ArticlePDF AvailableLiterature Review

Abstract

Children with autism are commonly affected by 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.
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
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DOI: 10.3748/wjg.v22.i46.10093
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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 inuence 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 inammatory 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 modication could have a benecial 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 inamed colon[19].
However, the authors did not identify why these tissues
of ASD children had different transcriptional proles; for
example, they did not look for evidence of inammation
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 signicant 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 inltra-
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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 inammation,
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 inammation, 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 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 criteria are validated in adults
with normal IQ but are somewhat difcult 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 inu-
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 inammatory
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
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Navarro F
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. 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 Bido-
bacteria, a species known to have anti-inammatory
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
microora that confers benets upon host well-being
and health”. The potentially synergistic combinations of
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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 benecial effect of probiot-
ics. Evidence for probiotic efcacy 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 identied[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
Bidobacteria[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 inammation[70]. In
newborn rat pups, another probiotic, Bidobacterium
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
Bufngton 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 signicant 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 benecial 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 difculties 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
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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 benets in
ASD in children and rodents models.)
[65,72,102-104]
Mild inammation 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 inammation (Shown in animal models and in human diseases) [70,105-108]
Systemic inammation 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
benecial effects of a 4-mo treatment with a combina-
tion probiotic (comprising 3 Lactobacilli, 2 Bidobacilli,
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
benecial 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 inammatory bowel disease, fecal
microbiota transplantation (FMT) had the potential for
more signicant and prolonged effects. FMT was effec-
tive in many cases of antibiotic-associated C. difcile
colitis and is now used around the world for severe
or multiply recurrent C. difcile 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 specic 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.
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S- Editor: Gong ZM L- Editor: A E- Editor: Liu WX
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... The gut is a natural habitat for trillions of diverse microbes (anaerobic bacteria, yeasts, viruses, and bacteriophages) where the phyla Firmicutes, Bacteroidetes, and Actinobacteria are the most common (1). The gut microbiome is a complex ecosystem where microbes and their metabolites interact with host cells to influence body functions. ...
... Probiotics potentially impact gut microbiota communities to alter the levels of harmful metabolites in ASD children, reducing GI inflammation and intestinal permeability (1,99). However, the results of probiotic supplementation in individuals with ASD remain inconclusive and controversial. ...
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The human gut is home to trillions of microbes that interact with host cells to influence and contribute to body functions. The number of scientific studies focusing on the gut microbiome has exponentially increased in recent years. Studies investigating factors that may potentially affect the gut microbiome and may be used for therapeutic purposes in diseases where dysbioses in the gut microbiome have been shown are of particular interest. This review compiles current evidence available in the scientific literature on the use of probiotics to treat metabolic diseases and autism spectrum disorders (ASDs) to analyze the efficacy of probiotics in these diseases. To do this, we must first define the healthy gut microbiome before looking at the interplay between the gut microbiome and diseases, and how probiotics affect this interaction. In metabolic diseases, such as obesity and diabetes, probiotic supplementation positively impacts pathological parameters. Conversely, the gut–brain axis significantly impacts neurodevelopmental disorders such as ASDs. However, manipulating the gut microbiome and disease symptoms using probiotics has less pronounced effects on neurodevelopmental diseases. This may be due to a more complex interplay between genetics and the environment in these diseases. In conclusion, the use of microbe-based probiotic therapy may potentially have beneficial effects in ameliorating the pathology of various diseases. Validation of available data for the development of personalized treatment regimens for affected patients is still required.
... (c) Studies have proved that there is a correlation between intestinal inflammation and immune dysfunction in ASD patients, such as abnormal balance of T cells in the intestine of ASD patients and increased GI problems in ASD patients (Navarro et al., 2016;Vuong and Hsiao, 2017;Rose et al., 2018). Recently, it has been clearly demonstrated that high concentrations of pro-inflammatory microbiota in the gut can lead to increased intestinal permeability and inflammation, resulting in mild systemic inflammation and immune dysregulation (Felix et al., 2018). ...
