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Shannon Thomas
Dr. Jeffrey
BIOL 230
April 30, 2014



The relevance of intestinal microflora in autism

Gut and behavior

There is increasing scientific awareness of a link between intestinal health and behavior. Signals
travel back and forth from the gut to the brain via the vagus nerve. Healthy communication via this nerve
pathway is essential for optimum functioning in any human being. This communication not only
maintains digestive and nutritional balance, but hormonal levels and immune system function. If this
complex system is not working properly, there will be alterations in the stress-response and overall
behavior. (Cryan & OMahony, 2011)

The presence of microorganisms is normal in the digestive system. However, studies are
revealing some specific types of microbial overgrowths that are common in children with autistic
symptoms. In children on the autism spectrum, gut abnormalities and chronic dysfunction are quite
common. There is a connection between the overall condition of the digestive system and the presentation
of symptoms in autistic patients. These symptoms range from severe dietary/or GI problems including
abdominal pain, constipation, diarrhea, and bloating to more subtle behavioral presentations. These
symptoms may be due to the disruption of the indigenous gut flora promoting the overgrowth of
potentially pathogenic microorganism. (Kauna-Czapliska & Baszczyk, 2012) These studies not only
show a correlation between the amount of microbial overgrowth with the severity of behavioral
symptoms, but have been able to show improvement of behavioral symptoms with treatment for the
overgrowth.




Candida and Autism
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Of particular significance is Candida, a naturally occurring yeast in the digestive tract. While
Candida is a normal presence in the body, when there is an overgrowth, it can be a problematic organism.
First, in any person with a Candida overgrowth, there will be toxins released by the yeast as it goes
through its life cycle. These toxins are known to impair the central nervous system and the immune
system. If this overgrowth is chronic, this damage can be severe. Studies in Japan show that some
Candida toxins can cause severe long-term disruption of the immune system and may also attack the
brain. In extreme cases, they claim, severe disorders, totally resistant to conventional treatment, can
occur as a result of candidiasis. These include depression, schizophrenia and, in some cases, autism.
(Mehl-Medrona, n.d.)
Candida albicans is of particular concern. C.albicans produces ammonia as a metabolite.
Propionic acid is produced by the body during the breakdown of certain amino acids. If propionic acid is
in the presence of ammonia metabolites in the gastrointestinal tract, it could be converted to beta-alanine
(C3H9NO2). (Burrus, 2012) Beta-alanine is almost identical to GABA, an inhibitory neurotransmitter
which has been shown to be present in higher quantities in autistic patients. Beta-alanine could possibly
block GABA receptors in the brain, leading the body to over produce GABA to maintain equilibrium.

Neuroinflammation

In addition to the possible link with GABA production, there is a connection with autism and
inflammation in the brain linked to Candida. Results of animal testing show that Candida not only slows
the healing of inflammation, but that its growth is aided by the inflammation itself. Candida colonization
is associated specifically with pro-inflammatory cytokine IL-17. This particular cytokine induces the
recruitment of neutrophils in response to the presence of a microbial antigen. Research at Johns Hopkins
University shows autistic patients have increased activity and inflammation in the astroglial and
microglial cells of the brain, the CNSs first line of defense against infection. This increased activity and
inflammation is occurring without other common signs of infection, like lymphocyte infiltration or the
presence of immunoglobulin in the CNS. Neuroimmune reactions and cytokines in the cerebrospinal
fluid were consistent in all autistic patients studied. In autism, there is NO evidence of lymphocyte
infiltration or antibody mediated reactions; the most prominent immune response is characterized by
activation of microglia and astrocytes, features that characterize innate immune responses within the
CNS. These observations suggest that the adaptive immune system does not play a significant pathogenic
role in this disorder, at least not during its chronic phase, and that the main immune mechanism involves
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predominantly innate immune reactions ("FAQs: The Meaning of Neuroinflammatory Findings in
Autism," n.d.)

