A Gut Feeling about Autism?
Max Bingham and Glenn Gibson
Food Microbial Sciences Unit, School of Food Biosciences, The
University of Reading, Whiteknights PO Box 2**, Reading, Berk****re
For many parents, they do not need to be told that often their
autistic children have some quite serious bowel troubles. Re****ts
from parents often tell of symptoms as diverse as profuse diarrhoea,
constipation, excess wind and bloated stomachs. One contributing
factor for many of these re****ts might include a severe imbalance in
the gut bacteria, where for some reason, more undesirable and possibly
toxic bacteria have replaced the more beneficial and protective
bacteria. The work of Dr William Shaw has helped highlight the
possibility of a Candida or yeast overgrowth. More recently the
research of Dr Sydney Finegold and company has highlighted the
possibility of a clostridia overgrowth in a number of autistic
children. Many other conceivable theories are doing the rounds, but
in most cases they remain unproven and untested. From a parental or
carer point of view, it must remain a daunting prospect to consider
treatments and advice, when the scientific community cannot agree on
approaches and the orthodox medical establishment are reluctant to
endorse unproven avenues of relevance. One emerging area of
scientific research into Autism and ASD's is the question of whether
something unusual is going on with the bacteria naturally found in all
our guts. At the University of Reading, the Food Microbial Sciences
Unit has started to ask exactly that question. While we are still
very much in the dark as to what might be going on with these bacteria
in autistic individuals, a number of theories have emerged recently.
To put the record straight, Max Bingham and Glenn Gibson explain all.
Gut Microbiology at Reading
Research at the Food Microbial Sciences Unit utilises expertise in gut
microbiology, anaerobic bacteriology and molecular biology to reliably
identify species and systems involved in a wide variety of
applications. The Human Gut Microflora is an extremely complex mixed
culture comprising mainly of bacteria living in a state of dynamic
equilibrium. It is estimated that as many as 500 different species
reside in the colon at any one time. In the small intestine and
stomach much lower numbers can be found. The colon is regarded as one
of the most metabolically active sites in the human body and this is
due to the human gut microflora. Until recently, research on the
human gut microflora has been limited by the fact that only about 88%
of cells observed under the microscope are cultureable. A much
smaller number are easily cultureable. More recently, the use of
molecular based techniques such as DNA extraction and sequencing has
meant research can be extended into areas that were previously not
possible.
Using the latest molecular and DNA techniques, the bacterial
populations naturally found in the gut can be tracked and then using
models of the gut probiotics and prebiotics can be used to alter these
populations beneficially. Recent successes in using this approach at
the Food Microbial Sciences Unit have included the development of food
product concepts that have been clinically proven to promote
beneficial bacteria such as lactobacilli and bifidobacteria and thus
possibly offer protection from a whole range of pathogenic infections
and diseases.
Autism and gut bacteria
A number of theories have emerged recently suggesting a possible role
for abnormal components of the human gut microflora in the development
of certain autistic characteristics. It now seems increasingly likely
that imbalances in the gut microflora and the development of autistic
symptoms may be linked. Certain unusual species of microorganisms are
looking particularly suspicious.
Candida species
Candida normally constitutes only a very small pro****tion of the human
gut microflora. Over 160 species of Candida have been identified.
They are described as ovoid budding yeasts that typically reproduce
vegetatively and may exhibit hyphae. Competitive inhibition and
certain immune functions normally keep growth under control. Previous
research has led some groups to suggest that certain autistic
characteristics may partially be a consequence of an overgrowth of
Candida. Well-do***ented effects of a Candidia overgrowth can include
vitamin deficiencies, fatty acid deficiencies, chronic CO2 and ethanol
production, and possibly most im****tantly, some Candida species are
known to produce a whole range of toxins. The symptoms that result
vary widely, but can include fatigue, mood lability, depression,
inability to concentrate, headaches, loss of energy, food cravings,
mold sensitivity, multiple food and chemical intolerance and
neuropathic problems. The question of how the overgrowth starts is
often relatively simple. Many parents of autistic children tell of
how multiple courses of antibiotics are often prescribed to their
children. This is often for illnesses early in life such as ear
infections. However after hundreds of rounds of antibiotics
(presumably because of secondary infections or the illness didn't
clear up) the normal protective bacteria simply do not exist in the
gut. This provides a perfect set of conditions for the Candida to
thrive.
Treatments for a yeast overgrowth typically take the form of
antifungal drugs such as nystatin or diflucan. Following the start of
anti-fungal treatment, patients often exhibit a transient worsening of
symptoms. This reaction is rarely an allergic reaction; it is
possibly a systemic 'Herxheimer' reaction due to the rapid killing of
Candida cells. Values for microbial metabolites often increase
dramatically during the immediate period. However levels then fall
after 4 days to two weeks. This is a systemic reaction due to the
rapid killing of yeast and the consequent absorption of large
quantities of fragmented yeast products. Controlling a Candida
overgrowth and recolonisation of the gut with beneficial and
protective bacteria such as lactobacilli and bifidobacteria may help
alleviate some symptoms of autism.
