The Gut Microbiome in Children With Mood Anxiety and Neurodevelopmental Disorders An Umbrella Review

Gut Microbiome (2023), 4, e18, 1–26
doi:10.1017/gmb.2023.16
REVIEW
The gut microbiome in children with mood, anxiety, and

neurodevelopmental disorders: An umbrella review
Kaitlin Romano1, Ashka N. Shah2, Anett Schumacher3, Clare Zasowski3, Tianyi Zhang1,
Glyneva Bradley-Ridout4, Kaitlyn Merriman4, John Parkinson5,6,7, Peter Szatmari3,8,9,
Susan C. Campisi1,3 and Daphne J. Korczak3,9
1
Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
2
Royal College of Surgeons in Ireland, Dublin, Ireland
3
Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada
4
Gerstein Science Information Centre, University of Toronto, Toronto, ON, Canada
5
Program in Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada
6
Department of Biochemistry, University of Toronto, Toronto, ON, Canada
7
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
8
Cundill Centre for Child and Youth Depression, The Centre for Addiction and Mental Health, Toronto, ON, Canada
9
Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Corresponding author: Daphne J. Korczak; Email: [email protected]
K.R. and A.N.S. contributed equally to this work.
(Received 24 April 2023; revised 07 September 2023; accepted 08 September 2023)
Abstract
Research on the gut microbiome and mental health among children and adolescents is growing. This
umbrella review provides a high-level overview of current evidence syntheses to amalgamate current
research and inform future directions. Searches were conducted across seven databases for peer-reviewed
pediatric (<18 years) review literature. Studies reporting gut microbiome composition and/or biotic
supplementation on depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder, autism
spectrum disorder (ASD), or obsessive-compulsive disorder (OCD) were included. Deduplication and
screening took place in Covidence. A sensitivity analysis was conducted to assess the degree of primary study
overlap. Among the 39 included review studies, 23 (59%) were observational and 16 (41%) were interven-
tional. Most reviews (92%) focused on ASD. Over half (56%) of the observational and interventional reviews
scored low or critically low for methodological quality. A higher abundance of Clostridium clusters and a
lower abundance of Bifidobacterium were consistently observed in ASD studies. Biotic supplementation was
associated with ASD symptom improvement. Gut microbiome-mental health evidence syntheses in child
and youth depression, anxiety, bipolar disorder, and OCD are lacking. Preliminary evidence suggests an
association between specific microbiota and ASD symptoms, with some evidence supporting a role for
probiotic supplementation ASD therapy.
Keywords: autism; children and adolescents; mental health; microbiome; umbrella review
Background
Worldwide, approximately 15% of children and adolescents suffer from mental health and/or neuro-
developmental disorders, including anxiety, depression, bipolar disorder, obsessive-compulsive disorder
© The Author(s), 2023. Published by Cambridge University Press in association with The Nutrition Society. This is an Open Access article,
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https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

2 Kaitlin Romano et al.
(OCD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), con-
tributing to lifelong morbidity and leading mental health problems among children to be of immense
public health concern (Dalsgaard et al., 2002; Fergusson et al., 2007). However, the current management
of mental health disorders, including pharmacological, psychological, and/or combined approaches, has
frequently yielded suboptimal response rates, underscoring the need for new treatment approaches
(Holmes et al., 2018).
A growing body of evidence demonstrates that diet quality may be a modifiable risk factor for mental
disorders. The gut microbiome is a leading hypothesized mechanism of the diet–mental health
association as its composition is driven by dietary intake (Marx et al., 2017). Loss of beneficial microbes
in the gastrointestinal tract, the emergence of pathobionts (that is bacteria that cause disease only
sporadically), and gut microbiome dysbiosis may influence disease progression and/or severity (Petersen
and Round, 2014). Systematic reviews of observational studies have reported consistently significant
associations between decreased gut microbial diversity and greater psychopathology in adults (Sanada
et al., 2020; Simpson et al., 2021). Several pathophysiological mechanisms have been hypothesized to
underlie these findings and require data to either support or refute these theories. Emerging paediatric
research has documented disruptions to the gut microbiome across a range of chronic health conditions,
including asthma (Patrick et al., 2020; Wang et al., 2021), ASD (Iglesias-Vazquez et al., 2020), ADHD
(Ligezka et al., 2021), and cystic fibrosis (Nielsen et al., 2016).
Both the gut microbiome and the brain undergo significant developmental change over the first
years of life, with numerous microbiota colonizing the gastrointestinal tract while simultaneous
neurodevelopmental changes take place. Research has demonstrated a link between the gut micro-
biome and neurodevelopment in young children, suggesting that the alpha diversity of the gut
microbiome as well as the level of abundance of specific gut bacteria affect cognitive functioning at
an early age (Jena et al., 2020). The microbiota–gut–brain axis, an intricate communication network
between the gut microbiota, the gastrointestinal tract, and the brain, is thought to be a conduit of
bidirectional communication between the gut microbiome and the brain. The gut microbiota can
produce neurotransmitters and neuroactive compounds that directly influence the central nervous
system through the neuroendocrine pathway (Niazi et al., 2023). Additionally, the immune pathway
allows immune cells and signalling molecules to affect the brain function (Verma et al., 2022). The
vagus nerve pathway acts as a major route of communication connecting the gut and the brain. This
bidirectional communication system plays a crucial role in regulating physiological processes and has
been implicated in influencing brain function, behaviour, and overall health. Research on the micro-
biome–gut–brain axis is rapidly growing and has revealed several associations between the gut
microbiome and neurologic and psychiatric disorders across the lifespan (Bäckhed et al., 2015; Marx
et al., 2017; Dickerson et al., 2022). While the adult microbiome is relatively stable, the microbiome of a
child continues to evolve through adolescence, potentially serving as a prime opportunity for
preventive intervention (Agans et al., 2011; Ringel-Kulka et al., 2013; Flannery et al., 2020). Moreover,
the microbial profiles associated with adult mental health disorders may differ from those for children
and adolescents.
Understanding current evidence syntheses is a necessary next step in advancing knowledge in this
area of research. The rigorous application of umbrella review methodology fulfils this need as it provides
a high-quality overview to guide future research. This umbrella review aims to assess current knowledge
about the relationship between the gut microbiome and psychiatric disorders and opportunities for
future research among children and adolescents.
Methods
A protocol was created for this umbrella review following the PRISMA extension for Protocols
(Rethlefsen et al., 2021) and was registered on Open Science Framework (Campisi et al., 2022).
The umbrella review was conducted using the Joanna Briggs Institute Umbrella Review guidelines