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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with unclear etiology, and due to the lack of effective treatment, ASD patients bring enormous economic and psychological burden to families and society. In recent years, many studies have found that children with ASD are associated with gastrointestinal diseases, and the composition of intestinal microbiota (GM) is different from that of typical developing children. Thus, many researchers believe that the gut-brain axis may play an important role in the occurrence and development of ASD. Indeed, some clinical trials and animal studies have reported changes in neurological function, behavior, and comorbid symptoms of autistic children after rebalancing the composition of the GM through the use of antibiotics, prebiotics, and probiotics or microbiota transfer therapy (MMT). In view of the emergence of new therapies based on the modulation of GM, characterizing the individual gut bacterial profile evaluating the effectiveness of intervention therapies could help provide a better quality of life for subjects with ASD. This article reviews current studies on interventions to rebalance the GM in children with ASD. The results showed that Lactobacillus plantarum may be an effective strain for the probiotic treatment of ASD. However, the greater effectiveness of MMT treatment suggests that it may be more important to pay attention to the overall balance of the patient’s GM. Based on these findings, a more thorough assessment of the GM is expected to contribute to personalized microbial intervention, which can be used as a supplementary treatment for ASD.
... Previous studies have shown that application of certain probiotics have beneficial effects on antibiotics-induced physiological and psychological abnormalities 54,55 . Moreover, as different gut microbial community was found in ASD patients in contrast to the healthy individuals, researchers attempted to modify the gut microbiome via probiotics and some results indicate beneficial effects on both behavioral and GI manifestations of ASD [56][57][58][59] . In addition, VPA rat model not just imitate ASD symptoms, it also has a transgenerational impact on the gut www.nature.com/scientificreports/ ...
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The prevalence of autism spectrum disorder (ASD) has rapidly increased in the past decades, and several studies report about the escalating use of antibiotics and the consequent disruption of the gastrointestinal microbiome leading to the development of neurobehavioral symptoms resembling to those of ASD. The primary purpose of this study was to investigate whether depletion of the gastrointestinal microbiome via antibiotics treatment could induce ASD-like behavioral symptoms in adulthood. To reliably evaluate that, validated valproic acid (VPA) ASD animal model was introduced. At last, we intended to demonstrate the assessed potential benefits of a probiotic mixture (PM) developed by our research team. Male Wistar rats were used to create antibiotics treated; antibiotics and PM treated; PM treated, VPA treated; VPA and PM treated; and control groups. In all investigations we focused on social behavioral disturbances. Antibiotics-induced microbiome alterations during adulthood triggered severe deficits in social behavior similar to those observed in the VPA model. Furthermore, it is highlighted that our PM proved to attenuate both the antibiotics- and the VPA-generated antisocial behavioral symptoms. The present findings underline potential capacity of our PM to improve social behavioral alterations thus, indicate its promising therapeutic power to attenuate the social-affective disturbances of ASD.
... The word dietary prebiotics refers to the fermented ingredients that permit similar changes in the structure and activity of GI microflora that benefit host health and well-being [99]. The clinical studies based on ASD patients have proposed a functional link between gm and ASD. ...
Article
Autism spectrum disorder (ASD) is a serious multifactorial neurodevelopmental disorder often accompanied by strained social communication, repetitive behaviour, immune dysregulation, and gastrointestinal (GI) issues. Recent studies have recorded a link between dysbiosis in the gut microbiota (gm) and the primary stages of ASD. A bidirectional connection (also called microbiota-gut-brain-axis) exchanges information between the gut bacteria and central nervous system. When the homeostasis of the microenvironment of the gut is dysregulated, it causes oxidative stress, affecting neuronal cells and neurotransmitters, thereby causing neurodevelopmental disorders. Studies have confirmed a difference in the constitution of gut bacteria among ASD cases and their controls. Numerous studies on animal models of ASD have shown altered gm and its association with abnormal metabolite profile and altered behaviour phenotype. This process happens due to an abnormal metabolite production in gm, leading to changes in the immune system, especially in ASD. Hence, this review aims to question the current knowledge on gm dysbiosis and its related GI discomforts and ASD behavioural symptoms and shed light on the possible therapeutic approaches available to deal with this situation. Thereby, though it is understood that more research might be needed to prove an association or causal relationship between gm and ASD, therapy with the microbiome may also be considered as an effective strategy to combat this issue.
