Autism and the Human Gut Microflora

[Guest guest]

Autism and the Human Gut Microflora

 

Max Bingham

 

Food Microbial Sciences Unit

 

 

Science and Technology Centre, Earley Gate, University of Reading,

Whiteknights Road, Reading, Berkshire, UK. RG6 6BZ

 

 

Contents

 

 

Introduction

Gut Microbiology

Factors affecting the Human Gut Microflora

Antibacterial Drugs

Age as a factor affecting the Gut Microflora

The Autistic Human Gut Microflora

Candida spp

The Herxheimer Reaction

Considerations of Gluten and Casein Removal

Clostridia and Autism

Sulphate Reducing Bacteria

Dermorphin and Deltorphin

Treatments

Probiotics, Prebiotics and Synbiotics

Probiotics

The alternative approach - prebiotics

Synbiotics

Relevance to Autistic Symptoms

On going research at Reading

Summary

References

 

Introduction

 

Research to date has suggested that there may be a link between the

development of autistic symptoms and an abnormal human gut

microflora. It has been shown previously, that autistic subjects tend

to exhibit an elevated level of yeasts (particularly Candida spp)

(Shaw, Kassen & Chaves, 1995) and/or certain gut anaerobes in their

lower intestines. Other reports have suggested that the onset of

certain Autistic Spectrum Disorders may be related to the occurrence

of otitis media (ear infections) (Kontstantareas & Homatidis, 1987)

or maybe other typical childhood illnesses. It is common to treat

this sort of infection with some sort of broad-spectrum antibiotic.

Intestinal overgrowth of yeast and certain anaerobic bacteria are a

well documented outcome of administration of broad spectrum

antibiotics (Kennedy & Volz, 1983; Danna et al, 1991; Ostfield et al,

1977; Kinsman et al, 1989; Van der Waaij, 1987; Samsonis et al, 1993,

1994a,b).

 

While the onset of otitis media/ other childhood illnesses and the

occurrence of a yeast/ selected gut anaerobe overgrowth may not be

the cause of autistic symptoms, it appears there may be a link.

Products of the human gut microflora in relation to autism and its

symptoms appear to have been largely ignored in the past. However

they appear to be relevant certainly in terms of yeast species and

certain gut anaerobes.

 

This report will outline the currently available evidence for a

possible link between the development of autistic symptoms and

abnormal human gut microflora. It will consider the roles species may

take in this development and consider methods currently available

that may help treat these abnormalities and as a result help

alleviate the severity of some symptoms seen in autism.

 

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 (Figure 1).

 

 

 

 

 

 

Figure 1: Location of the Human Gut Microflora

 

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.

 

 

 

 

 

 

 

 

Figure 2: A micrograph of human faeces showing various bacteria and

food particles

 

 

 

Figure 3: The major groups of bacterial species found in the human

gut with some functions described

 

 

 

Figure 4: The alternative view of the human gut microflora

 

Factors affecting the Human Gut Microflora

 

The population of bacteria in the gastro-intestinal tract is

determined by a great variety of factors. The most important of these

factors are drugs, disease, age and diet. The consequences of these

factors may be wide and varied. Figure 5 shows many of the factors.

 

 

 

 

 

 

Figure 5: Factors affecting the Human Gut Microflora (Adapted from

Mallet and Rowland, 1988)

 

Antibacterial Drugs

 

The use of antibiotics, particularly via the oral route, often

results in the suppression of some, though not all, components of the

human gut microflora. This suppression will depend upon the

antibiotic used and partly on the resistance of the bacteria in the

gut. Once established, the gut microflora exhibits a remarkable

stability in terms of a dynamic equilibrium. It is a major factor in

preventing the establishment of potentially pathogenic or exogenous

organisms. This is colonisation resistance. This factor can be

significantly disrupted through the use of antibiotics. The strictly

anaerobic components of the microflora appear to be the most crucial

to the maintenance of colonisation resistance (Van der Waaij, 1979)

 

Age as a factor affecting the Gut Microflora

 

At birth the gut exhibits sterility but becomes rapidly colonised by

microorganisms passed from the mother and from the environment.

