Content uploaded by Jon Rhoads
Author content
All content in this area was uploaded by Jon Rhoads on Dec 30, 2020
Content may be subject to copyright.
gastrointestinal problems such as abdominal pain,
constipation and diarrhea. In recent years, there has
been a growing interest in the use of probiotics in this
population, as it hypothetically may help to improve
bowel habits and the behavioral and social functioning
of these individuals. The gut microbiome plays an
important role in the pathophysiology of organic as
well as functional gastrointestinal disorders. Microbial
modification with the use of antibiotics, probiotics,
and fecal transplantation have been effective in the
treatment of conditions such as recurrent
Clostridium
difficile
infection, pouchitis, and irritable bowel
syndrome. The present review presents a number
of reported clinical, immunological and microbiome-
related changes seen in children with autism compared
to normally developed children. It also discusses gut
inflammation, permeability concerns, and absorption
abnormalities that may contribute to these problems.
Most importantly, it discusses evidence, from human
and animal studies, of a potential role of probiotics in
the treatment of gastrointestinal symptoms in children
with autism.
Key words: Microbiome; Gastrointestinal; Inflammation;
Functional bowel disease; Probiotics; Autism
© The Author(s) 2016. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: Important new information has identified an
abnormal intestinal microbial community in children
with autism, an abnormality reported in many gastro-
intestinal (GI) conditions, including inflammatory bowel
disease and irritable bowel syndrome (IBS). There
is a complex interplay in these conditions between
GI function (motility, secretion, permeability), the
immune system, and the microbiota. Many parents of
children with autism complain of GI symptoms, and
they administer probiotics, a treatment which has
been found to be safe and effective for adults with
IBS. Future investigations are needed to determine if
Fernando Navarro, Yuying Liu, Jon Marc Rhoads, Department
of Pediatrics, Division of Gastroenterology, the University of
Texas Health Science Center at Houston McGovern Medical
School, Houston, TX 77030, United States
Author contributions: Navarro F and Rhoads JM wrote the
manuscript; Liu Y performed the literature search, reviewed
manuscript, and added references.
Conflict-of-interest statement: Authors declare no conflict of
interests for this article.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited
and the use is non-commercial. See: http://creativecommons.
org/licenses/by-nc/4.0/
Manuscript source: Invited manuscript
Correspondence to: Jon Marc Rhoads, MD, Professor of
Pediatrics, Department of Pediatrics, the University of Texas
Health Science Center at Houston McGovern Medical School,
6431 Fannin Street, MSB 3.137, Houston, TX 77030,
United States. j.marc.rhoads@uth.tmc.edu
Telephone: +1-713-5005663
Fax: +1-713-5005770
Received: August 28, 2016
Peer-review started: September 1, 2016
First decision: September 20, 2016
Revised: October 5, 2016
Accepted: November 12, 2016
Article in press: November 13, 2016
Published online: December 14, 2016
Abstract
Ch ildre n with aut is m are co mmonl y affec ted b y
Submit a Manuscript: http://www.wjgnet.com/esps/
Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx
DOI: 10.3748/wjg.v22.i46.10093
10093 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
World J Gastroenterol 2016 December 14; 22(46): 10093-10102
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2016 Baishideng Publishing Group Inc. All rights reserved.
REVIEW
Can probiotics benefit children with autism spectrum
disorders?
Fernando Navarro, Yuying Liu, Jon Marc Rhoads
probiotic treatment would benefit the symptoms and
behavior of these children.
Navarro F, Liu Y, Rhoads JM. Can probiotics benefit children
with autism spectrum disorders? World J Gastroenterol 2016;
22(46): 10093-10102 Available from: URL: http://www.wjgnet.
com/1007-9327/full/v22/i46/10093.htm DOI: http://dx.doi.
org/10.3748/wjg.v22.i46.10093
IntroductIon
The inuence of the enteric microbiota on the human
body has only started to be unveiled. Its impact is
wide, as it has been shown to affect a number of
processes including the immune response, metabo-
lism, and neurologic function[1-3]. The disruption of the
normal commensal microbial community in humans,
also called “dysbiosis”, is associated with an increas-
ing number of disorders such as inammatory bowel
disease, irritable bowel syndrome, obesity, hyperten-
sion, diabetes, and autism[4-8]. The aim of the present
review is to synthetize current data on the association
between microbiota dysbiosis and autism, and to
assess if its modication could have a benecial effect
in children with autism.
GastroIntestInal abnormalItIes In
autIsm
Autism is a neurodevelopmental disorder which affects
social interaction, verbal and non-verbal communica-
tion, and behavior. A recent report from the Centers for
Disease Control and Prevention indicates a rise in the
prevalence of autism in children to one in 68 children
in the United States (78% increase since 2007)[9].
Children with autism spectrum disorders (ASD) are
among the populations that are most often referred to
the Pediatric Gastroenterology clinic. During a two-year
period, 3% (121/4013) of children seen by 4 pediatric
gastroenterologists for various abdominal complaints
in our clinic had an underlying ASD (C. Bearden, U.T.
Bioinformatics, personal communication 9-24-2016).
The true prevalence of gastrointestinal symptoms
(GIS) in ASD is not known, but available data suggest
a gure approximately 40%[10]. Wang et al[11] reported
data obtained from families with children with ASD
registered in the Autism Genetic Resource Exchange
(AGRE). In their study of 589 affected children, 42%
had GIS. Increased autism symptom severity was
associated with higher odds of having GIS[11]. Abdomi-
nal pain, constipation, diarrhea, nausea, and bloating
were the most common symptoms. In the largest
study, Mazurek et al[12] reported that of 2,973 children
in an ASD network, 42% reported GIS lasting > 3
mo. A wide range of gastrointestinal (GI) problems
have been reported, including feeding abnormalities,
gastroesophageal reflux, abdominal pain, diarrhea,
fecal incontinence, constipation, and alternating diar-
rhea and constipation have been reported in one out
of three children in the autism spectrum[13,14]. More
recently, based on a large epidemiological study,
eosinophilic esophagitis in children with ASD and
dysphagia has been added to the list of disorders with
increased risk in this population, compared to the gen-
eral population[15]. This group of children with autism
reportedly also has severe anxiety, irritability and social
withdrawal symptoms, which may overshadow their GI
complaints[16].
Some researchers such as Pusponegoro et al[17]
have reported no differences between children with
autism and controls with regard to gastrointestinal
symptoms, intestinal inflammation (based on fecal
calprotectin), microbiota (based on urinary D-lactate)
or intestinal permeability (based on urinary lactu-
lose/mannitol ratio). However, this group reported an
increased urinary I-FABP (marker of enterocyte dam-
age) in children with autism who had severe behavioral
abnormalities, compared with autistic children with
mild maladaptive behavior and compared with normal
children[17].
InflammatIon hypothesIs
A number of recent studies have suggested that the
GIS in ASD may be a manifestation of an underly-
ing inflammatory process. Systemic inflammation
has been suggested by an excessive accumulation
of receptors for advanced glycation end products
(RAGE) in blood and their proinflammatory ligand
S100A9 in the plasma of individuals with ASD[18]. The
level of S100A9 in plasma correlated with the autism
severity score. Another study hypothesized that the
inflammation may be pathophysiologically related to
an abnormal microbiota. They compared the metage-
nomic profile of ileal and colonic biopsies in children
with ASD, ulcerative colitis (UC), and Crohn’s disease
(CD). These investigators found that the transcriptome
profiles of these tissues of children with ASD segre-
gated apart from normal controls and alongside those
with CD and UC when they used principal components
analysis, as would be seen with an inamed colon[19].
However, the authors did not identify why these tissues
of ASD children had different transcriptional proles; for
example, they did not look for evidence of inammation
by assessing serum cytokines or fecal inflammatory
markers such as calprotectin or interleukin-8. Other
groups studying ASD have failed to show changes in gut
biopsy cytokine levels[20] or changes in fecal calprotec-
tin[21]. One must keep in mind that these studies were
small, and measurable abnormalities were observed in
a signicant subset of with ASD (approximately 25% of
those studied).