... Elimination diets mainly include GFCF diets (Mulloy et al., 2010) and ketogenic diets (El-Rashidy et al., 2017). Dietary supplementation includes probiotics (Navarro et al., 2016), omega-3 fatty acids (Amminger et al., 2007), antioxidants, multi-vitamin and mineral supplements (Lobo et al., 2010). By combining dietary interventions keywords (Tas, 2018) and China common food names (Chinese Center for Disease Control and Prevention, 2018), 704 relevant keywords were identified. ...
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Dietary interventions are common but controversial treatments for autistic people. This study aims to understand the adoption of dietary interventions based on diffusion of innovations theory in the autism online community from four aspects: popularity, adoption process, the influence of opinion leaders, and post-adoption feedback. Our data was extracted from a Chinese autism community named Baidu Tieba autism forum. We applied a mixed-method including four analytical approaches: descriptive statistics for popularity analysis; machine learning models for automatic data classification and topic detection; social network analysis for exploring the influence of opinion leaders on the adoption phase; content analysis for revealing the family caregiver-reported feedback after adoption. Dietary interventions have become increasingly popular in the autism online community since 2018. Analysis of the adoption process revealed that family caregivers at different stages of adoption focused on different topics, and the number of interactions with opinion leaders had a significant effect on the highest level (p < .001) and stage span (p < .001) of health information adoption. According to findings from the feedback of family caregivers, the effects of dietary interventions varied from individuals with autism. Our study revealed the diffusion of unproven interventions, which is of great significance in promoting evidence-based practices.
... As a matter of fact, the transcriptional profile of ileal and colonic tissues of autistic subjects overlaps significantly with the one of IBD patients (132). Besides, examination of intestinal biopsies from autistic children has revealed infiltration of inflammatory cells mimicking IBD and food allergies (133), as well as an excess accumulation of advanced glycation end products (AGEs) believed to induce neuroinflammation and neurodegeneration (134). Owing to a disrupted gut mucosa, the CNS is highly exposed also to proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, IL-12, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β (135), which overcome their confinement to the gut and promote CNS inflammation and alteration of neuronal signaling. ...
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Full-text available
The interest elicited by the large microbial population colonizing the human gut has ancient origins and has gone through a long evolution during history. However, it is only in the last decades that the introduction of high-throughput technologies has allowed to broaden this research field and to disentangle the numerous implications that gut microbiota has in health and disease. This comprehensive ecosystem, constituted mainly by bacteria but also by fungi, parasites, and viruses, is proven to be involved in several physiological and pathological processes that transcend the intestinal homeostasis and are deeply intertwined with apparently unrelated body systems, such as the immune and the nervous ones. In this regard, a novel speculation is the relationship between the intestinal microbial flora and the pathogenesis of some neurological and neurodevelopmental disorders, including the clinical entities defined under the umbrella term of autism spectrum disorders. The bidirectional interplay has led researchers to coin the term gut-brain-immune system axis, subverting the theory of the brain as an immune-privileged site and underscoring the importance of this reciprocal influence already from fetal life and especially during the pre- and post-natal neurodevelopmental process. This revolutionary theory has also unveiled the possibility to modify the gut microbiota as a way to treat and even to prevent different kinds of pathologies. In this sense, some attempts have been made, ranging from probiotic administration to fecal microbiota transplantation, with promising results that need further elaboration. This state-of-art report will describe the main aspects regarding the human gut microbiome and its specific role in the pathogenesis of autism and its related disorders, with a final discussion on the therapeutic and preventive strategies aiming at creating a healthy intestinal microbial environment, as well as their safety and ethical implications.