3
and reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses
(Aromataris et al., 2015).
Search methodology
The database search strategies were developed by two academic health sciences librarians (K.M. and
G.B.R.) and peer-reviewed by an independent librarian following the Peer Review of Electronic Search
Strategies for systematic review guidelines (McGowan et al., 2016). The search strategy was developed
in Ovid Medline and translated into each database using that platform’s command language, including
text words, controlled vocabulary, and subject headings when possible. Searches include articles
published up until February 2023. The following databases were searched: Child Development and
Adolescent Studies (EBSCOhost), Ovid MEDLINE (1946 to present including Epub ahead of print,
in-process, and other non-indexed citations), Ovid EMBASE (1947 to present), Ovid APA PsycINFO
(1806 to present), EBSCO CINAHL Plus with Full Text (1981 to present), Scopus (Elsevier), and the
Cochrane CENTRAL. A modified version of the CADTH SR / MA / HTA / ITC filter was used in the
Ovid Medline and Ovid Embase search strategies (CADTH, 2023). Full search strategies can be found
in Supplementary Table S1.
Inclusion and exclusion criteria

Review articles were considered eligible if they (1) examined a paediatric population (<18 years of age);
(2) included participants with a diagnosis of depression, anxiety, bipolar disorder, ADHD, ASD, or
OCD; (3) ensured participants did not have comorbid chronic medical conditions; (4) reported the
association between the gut microbiome (i.e. alpha diversity, beta diversity, relative abundances of
clusters of DNA or RNA fragment sequences commonly called operational taxonomic units [OTUs])
and mental health disorder or the effect of gut microbiome-targeted treatments (e.g. prebiotic,
probiotic, and synbiotic supplementation) on symptoms of mental health disorder with or without
the resulting gut microbiome composition changes, in terms of OUT abundance; (5) were peer-
reviewed; and (6) were systematic reviews (observational or interventional studies). No limits were
imposed on the publication date of records, geographical location, sociodemographic factors, or
setting. Primary research, animal studies, narrative reviews, conference abstracts, comments, opin-
ions, letters, and editorials were excluded. Due to the limited capacity within the study for a translator,
seven non-English records were excluded.
Study selection and data collection

Deduplication of the search results took place in Covidence online software (Covidence Systematic
Review Software, 2023). Screening of all references generated by the database searches occurred
independently by four authors (K.R., T.Z., S.C.C., and A.S.) in a two-step process: title and abstract
screening were followed by full-text screening. Discrepancies were resolved via discussion with a third
author (K.R. or T.Z.). The data extraction template was pilot tested on five included systematic reviews.
The following items were extracted: title, author, year, journal, mental health disorder, study review type,
date range of studies included in each systematic review, number of studies in the review, sample size, age
range, type of intervention and the intervention details (duration of intervention, frequency, timing, and
method of intervention delivery, presence of a control group), human gut microbiota data (sequencing
platform, relative abundance, richness, alpha and beta diversity), and mental health outcome data
(diagnostic tool to assess mental health symptoms, symptom severity/impact). All extracted data were
verified by SCC and/or AS.