Enhanced T cell activation, heightened immuno-
globulin and cytokine profiles, as well as histologic
changes assessed in intestinal biopsies such as inltra-
10094 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Navarro F
et al
. Probiotics for children with autism
tion of lymphocytes, monocytes, natural killer cells
and eosinophils have been described in children with
autism[22-26]. These findings can be present in other
gastrointestinal conditions such as food allergies and
immunodeficiency[27]. In contrast, other laboratory
measures of intestinal health, such as fecal levels of
calprotectin, lactoferrin, secretory IgA, and elastase
have found to be normal in children with autism[21,28].
In addition, reports of intestinal permeability (IP) in
children with autism have been conflicting. Studies
have reported abnormal IP in these children compared
to controls[29,30]. Some have also reported increased
IP to occur in first degree relatives of patients with
autism et al[31]. In contrast, our group as well as others
(mostly in small series) have found that the intestinal
permeability of children with autism was not different
from normal controls[17,32-34].
A recent report indicated that children with autism
also have an abnormal carbohydrate digestion based
on significant decrease in the expression on their
intestinal biopsies of disaccharidases (sucrose-iso-
maltase, maltase-glucoamylase, and lactase), as well
as the hexose transporters (SGLT1 and GLUT-2)[35],
a finding which agreed with a previous uncontrolled
study[36]. This nding was not supported by extensive
observations of Kushak et al[37] from a center that
performs many intestinal biopsies. These investigators
had originally found that more than half of a group
of children with autism had low levels of the enzyme
lactase in duodenal biopsies[38]. However, in a follow-
up study which included neurotypical controls, mucosal
disaccharidase activity was not different comparing
autistic and nonautistic individuals. Interestingly, even
though the disaccharidases were within the normal
range, the investigators found that children with ASD
had evidence of mucosal inflammation on intestinal
biopsy. Standard fecal indicators of gut inammation,
fecal calprotectin and lactoferrin were similar in both
groups. A measure of gut permeability, lactulose/
rhamnose ratio in urine after oral administration, was
also not statistically different in patients with and with-
out autism. Larger controlled studies are required to
determine if the gastrointestinal symptoms in children
with autism are in fact related to reproducible, “organic”
ndings, such as intestinal inammation, to differen-
ces in nutrient digestion, or to an abnormal intestinal
permeability[27].
functIonal bowel dIsease
hypothesIs
Gastrointestinal symptoms in ASD may be simply a
reflection of sensory over-responsivity to abdominal
signals. However, in the authors’ opinion, the most
common gastrointestinal complaints in children with
ASD resemble those of adults and teens with func-
tional bowel diseases such as irritable bowel syndrome
(IBS). Irritable bowel syndrome is characterized by
symptoms of diarrhea and/or constipation, typically
with the relief of pain accompanying the passage of a
stool, symptoms which fulfill the Rome Ⅲ criteria[39].
Many children with ASD have diffuse abdominal pain
and an irregular stool pattern with either diarrhea or
constipation, or alternating diarrhea and constipation.
We have postulated that a significant proportion of
children with ASD and chronic GIS, have a form of IBS.
However, the Rome Ⅲ criteria are validated in adults
with normal IQ but are somewhat difcult to apply to
normal children, and even more so in those with ASD.
When compared to GI symptom scores in ASD, which
have been useful but are not validated, there is much
broader experience in quantifying autistic behavior
changes, such as irritability as measured by the Aber-
rant Behavior Checklist[40]. As mentioned, studies have
shown that the presence and severity of GI symptoms
correlate with the severity of underlying autism[11,28,41].
Gut mIcrobIome In autIsm
Trillions of microbes and 500-1000 species of microor-
ganisms are natural inhabitants of our gastrointestinal
tract, wherein the phyla Firmicutes, Bacteriodetes,
and Actinobacteria are the most common. Anaerobic
bacteria, yeasts, viruses, and bacteriophages (viruses
which reside and proliferate within bacteria) also inu-
ence the gut microbial diversity[42,43]. The gut microbi-
ome has a symbiotic interaction with the various organ
systems of our body, and it is known to contribute to
many GI functions, such as maintaining the integrity of
the epithelial barrier, stimulating immune interactions,
participating in gastrointestinal motility, and regulat-
ing drug and nutrient metabolism[44]. This normal
interaction can be disturbed by a number of events,
such as infections, gastrointestinal diseases, dietary
changes, and neurologic disorders. Drugs such as acid
suppressants, antibiotics, and corticosteroids have also
been reported to perturb this homeostatic equilibrium.
This dysbiosis contributes to the pathophysiology of
many gastrointestinal conditions such as inammatory
bowel disease, functional gastrointestinal disease, food
allergy, obesity, and liver disease[45].
The enteric microbiome of children with ASD is dif-
ferent from that of typically developed children. Abnor-
mal colonization could be related to diverse factors,
including a more restricted diet and exposure to more
antibiotic early in life. For example, two studies found
that children with ASD were more likely to be treated
with antibiotics for otitis media[46,47]. Finegold et al[48]
reported different levels of bacterial phyla in children
with ASD by pyrosequencing. When comparing autistic
children with controls there were changes in phyla
Firmicutes (63% vs 39%, respectively), Bacteriodetes
(30% vs 51%), Actinobacteria (0.7% vs 1.8%), and
Proteobacteria (0.5% vs 3.1%)[48]. In a different study,
this same group also reported the presence of non-
spore-forming anaerobes and microaerophilic bacteria
10095 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Navarro F
et al
. Probiotics for children with autism
in gastric and duodenal aspirates from children with
autism, organisms which were not present in control
children[48].
As mentioned, a less diverse microbial community
in gut of children with autism with lower levels of some
genera (Prevotella, Coprococcus and Veillonellacae)
has been reported. Interestingly, these particular spe-
cies are known to be versatile carbohydrate metaboliz-
ers; and in a controlled trial, reduced colonization
correlated with autistic symptoms but not with diet
pattern[49]. Other differences in individuals with ASD
include the overgrowth of Clostridium species, includ-
ing Clostridium histolyticum (linked to the presence of
GI symptoms in one study), and low levels of Bido-
bacteria, a species known to have anti-inammatory
effects[48,50,51].
Overgrowth of other bacteria such as Desulfovibrio
species has also been found in children with autism
and their relatives, compared to controls[52]. Addition-
ally, higher levels of Caloramator, Sarcina, Alistipes,
Akkermansia, Sutterellaceae and Enterobacteriaceae
were found in children with autism compared with
typically developed children[53,54]. Kang et al[49] reported
a less diverse fecal microbiome by pyrosequencing of
16S rDNA in children with autism. Despite these stud-
ies, it should be noted that when bacteria tag-encoded
pyrosequencing was used, Gondalia et al[55] did not nd
differences in the gut microbiome, comparing children
with autism with their siblings.
Much work needs to be done in determining the
metabolic consequences of an abnormal microbiota in
ASD. Bacterial by-products are the likely mediators of
systemic effects that could lead to alterations in the
children’s behavior. Some investigators have hypoth-
esized that the abnormal microbiota in children with
ASD produces changes in behavior via a mechanism
involving excessive production of short chain fatty
acids (SCFA), such as propionate and butyrate, which
represent the major anions of human feces. These
SCFA can produce behavioral changes in rodents when
injected into the brain ventricles or systemically via
intermediates such as p-cresol that alter dopamine
metabolism[56]. Ongoing investigations have begun to
highlight the importance of SCFA in ASD[57,58].
tarGetInG the Gut mIcrobIome
as a potentIal treatment for
chIldren wIth autIsm
Probiotics
The internationally accepted definition of probiotics
is “live microorganisms which when administered
in adequate amounts confer a health benefit on the
host”. Dietary prebiotics are “selectively fermented
ingredients that allows specific changes, both in the
composition and/or activity in the gastrointestinal
microora that confers benets upon host well-being
and health”. The potentially synergistic combinations of
10096 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
pro- and prebiotics are called synbiotics[59]. Functional
bowel disorders (including IBS, functional abdominal
pain, functional dyspepsia, and cyclic vomiting syn-
drome) are the most common conditions leading to
referral of children to the pediatric gastroenterology
clinic[60]. Recent evidence suggests that an abnormal
fecal microbiota may play a causal or contributory role
to IBS in adults[61] and children[62].