Further Reading:
Shaw, W., Kassen, E. and Chaves, E. (1995) Increased excretion of
analogs of Krebs cycle metabolites and arabinose in two brothers with
autistic features. Clinical Chemistry 41: 1094-1104
Shaw W, (1999) Role for certain yeast and bacteria byproducts
discovered by organic acid testing in the etiology of a wide variety
of human diseases. Bulletin of The Great Plains Laboratory. Overland
park, KS 66204 (913) 341-8949
Clostridia species
Ellen Bolte (1998) outlined the possibility of a subacute, chronic
tetanus infection of the gut as an underlying cause of autism in some
individuals. Extensive antibiotic use creates a favourable
environment for colonisation by op****tunistic pathogens. Clostridium
tetani is a ubiquitous anaerobic bacillus known to produce a potent
neurotoxin. The normal site of binding for the toxin is the spinal
cord. However, the vagus nerve is capable of trans****ting tetanus
neurotoxin, thus providing a route of ascent from the intestinal tract
to the central nervous system and thus bypassing the spinal cord.
Once in the brain this may disrupt the release of neurotransmitters.
This may explain the characteristics of some autistic symptoms. More
recent studies by Dr Sydney Finegold have given us a more extensive
insight into the possible role of clostridia in Autism. The number of
clostridia species found in the stools of autistic children and
control children were *****sed. In all, the autistic children had
eight species of clostridia not found in the controls whereas the
controls only yielded three species not found in the autistic
subjects. Overall levels of clostridia and ruminocoocus species were
higher in the stools of the autistic subjects and upon identification
it was found that one or more of the species found only in the
autistic children were toxin producers.
The significance of this finding should not be underestimated. When a
group of autistic children were treated with oral vancomycin or
metronidazole improvements were noted in both social interactions and
intellectual function as determined by blinded review of videotapes.
The children regressed within two weeks of discontinuing therapy. The
vancomycin was effectively used as a probe drug to help determine
whether or not the hypothesis was valid. Seemingly it was - the group
is now planning some double-blind placebo controlled studies to look
at the usefulness of antimicrobial therapies.
Further Reading:
Bolte ER, (1998). Autism and Clostridium tetani. Medical Hypotheses
51(2): 133-144.
Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP, Vaisanen
ML, Nelson MN, Wexler HM (2000). Short-term benefit from oral
vancomycin treatment of regressive-onset autism. Journal of Child
Neurology 15(7): 429-435.
Finegold SM, Molitoris D, Song Y, Liu C, Vaisanen M-L, Bolte E,
McTeague M, Sandler R, Wexler H, Marlowe EM, Collins MD, Lawson P,
Summanen P, Baysallar M, Tomzynski T, Read E, Johnson E, Rolfe R, Shah
H, Manning P and Kaul A (2002). Gastointestinal Microflora Studies in
Late onset autism. Clinical Infectious Diseases. In press.
Indole acryloglycine (IAG)
Indole acryloglycine (IAG) is a metabolic product of the amino acid
tryptophan and can be found in trace amounts in the urine of
apparently normal healthy individuals. It was first described in the
urine of a patient with a light sensitive dermatitis in 1958. A number
of groups have described its presence in the urine in a variety of
dietary disorders and each proposed that the presence of unusual
bacteria in the gut might be responsible. More recently the work of
Dr Paul Shattock of the Autism Research Unit, University of
Sunderland, has shown the presence of IAG in the urine of a number of
subjects diagnosed with autistic spectrum disorders.
So what is the significance of this unusual metabolite?
Under normal conditions tryptophan is converted to indole pyruvate and
indole acetate and can be detected in the urine of normal subjects.
Elsden et al(1976) discussed the end products of metabolism of
aromatic amino acids including tryptophan by clostridia species. More
recently Smith and Macfarlane (1997) carried out similar studies in
anaerobic batch cultures and were able to investigate the effects of
pH and carbohydrate availability on the production of toxic
metabolites. Here it was proposed that under certain abnormal gut
conditions, anaerobic coliforms can convert trytophan to indole
proprionic acid, which is subsequently absorbed and oxidised to indole
acrylic acid and conjugated in the liver to indole acyloglycine
(IAG).
Szeinberg et al(1965) re****ted the disappearance of IAG from the urine
of a patient given neomycin who had previously excreted large amounts
of the compound. Following completion of the course of antibiotics
and discharge from hospital the IAG reappeared in the urine. They
concluded that the production of IAG was likely to be mediated by
unusual gut bacteria and that it was probably passed between members
of the family of the patient.