Methodological quality evaluation

A MeaSurement Tool to Assess Systematic Reviews version 2 (AMSTAR-2) was used to assess the quality
of the included systematic reviews and meta-analyses (Shea et al., 2017). Quality assessment was
performed in duplicate (A.S. and C.Z.) and compared to ensure inter-rater reliability. Further details
about individual AMSTAR-2 checklist items can be found in Supplementary Figure S1 (Shea et al., 2017).
Each item on the AMSTAR-2 checklist was answered with “yes,” “no,” “partial yes,”, or “no meta-
analysis conducted”; however, only the “yes” answer counted as a point towards the total score for the
assessed review. Based on the total point scores, systematic reviews and meta-analyses were categorized
as high-quality, moderate-quality, low-quality, or critically low-quality reviews using previously estab-
lished definitions (Shea et al., 2017).
Taxonomic evidence synthesis

Due to significant heterogeneity among the included systematic reviews, the findings are reported for
OTUs that consistently exhibited an association or demonstrated efficacy across multiple reviews
concerning mental health disorders. By focusing on the OTUs that demonstrated consistent patterns
across the reviewed literature, we aimed to highlight robust signals of these particular associations or
efficacies. Results are presented with phylogenetic trees and counts of OTUs reported in systematic
reviews. Phylogenetic trees were created using the ‘ape’ package in R (Paradis et al., 2019).
Sensitivity analysis: overlap minimization

A sensitivity analysis was carried out to examine whether the strength of observed signals between
mental health disorders and gut OTUs, as well as the effectiveness of prebiotic/probiotic supplemen-
tation in treating mental health disorders, were influenced by the inclusion of the same primary studies in
multiple systematic reviews. This issue is particularly relevant in umbrella reviews, as the degree of
overlap or inclusion of the same primary study in multiple systematic reviews can potentially introduce
bias and affect the accuracy of the findings (Pieper et al., 2014).
Overlap minimization followed a multi-step procedure to align the primary studies with the current
umbrella review’s inclusion criteria. Initially, the primary studies were assessed to determine their
alignment with our predefined inclusion criteria, excluding any studies that did not meet the criteria for
inclusion. Next, the degree of overlap in primary studies was calculated using the corrected covered area
(CCA) formula: (N – r)/(rc – r), where N represents the number of included primary studies accounting
for double counting, r is the number of index publications, and c is the number of included systematic
reviews (Hennessy and Johnson, 2020). A CCA within the range of 0%–5% indicates a slight overlap,
6%–10% suggests a moderate overlap, 11%–15% indicates a high overlap, and > 15% shows a very high
overlap (Hennessy and Johnson, 2020). We generated a CCA and an overlap matrix for observational
and interventional systematic reviews separately with the use of the Graphical Representation of Overlap
for OVErviews tool (GROOVE) (Pérez-Bracchiglione et al., 2022; Gosling et al., 2023). Whenever
possible, higher quality reviews were given priority for retention. To minimize overlap and improve the
CCA, systematic reviews with a primary study overlap exceeding 25% were identified, and the review
with fewer primary studies was eliminated, prioritizing the retention of higher quality reviews whenever
feasible (Lipsey and Wilson 2001, Lunny et al., 2018). The systematic reviews that remained after the
overlap optimization were included in the taxonomic evidence sensitivity analysis.
Results
The database searches yielded 2,099 potential records for this umbrella review following the removal of
duplicates (Figure 1). Among the 39 included review studies, 23 (59%) were observational and 16 (41%)
were interventional. Of the included reviews, 36 (92%) examined ASD, 6 (15%) examined ADHD, 1 (3%)

5
Identification of studies via databases and registries
Records identified from Databases

(2747):
Identification
Ovid Embase (n=892) Records removed before

Ovid Medline (n=582) screening:
Ovid PsychINFO (n=582) Duplicate records removed
Scopus (n=72) (n=648)
EBSCO CINAHL (n=558)
EBSCO Child Development (n=36)
Wiley Cochrane Library (n=25)
Records screened Records excluded

(n=2099) (n=1858)
Reports sought for retrieval Reports not retrieved

(n=241) (n=1)
Screening
Reports excluded:
Narrative reviews (n=37)
Reports assessed for eligibility Wrong publication type (n=38)
(n=277 Wrong outcomes (n=31)
Animal population (n=21)
Wrong patient population (n=19)
Wrong intervention (n=13)
Wrong indication (n=12)
Not in English (n=7)
Adult population (n=6)
Not the gut microbiome (n=6)
Duplicate (n=4)
Wrong study design (n=4)
Not peer reviewed (n=2)
Wrong comparator (n=1)
Review studies included in the

Umbrella Review
(n=39)
Included
Observational Interventional
reviews (n=23) reviews (n=16)
Figure 1. PRISMA flowchart.
examined depression, 1 (3%) examined anxiety, and no reviews examined OCD or bipolar disorder
[Note: totals add to more than 100% as some reviews examined more than one disorder]. The publication
date for the included review studies ranged from 2013 to 2023, with 31 (80%) published between 2020
and 2023. There was significant heterogeneity among the included primary studies regarding demo-
graphics (participant characteristics, age range, sex), methodological reporting (stool collection, storage
and sequencing approach that is 16S rRNA or shotgun metagenomics), statistical reporting (library
preparation that is collection of DNA fragments for sequencing, choice of sequencing platform), and

intervention parameters (prebiotic or probiotic combination trialled, intervention duration). Review

study characteristics can be found in Supplementary Tables S2, S3 and Table 1.
Methodological quality assessment