Lactobacillus spp and Bifidobacterium spp reach high numbers

initially. Shortly after birth, facultative anaerobes such as

Streptococcus spp and E.coli can be detected. This population remains

fairly stable during suckling. With the introduction of solid food,

major changes occur as strict anaerobes such as Bacteroides spp gain

supremacy. These changes may significantly affect the susceptibility

of the infant to foreign substances. Any disruption to the gut

microflora might therefore affect the development of the child. The

use of antibiotics could affect this balance of gut microflora.

 

The Autistic Human Gut Microflora

 

Many autistic subjects exhibit a range of gut disorders. These can

include diarrhoea, constipation, gas retention and abnormal faeces.

Imbalances in the gut microflora may be responsible for these

problems. Research into the characteristics of the autistic human gut

microflora has been extremely limited. 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 may be implicated. These include certain yeasts

(Candida spp), certain clostridia may be important and most recently

it is thought that sulphate reducing bacteria could be included in

this list. Controlling the growth of these organisms may help to

alleviate some symptoms of autism.

 

Candida spp

 

Candida normally constitutes only a very small proportion of the

human gut microflora. Competitive inhibition and certain immune

functions 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 spp. Elevated yeast

metabolites such as tartaric acid and arabinose appear to be

relatively common in autism. The arabinose appears to be involved in

abnormal protein binding which may adversely affect neuron connection

and this may have relevance to the appearance of autistic symptoms

(Sell & Monnier, 1989; Shaw et al, 1999). Given the intolerance that

autistic subjects appear to have to gluten and casein, an involvement

of arabinose and pentosidine formation may be important. However the

exact biochemical role of arabinose remains unclear.

 

Tartaric acid from a yeast overgrowth may have a direct toxic effect

on muscles and is a key inhibitor of the Krebs cycle that supplies

raw materials for gluconeogenesis (Shaw, Cassen & Chaves, 1995). The

implications of this appear to be detrimental to autistic function.

Furthermore, it has been shown that Candida albicans can produce

gliotoxins (Shah & Larsen, 1991, 1992) and immunotoxins (Podorski et

al, 1989; Witken, 1985), which may have further relevance to the

development of autisitic symptoms.

 

Over 160 species of Candida have been identified (Barnett et al,

1990). They are described as ovoid budding yeasts that typically

reproduce vegetatively and may exhibit hyphae. Figures 6 and 6a are

micrographs demonstrating certain characteristics of Candida.

 

 

 

Figure 6: An ovoid budding Candida cell. Micrograph from

http://research.amnh.org/exhibitions/epidemic/microbes.html

 

 

 

Figure 6a: Candia exhibiting hyphae and reproducing vegetatively

http://www.medsch.wisc.edu/medmicro/myco/Images/c_albicans.html

 

Six Candida species have been implicated as human pathogens. Candida

albicans and Candida tropicalis are thought to cause the majority of

Candida infections. Clinical manifestations of a Candida overgrowth

vary widely but can include fatigue, mood lability, depression,

inability to concentrate, headaches, loss of energy, food cravings,

mould sensitivity and multiple food and chemical intolerances. In

children, chronic recurrent infections are common and these often

require antibiotics. Carbohydrate cravings and central nervous system

dysfunction are also seen (Kroker, 1987).

 

Candida albicans may interfere with immune function at a number of

levels. This can include interfence with correct Candida antigen

presentation by macrophages; secretion of hyphal substances;

subsequent release of by-products and toxins into circulation and

this generalised impairment in cellular immunity may encourage

further development of Candida colonisation.

 

The metabolic and toxic potential of Candida albicans includes the

capacity to produce multiple toxins. Many yeast organisms can

metabolise sugars to pyruvate and this in turn is anaerobically

converted to acetaldehyde and carbon dioxide. Chronic CO2 production

may account for the persistent bloating and gas noted clinically by

many patients with chronic candidiasis. Some strains of Candida can

reduce acetaldehyde to ethanol. This would be rapidly absorbed and

contribute to a raised blood alcohol level and state of chronic

alcohol intoxication can ensue. It may be that chronic acetaldehyde

production is important. Truss (1984) proposes that this may be

responsible for multiple central nervous system dysfunctions through:

 

Acetaldehyde induced loss of red blood cell flexibility with

resultant diminished oxygen tissue delivery.

Acetaldehyde binding to amine groups of neurotransmitters.