Symptoms and pathogenesis

General symptoms

Candida overgrowth is not pleasant for anyone. The overgrowth of Candida in the gut can lead
to a myriad of symptoms, which include but are not limited to: chronic fatigue, especially after an
increase in body temperature, depression, gastrointestinal problems such as: bloating, gas, intestinal
cramps, chronic diarrhea, constipation, or heartburn, allergies (including both food and airborne).
(Kauna-Czapliska, Grys, Rozetti-Szymaska, & Rynkowski, 2013) The toxins released by Candida as
it eats, multiplies, and dies can make anyone sick.

Autism related symptoms

In patients with autism, Candida overgrowth is not only particularly common, but particularly
problematic. Goodwin et al studied 15 randomly selected children with autism and found that 6 had
either bulky, odorous, or loose stools or intermittent diarrhea; one had celiac disease. In a recent study,
43% of the autistic patients without symptoms or evidence of any gastrointestinal disease had altered
intestinal permeability. (Horvath, Papadimitriou, Rabsztyn, Drachenberg, & Tildon, 1999) This altered
intestinal permeability, or leaky gut, in addition to the presence of peptides, microbial toxins, and other
possible antigens, is a leading theory in autism research.

Complications/outcome

Abnormal or damaged intestines

It is unclear whether intestinal abnormalities are present in all children with autism. However,
digestive issues are prevalent.The most frequently detected abnormalities in children with autistic
disorder included a high prevalence of reflux esophagitis, hyperplasia of duodenal Paneths cells,
intestinal carbohydrate digestive enzyme deficiencies, and an unusual hypersecretory response to
intravenous secretin administration. (Horvath, Papadimitriou, Rabsztyn, Drachenberg, & Tildon, 1999)
These abnormalities make autistic patients more digestively fragile than a normal person, and can
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contribute to imbalances of normal occurring gut flora. These imbalances can then contribute to further
damage to the digestive system. Many autistic patients show signs of chronic gastrointestinal
inflammation. In colonoscopies with histologic examinations on 12 children on the autism spectrum, all
had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. In (the)
study chronic inflammation of the esophagus, stomach, and duodenum was the major and most consistent
finding. (Horvath, Papadimitriou, Rabsztyn, Drachenberg, & Tildon, 1999) Of particular interest is the
hyperplasia (overproduction) of Paneths cells, which produce and release substances such as lysozyme,
defensins,15 and 1-antitrypsin. Defensins, specifically human intestinal defensin 5, have antimicrobial
activities against Candida albicans.

Methods of diagnosis

There are two main methods for detecting Candida overgrowth and other gut flora imbalances. These are
urine testing and fecal testing.

Urine testing for Candida

Microbial metabolites can be found in the urine of autistic patients. Darabinitol is the main
metabolite characteristic of several Candida species. The urine D to Larabinitol concentration ratio
reflects the same ratio in blood. There is evidence that elevated levels of D-arabinitol in urine or serum is
a positive indication of Candida overgrowth. Its extraction in urine is elevated in many autistic patients.

Fecal testing for other microflora

Pyrosequencing has proven very useful in determining the specific flora in the digestive system.
It is a method of DNA sequencing based on "sequencing by synthesis. This involves taking a single
strand of the DNA to be sequenced and then synthesizing its complementary strand enzymatically. The
pyrosequencing method is based on detecting the activity of DNA polymerase (a DNA synthesizing
enzyme) with another chemiluminescent enzyme. In a study by Finegold et al, the fecal microbial flora
were studied of 33 subjects with various severities of autism with gastrointestinal symptoms, 7 siblings
not showing autistic symptoms (sibling controls) and eight non-sibling control subjects, using the
bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP) procedure. Results of that study provided
a compelling picture of unique fecal microflora of children with autism with gastrointestinal symptoms.
Bacteroidetes and Firmicutes showed the most difference between groups of varying severities of
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autism. Bacteroidetes was found at high levels in the severely autistic group, while Firmicutes were more
predominant in the control group. Smaller, but significant, differences also occurred in the
Actinobacterium and Proteobacterium phyla. Desulfovibrio species and Bacteroides vulgatus are present
in significantly higher numbers in stools of severely autistic children than in controls. If the unique
microbial flora is found to be a causative or consequent factor in this type of autism, it may have
implications with regard to a specific diagnostic test, its epidemiology, and for treatment and prevention.
(Finegold et al., 2010)