Methodological quality assessment was performed for observational and interventional systematic
reviews. Among observational systematic reviews (n = 23), two scored in the high-quality range, eight
scored in the moderate-quality range, three scored in the low-quality range, and 10 reviews scored in the
critically low-quality range. Interventional systematic reviews and meta-analyses (n = 16) included seven
reviews of moderate quality, two of low quality, and seven of critically low quality, using AMSTAR-2
evaluation guidelines. Several criteria of the AMSTAR-2 checklist were under-reported in the included
reviews, leading to the heterogeneous outcome of the quality assessment. In detail, none of the reviews
reported on the sources of funding for the included studies. Only one review (3%) provided a list of
excluded primary studies, and similarly, only one review (3%) used a comprehensive literature search
strategy. Furthermore, only 7 (18%) reviews had described their review methods in advance via study
registration. Adequate detail regarding the included studies was described in only 9 (23%) reviews. The
assessment of the risk of bias was adequately performed in 21 (54%) reviews, and 20 (51%) reviews took
into consideration the risk of bias in primary outcomes when discussing the results. No systematic
reviews were eliminated from further synthesis based on methodological quality since this was not one of
the a priori exclusion criteria. Further detail regarding the quality assessment of individual reviews is
presented in Supplementary Table S4.
Gut microbiome taxonomic evidence synthesis

Very few reviews examined the richness and diversity between the gut microbiome and mental health
disorders in children. Therefore, it was not feasible to include these findings in the evidence synthesis. As
a result, the focus of this umbrella review is on reported OTUs.
Observational systematic reviews – ASD

Among the 23 observational systematic reviews, there were consistent findings regarding the increased
relative abundance of certain OTUs in youth with ASD. The most commonly reported OTUs across the
reviews were Clostridium clusters, Candida, Dorea, Roseburia, Bacteroides, Oscillospira, Ruminococcus,
Barnesiella, Desulfovibrio, and Lactobacillus.
On the other hand, a decreased abundance of specific OTUs was repeatedly observed in youth with
ASD. These OTUs included Bifidobacterium, Prevotella, Dialister, Veillonella, Escherichia, Fusobacter-
ium, Streptococcus, and Coprococcus.
It is worth noting that the remaining OTUs were only reported in one review, suggesting limited
evidence regarding their association with ASD. Figures 2 and 3 offer a comprehensive overview of the
OTUs reported in the observational systematic reviews for ASD and ADHD, including the specific
studies that reported them and the corresponding patterns of increased or decreased abundance.
Observational systematic reviews – ADHD

Only two reviews reported an abundance of OTUs in youth with ADHD. Observational reviews
consistently reported an increase in the relative abundance of OTUs belonging to the Bacteroides genus
in youth with ADHD. On the other hand, a consistent decrease in the relative abundance of certain OTUs
belonging to the Faecalibacterium genus was reported in observational reviews in youth with ADHD.
The remaining OTUs were only reported in one review, suggesting limited evidence regarding their
association with ADHD (Figure 2).

Table 1. Summary of prebiotic, probiotic, and synbiotic interventions along with reported gut microbiome and mental health outcomes among the interventional reviews (n = 16).
Intervention Outcome
Review Biotic Duration/dosage Supplement Gut microbiome Mental health
Autism
Alvares et al. (2021) Probiotic 1 month Lactobacillus Not reported • Reduction of the total scores of Social
Not reported plantarum Responsiveness Scale (SRS) (p = 0.04)
and Swanson, Nolan and Pelham
(SNAP) questionnaire version IV (SNAP-
IV) (p = 0.02)
• Improvement in anxiety and rule-
breaking behaviours (p = 0.02) in Child
Behavior Checklist
• Improvement with body and object use
(p = 0.04) in the Autism Behavior
Checklist–Taiwan
• Improvement in hyperactivity and
impulsivity (p = 0.04) using Version IV,
adapted for Brazil
Amadi et al. (2022) Probiotic 3 months Bifidobacterium Increased Bifidobacteria, • Improved behavioural pattern using
Not reported longum, Lactobacillus Lactobacilli Autism Treatment Evaluation Checklist
acidophilus, Lactobacillus
rhamnosus
Probiotic 4 months 3 Lactobacillus strains, Decreased the level of • Beneficial effects were seen (tool
Not reported 2 Bifidobacterium strains, Desulfovibrio spp., unspecified)
1 Streptococcus strain Bifidobacteria, and
(species not reported) also normalized the
Bacteroidetes/Firmicutes
ratio
Probiotic 1–3 months L. plantarum Increased lactobacillus • Improved behavioural pattern as well as
Not reported and enterococcus improved total score of SNAP-IV and
Decreased improvement in Total Behaviour Prob-
Clostridium lem Score
cluster
Prebiotics– 6 weeks Galactooligosaccharide Increased Faecalibacterium • Improved anti-social behaviour (tool

Not reported prausnitzii, Bacteroides unspecified)
spp.
7
Decreased
Table 1. Continued
8
Kaitlin Romano et al.