In adults with a functional GI disorders, there is
accumulating evidence for a benecial effect of probiot-
ics. Evidence for probiotic efcacy in IBS now includes
23 randomized controlled trials (RCTs) (2575 patients)
and the demonstration of improvement in global
symptoms, abdominal pain, bloating and flatulence;
however there was heterogeneity among the studies
and authors concluded the optimal probiotic has not
been identied[63]. In the most recent meta-analysis,
which included 21 RCT’s, a 1.82-fold (CI: 1.27-2.60)
relative rate of improvement vs placebo was noted[64].
Fewer studies have been done in children; the only
systematic review concluded that 4 probiotics were
associated with improvement in symptoms in children
with IBS: L. rhamnosus GG, L. reuteri DSM 17938,
VSL#3, and a combination probiotic containing 3
Bidobacteria[65].
The differences in the gut microbiome comparing
autistic and typically developed children described in
the previous section may provide a clue to the cause
for GI symptoms. One early study of vancomycin, a
poorly absorbed antibiotic known to destroy Clostridia
and other gram positive organisms, demonstrated an
improvement in diarrhea and more normal behavior,
as evidenced by videotape, when vancomycin was
given short-term[66]. As mentioned, the gut microbi-
ome can be altered by the use of antibiotics, prebiot-
ics, probiotics, or synbiotics (prebiotics plus probiotics)
administered by physicians or parents to ameliorate
symptoms in children with ASD[57,67-69].
Virtually all of the GI functions postulated to be
impaired in ASD have been shown to be improved by
probiotics in animal studies. For example, we previous-
ly found that a human breast milk and gut commensal,
Lactobacillus. reuteri, when fed daily, reduced lipopoly-
saccharide (LPS)-induced intestinal inammation[70]. In
newborn rat pups, another probiotic, Bidobacterium
bifidum reduced gut permeability across the tight
junctions that “seal together” the epithelial cells in a
model of necrotizing enterocolitis[71]. A recent study by
Bufngton et al[72], which aimed to study mechanisms
of abnormal behavior in autism, utilized a maternal
high fat diet to induce abnormal social (withdrawal)
behavior in the offspring. It is worthy to mention that
in humans, too, maternal obesity[73,74], and maternal
diabetes[75] been shown to be linked to autism in the
offspring. In the mice, high-fat maternal diet produced
changes in neurotransmission in the hypothalamus
of the newborns. Abnormal behavior was found to be
correctable by co-housing “autistic pups” with normal
infant pups whose mothers did not take a high fat diet,
Navarro F
et al
. Probiotics for children with autism
Table 1 Evidence supporting a role for probiotics in treating gastrointestinal symptoms in autism spectrum disorders
indicating a microbial effect which was evidenced by
a change in microbiota. Following this hypothesis, the
authors found that by administering a probiotic, Lacto-
bacillus reuteri, the antisocial behaviors and aberrant
neurotransmission could be reversed[72].
The lay press and internet have certainly embraced
the concept that gut bacteria are linked to autism. A
particularly fascinating recent publication from Pärtty
et al[76] randomized 75 infants at birth to a supplement
of Lactobacillus rhamnosus GG (LGG) or placebo for
the first 6 mo of life and measured microbiota and
psycho-behavioral diagnoses 2 and 13 years later.
They found no major changes in microbiota. However,
at the age of 13, 17% of the children treated with
placebo had attention deficit disorder or Asperger’s
syndrome, compared to none who received LGG.
Recent reviews concluded that probiotics should be
studied in children with ASD[50,77]. Our interpretation
of the rationale for probiotic investigation in ASD is
summarized in Table 1. However, it is controversial
whether oral probiotics can produce positive effects
in such a complex condition. Currently available
probiotics are mainly aerobic, derived from milk
cultures, not normally a signicant part of the human
gut microbiome which are primarily anaerobic; and
they are short-lived in the human gut. Kristensen
et al[78] looked at normal humans given probiotics and
showed in a meta-analysis of 6 RCTs limited to adults
that there was no change in alpha-diversity (number
of species) or evenness with probiotic treatment.
One trial did show a change in beta-diversity (relative
contributions of the various species)[78]; however,
virtually all studies which have shown changes in fecal
microbial composition during probiotic administration
were done in babies, for example preterm infants[79,80].
One study that did show that a probiotic could alter
the fecal microbiota focused on older children with
cystic brosis[81] and another showed changes in adults
with alcoholic cirrhosis[82]. Most of these trials used
quantitative polymerase chain reaction (PCR), rather
than 16S ribosomal RNA gene sequencing. Using 16S
rRNA techniques, we[83] and others[78] have not shown
differences in microbial composition in adults treated
with probiotics. The same lack of effect on the infant’s
fecal microbiome was observed in a number of studies
of infants whose mothers were treated with probiotics
before birth and/or during breast feeding[84-86].
Therefore, alternative mechanisms may account
for potentially benecial effects of probiotics in IBS and
possibly ASD. An important alternative mechanism by
which a probiotic be beneficial is via the metabolites
that these organisms release in the gut lumen which
may reach the circulating blood. A number of studies
have shown abnormal fecal metabolites, such as
short chain fatty acids (SCFA) related to changes in
microbiota[87]. Para-cresol (a phenolic compound) has
been suggested to be a urinary marker for autism[88],
especially in those with constipation and ASD[89]. In a
mouse model of autism induced by maternal immune
activation, autistic behaviors such as communication
abnormalities, stereotypies, and anxiety behaviors
were associated with abnormal serum metabolities
produced by the microbiota, including 4-ethylphenyl
sulfate (the major metabolite) and p-cresol (to a
lesser extent)[57]. These abnormalities and some of
the behaviors were improved by giving orally a human
commensal B. fragilis (not traditionally viewed as a
probiotic). In a biomarker discovery study in 52 young
children with ASD who were compared to neurotypical
controls, a number of plasma markers were found to
be altered, many of them were directly related to mito-
chondrial metabolism. These included elevated succinic
acid, aspartate, glutamate, and aminoisobutyrate and
decreased citric acid, isoleucine, and creatinine[90].
Despite these gaps in our knowledge regarding “if
and why” probiotics may work in autism, in a recent
survey of more than 500 physicians who treat children
with autism, 19% reported using probiotics[91]. Many
autism websites also advocate treatment of children
with ASD with probiotics. These recommendations
are not evidence-based. A recent review summarized
the existing 4 trials of probiotics for ASD[92]. There
were methodological difculties in most; for example,
one was a case-control study that had a high risk of
selection bias which showed improvement in mental
concentration (but not in behavior) in ASD patients
treated with Lactobacilus acidophilus[93]. Another man-
uscript which was included as part of a retrospective
10097 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Clinical symptoms Ref.
Children with ASD have an abnormal fecal microbiota [28,35,48,51,54,98-100]
GI symptoms common in ASD are similar to those in IBS [11,12]
IBS also is associated with an abnormal fecal microbiota [61,62,101]
Meta-analysis shows IBS symptoms are improved by probiotic treatment. (Preliminary evidence suggests potential benets in
ASD in children and rodents models.)