Acetaldehyde oxidation leading to a chronically elevated NADH/NAD

ratio with multiple potential neuronal metabolic problems.

Vitamin deficiencies are commonly seen with a Candida overgrowth.

Lowered vitamin B6 and B2 are most often seen. This could conceivably

contribute to multiple symptoms including fatigue, depression,

neuropathic problems, heightened oedema formation and additional

metabolic dysfunction.

 

Clinical expression of fatty acid deficiency is often seen in-

patients with candidiasis. Galland (1985) reported nearly 66% of

candidiasis patients he studied had two or more clinical signs of

fatty acid deficiency. Non-specific signs such as dry stiff hair, dry

scaly skin, brittle nails and follicular dermatitis where noted in

many of these patients.

 

 

 

Figure 7: A model of Candidiasis (adapted from Kroker, 1987)

 

Shaw et al (1999) speculated that many of the symptoms of autism

might be related to an overgrowth of Candida and a selective IgA

deficiency. Treatment with anti-fungal drugs and a gluten and casein

free diet led to the improvement in symptoms seen in a severely

autistic child. In further work Shaw (1999) was able to show that

children exhibiting autistic features have increased excretion of

abnormal metabolites (citramalic, tartaric and 3-oxoglutaric acids).

It was speculated the source of these might be yeasts. Gas

Chromatograpy/ Mass Spectrometry was used to evaluate the urinary

content of metabolites on autistic subjects following the

administration of Nystatin. Urinary tartaric acid declined to zero

after 60 days. Associated changes included improvement in eye

contact, a reduction in hyperactivity and an improvement in sleep

patterns. When Nystatin dose was cut to half, levels rose and the

improvement regressed.

 

The Herxheimer Reaction

 

Following the start of anti-fungal treatment, patients often exhibit

a transient worsening of symptoms. 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.

 

Considerations of gluten and casein removal

 

It is commonly found that children with autism experience an

improvement in symptoms following the removal of these proteins. Many

systems have been proposed for the success of this intervention.

Certain Candida spp are known to secrete enzymes including

phospholipase and proteases. This might have consequences for gut

permeability. It is also known that the mycelium and chlamydospore of

certain strains are capable of tissue invasion. This would have

significant and important consequences for food absorption and

digestion. This may be important for autistic symptoms.

 

Clostridia and Autism

 

Bolte (1998) outlined the possibilty 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 opportunistic 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 transporting 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

 

Sulphate Reducing Bacteria

 

These strictly anaerobic bacteria are spherical, ovoid, rod-shaped,

spiral, or vibrioid shaped. They are 0.4 to 3.0 m m in length and

occur singly, in pairs or sometimes as aggregates. This group of

bacteria has the capacity to reduce sulphate to H2S. These bacteria

can metabolise both hydrogen (from the fermentation of other

bacteria) and sulphate (from dietary sources). The products are

sulphite and/or hydrogen sulphide (H2S). Hydrogen sulphide is a toxic

gas with a characteristic smell of rotten eggs.

 

Sulphation problems in autism have been proposed for many years now.

Waring (2001) has shown that around 95% of autistic children have low

serum sulphate, about 15% of that found in control children. This is

seen as significant since sulphation is required in the inactivation

of certain neurotransmitters in the brain involved in the modulation

of mood and behaviour. Reduced sulphation also affects the mucin

proteins that line the gastrointestinal tract and this finding is

linked with increased gut permeability and inflammatory bowel

disease.

 

The important question remains of why autistic children tend to

exhibit such low levels of serum sulphate. Waring (2001) outlined the

possibility the cytokines, which are peptides produced in

inflammatory processes, may be responsible. It was found that

autistic children often have high cytokine levels, and this would

have the indirect effect of greatly reducing the production of

sulphate. Continuing Waring (2001) describes other studies that shown

many autistic children excrete high levels of sulphite in the urine.

 

This raises the possibility that sulphate-reducing bacteria in the

gut have a role in this process. These strains of bacteria would have

the capacity to reduce levels of sulphate in the gut by metabolising

it to H2S and/or sulphite particularly if the population levels are

abnormally high. No research has been completed to date and this

remains pure speculation. However, it seems inevitable that these

bacteria would have some role to play in this process and may

therefore be of importance in the development of the symptoms of

autism.