Autism
Bifidobacterium
spp., Veillonellaceae
Prebiotics– 2 months Hydrolyzed guar gum Not reported • Improved behavioural irritability as per
Not reported Autism Behaviour Checklist (ABC), Jap-
anese Version
Synbiotic 3 months Bifidobacterium Improved gut microbiota • Improved ASD behaviour gut microbiota
Not reported infantis + Bovine
colostrum product
Brzóska-Konkol et al. Probiotic Not reported B. longum, L. acidophilus, Not reported • Lower symptom severity on the Autism
(2022) Enterococcus faecalis Treatment Evaluation Checklist scale
Probiotic 5 weeks B. infantis Not reported • Improved Aberrant Behavior Checklist

Not reported
Probiotic 3 weeks L. plantarum Not reported • Lower symptom severity on the Autism
Not reported Treatment Evaluation Checklist ques-
tionnaire
Vargas and Prebiotic 12 weeks B. infantis + Bovine Not reported • Reduction in irritability (p = 0.003),
Rodríguez (2022) 0.15 g/lb of colostrum product stereotypy (p = 0.006), hyperactivity
weight/day (p = 0.007), and total scores (p = 0.006),
along with a trend toward a significant
reduction in lethargy (p = 0.076) on the
Aberrant Behavior Scales
Probiotic 10 weeks Galactooligosaccharide Not reported • Improvements in anti-social behaviour

Not reported (GOS) of the Autism Treatment Evaluation
Checklist questionnaire (p = 0.05)
Probiotic 4 weeks Bifidobacterium fragilis Not reported • Reduced hyperactivity and impulsivity
425 +/ 25 mg (p = 0.04), opposition and defiance
(p = 0.045)
Table 1. Continued
Autism
Lasheras et al. (2021) Probiotic 3 weeks L. plantarum Increased lactobacilli • Lower overall behavioural/emotional
4.5 × 1010 CFU/g and enterococci, disturbances scores. Scores for disrup-
Decreased Clostridium tive behaviour, anxiety, self-absorbed
clusters behaviour, and communication dis-
turbances were lower than baseline
during probiotic feeding
Probiotic 4 months 3 Lactobacillus Decrease in Firmicutes, • Beneficial effects were seen (tool
Not reported strains, 2 Bifidobacterium which results in the unspecified)
strains, 1 Streptococcus increase of the
strain (species not Bacteroidetes/Firmicutes
reported) ratio to the level
of healthy individuals.
Levelling of the amount
of Bifidobacterium, high
in
ASD children at baseline,
to that of healthy
controls.
Increased Lactobacillus
Decreased Candida,
Desulfovibrio, Clostridia,
Bifidobacterium,
Candida
Probiotic 2 months L. acidophilus Not reported • Improvement in concentration and

11.5 × 109 CFU/g) ability to carry out orders on probiotic
twice a day therapy
Probiotic 1 month Bifidobacterium animalis Not reported • Decrease in Autism Behaviour Checklist
Not reported mean values after two therapeutic
course treatments. Amelioration of
9
Table 1. Continued
10

Autism
communication and eye contact in 90%
of ASD children, but no improvement in
stereotyped behaviour
Ligezka et al. (2021) Prebiotic 10 weeks Galactooligosaccharide Increased Clostridium • Improvement in anti-social behaviour
Not reported clusters (tool unspecified)
Decreased
Bifidobacteria
Probiotic 5 weeks B. infantis Not reported • Decreased score for certain aberrant
Not reported behaviours based on the ABS question-
naire: irritability (p = 0.003), stereotypy
(p = 0.006), hyperactivity (p = 0.007)
Martinez-Gonzalez Probiotic 2 months L. plantarum Increased Lactobacillus, • No statistically significant effect on

and Andreo-Martinez 4.5 × 1010 CFU by Bifidobacterium emotional symptoms
(2020) capsule daily
Prebiotic 6 months Galactooligosaccharide Decreased Bifidobacterium • Improvements in anti-social behaviour

1.8 g: 80% GOS spp and Veillonellaceae (p < 0.05) (tool unspecified)
content Increased F. prausnitzii
and
Bacteroides spp.
Probiotic 3 months B. longum, L. acidophilus, Increased Bifidobacterium • Improvements in severity of autism

5 g/day; each gram L. rhamnosus and Lactobacillum (p = 0.0001) (tool unspecified)
contains 100 × 106 CFU
Probiotic 12 months B. infantis Not reported • Reduced occurrence of aberrant

20 thousand million behaviour (tool unspecified)
CFU/day
Probiotic 4 months Bifidobacterium breve, Not reported • Improvement in anxiety (tool unspeci-
900 thousand million B. infantis, B. longum, fied)
bacteria/half pack in L. acidophilus, Lactobacillus
powder packs. casei, Lactobacillus
Half pack/twice a day delbrueckii subsp.
Table 1. Continued
Autism
for the first 4 weeks. Bulgaricus, L. plantarum,
Full pack/twice a Streptococcus
day if no effect thermophilus
observed at medical
check at 4 weeks
and 15 weeks.
Probiotic 1 month L. plantarum Not reported • A trend towards a reduction in body and
3 × 1010 CFU/capsule with object use scores (p = 0.04); SRS–total
microcrystalline cellulose/ score (p = 0.04), anxiety (p = 0.02),
day hyperactivity and impulsivity (p = 0.04),
and defiance (p = 0.045). (tool unspeci-
fied)
Prebiotic Not reported Partially hydrolyzed guar gum Increased Blautia and • Reduction in irritability symptoms (tool
6 g daily Acidaminococcus unspecified)
Decreased
Streptococcus,
Odoribacter, and
Eubacterium
Mitchell and Davies Synbiotic 108 days B. infantis, Bifidobacterium Decreased Ruminococcus • Reduction in ASD severity (tool
(2021) 1010 CFU/pack/day lactis, Lactobacillus and Clostridium unspecified)
paracasei L. rhamnosus +
Fructooligosaccharide
Probiotic 21 days L. acidophilus, L. casei, Increased Bifidobacteria • Reduction in ASD severity (tool
1 × 108 CFUs 3x /day L. delbrueckii, Bifidobacterium and Lactobacillus unspecified)
bifidum, B. longum
Probiotic 6 months B. breve, B. infantis, No shift in gut microbiome • Improved adaptive skills (repetitive,
450 billion CFU/pack B. longum, L. acidophilus, diversity or family level p = 0.0104; domestic, p = 0.047; coping
2 packets/day in the L. delbrueckii subsp. composition of species skills, p = 0.0115).
first month; Bulgaricus, L. paracasei, • Normalization of sensory profile scores
1 packet/day for the L. plantarum, Streptococcus
following 5 months thermophiles
11
Table 1. Continued
12