[65,72,102-104]
Mild inammation in the GI tact may be seen in children with ASD. (There is evidence to support or refute this contention:
abnormal duodenal and ileal biopsies and high plasma S100A9 but normal fecal calprotectin and lactoferrin levels)
[19,22-26,31,37]
Probiotics reduce gut inammation (Shown in animal models and in human diseases) [70,105-108]
Systemic inammation can be also seen in children with ASD [18,109-111]
Immune modulation of children with ASD may reduce clinical symptoms [41,112]
ASD: Autism spectrum disorders; GI: Gastrointestinal; IBS: Irritable bowel syndrome.
Navarro F
et al
. Probiotics for children with autism
case-cohort analysis, reported that probiotic treatment
improved an autism treatment evaluation checklist,
although the authors did not report which probiotics
were given and which dose[28]. A third study was a
double-blind placebo-controlled crossover trial which
reported reduced disruptive behavior, anxiety and
communicative disturbance when the children were on
probiotic (Lactobacillus plantarum) but is not readily
available in reference libraries[94]. A 4th study reported
benecial effects of a 4-mo treatment with a combina-
tion probiotic (comprising 3 Lactobacilli, 2 Bidobacilli,
and 1 Streptococcus species). In this latter study, the
probiotic increased the qPCR-determined ratio of fecal
Bifidobacilli to Firmicutes and total Lactobacilli, while
reducing fecal Clostridia and fecal tumor necrosis
factor (TNF)-alpha levels. This latter study did suggest
benecial effects on the microbiome, although effects
of this combination probiotic on autistic behaviors were
not reported[77].
Fecal microbiota transplantation
In children and adults with severe gastrointestinal
diseases, such as Clostridium difficile (C. difficile)-
associated colitis or inammatory bowel disease, fecal
microbiota transplantation (FMT) had the potential for
more signicant and prolonged effects. FMT was effec-
tive in many cases of antibiotic-associated C. difcile
colitis and is now used around the world for severe
or multiply recurrent C. difcile infection, and it may
have a role in the treatment of inflammatory bowel
disease (particularly Crohn's disease) and autoimmune
conditions. However, fecal transplantation carries many
risks, including aspiration, transmission of norovirus,
bacteremia, induction of obesity, and possible trans-
mission of autoimmune conditions, including rheuma-
toid arthritis and Sjogren’s syndrome[95,96]. We do not
believe this treatment will have a role in the treatment
of gastrointestinal symptoms in autism, although
there may be successful reductionist approaches,
for example combinations of defined communities of
culturable commensal organisms, such as those used
in the “RePOOPulate” studies in Canada, in which 33
carefully selected isolates from healthy donors were
able to eradicate C. difficile from patients who had
encountered multiple recurrences[97].
conclusIon
Gastrointestinal symptoms in children with autism
are common and are often linked to the children’s
abnormal behavior and social interactions. Probiotics
are hypothesized to positively impact gut microbial
communities and alter the levels of specic potentially
harmful metabolites in children with ASD. Whether
probiotics improve behavior and these markers has yet
to be determined. Although the evidence presented
in this review does not confirm benefit of probiotics
in this population, it provides a solid rationale for the
design of larger prospective trials.
references
1 Collins S M, Surette M, Bercik P. The interplay between the
intestinal microbiota and the brain. Nat Rev Microbiol 2012; 10:
735-742 [PMID: 23000955 DOI: 10.1038/nrmicro2876]
2 Wang Y, Kasper LH. The role of microbiome in central nervous
system disorders. Brain Behav Immun 2014; 38: 1-12 [PMID:
24370461 DOI: 10.1016/j.bbi.2013.12.015]
3 O’Hara AM, Shanahan F. Gut microbiota: mining for therapeutic
potential. Clin Gastroenterol Hepatol 2007; 5: 274-284 [PMID:
17368226]
4 Gevers D, Kugathasan S, Denson LA, Vázquez-Baeza Y, Van
Treuren W, Ren B, Schwager E, Knights D, Song SJ, Yassour
M, Morgan XC, Kostic AD, Luo C, González A, McDonald D,
Haberman Y, Walters T, Baker S, Rosh J, Stephens M, Heyman
M, Markowitz J, Baldassano R, Griffiths A, Sylvester F, Mack D,
Kim S, Crandall W, Hyams J, Huttenhower C, Knight R, Xavier
RJ. The treatment-naive microbiome in new-onset Crohn’s disease.
Cell Host Microbe 2014; 15: 382-392 [PMID: 24629344 DOI:
10.1016/j.chom.2014.02.005]
5 Morgan XC, Tickle TL, Sokol H, Gevers D, Devaney KL, Ward
DV, Reyes JA, Shah SA, LeLeiko N, Snapper SB, Bousvaros A,
Korzenik J, Sands BE, Xavier RJ, Huttenhower C. Dysfunction
of the intestinal microbiome in inflammatory bowel disease and
treatment. Genome Biol 2012; 13: R79 [PMID: 23013615 DOI:
10.1186/gb-2012-13-9-r79]
6 Vindigni SM, Zisman TL, Suskind DL, Damman CJ. The
intestinal microbiome, barrier function, and immune system
in inflammatory bowel disease: a tripartite pathophysiological
circuit with implications for new therapeutic directions. Therap
Adv Gastroentero l 2016; 9: 606-625 [PMID: 27366227 DOI:
10.1177/1756283X16644242]
7 Barbara G, Feinle-Bisset C, Ghoshal UC, Quigley EM,
Santos J, Vanner S, Vergnolle N, Zoetendal EG. The Intestinal
Microenvironment and Functional Gastrointestinal Disorders.
Gastroenterology 2016; Epub ahead of print [PMID: 27144620
DOI: 10.1053/j.gastro.2016.02.028]
8 Shen J, Obin MS, Zhao L. The gut microbiota, obesity and insulin
resistance. Mol Aspects Med 2013; 34: 39-58 [PMID: 23159341
DOI: 10.1016/j.mam.2012.11.001]
9 Centers for Disease Contro and Prevention. Identified Prevalence
of Autism Spectrum Disorder. 2016 Available from: URL: http://
www.cdc.gov/ncbddd/autism/data.html
10 Valicenti-McDermott M, McVicar K, Rapin I, Wershil BK, Cohen
H, Shinnar S. Frequency of gastrointestinal symptoms in children
with autistic spectrum disorders and association with family history
of autoimmune disease. J Dev Behav Pediatr 2006; 27: S128-S136
[PMID: 16685179]
11 Wan g LW, Tancredi DJ, Thomas DW. The prevalence of
gastrointestinal problems in children across the United States with
autism spectrum disorders from families with multiple affected
members. J Dev Behav Pediatr 2011; 32: 351-360 [PMID:
21555957 DOI: 10.1097/DBP.0b013e31821bd06a]
12 Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D,
Keefer A, Murray DS, Freedman B, Lowery LA. Anxiety, sensory
over-responsivity, and gastrointestinal problems in children with
autism spectrum disorders. J Abnorm Child Psychol 2013; 41:
165-176 [PMID: 22850932 DOI: 10.1007/s10802-012-9668-x]
13 Horvath K, Perman JA. Autism and gastrointestinal symptoms.
Curr Gastroenterol Rep 2002; 4: 251-258 [PMID: 12010627]
14 Molloy CA, Manning-Courtney P. Prevalence of chronic
gastrointestinal symptoms in children with autism and autistic
spectrum disorders. Autism 2003; 7: 165-171 [PMID: 12846385]
15 Heifert TA, Susi A, Hisle-Gorman E, Erdie-Lalena CR, Gorman G,
Min SB, Nylund CM. Feeding Disorders in Children With Autism
Spectrum Disorders Are Associated With Eosinophilic Esophagitis.