 

Dermorphin and Deltorphin

 

The concept of a gluten and casein free diet for alleviating the

symptoms of autism is accepted now as relevant intervention. However

more recent research into this has raised the possibility of a role

for dermorphin and deltorphin in autistic symptomology.

 

In unpublished work, Friedman (2000) has found dermorphin and

deltorphin in the urine of autistic children. Dermorphin and

deltorphin are compounds which until now had only been found in the

skin secretions of certain frogs belonging to the genus

Phyllomedusinae. These include poison dart frogs which have been used

for their hallucinogenic properties and also for tipping darts to

stun targets. These compounds have been estimated to be many times

more potent than morphine on a molar basis. Of great interest is the

fact that these compounds are only generated on the skin of these

frogs when they are in the wild, but not when raised in captivity

outside their natural environment. It is possible that these products

might be the consequence of a bacteria or fungal organism on the

skin. Since dermorphin and deltorphin have been found in urine from

autistic children, it is possible that a bacterial species or fungal

organisms are responsible for generating such substances. In support

of this, the amino acid form is the D enantiomer and therefore of non-

human origin.

 

It has been suggested by Friedman (2000) that autistic children are

deficient in dipeptydyl peptidase IV which appears to be responsible

for breaking down morphine related peptides in the gut. The absence

of this enzyme might be responsible for the failure to break down

these opiate peptides. There are two possibilites for this

dysfunction - the enzyme is missing or the enzyme is being inhibited.

The bacteria responsible for producing these opiates may be present

ubiquitously. However, since autistic children are known to have

significant gastro-intestinal problems, it might be that dermorphin

and deltorphin are absorbed abnormally and affect the central nervous

system. We will have to wait for data to be published before this

hypothesis can be reviewed and verified. No research has been

completed thus far and so this remains somewhat speculative.

 

Treatments

 

Many interventions and treatments have been suggested previously.

These include pharmacological treatment, dietary interventions,

nutritional supports and phytochemical preparations. Many remain

unresearched and questionable in terms of their effectiveness.

 

Approaches towards Candida Infection

 

Antifungal therapy is an exceedingly important part of treatment.

Nystatin or Diflucan are examples of anti-fungal treatment. This will

remove the Candida infection but does not affect bacteria in the gut.

Nutritional management is required such that food substrates known to

stimulate Candida spp are limited in the diet. Since a Candida

infection can induce certain nutritional deficiencies,

supplementation is often useful.

 

Approaches towards an overgrowth of gut bacteria outlined above

 

There are limited possibilities. Antibiotics are about the only

option. However, these may not work since some are now resistant to

antibiotics. Also, since antibiotics are thought to have been a root

cause of many problems, a reoccurrence of infection may be an

outcome.

 

Probiotics, Prebiotics and Synbiotics

 

It has been speculated that autistic symptoms and imbalances in the

human gut microflora may be linked. This raises the possibility that

some autistic symptoms may be managed effectively through dietary

procedures that target the gut microflora. Reports suggest that these

products have been used as part of interventions aimed at alleviating

symptoms of autism.

 

Probiotics

 

These are a live microbial feed supplement which beneficially affects

the host (Fuller, 1989). Examples include lactobacilli and

bifidobacteria. Many strains are used including Lactobacillus

acidophillus, Lactobacillus caesi Shirota and Bifidobacterium

bifidum. The choice of strain and the number of strains used varies

considerably between products. Various mechanisms have been proposed

for their success including the production of short-chained fatty

acids, lowering of gut pH, competition for nutrients, competition for

mucosal adhesion sites, production of antimicrobials (bacteriocins),

modulation of the immune system, modulation of the human gut

microflora and modification of microbial enzyme activities.

 

However the success of probiotics is seen as limited for a number of

reasons. Initially there is a question of survivability in the

product. Often the nutritional environment and transportation

conditions mean that many cells are non-vialble by the time the

product is consumed. Often the products are not aesthetically

pleasing i.e. taste, smell and mouth feel are not pleasent. This also

raises a question over their use in infants. A major barrier to

success is that the bacteria must survive the extreme conditions of

the stomach (i.e gastric acid gives a stomach pH of about 2) and the

small intestines (where bile and pancreatic secretions mean survival

is questionable. The residual population of ingested bacteria then

have to compete with the resident bacteria of the large intestine

where it is questionable whether such a limited population would

survive.