Autism
Probiotic 2 months L. acidophilus Increased Lactobacillus, • Improved some ASD symptoms (con-
5 × 109 CFU/g Enterococcus centration and ability to follow instruc-
twice daily Decreased desulfovibrio, tions)
Clostridium clusters
Prebiotic 8 weeks Galactooligosaccharide Increased Bifidobacterium • Improved ASD behaviour

Not reported
Synbiotic 12 weeks B. infantis + Bovine Increased Bifidobacterium • Decreased total aberrant behaviour
BCP 0.15 g/lb body colostrum product Decreased Ruminococcus, scores
weight/day Clostridium
B. infantis 2 × 109 CFU/
day
Ng et al. (2019) Probiotic 1 month L. acidophilus Not reported • Significant improvement in the ability to
Not reported concentrate and carry out orders
Probiotic 3 weeks L. plantarum Decreased Clostridium • No major differences in behaviour

Not reported (Developmental Behaviour Checklist
scores)
Probiotic 3 months Bifidobacteria longum, Increased Bifidobacteria • Improved behaviour after probiotics
Not reported L. acidophilus, Autism Treatment Evaluation Checklist
L. rhamnosus scores
Probiotic 3 months 3 strains of Lactobacillus, Decreased Bifidobacteria • Decreased ASD severity

Not reported 2 strains of Bifidobacteria, and Lactobacillus
1 strain of Streptococcus
(species not reported)
Nogay and Nahikian- Probiotic 3 weeks L. plantarum Not reported • No effects on behavioural problems
Nelms (2022) Not reported
Probiotic 4 weeks L. plantarum Not reported • Improved opposition/defiance behav-

Not reported iour, and it did so even more for the
younger children than for the older ones
Table 1. Continued
Autism
Patel et al. (2022) Probiotic Not reported L. plantarum Not reported • Beneficial effects were seen (tool
unspecified)
Prosperi et al. (2022) Probiotic 2 months L. acidophilus Not reported • Improvement in the ability to concen-
5 × 109 CFU/g2/day trate and carry out orders; no difference
in reacting to other people’s emotions
or using eye contact
Prosperi et al. (2022) Probiotic 3 weeks L. plantarum Increased Lactobacillus, • Improvement of the anti-social behav-
4.5 × 1010 CFU/day Enterococci iours, anxiety, and communication
Decreased Clostridium problems
coccoides
Prebiotic 6 months Galactooligosaccharide Increased Lachnospiraceae • Improvements in anti-social behaviour

1.8 g in powder
(unknown frequency)
Synbiotic 3 months B. longum, L. acidophilus, Increased Bifidobacterium • Significant improvements in ASD sever-
1 g = 100 × 106 CFU L. rhamnosus + Dried carrot and Lactobacillus ity using Autism Treatment Evaluation
for each species 5 g/day Checklist
Prebiotic 2–15 months Partially hydrolyzed Not reported • Significant decrease in irritability
6 g/day guar gum
Probiotic 1 month B. bifidum, B. infantis, Not reported • Decrease in anxiety, hyperactivity, and
6 g/day (36 billion B. longum, L. acidophilus, opposition/defiance behaviours; no
CFU in total) Lactobacillus bulgaricus, change in ASD symptoms
L. casei
Synbiotic 1, 2, or 3.6 months B. infantis, Not reported • Decrease in total and subdomain
1010 CFU/pack/day B. lactis, Autism Treatment Evaluation Checklist
L. paracasei, scores
L. rhamnosus +
Fructooligosaccharide
Probiotic 6 months L. plantarum Not reported • Increased level of shared attention,
13
3 × 1010 CFU if weight < 30 kg, decreased stereotyped movements,
Table 1. Continued
14

Autism
6 × 1010 CFU if communication skills, and personal
weight > 30 kg autonomy
Tan et al. (2021) Probiotic 4 weeks B. bifidum, B. infantis, Not reported • Decrease in total and subdomain
6 g/day (36 billion CFU in B. longum, Autism Treatment Evaluation
total) L. acidophilus, Checklist scores
L. bulgaricus, L. casei
Probiotic 3 months B. longum, Not reported • Decrease in total and subdomain