J Pediatr Gastroenterol Nutr 2016; 63: e69-e73 [PMID: 27276430
10098 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Navarro F
et al
. Probiotics for children with autism
DOI: 10.1097/MPG.0000000000001282]
16 Nikolov RN, Bearss KE, Lettinga J, Erickson C, Rodowski M,
Aman MG, McCracken JT, McDougle CJ, Tierney E, Vitiello B,
Arnold LE, Shah B, Posey DJ, Ritz L, Scahill L. Gastrointestinal
symptoms in a sample of children with pervasive developmental
disorders. J Autism Dev Disord 2009; 39: 405-413 [PMID:
18791817]
17 Pusponegoro HD, Ismael S, Sastroasmoro S, Firmansyah
A, Vandenplas Y. Maladaptive Behavior and Gastrointestinal
Disorders in Children with Autism Spectrum Disorder. Pediatr
Gastroenterol Hepatol Nutr 2015; 18: 230-237 [PMID: 26770897
DOI: 10.5223/pghn.2015.18.4.230]
18 Boso M, Emanuele E, Minoretti P, Arra M, Politi P, Ucelli di Nemi
S, Barale F. Alterations of circulating endogenous secretory RAGE
and S100A9 levels indicating dysfunction of the AGE-RAGE axis
in autism. Neurosci Lett 2006; 410: 169-173 [PMID: 17101220
DOI: 10.1016/j.neulet.2006.08.092]
19 Walker SJ, Fortunato J, Gonzalez LG, Krigsman A. Identification
of unique gene expression profile in children with regressive
autism spectrum disorder (ASD) and ileocolitis. PLoS One 2013; 8:
e58058 [PMID: 23520485 DOI: 10.1371/journal.pone.0058058]
20 DeFelice ML, Ruchelli ED, Markowitz JE, Strogatz M, Reddy
KP, Kadivar K, Mulberg AE, Brown KA. Intestinal cytokines
in child ren with pe rv asive de velop me ntal dis order s. Am J
Gastroenterol 2003; 98: 1777-1782 [PMID: 12907332 DOI:
10.1111/j.1572-0241.2003.07593.x]
21 Fernell E, Fagerberg UL, Hellström PM. No evidence for a clear
link between active intestinal inflammation and autism based
on analyses of faecal calprotectin and rectal nitric oxide. Acta
Paediatr 2007; 96: 1076-1079 [PMID: 17465982]
22 Ashwood P, Anthony A, Pellicer AA, Torrente F, Walker-
Smith JA, Wakefield AJ. Intestinal lymphocyte populations in
children with regressive autism: evidence for extensive mucosal
immunopathology. J Clin Immunol 2003; 23: 504-517 [PMID:
15031638]
23 Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous
mucosal lymphocyte cytokine profiles in children with autism
and gastrointestinal symptoms: mucosal immune activation and
reduced counter regulatory interleukin-10. J Clin Immunol 2004;
24: 664-673 [PMID: 15622451]
24 Ashwood P, Wakefield AJ. Immune activation of peripheral blood
and mucosal CD3+ lymphocyte cytokine profiles in children with
autism and gastrointestinal symptoms. J Neuroimmunol 2006; 173:
126-134 [PMID: 16494951]
25 Fu rl an o RI, Anthony A, Day R, Brown A, McGarvey L,
Thomson MA, Davies SE, Berelowitz M, Forbes A, Wakefield
AJ, Walker-Smith JA, Murch SH. Colonic CD8 and gamma
delta T-cell infiltration with epithelial damage in children with
autism. J Pediatr 2001; 138: 366-372 [PMID: 11241044 DOI:
10.1067/mpd.2001.111323]
26 Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony
A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA,
Murch SH. Small intestinal enteropathy with epithelial IgG and
complement deposition in children with regressive autism. Mol
Psychiatry 2002; 7: 375-382, 334 [PMID: 11986981]
27 Buie T, Campbell DB, Fuchs GJ, Furuta GT, Levy J, Vandewater
J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, Carr EG,
Gershon MD, Hyman SL, Jirapinyo P, Jyonouchi H, Kooros K,
Kushak R, Levitt P, Levy SE, Lewis JD, Murray KF, Natowicz
MR, Sabra A, Wershil BK, Weston SC, Zeltzer L, Winter H.
Evaluation, diagnosis, and treatment of gastrointestinal disorders
in individuals with ASDs: a consensus report. Pediatrics 2010; 125
Suppl 1: S1-S18 [PMID: 20048083]
28 Adams JB, Johansen LJ, Powell LD, Quig D, Rubin RA.
Gastrointestinal flora and gastrointestinal status in children with
autism--comparisons to typical children and correlation with autism
severity. BMC Gastroenterol 2011; 11: 22 [PMID: 21410934 DOI:
10.1186/1471-230X-11-22]
29 Boukthir S, Matoussi N, Belhadj A, Mammou S, Dlala SB,
Helayem M, Rocchiccioli F, Bouzaidi S, Abdennebi M. [Abnormal
intestinal permeability in children with autism]. Tunis Med 2010;
88: 685-686 [PMID: 20812190]
30 D’Eufemia P, C elli M, Finocchi aro R, Pacifico L , Viozzi L ,
Zaccagnini M, Cardi E, Giardini O. Abnormal intestinal permeability
in children with autism. Acta Paediatr 1996; 85: 1076-1079 [PMID:
8888921]
31 de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A,
Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G,
Militerni R, Bravaccio C. Alterations of the intestinal barrier in
patients with autism spectrum disorders and in their first-degree
relatives. J Pediatr Gastroenterol Nutr 2010; 51: 418-424 [PMID:
20683204]
32 Dalton N, Chandler S, Turner C, Charman T, Pickles A, Loucas
T, Simonoff E, Sullivan P, Baird G. Gut permeability in autism
sp ectru m dis order s. Autism Res 201 4; 7: 305 -313 [PM ID :
24339339 DOI: 10.1002/aur.1350]
33 Navarro F, Pearson DA, Fatheree N, Mansour R, Hashmi SS,
Rhoads JM. Are ‘leaky gut’ and behavior associated with gluten
and dairy containing diet in children with autism spectrum
disorders? Nutr Neurosci 2015; 18: 177-185 [PMID: 24564346
DOI: 10.1179/1476830514Y.0000000110]
34 Souza NC, Mendonca JN, Portari GV, Jordao Junior AA, Marchini
JS, Chiarello PG. Intestinal permeability and nutritional status in
developmental disorders. Altern Ther Health Med 2012; 18: 19-24
[PMID: 22516881]
35 Williams BL, Hornig M, Buie T, Bauman ML, Cho Paik M, Wick
I, Bennett A, Jabado O, Hirschberg DL, Lipkin WI. Impaired
carbohydrate digestion and transport and mucosal dysbiosis in the
intestines of children with autism and gastrointestinal disturbances.
