Gut Pathogens And Autism Spectrum Disorder (ASD)




Elaine Gottschall's Research

Medical Veritas Journal:
Gut Pathogens and ASD
GI Symptoms of ASD
Brain/Gut Connection

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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@xxxxxxxxx

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@xxxxxxx

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@xxxxxxx

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]

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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)

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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@xxxxxxxxxxxxx

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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