5 g/day L. acidophilus, Autism Treatment Evaluation
(containing 0.5 billion CFU) L. rhamnosus Checklist scores
Probiotic 6 weeks Bifidobacterium ongum, Not reported • Decrease in total and subdomain
20 billion CFU in total/ day L. paracasei, Autism Treatment Evaluation
L. rhamnosus Checklist scores
Probiotic 3 weeks B. bifidum, B. longum, Not reported • Decrease in total and subdomain Aut-
450 billion CFU/ pack L. acidophilus, L. casei, ism Treatment Evaluation Checklist
2 packets/day in Lactobacillus delbruecki scores
the first month; 1
packet/day for the
following 5 months
Prebiotic 2–15 months Galactooligosaccharide Not reported • Decrease in autism behaviour

6 g/day checklist scores
Prebiotic 6 weeks Galactooligosaccharide Not reported • Decrease in Autism Treatment

1.8 g: 80% GOS content Evaluation Checklist scores,
anti-sociability
Probiotic 1, 2, or 3.6 months B. infantis, B. lactis, Not reported • Decrease in total and subdomain
Not reported L. paracasei, L. rhamnosus Autism Treatment Evaluation
Checklist scores
Probiotic 5 weeks Bifidobacterium Not reported • Decrease in autism behaviour checklist

20 billion CFU/day longum infantis scores
Table 1. Continued
Autism
Yang et al. (2020) Probiotic 3 weeks to 6 months Bifidobacterium, Increased • Improved ASD behaviour (tool unspeci-
1 capsule 3imes a day Lactobacillus, Bifidobacterium, fied)
(specific dose not reported) Streptococcus Lactobacillus,
(species not reported) Enterococcus
Decreased
Firmicutes,
Desulfovibrio,
Clostridium
Prebiotic 4–6 weeks Galactooligosaccharide; Increased B. longum • Improved ASD behaviour (tool unspeci-
6 g/day Hydrolyzed guar gum fied)
Synbiotic 3–4 months B. infantis, B. lactis, Increased B. longum, • Improved ASD behaviour (tool unspeci-
1010 CFU/pack/day L. paracasei, Bifidobacteriales fied)
L. rhamnosus + Decreased
Fructooligosaccharide; Clostridium
B. infantis + Bovine
colostrum product
Basso et al. (2022) Probiotic 1 month Multi-strains Not reported • Decreased worrying measured by the
Varied: 50 × 109 CFU/ day; (unspecified) Penn State Worry Questionnaire
15 × 109 CFU/ day;
10 × 109 CFU/ day
Prebiotics 21 days Galactooligosaccharide Not reported • Decreased attentional bias towards

5500 mg/ day negative emotion stimuli
Prebiotics 8 days Fermented ginseng Not reported • Decrease in total anxiety scores
205 mg nine times/day
Probiotic 84 days L. plantarum Not reported • Improvements in anxiety and stress

1 × 109 CFU/day scores using the Depression Anxiety
Stress Scale (DASS-42)
15
16
Figure 2. Reported abundance of gut operational taxonomic units in youth with ASD and ADHD (n = 23). The outer circle represents the genus level, with outer colours distinguishing the phylum. Dark
blue arrows indicate reviews of ASD, and light blue arrows indicate reviews of ADHD. ↑ indicates higher abundance in youth with the disorder, while ↓ indicates lower abundance in the disorder.
17
Figure 3. Reported changes in gut microbiota operational taxonomic units following prebiotic, probiotic, and synbiotic supplemen-
tation among youth with ASD (n = 16). The outer circle represents the genus level, with outer colours distinguishing phylum. Dark blue
arrows indicate reviews of ASD. ↑ indicates higher abundance in youth with the disorder compared to baseline, while ↓ indicates lower
abundance in the disorder compared to baseline.
Interventional systematic reviews

Among the 16 interventional reviews, 15 examined the efficacy of probiotics, eight examined the efficacy
of prebiotics, and four examined the efficacy of synbiotics on ASD symptoms. One review examined the
efficacy of probiotics and prebiotics on anxiety. All supplements were administered orally, as a capsule or
packet, one, two, or three times daily, with dosages ranging from 0.5 to 90 × 1010 colony-forming units of
bacteria. Treatment duration ranged from 21 days to 15 months.
Improvements in ASD symptoms were reported in all reviews following prebiotic, probiotic, and
synbiotic supplementation. One review (Basso et al., 2022) reported improvement in anxiety symptoms
following probiotic or prebiotic supplementation. Details regarding supplement types, duration, dosage,
and species as well as gut microbiome and mental health outcomes can be found in Table 1.
Eight reviews reported changes in OTUs. Consistent findings were for the effect of prebiotics,
probiotics, and synbiotics on specific bacterial groups. The use of prebiotics consistently increased the
abundance of Lachnospira, while the use of probiotics increased the abundance of Lactobacillus and
Enterococcus. Furthermore, probiotic intervention decreased the abundance of Desulfovibrio, and
probiotics as well as synbiotic treatment consistently decreased the abundance of Clostridium clusters.
The impact of prebiotic, probiotic, and synbiotic supplementation on Bifidobacterium in the gut was
inconsistent. Some studies (Yang et al., 2020; Mitchell and Davies, 2021; Prosperi et al., 2022) reported an
increase in Bifidobacterium levels, while others reported decreased levels (Lasheras et al., 2021; Amadi
et al., 2022).