Paul Shattock and Dawn Savery have estimated (although they admit
crudely) that about 75% of subjects with autism exhibit the presence
of IAG in the urine. Interestingly they have also estimated that
about 50% of fathers, mothers and siblings show unusually high levels
of IAG. Shattock and Savery have suggested that IAG represents a
detoxified version of a parent compound that may affect the
permeability of membranes throughout the body. This is significant
since we know that many autistic subjects are affected by opiate
substrates and other unusual dietary factors because of problems with
the permeability of membranes in the gastrointestinal tract and other
organs. With this knowledge, we may be able to set about managing the
appearance of IAG and other unusual metabolites in the urine of
affected subjects and affect a consequential improvement in
symptomology.
Further Reading:
Shattock P, Whitetley P, and Savery D (2001). Autism as a metabolic
disorder: Guidelines for gluten and casein - free dietary
intervention, 2nd Edition. Sunderland: Autism Research Unit,
University of Sunderland, UK
Managing the Gut Bacteria
So we are now fairly confident that something unusual might be going
on with the gut bacteria in autistic children. The natural question
is what are we going to do about it? Part of the work of the Food
Microbial Sciences Unit is molecular tracking of gut bacteria
populations and the development of dietary procedures that target the
gut bacteria to help us manage these populations so they become more
beneficial and protective. These tools are probiotics and
prebiotics. In simple terms probiotics are the beneficial bacteria
and prebiotics are their lunch.
Examples of probiotics are lactobacilli species and bifidobacteria
species. These are live microbial feed supplements which beneficially
affects the host. Many different strains are used including
Lactobacillus acidophillus, Lactobacillus casei, Bifidobacterium
bifidum andLactobacillus plantarum. A number of clinical trials have
been completed and various mechanisms for their effectiveness have
been proposed. In terms of Autism and ASD's it has been suggested
that probiotic supplementation is useful following anti-fungal
treatments - since once the yeasts have been destroyed, the resulting
gap is then recolonised with beneficial and protective bacteria.
However the barriers to success are seen as quite high since the
bacterial cells must survive intact such obstacles as trans****tation
and temperature abuses, stomach acid, bile secretions and competitive
inhibition once in the gut.
The alternative approach is that of prebiotics. These are non-
digestible food ingredients that selectively stimulate a limited
number of bacteria in the colon to improve host health. Prebiotics
are thought to selectively stimulate the beneficial bacteria (e.g.
lactobacilli and bifidobacteria) and selectively inhibit non-
beneficial organisms that may cause intestinal upset or other gut
problems. Im****tantly, prebiotics can inhibit pathogen colonisation
in the gut by competitive inhibition.
The relation****p between the health of the gut and beneficial and
protective bacteria has been known for many years. Recolonisation of
the gut with beneficial bacteria is the aim following the removal of
pathogenic bacteria. Prevention of colonisation by non-beneficial
bacteria is necessary. Probiotics may not survive or re-colonise the
gut on their own. Prebiotics may help boost their ability to
recolonise in the autistic gut. Both may provide the host with
adequate protection from recolonisation by pathogenic microorganisms
(such as candida or certain gut anaerobes. A transient improvement in
the gut environment may be seen. A transient improvement in autistic
symptoms may be seen. The chances of recolonisation by pathogenic
bacteria and subsequent relapse of symptoms may be reduced.
Further Reading:
Gibson GR and Roberfroid MB (1995). Dietary Modulation of the human
colonic microbiota: Introducing the concept of prebiotics. Journal of
Nutrition 125: 1401-1412.
Gibson GR, BerryOttaway P and Rastall RA (2000). Prebiotics: New
Developments in Functional Foods. Chandos Publi****ng Limited,
Oxford.
Current Research at Reading
The Food Microbial Sciences Unit is now looking to start some
preliminary research into the diversity of gut bacteria of autistic
spectrum disorder children. Using a recently developed molecular
technique called FISH, we can identify and quantify a whole range of
bacterial and yeast species from a faecal sample. By doing this we
hope to try to understand how differences in gut bacteria populations
relate to autistic symptoms. We are hoping to recruit a number of
autistic and autistic spectrum disorder children to take part in this
study. Very simply, all that is required is the completion of a short
questionnaire and the collection of one fecal sample from your
autistic child. If you wish to take part in the study, you will be
provided with the necessary equipment and sampling tubes and full
instructions on how to collect a sample. It=92s very easy to do and it
will mean that you receive a detailed description of the fecal gut
bacteria found and a full explanation of what it all means. The best
part is that taking part is completely free. If you are interested in
participating, you can contact the AutismFile for more details.
Our future work is likely to take us into many different areas of the
Autistic Spectrum. We will be using a number of different techniques
in the near future to help us understand in much more detail the
nature of the gut bacteria populations in the autistic spectrum. It
is likely that we will want to recruit some volunteers for more
detailed work. If you are interested in taking part please contact
the AutismFile.
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