 

The alternative approach - prebiotics

 

These are non-digestible food ingredients that selectively stimulate

a limited number of bacteria in the colon, to improve host health

(Gibson and Roberfroid, 1995)

 

 

 

Figure 8: Characteristics of prebiotic ingredients

 

 

 

Figure 9: The Bifidobacterium Barrier. Activities resulting from

promotion of bifidobacteria

 

Recognised prebiotics in Europe include:

 

Fructo-oligosaccharides

Lactulose

Trans-oligosaccharides

Prebiotics under evaluation

 

Soybean oligosaccharides

Lactosucrose

Xylo-oligosaccharides

Isomalto-oligosaccharides

Gluco-oligosaccharides

Second generation prebiotics

Multifunctional prebiotics

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. Importantly, prebiotics can inhibit pathogen

colonisation in the gut by competitive inhibition. Some reported

health benefits of prebiotics include prevention of gut infections,

reduced risk of colon cancer, reduction in cholesterol and blood

lipids and increased bioavailability of minerals. Applications for

prebiotics include (currently) beverages and fermented milks, health

drinks and spreads, infant formulae and weaning foods, cereals,

biscuits and food supplements. Table sugar, candy, frozen yoghurt,

ready to eat puddings, drinks, vinegar, biscuits, sausages, powdered

drinks and chocolate are all typical vehicles for prebiotics in

Japan.

 

Synbiotics

 

Synbiotics are a combination of probiotics and prebiotics. They may

allow for the dual benefits of both applications to be promoted while

reducing the limitations. Appropriate prebiotic use should enhance

probiotic survival. Much research is currently ongoing and certain

products are now available in Europe. Symbalance, enriched yoghurt

from the Swiss dairy company Tonilait, was one of the first

synbiotics. It contains three probiotic strains and the branded

prebiotic Raftiline from Orafti. More recent launches include Jour

apres Jour, a UHT skimmed milk enriched with vitamins, trace elements

of micronutrients and the branded soluble fiber Actilight from Beghin

Meiji Industries. The European Commission's Scientific Committee on

Food (SCF) has approved Actilight, made up of fructo-oligosaccharides

obtained from beets. It is said to have technical functions similar

to sugar, such as water retention; high viscosity; stability at

different temperatures; and a stable pH level.

 

German companies have also been active in developing these synbiotic

products. Bauer launched Probiotic Plus Oligofructose, which contains

two probiotic strains and the prebiotic, Raftilose. In addition,

prebiotics are suitable for a wider application range than

probiotics, such as the recently launched Ligne Bifide range from

Vivis in France, which includes biscuits, soups and ready meals that

contain Actilight.

 

Relevance to Autistic Symptoms

 

Recolonisation of the gut with beneficial bacteria is the aim

following the removal of pathogenic bacteria (outlined above).

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 (synbiotics) 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 is reduced.

 

On going research at Reading

 

Major themes include, molecular tracking of the human gut microflora,

the fermentation process, gastrointestinal health and disease, in-

vitro human gut modelling and isolation and development of specific

probiotics, prebiotics and synbiotics. Research into autism, until

recently, was not an area that the Food Microbial Sciences Unit has

been involved with. However, over the past year we have been

reviewing on-going research in the area. We now view this as an

important area of gut microbiology. We are currently involved with a

collaberative research project aimed at characterising about 140

faecal bacterial isolates from autistic children. We have also been

investigating the proliferation of Candida species in in vitro human

gut models and have been able to isolate and characterise a bacterial

species with possible anti-candidal properties. It is hoped that by

the end of 2001, the Food Microbial Sciences Unit will be in a

position to launch a full research programme looking at the human gut

microflora and autism.

 

Summary

 

Some autistic symptoms may be the result of unusual gut flora

activity. Certain yeast and gut anaerobe species may be responsible.

The release of toxins and other unusual metabolites may result in the

development of some autistic characteristics. This raises the

possibility of managing some symptoms through dietary techniques

aimed at the gut microflora. Probiotics, prebiotics and synbiotics

may help alleviate the severity of some autistic symptoms.

 

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Candida Archive

 

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