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Autism is a complex neurodevelopmental disorder which disrupts communication, social and interactive skills followed by appearance of repetitive behavior. The underlying etiology remains incomprehensible but genetic and environmental factors play a key role. Accumulated evidence shows that alteration in level of gut microbes and their metabolites are not only linked to gastrointestinal problems but also to autism. So far the mix of microbes that is present in the gut affects human health in numerous ways through extensive bacterial-mammalian cometabolism and has a marked influence over health via gut-brain-microbial interactions. Healthy microbiota may even ease the symptoms of autism, as microbial balance influences brain development through the neuroendocrine, neuroimmune, and autonomic nervous systems. In this article, we focused on reviewing the correlation between gut microbiota and their metabolites on symptoms of autism by utilizing prebiotics, probiotics and herbal remedies to target gut microflora hence autism.
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Fermented food and beverages provide huge benefits to humans. The nutritionally rich Palm wine (toddy) is a popular fermented beverage in India. The present study reveals the bacterial diversity and metabolic profile of Indian palm wine using next-generation sequencing of the V3-V4 regions of the 16S rRNA gene. The metagenomic sequencing reveals the dominance of the phyla Proteobacteria, Firmicutes, and Tenericutes in the Indian palm wine. Bacteria such as Acetobacter, Lactobacillus, Candidatus phytoplasma, and Gluconobacter were abundant in palm wine. The sequence-based metagenomics approach revealed that Acetobacter sp. and Lactobacilli sp., which are beneficial bacteria, were the most predominant microbial populations in the Indian palm wine. The metabolic functional profile of the palm wine microbiome was studied based on gene ontology terms to identify industrial by-products and bio-prospecting genes. Metabolic profiling revealed that a major microbial population was involved in ammonia oxidation, sulfate reduction, nitrite reduction, atrazine metabolization, and acid production. The results can aid in developing probiotics from palm wine for human consumption with a multitude of health benefits.
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Maternal obesity during pregnancy has been associated with increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. Here, we report that maternal high-fat diet (MHFD) induces a shift in microbial ecology that negatively impacts offspring social behavior. Social deficits and gut microbiota dysbiosis in MHFD offspring are prevented by co-housing with offspring of mothers on a regular diet (MRD) and transferable to germ-free mice. In addition, social interaction induces synaptic potentiation (LTP) in the ventral tegmental area (VTA) of MRD, but not MHFD offspring. Moreover, MHFD offspring had fewer oxytocin immunoreactive neurons in the hypothalamus. Using metagenomics and precision microbiota reconstitution, we identified a single commensal strain that corrects oxytocin levels, LTP, and social deficits in MHFD offspring. Our findings causally link maternal diet, gut microbial imbalance, VTA plasticity, and behavior and suggest that probiotic treatment may relieve specific behavioral abnormalities associated with neurodevelopmental disorders. No video support
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Background Irritable bowel syndrome (IBS) is one of the most common functional gastroenterological diseases, affecting 11.2 % of people worldwide. Previous studies have shown that probiotic treatment may benefit IBS patients. However, the effect of probiotics and the appropriate type, dose, and treatment duration for IBS are still unclear. The aim of the current study was to assess the efficacy of different probiotic types, doses and treatment durations in IBS patients diagnosed by Rome III criteria via a meta-analysis of randomized controlled trials (RCTs). Methods Medline, EMBASE, and the Cochrane Central Register of Controlled Trials up to October 2015 were searched. RCTs including comparisons between the effects of probiotics and placebo on IBS patients diagnosed by Rome III criteria were eligible. Dichotomous data were pooled to obtain the relative risk (RR) with a 95 % confidence interval (CI), whereas continuous data were pooled using a standardized mean difference (SMD) with a 95 % CI. ResultsTwenty-one RCTs were included in this meta-analysis. Probiotic therapy was associated with more improvement than placebo administration in overall symptom response (RR: 1.82, 95 % CI 1.27 to 2.60) and quality of life (QoL) (SMD: 0.29, 95 % CI 0.08 to 0.50), but not in individual IBS symptoms. Single probiotics, a low dose, and a short treatment duration were more effective with respect to overall symptom response and QoL. No differences were detected in individual IBS symptoms in the subgroup analyses. Conclusion Probiotics are an effective pharmacological therapy in IBS patients. Single probiotics at a low dose and with a short treatment duration appear to be more effective in improving overall symptom response and QoL, but more evidence for these effects is still needed.