PLoS One 2011; 6: e24585 [PMID: 21949732 DOI: 10.1371/
journal.pone.0024585]
36 Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C,
Tildon JT. Gastrointestinal abnormalities in children with autistic
disorder. J Pediatr 1999; 135: 559-563 [PMID: 10547242 DOI:
S0022-3476(99)70052-1]
37 Kushak RI, Buie TM, Murray KF, Newburg DS, Chen C,
Nestoridi E, Winter HS. Evaluation of Intestinal Function in
Children With Autism and Gastrointestinal Symptoms. J Pediatr
Gastroenterol Nutr 2016; 62: 687-691 [PMID: 26913756 DOI:
10.1097/MPG.0000000000001174]
38 Kusha k RI, Lauwers GY, Winter HS, Buie TM. Intestinal
disaccharidase activity in patients with autism: effect of age,
gender, and intestinal inflammation. Autism 2011; 15: 285-294
[PMID: 21415091 DOI: 10.1177/1362361310369142]
39 Gijsbers CF, Benninga MA, Schweizer JJ, Kneepkens CM,
Vergouwe Y, Büller HA. Validation of the Rome III criteria and
alarm symptoms for recurrent abdominal pain in children. J
Pediatr Gastroenterol Nutr 2014; 58: 779-785 [PMID: 24866784
DOI: 10.1097/MPG.0000000000000319]
40 Aman MG, Singh NN. Aberrant Behavior Checklist: Community
Supplementary Manual. 1994; East Aurora, NY: Slosson
Educational Publications
41 Schneider CK, Melmed RD, Barstow LE, Enriquez FJ, Ranger-
Moore J, Ostrem JA. Oral human immunoglobulin for children
with autism and gastrointestinal dysfunction: a prospective, open-
label study. J Autism Dev Disord 2006; 36: 1053-1064 [PMID:
16845577 DOI: 10.1007/s10803-006-0141-y]
42 Ianiro G, Bruno G, Lopetuso L, Beghella FB, Laterza L, D’Aversa
F, Gigante G, Cammarota G, Gasbarrini A. Role of yeasts in
healthy and impaired gut microbiota: the gut mycome. Curr Pharm
Des 2014; 20: 4565-4569 [PMID: 24180411]
43 Lepage P, Leclerc MC, Joossens M, Mondot S, Blottière HM,
Raes J, Ehrlich D, Doré J. A metagenomic insight into our gut’
s microbiome. Gut 2013; 62: 146-158 [PMID: 22525886 DOI:
10.1136/gutjnl-2011-301805]
44 Sommer F, Bäckhed F. The gut microbiota--masters of host
development and physiology. Nat Rev Microbiol 2013; 11: 227-238
[PMID: 23435359 DOI: 10.1038/nrmicro2974]
45 Cammarota G, Ianiro G, Bibbò S, Gasbarrini A. Gut microbiota
modulation: probiotics, antibiotics or fecal microbiota transplantation?
10099 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Navarro F
et al
. Probiotics for children with autism
Intern Emerg Med 2014; 9: 365-373 [PMID: 24664520 DOI:
10.1007/s11739-014-1069-4]
46 Konstantareas MM, Homatidis S. Ear infections in autistic and
normal children. J Autism Dev Disord 1987; 17: 585-594 [PMID:
3680158]
47 Niehus R, Lord C. Early medical history of children with autism
spectrum disorders. J Dev Behav Pediatr 2006; 27: S120-S127
[PMID: 16685178]
48 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. Gastrointestinal microflora studies in late-onset autism. Clin
Infect Dis 2002; 35: S6-S16 [PMID: 12173102 DOI: 10.1086/
341914]
49 Kang DW, Park JG, Ilhan ZE, Wallstrom G, Labaer J, Adams
JB, Krajmalnik-Brown R. Reduced incidence of Prevotella and
other fermenters in intestinal microflora of autistic children. PLoS
One 2013; 8: e68322 [PMID: 23844187 DOI: 10.1371/journal.
pone.0068322]
50 Critchfield JW, van Hemert S, Ash M, Mulder L, Ashwood P. The
potential role of probiotics in the management of childhood autism
spectrum disorders. Gastroenterol Res Pract 2011; 2011: 161358
[PMID: 22114588 DOI: 10.1155/2011/161358]
51 Song Y, Liu C, Finegold SM. Real-time PCR quantitation of
clostridia in feces of autistic children. Appl Environ Microbiol
2004; 70: 6459-6465 [PMID: 15528506]
52 Finegold SM. Desulfovibrio species are potentially important in
regressive autism. Med Hypotheses 2011; 77: 270-274 [PMID:
21592674 DOI: 10.1016/j.mehy.2011.04.032]
53 De Angelis M, Piccolo M, Vannini L, Siragusa S, De Giacomo
A, Serrazzanetti DI, Cristofori F, Guerzoni ME, Gobbetti M,
Francavilla R. Fecal microbiota and metabolome of children
with autism and pervasive developmental disorder not otherwise
specified. PLoS One 2013; 8: e76993 [PMID: 24130822 DOI:
10.1371/journal.pone.0076993]
54 Finegold SM, Dowd SE, Gontcharova V, Liu C, Henley KE,
Wolcott RD, Youn E, Summanen PH, Granpeesheh D, Dixon D,
Liu M, Molitoris DR, Green JA. Pyrosequencing study of fecal
microflora of autistic and control children. Anaerobe 2010; 16:
444-453 [PMID: 20603222 DOI: 10.1016/j.anaerobe.2010.06.008]
55 Gondalia SV, Palombo EA, Knowles SR, Cox SB, Meyer D, Austin
DW. Molecular characterisation of gastrointestinal microbiota of
children with autism (with and without gastrointestinal dysfunction)
and their neurotypical siblings. Autism Res 2012; 5: 419-427 [PMID:
22997101 DOI: 10.1002/aur.1253]
56 Louis P. Does the human gut microbiota contribute to the etiology
of autism spectrum disorders? Dig Dis Sci 2012; 57: 1987-1989
[PMID: 22736019 DOI: 10.1007/s10620-012-2286-1]
57 Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue
T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson
PH, Mazmanian SK. Microbiota modulate behavioral and
physiological abnormalities associated with neurodevelopmental
disorders. Cell 2013; 155: 1451-1463 [PMID: 24315484 DOI:
10.1016/j.cell.2013.11.024]
58 Wang L, Conlon MA, Christophersen CT, Sorich MJ, Angley MT.
Gastrointestinal microbiota and metabolite biomarkers in children
with autism spectrum disorders. Biomark Med 2014; 8: 331-344
[PMID: 24712423 DOI: 10.2217/bmm.14.12]
59 de Vrese M, Schrezenmeir J. Probiotics, prebiotics, and synbiotics.
Adv Biochem Eng Biotechnol 2008; 111: 1-66 [PMID: 18461293
DOI: 10.1007/10_2008_097]
60 Barad AV, Saps M. Factors influencing functional abdominal pain
in children. Curr Gastroenterol Rep 2008; 10: 294-301 [PMID:
18625141]
61 Carroll IM, Ringel-Kulka T, Siddle JP, Ringel Y. Alterations
in composition and diversity of the intestinal microbiota in
patients with diarrhea-predominant irritable bowel syndrome.
Neurogastroenterol Motil 2012; 24: 521-530, e248 [PMID:
22339879 DOI: 10.1111/j.1365-2982.2012.01891.x]
62 Saulnier DM, Riehle K, Mistretta TA, Diaz MA, Mandal D, Raza
S, Weidler EM, Qin X, Coarfa C, Milosavljevic A, Petrosino JF,
Highlander S, Gibbs R, Lynch SV, Shulman RJ, Versalovic J.
Gastrointestinal microbiome signatures of pediatric patients with
irritable bowel syndrome. Gastroenterology 2011; 141: 1782-1791
[PMID: 21741921 DOI: 10.1053/j.gastro.2011.06.072]
63 Ford AC, Quigley EM, Lacy BE, Lembo AJ, Saito YA, Schiller
LR, Soffer EE, Spiegel BM, Moayyedi P. Efficacy of prebiotics,
probiotics, and synbiotics in irritable bowel syndrome and chronic
idiopathic constipation: systematic review and meta-analysis. Am
J Gastroenterol 2014; 109: 1547-1561; quiz 1546, 1562 [PMID:
25070051 DOI: 10.1038/ajg.2014.202]
64 Zhang Y, Li L, Guo C, Mu D, Feng B, Zuo X, Li Y. Effects of
probiotic type, dose and treatment duration on irritable bowel
syndrome dia gno sed by Rome II I criteria: a met a-a nalysis.