Treatments

If a Candida overgrowth is detected, major methods of treatment include anti-fungals, probiotic
therapy, dietary modifications, and supplements.

Antifungals

Doctors have observed a decrease in urinary organic acids as well as decreases in hyperactivity and self-
stimulatory, stereotyped behavior; and increases in eye contact, vocalization, and concentration, when
autistic children were given anti-fungal drugs. Potent anti-fungals such as Diflucan or Nizoral can have
side effects for the liver. Liver function is often monitored on a monthly basis. If anti-fungal treatment
must continue beyond a six month period, some physicians will switch to the use of Amphoteracin-B.
During anti-fungal treatment, something often called yeast die-off will occur. This consists of
sensitization reaction to products released when the yeast is killed that can contribute to negative
symptoms in a patient, including hyperactivity, gastrointestinal distress, and irritability. Die-off can last
for 1-2 weeks, with a dramatic improvement after symptoms subside.

Probiotics

Probiotic therapy can help correct dysbiosis and decrease gut permeability. It has also been
shown to reduce the amount of D-arabinitol in the urine. There is building clinical evidence to show
probiotic therapy can improve behavioral symptoms, not just physical, reducing stress responses and
improving mood. Lactobacillus helveticus and Bifidobacterium longum on both human subjects and rats
showed that these probiotics reduced anxiety in animals and had beneficial psychological effects with a
decrease in serum cortisol in patients. Some probiotics also have the potential to lower inflammatory
cytokines, which are an issue in the nervous system of many autistic patients. Distinct improvement in
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concentration and following directions have been observed, while the influence of (probiotic)
supplementation on behavioral reactions to other peoples emotions or eye contact is not so distinct.
(Kauna-Czapliska & Baszczyk, 2012)

Dietary modifications

If leaky gut does play a role in autism in some patients, dietary changes can be helpful. Some of
these changes could include controlling the levels of propionic acid (a common food preservative),
sugars, and other food items that help C. albicans thrive, and possibly avoiding other fungus and yeasts.
Other allergens and sources of inflammation should also be avoided, to reduce the damage and over-
permeability of the intestines. There are consumable non-prescription substances that have anti-candida
effects, such as caprylic acid, garlic oil, colloidal silver, and other over the counter substances, some of
which have been used to treat candida for hundreds of years.


Prevention and control

Screenings could be developed in the future, such as newborn testing for sensitivity to propionic
acid and/or beta-alanine, or a test for sensitivity to C. albicans. Efforts can be made to maintain proper gut
flora balance by avoiding overuse of antibiotics, eating a healthy diet, and taking preventative probiotics.
It has been suggested that children showing a sensitivity to fungus and yeast take preventative anti-
fungals as well, but this has not been studied.






References

Brown, A. C., & Mehl-Madrona, L. (2011). Autoimmune and gastrointestinal dysfunctions: Does a subset
of children with autism reveal a broader connection? Expert Review of Gastroenterology &
Hepatology, 5(4), 465-477. doi: 10.1586/egh.11.46
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Burrus, C. J. (2012). A biochemical rationale for the interaction between gastrointestinal yeast and
autism. Medical Hypotheses, 79(6), 784-785. doi: 10.1016/j.mehy.2012.08.029
Cryan, J. F., & OMahony, S. M. (2011). The microbiome-gut-brain axis: From bowel to behavior.
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