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Objective: Eosinophilic esophagitis (EoE) can present as food selectivity or feeding disorders in children. Children with autism spectrum disorders (ASD) commonly demonstrate behavioral food selectivity in type and texture, which often leads to the diagnosis of feeding disorder. We sought to evaluate the association of ASD with EoE. Methods: A retrospective matched case-cohort study was performed using the Military Health System database from Oct 2008 to Sept 2013. We performed a 1:5 case:control match by age, gender, and enrollment timeframe. Feeding disorders, EoE, and atopic disorders were defined utilizing diagnostic and procedure codes. Results: There were 45,286 children with ASD and 226,430 matched controls. EoE was more common in children with ASD (0.4%) compared to controls (0.1%). Feeding disorders were associated with EoE in both children with ASD and controls. Feeding disorders also had a higher odds ratio for EoE compared to other atopic conditions, among both children with ASD (7.17, 95% CI 4.87-10.5) and controls (11.5, 95% CI 7.57-17.5). Compared to controls with a feeding disorder, children with ASD and a feeding disorder had no difference in the rate of diagnosed EoE (0.85, 0.95% CI 0.39-1.88). Conclusions: Children with ASD are more likely to be diagnosed with EoE compared to controls; however, among children with feeding disorders, there is no difference in the odds of EoE. A diagnosis of feeding disorder was strongly associated with EoE. Feeding disorders in children with ASD should not be assumed to be solely behavioral and an esophagogastroduodenoscopy should be performed to evaluate for EoE.
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Background The effects of probiotic supplementation on fecal microbiota composition in healthy adults have not been well established. We aimed to provide a systematic review of the potential evidence for an effect of probiotic supplementation on the composition of human fecal microbiota as assessed by high-throughput molecular approaches in randomized controlled trials (RCTs) of healthy adults. Methods The survey of peer-reviewed papers was performed on 17 August 2015 by a literature search through PubMed, SCOPUS, and ISI Web of Science. Additional papers were identified by checking references of relevant papers. Search terms included healthy adult, probiotic, bifidobacterium, lactobacillus, gut microbiota, fecal microbiota, intestinal microbiota, intervention, and (clinical) trial. RCTs of solely probiotic supplementation and placebo in healthy adults that examined alteration in composition of overall fecal microbiota structure assessed by shotgun metagenomic sequencing, 16S ribosomal RNA sequencing, or phylogenetic microarray methods were included. Independent collection and quality assessment of studies were performed by two authors using predefined criteria including methodological quality assessment of reports of the clinical trials based on revised tools from PRISMA/Cochrane and by the Jadad score. Results Seven RCTs investigating the effect of probiotic supplementation on fecal microbiota in healthy adults were identified and included in the present systematic review. The quality of the studies was assessed as medium to high. Still, no effects were observed on the fecal microbiota composition in terms of α-diversity, richness, or evenness in any of the included studies when compared to placebo. Only one study found that probiotic supplementation significantly modified the overall structure of the fecal bacterial community in terms of β-diversity when compared to placebo. Conclusions This systematic review of the pertinent literature demonstrates a lack of evidence for an impact of probiotics on fecal microbiota composition in healthy adults. Future studies would benefit from pre-specifying the primary outcome and transparently reporting the results including effect sizes, confidence intervals, and P values as well as providing a clear distinction of between-group and within-group comparisons.
