiple pre- and post-therapy evaluations. These included coded, paired videotapes scored by a clinical psychologist blinded to treatment status; these noted improvement in 8 of 10 children studied. Unfortunately, these gains had largely waned at follow-up. Although the protocol used is not suggested as useful therapy, these results indicate that a possible gut flora-brain connection warrants further investigation, as it might lead to greater pathophysiologic insight and meaningful prevention or treatment in a subset of children with autism.

PMID: 10921511 [PubMed - indexed for MEDLINE]


Adv Virus Res. 2001;56:557-82.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11450312&dopt=Abstract

Bornavirus tropism and targeted pathogenesis: virus-host interactions in a neurodevelopmental model.

Hornig M, Briese T, Lipkin WI.

Emerging Diseases Laboratory, Gillespie Neuroscience Research Facility, University of California, Irvine, California 92697, USA.

Animal models provide unique opportunities to explore interactions between host and environment. Two models have been established based on Bornavirus infection that provide new insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior. Distinct losses in DA pathways in the adult infection model, and the associated dramatic movement disorder that accompanies it, make it an intriguing model for tardive dyskinesia and dystonic syndromes. The neuropathologic, physiologic, and neurobehavioral features of BDV infection of neonates indicate that it not only provides a useful model for exploring the mechanisms by which viral and immune factors may damage developing neurocircuitry, but also has significant links to the range of biologic, neurostructural, locomotor, cognitive, and social deficits observed in serious neuropsychiatric illnesses such as autism.

PMID: 11450312 [PubMed - indexed for MEDLINE]


GI Symptoms of ASD

Am J Gastroenterol. 2000 Sep;95(9):2285-95.

http://www-east.elsevier.com/ajg/issues/9509/ajg3248fla.htm

* Am J Gastroenterol. 2000 Sep;95(9):2154-6.

Enterocolitis in children with developmental disorders.
Wakefield AJ, Anthony A, Murch SH, Thomson M, Montgomery SM, Davies S, O'Leary JJ, Berelowitz M, Walker-Smith JA.

University Department of Medicine, Royal Free and University College Medical School, London, United Kingdom.

OBJECTIVE: Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. METHODS: Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). Severity of ileal LNH was graded (0-3) in both affected children and 37 developmentally normal controls (median age 11 yr, range 2-13 yr) who were investigated for possible inflammatory bowel disease (IBD). Tissue sections were reviewed by three pathologists and scored on a standard proforma. Data were compared with ileocolonic biopsies from 22 histologically normal children (controls) and 20 children with ulcerative colitis (UC), scored in an identical manner. Gut pathogens were sought routinely. RESULTS: Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected children but not in controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls (p < 0.001). CONCLUSIONS: A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.

PMID: 11007230 [PubMed - indexed for MEDLINE]

Gastrointestinal abnormalities in children with autistic disorder

http://trainland.tripod.com/gastroin.htm

Journal of Pediatrics
Volume 135 * Number 5 * November 1999
Copyright 1999 Mosby, Inc.

Karoly Horvath MD, PhD
John C. Papadimitriou MD, PhD
Anna Rabsztyn
Cinthia Drachenberg MD
J. Tyson Tildon PhD

From the Departments of Pediatrics and Pathology, University of Maryland School of Medicine, Baltimore.

Supported by an intramural grant by the University of Maryland School of Medicine.
Submitted for publication Dec 31, 1998.
Revision received May 20, 1999
. Accepted July 21, 1999.

Reprint requests: Karoly Horvath, MD, PhD, Department of Pediatrics, 22 S Greene St, N5W70, Box 140, Baltimore, MD 21201-1595.

Copyright 1999 by Mosby, Inc..

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. (J Pediatr 1999;135:559-63)


Brain/Gut Connection

J Pediatr Gastroenterol Nutr. 2002 May-Jun;34 Suppl 1:S14-7.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12082381&dopt=Abstract

The gut-brain axis in childhood developmental disorders.

Wakefield AJ.

Experimental Gastroenterology, Centre for Gastroenterology, Royal Free and University College Medical School, London, United Kingdom.

awakefield@rfc.ucl.ac.uk

Here are some quotes from his article:

D-lactic acidosis, a complication of acid-tolerant bacterial overgrowth in patients with short bowel syndrome and those undergoing intestinal bypass surgery for obesity, is associated with a range of psychiatric and neurologic sequelae (24). Patients may experience altered mental state, aggression, stupor, ataxia, and asterixis; these symptoms respond rapidly to oral antibiotic treatment. Encephalopathy is a recognized presenting feature of intestinal intussusception in infants (25-27) and, intriguingly, may be reversible with naloxone (25).

In summary, within the autistic spectrum, a substantial group of children have what may be primary intestinal pathology. The constellation of developmental disorder and gastrointestinal pathology (provisionally termed "autistic enterocolitis") combines the paradoxic elements of a motility disorder-esophageal reflux and constipation with spurious diarrhea-and enterocolonic mucosal inflammation, a feature more commonly associated with frank diarrhea. Understanding the neurochemical basis of any gut-brain interaction in autistic enterocolitis may help to resolve this paradox and help to develop rational therapeutic approaches.

PMID: 12082381 [PubMed - indexed for MEDLINE


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