BM C Gastro enter ol 2016; 16 : 62 [PMID: 27296254 DOI:
10.1186/s12876-016-0470-z]
65 Giannetti E, Staiano A. Probiotics for Irritable Bowel Syndrome:
Clinical Data in Children. J Pediatr Gastroenterol Nutr 2016;
63 Suppl 1: S25-S26 [PMID: 27380595 DOI: 10.1097/MPG.
0000000000001220]
66 Sandler RH, Finegold SM, Bolte ER, Buchanan CP, Maxwell AP,
Väisänen ML, Nelson MN, Wexler HM. Short-term benefit from
oral vancomycin treatment of regressive-onset autism. J Child
Neurol 2000; 15: 429-435 [PMID: 10921511]
67 Bested AC, Logan AC, Selhub EM. Intestinal microbiota,
probiotics and mental health: from Metchnikoff to modern
advances: part III - convergence toward clinical trials. Gut Pathog
2013; 5: 4 [PMID: 23497650 DOI: 10.1186/1757-4749-5-4]
68 Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J. Mood
and gut feelings. Brain Behav Immun 2010; 24: 9-16 [PMID:
19481599 DOI: 10.1016/j.bbi.2009.05.058]
69 Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi
A, Bisson JF, Rougeot C, Pichelin M, Cazaubiel M, Cazaubiel
JM. Assessment of psychotropic-like properties of a probiotic
formulation (Lactobacillus helveticus R0052 and Bifidobacterium
longum R0175) in rats and human subjects. Br J Nutr 2011; 105:
755-764 [PMID: 20974015 DOI: 10.1017/S0007114510004319]
70 Liu Y, Fatheree NY, Mangalat N, Rhoads JM. Human-derived
probiotic Lactobacillus reuteri strains differentially reduce
intestinal inflammation. Am J Physiol Gastrointest Liver Physiol
2010; 299: G1087-G1096 [PMID: 20798357]
71 Khailova L, Dvorak K, Arganbright KM, Halpern MD, Kinouchi
T, Yajima M, Dvorak B. Bifidobacterium bifidum improves
intestinal integrity in a rat model of necrotizing enterocolitis. Am J
Physiol Gastrointest Liver Physiol 2009; 297: G940-G949 [PMID:
20501441]
72 Buffington SA, Di Pr is co GV, Auch tu ng TA, Aj am i NJ ,
Petrosino JF, Costa-Mattioli M. Microbial Reconstitution
Reverses Maternal Diet-Induced Social and Synaptic Deficits in
Offspring. Cell 2016; 165: 1762-1775 [PMID: 27315483 DOI:
10.1016/j.cell.2016.06.001]
73 Getz KD, Anderka MT, Werler MM, Jick SS. Maternal Pre-
pregnancy Body Mass Index and Autism Spectrum Disorder
among Offspring: A Population-Based Case-Control Study.
Paediatr Perinat Epidemiol 2016; 30: 479-487 [PMID: 27239935
DOI: 10.1111/ppe.12306]
74 Li M, Fallin MD, Riley A, Landa R, Walker SO, Silverstein M,
Caruso D, Pearson C, Kiang S, Dahm JL, Hong X, Wang G, Wang
MC, Zuckerman B, Wang X. The Association of Maternal Obesity
and Diabetes With Autism and Other Developmental Disabilities.
Pediatrics 2016; 137: e20152206 [PMID: 26826214 DOI:
10.1542/peds.2015-2206]
75 Nahum Sacks K, Friger M, Shoham-Vardi I, Abokaf H, Spiegel
E, Sergienko R, Landau D, Sheiner E. Prenatal exposure to
gestational diabetes mellitus as an independent risk factor for
long-term neuropsychiatric morbidity of the offspring. Am J
Obstet Gynecol 2016; 215: 380.e1-380.e7 [PMID: 27018463 DOI:
10.1016/j.ajog.2016.03.030]
76 Pärtty A, Kalliomäki M, Wacklin P, Salminen S, Isolauri E. A
10100 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Navarro F
et al
. Probiotics for children with autism
possible link between early probiotic intervention and the risk
of neuropsychiatric disorders later in childhood: a randomized
trial. Pediatr Res 2015; 77 : 823-828 [PMID: 25760553 DOI:
10.1038/pr.2015.51]
77 Tomov a A, Husarova V, Lakatosova S, Bakos J, Vlko va B,
Babinska K, Ostatnikova D. Gastrointestinal microbiota in children
with autism in Slovakia. Physiol Behav 2015; 138: 179-187 [PMID:
25446201 DOI: 10.1016/j.physbeh.2014.10.033]
78 Kristensen NB, Bryrup T, Allin KH, Nielsen T, Hansen TH,
Pedersen O. Alterations in fecal microbiota composition by
probiotic supplementation in healthy adults: a systematic review
of randomized controlled trials. Genome Med 2016; 8: 52 [PMID:
27159972 DOI: 10.1186/s13073-016-0300-5]
79 Panigrahi P, Parida S, Pradhan L, Mohapatra SS, Misra PR,
Johnson JA, Chaudhry R, Taylor S, Hansen NI, Gewolb IH. Long-
term colonization of a Lactobacillus plantarum synbiotic preparation
in the neonatal gut. J Pediatr Gastroenterol Nutr 2008; 47: 45-53
[PMID: 18607268 DOI: 10.1097/MPG.0b013e31815a5f2c]
80 Underwood MA, Kalanetra KM, Bokulich NA, Lewis ZT,
Mir miran M, Tancredi DJ, Mills DA. A comparison of two
probiotic strains of bifidobacteria in premature infants. J Pediatr
2013; 163: 1585-1591.e9 [PMID: 23993139 DOI: 10.1016/j.
jpeds.2013.07.017]
81 del Campo R, Garriga M, Pérez-Aragón A, Guallarte P, Lamas A,
Máiz L, Bayón C, Roy G, Cantón R, Zamora J, Baquero F, Suárez L.
Improvement of digestive health and reduction in proteobacterial
populations in the gut microbiota of cystic fibrosis patients using
a Lactobacil lus r euteri probioti c pre paratio n: a d ouble blind
prospective study. J Cyst Fibros 2014; 13: 716-722 [PMID:
24636808 DOI: 10.1016/j.jcf.2014.02.007]
82 Koga H, Tamiya Y, Mitsuyama K, Ishibashi M, Matsumoto S,
Imaoka A, Hara T, Nakano M, Ooeda K, Umezaki Y, Sata M.
Probiotics promote rapid-turnover protein production by restoring
gut flora in patients with alcoholic liver cirrhosis. Hepatol Int 2013;
7: 767-774 [PMID: 26201812 DOI: 10.1007/s12072-012-9408-x]
83 Mangalat N, Liu Y, Fatheree NY, Ferris MJ, Van Arsdall MR,
Chen Z, Rahbar MH, Gleason WA, Norori J, Tran DQ, Rhoads JM.
Safety and tolerability of Lactobacillus reuteri DSM 17938 and
effects on biomarkers in healthy adults: results from a randomized
masked trial. PLoS One 2012; 7: e43910 [PMID: 22970150]
84 Dotterud CK, Avershina E, Sekelja M, Simpson MR, Rudi K,
Storrø O, Johnsen R, Øien T. Does Maternal Perinatal Probiotic
Supplementation Alter the Intestinal Microbiota of Mother and
Child? J Pediatr Gastroenterol Nutr 2015; 61: 200-207 [PMID:
25782657 DOI: 10.1097/MPG.0000000000000781]
85 Ismail IH, Oppedisano F, Joseph SJ, Boyle RJ, Robins-Browne
RM, Tang ML. Prenatal administration of Lactobacillus rhamnosus
has no effect on the diversity of the early infant gut microbiota.
Pediatr Allergy Immunol 2012; 23: 255-258 [PMID: 22136660
DOI: 10.1111/j.1399-3038.2011.01239.x]
86 Zeber-Lubecka N, Kulecka M, Ambrozkiewicz F, Paziewska A,
Lechowicz M, Konopka E, Majewska U, Borszewska-Kornacka M,
Mikula M, Cukrowska B, Ostrowski J. Effect of Saccharomyces
boulardii and Mode of Delivery on the Early Development of the
Gut Microbial Community in Preterm Infants. PLoS One 2016; 11:
e0150306 [PMID: 26918330 DOI: 10.1371/journal.pone.0150306]
87 MacFabe DF. Enteric short-chain fatty acids: microbial
messengers of metabolism, mitochondria, and mind: implications
in autism spectrum disorders. Microb Ecol Health Dis 2015; 26:
28177 [PMID: 26031685]
88 Altieri L, Neri C, Sacco R, Curatolo P, Benvenuto A, Muratori
F, Santocchi E, Bravaccio C, Lenti C, Saccani M, Rigardetto R,
Gandione M, Urbani A, Persico AM. Urinary p-cresol is elevated
in small children with severe autism spectrum disorder. Biomarkers
2011; 16: 252-260 [PMID: 21329489 DOI: 10.3109/1354750X.