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We discuss the tripartite pathophysiological circuit of inflammatory bowel disease (IBD), involving the intestinal microbiota, barrier function, and immune system. Dysfunction in each of these physiological components (dysbiosis, leaky gut, and inflammation) contributes in a mutually interdependent manner to IBD onset and exacerbation. Genetic and environmental risk factors lead to disruption of gut homeostasis: genetic risks predominantly affect the immune system, environmental risks predominantly affect the microbiota, and both affect barrier function. Multiple genetic and environmental ‘hits’ are likely necessary to establish and exacerbate disease. Most conventional IBD therapies currently target only one component of the pathophysiological circuit, inflammation; however, many patients with IBD do not respond to immune-modulating therapies. Hope lies in new classes of therapies that target the microbiota and barrier function.
Article
OBJECTIVES: Irritable bowel syndrome (IBS) and chronic idiopathic constipation (CIC) are functional bowel disorders. Evidence suggests that disturbance in the gastrointestinal microbiota may be implicated in both conditions. We performed a systematic review and meta-analysis to examine the efficacy of prebiotics, probiotics, and synbiotics in IBS and CIC. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Randomized controlled trials (RCTs) recruiting adults with IBS or CIC, which compared prebiotics, probiotics, or synbiotics with placebo or no therapy, were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardized or weighted mean difference with a 95% CI. RESULTS: The search strategy identified 3,216 citations. Forty-three RCTs were eligible for inclusion. The RR of IBS symptoms persisting with probiotics vs. placebo was 0.79 (95% CI 0.70-0.89). Probiotics had beneficial effects on global IBS, abdominal pain, bloating, and flatulence scores. Data for prebiotics and synbiotics in IBS were sparse. Probiotics appeared to have beneficial effects in CIC (mean increase in number of stools per week=1.49; 95% CI=1.02-1.96), but there were only two RCTs. Synbiotics also appeared beneficial (RR of failure to respond to therapy=0.78; 95% CI 0.67-0.92). Again, trials for prebiotics were few in number, and no definite conclusions could be drawn. CONCLUSIONS: Probiotics are effective treatments for IBS, although which individual species and strains are the most beneficial remains unclear. Further evidence is required before the role of prebiotics or synbiotics in IBS is known. The efficacy of all three therapies in CIC is also uncertain.
Article
The early origins of overweight and obesity and the opportunities for early prevention are explored. Overweight and obesity prevalence globally has increased at an alarming rate. No single intervention can halt the rise of the obesity epidemic. Particular attention is given to exploring causative factors and preventive measures in early life, when biological determinants of risk trajectories, feeding behaviour and dietary preferences are shaped. Some lifestyle and nutrition modifications in pregnancy and infancy can reduce subsequent obesity risk. Also postnatal infant gut colonisation may modify later obesity risk, but currently available evidence does not allow firm conclusions. Surprisingly, about 3.2 times more systematic reviews (SR) than randomized clinical trials (RCTs) were published on "probiotics" and health, and even 7.9 times more SR than RCTs on "probiotics" and obesity, which is not helpful. Multiple research opportunities exist for exploring the early origins of obesity to contribute towards halting the rise in obesity prevalence. Exploring the early development of the microbiome in its complexity, its dependence on dietary and other exogenous factors, and its metabolic and regulatory functions is promising. Meaningful progress for obesity prevention can most likely be achieved by combining several strategies.
Article
Background: Previous studies have attributed high maternal weight gain during pregnancy and pre-pregnancy obesity to a higher risk for autism spectrum disorder (ASD). Maternal underweight was not previously explored with respect to ASD risk. Methods: We evaluated the association between maternal pre-pregnancy body mass index (BMI) and ASD occurrence among singletons born into the General Practice Research Database from 1993 to 2008. Case subjects were children with a diagnosis of ASD from birth to 2010. Up to four control subjects were matched to each case subject on birth year, sex, and general practice. Restricted cubic splines were used to assess the non-linearity of the association between maternal BMI and ASD. All study subjects were classified as underweight, normal weight, overweight, or obese based on maternal pre-pregnancy BMI using the WHO Classification Standard. Conditional logistic regression was used to calculate unadjusted and multivariable adjusted odds ratios for the association between categorical BMI (reference=normal weight) and the occurrence of ASD. Results: The association between maternal BMI and ASD occurrence was non-linear and J-shaped. The adjusted ORs for maternal underweight and obesity were 1.43 (95% CI 1.01, 2.04) and 1.54 (95% CI 1.26, 1.89) respectively. Conclusions: Results suggest that extremes in maternal BMI may be associated with modest increases in the risk for ASD among offspring.
