A Microbial Association with Autism
Jorge L. Benach, Ellen Li, and Margaret M. McGovern
Departments of Molecular Genetics and Microbiology, Medicine and Pediatrics, Stony Brook University, Stony Brook, New York, USA
spectrum disorders (ASD), which are a heterogeneous group
etiologies. Understanding the pathophysiology of the GI clinical
symptoms in ASD is important for the early identification of GI
pathology and for guiding therapy.
The diagnosis of ASD is primarily based upon behavioral cri-
teria, rather than physical examination findings or laboratory
tests. Criteria include impaired social interactions, deficits in ver-
bal and nonverbal communication, and repetitive behaviors. The
specific diagnostic criteria for ASD are detailed in the American
Psychiatric Association’s Diagnostic and Statistical Manual of
Mental Disorders (DSM-IV) and define three subgroups of ASD.
These include autistic disorder (AD), Asperger syndrome (AS),
and pervasive developmental disorder-not otherwise specified
(PDD-NOS), or atypical autism (1). Signs of autism may be pres-
until after the second year of life, when they frequently come to
medical attention due to language delay. In others, there is a pe-
riod of essentially normal development followed by regression (2,
3). Medical comorbidities can appear at any age. Over the past
several decades, heightened awareness of the signs and symptoms
of autism among physicians, parents, and educators has led to
documentation of a prevalence rate for ASD as high as 1 in 110
8-year-old children (4). Since there is evidence for a beneficial
effect of early intervention in children with ASD, the American
Academy of Pediatrics (AAP) recommends screening for autism
tributed to an increased recognition of ASD.
make it difficult for patients to articulate their medical com-
illness that can present as nonspecific abdominal pain or as an
escalation of disruptive or self-injurious behavior. Therefore,
caregivers must have a high index of suspicion to provide prompt
and appropriate medical evaluations for GI manifestations.
Given the high prevalence of ASD, it is hardly surprising that
studies suggest that genetic factors do play an important role in
ASD. Progress in identifying these genetic factors has been ad-
vanced by the availability of DNA banks that facilitate genetic
genetically visible chromosomal abnormalities and copy number
variants are detectable by chromosomal microarray analysis (5).
Another 5% of ASD are associated with single-gene disorders.
Genome-wide association studies and the investigation of candi-
date genes are being carried out in numerous research laborato-
ries. These studies have successfully identified a number of neu-
rodevelopmental candidate genes associated with autism (6).
Rightly or wrongly, the etiology of autism has also been asso-
ciated with vaccination. The public concern over the association
of childhood vaccines with autism is certainly subsiding, but dis-
pelling generally accepted dogma, albeit erroneous or fraudulent,
is difficult. Hornig et al. (7) found no evidence of measles virus in
the mumps-measles-rubella (MMR) vaccine is linked to autism.
In comprehensive reviews, the Institute of Medicine concluded
that that no such link exists (8, 9).
itated by delineating specific phenotypes within this heteroge-
neous group of patients. However, the identification of such phe-
notypes has proven to be challenging. These efforts may be aided
by the careful medical evaluation of patients with ASD to identify
patterns of medical comorbidities. Approaches for such evalua-
and the American College of Medical Genetics (10, 11).
Similarly, systematic approaches to evaluation of the medical
comorbidities in ASD will permit the identification of patients
with GI symptoms. These include variable combinations of con-
Published 14 February 2012
Citation Benach JL, Li E, McGovern MM. 2012. A microbial association with autism. mBio
Copyright © 2012 Benach et al. This is an open-access article distributed under the
terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported
License, which permits unrestricted noncommercial use, distribution, and reproduction
in any medium, provided the original author and source are credited.
Address correspondence to Jorge L. Benach, email@example.com.
January/February 2012 Volume 3 Issue 1 e00019-12
stipation, diarrhea, abdominal pain, gastroesophageal reflux, and
symptoms in ASD as high as 70%, although an AAP consensus
determine the actual prevalence of GI disorders in ASD and their
pathophysiologic basis (12). In their publication in mBio, Wil-
GI comorbidities by presenting evidence of Sutterella species in
but not from control children with GI symptoms, suggesting a
specific role for Sutterella in ASD.
A number of studies designed to assess the relationship be-
tween GI symptoms in ASD patients and the microbiome have
already disclosed some interesting trends. The human intestinal
microbiome is comprised of a large number of highly diverse
commensal bacteria that confer benefit to the host, including, for
example, bolstering the function of the immune system in early
interest has been generated regarding the role of the microbiome
as an arbiter of a number of inflammatory and metabolic abnor-
malities. The use of the term “arbiter” is deliberate since the rela-
tionship of the microbiome to “dysbiosis” is only by association,
and not as a cause or consequence of diseases. Indeed, metag-
enomics applied to the microbiome has shown the presence of
significant individual variability in intestinal tract microbiome
composition and the identification of enterotypes (14, 15).
In patients with ASD, an early study of fecal flora, which was
finding was confirmed in a second study that also showed a higher
(17). Other investigations of the fecal microbiome in patients with
group, whereas Firmicutes were higher in controls (18). Similarly,
While the previous reports have examined fecal specimens,
Williams and coworkers (20) took a new approach and included
intestinal gene expression and identification of the microbiota in
the intestinal mucoepithelium. Their study revealed deficiencies
ers among the ASD patient group. These deficiencies suggest that
impaired digestion and transport of intestinal carbohydrates may
contribute to ASD GI symptoms. Consistent with the notion that
the human intestine needed to degrade carbohydrates, there were
also changes in the microbiota identified among the ASD group.
Metagenomic analyses disclosed a significant dysbiosis with re-
Bacteroidetes, as well as in Betaproteobacteria.
Williams et al. (13) report detecting Sutterella 16S rRNA gene
sequences in ileal mucosal biopsy specimens from 12 of 23 pa-
specimens from 9 control children with GI symptoms. Sutterella
wadsworthensis sp. nov. was described 15 years ago from clinical
isolates from patients with infections that were below the dia-
phragm (21). In addition to the molecular taxonomy that Wil-
All of the children studied had GI symptoms severe enough to
warrant diagnostic colonoscopy as part of their clinical care, and
ileal and colonic mucosa. In some ASD patients, Sutterella se-
quences represented ~1 to 7% of the total bacterial sequences.
on the ileal mucosal composition, rivaling or even exceeding the
effect size of the ileal Crohn’s disease phenotype.
This study is very important for its use of mucoepithelial bi-
opsy specimens of children with ASD and GI dysfunction. Such
specimens are not easily available, and the information that they
likely to be of great significance. In addition, the use of a pediatric
population with GI dysfunction but no autism as the control
in ASD versus non-ASD subjects. Finally, the pan-microbial py-
rosequencing technologies that were used to separate the various
Sutterella species are very robust.
The results of this study provide a strong rationale to conduct
additional investigations of the microbiome in larger cohorts of
patients with ASD and GI symptoms compared to control GI
groups, as well as patients with ASD without GI manifestations
and normally developing children with no GI disturbances. For
the latter group, for whom intestinal biopsies are not indicated,
fecal samples could be examined. Furthermore, efforts should be
made to correlate the relative frequencies of Sutterella in ileal and
fecal samples in both ASD and normally developing subjects with
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