2010.548010]
89 Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, Malvy J,
Barthelemy C, Bonnet-Brihault F, Persico AM. Urinary p-cresol is
elevated in young French children with autism spectrum disorder: a
replication study. Biomarkers 2014; 19: 463-470 [PMID: 25010144
DOI: 10.3109/1354750X.2014.936911]
90 West PR, Amaral DG, Bais P, Smith AM, Egnash LA, Ross ME,
Palmer JA, Fontaine BR, Conard KR, Corbett BA, Cezar GG,
Donley EL, Burrier RE. Metabolomics as a tool for discovery of
biomarkers of autism spectrum disorder in the blood plasma of
children. PLoS One 2014; 9: e112445 [PMID: 25380056 DOI:
10.1371/journal.pone.0112445]
91 Golnik AE, Ireland M. Complementary alternative medicine for
children with autism: a physician survey. J Autism Dev Disord 2009;
39: 996-1005 [PMID: 19280328 DOI: 10.1007/s10803-009-0714-7]
92 Srinivasjois R, Rao S, Patole S. Probiotic supplementation in
children with autism spectrum disorder. Arch Dis Child 2015; 100:
505-506 [PMID: 25809345 DOI: 10.1136/archdischild-2014-308002]
93 Kałużna-Czaplińska J, Błaszczyk S. The level of arabinitol
in autistic children after probiotic therapy. Nutrition 2012; 28:
124-126 [PMID: 22079796 DOI: 10.1016/j.nut.2011.08.002]
94 Parracho HM, Gibson GR, Bosscher D, Kleerebezem M,
McCartney AL. A double-blind, placebo-controlled, crossover-
designed probiotic feeding study in children diagnosed with autistic
spectrum disorders. Int J Probiotics Prebiotics 2010; 5: 69-74
95 Bowman KA, Broussard EK, Surawicz CM. Fecal microbiota
transplantation: current clinical efficacy and future prospects.
Clin Exp Gastroenterol 2015; 8: 285-291 [PMID: 26566371 DOI:
10.2147/CEG.S61305]
96 Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A,
Moore T, Wu G. Update on Fecal Microbiota Transplantation
2015: Indications, Methodologies, Mechanisms, and Outlook.
Gastroenterology 2015; 149: 223-237 [PMID: 25982290 DOI:
10.1053/j.gastro.2015.05.008]
97 Petrof EO, Gloor GB, Vanner SJ, Weese SJ, Carter D, Daigneault
MC, Brown EM, Schroeter K, Allen-Vercoe E. Stool substitute
transplant therapy for the eradication of Clostridium difficile
infection: ‘RePOOPulating’ the gut. Microbiome 2013; 1: 3 [PMID:
24467987 DOI: 10.1186/2049-2618-1-3]
98 Parracho HM, Bingham MO, Gibson GR,McCartney AL.
Differences between the gut microflora of children with autistic
spectrum disorders and that of healthy children. J Med Microbiol
2005; 54: 987-991 [PMID: 16157555]
99 Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT,
Conlon MA. Low relative abundances of the mucolytic bacterium
Akkermansia muciniphila and Bifidobacterium spp. in feces of
children with autism. Appl Environ Microbiol 2011; 77: 6718-6721
[PMID: 21784919 DOI: 10.1128/AEM.05212-11]
100 Williams BL, Hornig M, Parekh T, Lipkin WI. Application
of novel PCR-based methods for detection, quantitation, and
phylogenetic characterization of Sutterella species in intestinal
biopsy samples from children with autism and gastrointestinal
disturbances. MBio 2012; 3 [PMID: 22233678 DOI: 10.1128/
mBio. 00261-11]
101 Bonfrate L, Tac k J, G rattagliano I, Cuomo R, Portincasa P.
Microbiota in health and irritable bowel syndrome: current
knowledge, perspectives and therapeutic options. Scand J
Gastroenterol 2013; 4 8: 995-1009 [PMID: 23964766 DOI:
10.3109/00365521.2013.799220]
102 Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein
AE, Brandt LJ, Quigley EM. The efficacy of probiotics in the
treatment of irritable bowel syndrome: a systematic review. Gut
2010; 59: 325-332 [PMID: 19091823]
103 Ortiz-Lucas M, Tobías A, Saz P, Sebastián JJ. Effect of probiotic
species on irritable bowel syndrome symptoms: A bring up to date
meta-analysis. Rev Esp Enferm Dig 2013; 105: 19-36 [PMID:
23548007]
104 Whelan K. Probiotics and prebiotics in the management of irritable
bowel syndrome: a review of recent clinical trials and systematic
reviews. Curr Opin Clin Nutr Metab Care 2011; 14 : 581-587
[PMID: 21892075 DOI: 10.1097/MCO.0b013e32834b8082]
105 Jonkers D, Penders J, Masclee A, Pierik M. Probiotics in the
management of inflammatory bowel disease: a systematic review
of intervention studies in adult patients. Drugs 2012; 72: 803-823
[PMID: 22512365 DOI: 10.2165/11632710-000000000-00000]
10101 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Navarro F
et al
. Probiotics for children with autism
106 Liu Y, Fatheree NY, Mangalat N, Rhoads JM. Lactobacillus reuteri
strains reduce incidence and severity of experimental necrotizing
enterocolitis via modulation of TLR4 and NF-κB signaling in
the intestine. Am J Physiol Gastrointest Liver Physiol 2012; 302:
G608-G617 [PMID: 22207578]
107 Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of
necrotizing enterocolitis and mortality in preterm very low-birth-
weight infants: an updated meta-analysis of 20 randomized,
controlled trials. J Pedi atr Surg 2012; 47: 241-248 [PMID:
22244424]
108 Zhang L, Li N, des Robert C, Fang M, Liboni K, McMahon
R, Caicedo RA, Neu J. Lactobacillus rhamnosus GG decreases
lipopolysaccharide-induced systemic inflammation in a
gastrostomy-fed infant rat model. J Pediatr Gastroenterol Nutr
2006; 42: 545-552 [PMID: 16707979]
109 de Theije CG, Bavelaar BM, Lopes da Silva S, Korte SM, Olivier
B, Garssen J, Kraneveld AD. Food allergy and food-based therapies
in neurodevelopmental disorders. Pediatr Allergy Immunol 2014;
25: 218-226 [PMID: 24236934 DOI: 10.1111/pai.12149]
110 Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, di
Nemi SU, Politi P. Low-grade endotoxemia in patients with severe
autism. Neurosci Lett 2010; 471: 162-165 [PMID: 20097267]
111 Zimmerman AW, Jyonouchi H, Comi AM, Connors SL, Milstien
S, Varsou A, Heyes MP. Cerebrospinal fluid and serum markers of
inflammation in autism. Pediatr Neurol 2005; 33: 195-201 [PMID:
16139734]
112 Boris M, Kaiser CC, Goldblatt A, Elice MW, Edelson SM, Adams
JB, Feinstein DL. Effect of pioglitazone treatment on behavioral
symptoms in autistic children. J Neuroinflammation 2007; 4: 3
[PMID: 17207275 DOI: 10.1186/1742-2094-4-3]
P- Reviewer: Adams JB, Garcia-Olmo D, van Hemert S
S- Editor: Gong ZM L- Editor: A E- Editor: Liu WX
10102 December 14, 2016
|
Volume 22
|
Issue 46
|
WJG
|
www.wjgnet.com
Navarro F
et al
. Probiotics for children with autism