Article
Background: The reported rates of gestational diabetes mellitus are constantly escalating and little is known about long-term complications in the offspring. Evidence from the field of epigenetics strongly advocates the need for research on the neuropsychiatric complications in offspring prenatally exposed to gestational diabetes mellitus. Objective: We sought to assess whether in utero exposure to gestational diabetes mellitus increases the risk of long-term neuropsychiatric morbidity in the offspring. Study Design: A population-based cohort study compared the incidence of hospitalizations due to neuropsychiatric disease between singletons exposed and unexposed to gestational diabetes mellitus. Deliveries occurred in the years 1991 through 2014 in a regional tertiary medical center. Perinatal deaths, multiple gestations, mothers with pregestational diabetes or lack of prenatal care, and children with congenital malformations were excluded from the study. A multivariate generalized estimating equation logistic regression model analysis was used to control for confounders and for maternal clusters. Results: During the study period 231,271 deliveries met the inclusion criteria; 5.4% of the births were to mothers diagnosed with gestational diabetes mellitus (n = 12,642), of these 4.3% had gestational diabetes type A1 (n = 10,076) and 1.1% had gestational diabetes type A2 (n = 2566). During the follow-up period, a significant linear association was noted between the severity of the gestational diabetes (no gestational diabetes, gestational diabetes mellitus A1, gestational diabetes mellitus A2) and neuropsychiatric disease of the offspring (1.02% vs 1.36% vs 1.68%, respectively, P < .001). A Kaplan-Meier curve demonstrated that children born to women with gestational diabetes mellitus had higher cumulative incidence of neuropsychiatric morbidity. Using a generalized estimating equation multivariable logistic regression model, controlling for time-to-event, maternal age, gestational age at delivery, maternal obesity, maternal preeclampsia and fertility treatments, maternal gestational diabetes mellitus was found to be an independent risk factor for long-term neuropsychiatric disease of the offspring (gestational diabetes mellitus A1 [adjusted odds ratio, 1.83; 95% confidence interval, 1.53-2.19] and gestational diabetes mellitus A2 [adjusted odds ratio, 1.64; 95% confidence interval, 1.18-2.27]). Within the limits of our database, our findings also point to a possible association between in utero exposure to gestational diabetes mellitus and autistic spectrum disorder of the offspring (adjusted odds ratio, 4.44; 95% confidence interval, 1.55-12.69), which was found significant also after controlling for time-to-event, maternal age, gestational age at delivery, and offspring weight at birth. Conclusion: Exposure to maternal gestational diabetes mellitus is an independent risk factor for long-term neuropsychiatric morbidity in the offspring.
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For decades, interactions between the enteric neuromuscular apparatus and the central nervous system have served as the primary focus of pathophysiological research in the functional gastrointestinal disorders. The accumulation of patient reports, as well as clinical observations, has belatedly led to an interest in the role of various luminal factors and their interactions with each other and the host in functional gastrointestinal disorders. Most prominent among these factors has been the role of food. As a consequence, while not always evidence-based, dietary interventions are enjoying a renaissance in irritable bowel syndrome management. Not surprisingly, given its exploration in many disease states, the gut microbiota has also been studied in functional gastrointestinal disorders; data remain inconclusive. Likewise, there is also a considerable body of experimental and some clinical data to link functional gastrointestinal disorders pathogenesis to disturbances in epithelial barrier integrity, abnormal entero-endocrine signaling and immune activation. These data provide growing evidence supporting the existence of micro-organic changes, particularly in subgroups of patients with functional dyspepsia and IBS. However, their exact role in the complex pathophysiology and symptom generation of functional gastrointestinal disorders needs to be further studied and elucidated particularly with longitudinal and interventional studies.