The remaining OTUs were only reported in one review, indicating limited findings. Thus, the effects
of prebiotics, probiotics, and synbiotics on these specific OTUs remain uncertain and require further
investigation (Figure 3).
Sensitivity analysis
Reduction of overlap bias was conducted separately for observational and interventional systematic
reviews.
The 23 observational systematic reviews included 92 primary studies, of which 26 were excluded for
the following reasons: animal studies (n = 6), other mental health disorders (n = 15), and non-gut
microbiome studies (n = 5). Forty-two primary studies were unique and 50 primary studies were
reported in ≥2 systematic reviews, yielding a CCA of 12.5% and indicating a high degree of overlap
(Supplementary Figure S2). Reduction methods eliminated 13 observational systematic reviews that had
>25% overlap, leaving 80 primary studies (40 were unique, and 40 were reported in ≥2 systematic
reviews) reported in 10 observational systematic reviews. The CCA was 8.47%, indicating a moderate
degree of overlap (Supplementary Figure S3).
The overlap minimization reduced the number of reported OTUs among observational reviews of
ASD youth from 43 to 32. The 11 OTUs lost were Bacillus, Eubacterium, Lachnospira, Megasphaera,
Oscillospira, Ruminococcus, Butyricimonas, Collinsella, Bilophila, Desulfovibrio, and Pseudomonas.
Exaggeration, the replication of primary study’s findings in multiple reviews, was evident for increased
and decreased abundance of OTUs. Exaggerated increased abundance was reported for Clostridium
clusters, Dorea, Enterococcus, Roseburia, Barnesiella, and Candida. Exaggerated decreased abundance
was reported for Coprococcus, Dialister, Veillonella, Fusobacterium, and Escherichia. Reporting incon-
sistencies remained for Faecalibacterium, Lactobacillus, Prevotella, and Bacteroides, while clearer signals
emerged for Streptococcus, Turicibacter, Parabacteroides, Bifidobacterium, Corynebacterium, Akker-
mansia, and Sutterella (see Figure 4A,B).
The overlap minimization reduced the number of reported OTUs among observational reviews of
ADHD youth from seven to three. The four OTUs lost were Dialister, Lactobacillus, Parabacteroides, and
Bifidobacterium. Exaggeration in reporting was evident for increased and decreased abundance of OTUs.
Exaggerated increased abundance was reported for Bacteroides and decreased abundance for Faecali-
bacterium. A clearer signal emerged for Prevotella (see Figure 4A,B).
The 16 interventional systematic reviews included 36 primary studies, of which 26 were excluded for
the following reasons: not biotic supplementation (n = 11) and not a paediatric population (n = 15).
Thirteen primary studies were unique and 23 primary studies were reported in ≥2 systematic reviews
yielding a CCA of 18.9% indicating a high degree of overlap (Supplementary Figure S4). Reduction
methods eliminated 10 interventional reviews with >25% overlap leaving 28 primary studies (17 were
unique and 11 were reported in ≥2 systematic reviews) reported in six interventional systematic reviews.
The CCA was 9.3%, indicating a moderate degree of overlap (Supplementary Figure S5).
The overlap minimization reduced the number of reported OTUs among ASD youth for the
interventional reviews from 16 to 7. The eight OTUs removed were Acidaminococcus, Blautia, Eubac-
terium, Faecalibacterium, Ruminococcus, Streptococcus, Veillonella, Bacteroides, and Odoribacter. Exag-
gerated increased abundance was reported for Enterococcus and Lachnospira and decreased abundance
for Clostridium clusters and Desulfovibrio. Inconsistent reporting remained for Bifidobacterium, and a
clearer signal emerged for Lactobacillus (see Figure 5A,B).
Discussion
This umbrella review is the first to synthesize the current literature, to our knowledge, examining the gut
microbiome and psychiatric disorders among children and adolescents. Child and adolescent psychiatric
disorders were found to be unequally represented in the included systematic reviews. The majority of

19
Figure 4. Reported increase/decrease in abundance of gut operational taxonomic units in youth with autism spectrum disorder (ASD)
(dark blue) and ADHD (light blue) across (A) included systematic reviews (n = 23) and (B) after overlap bias was minimised (n = 10).
reviews focused on ASD, accounting for 92% of the total reviews. A smaller proportion of reviews
examined ADHD, with only 15% of the reviews dedicated to this disorder. Furthermore, there was one
review each on depression and anxiety, while no reviews specifically addressed OCD or bipolar disorder.
The nascency of this research area was further evident as 80% of reviews were published since 2020.
Findings from observational reviews reveal consistent signals of association between specific OTUs
and symptoms of ASD in youth. These findings remained following overlap minimization. The most
consistent evidence points to an increased abundance of Clostridium clusters and a decreased abundance
of Bifidobacterium. Clostridium clusters are spore-forming bacteria, known to release pro-inflammatory
toxins that have the potential to reach the brain through the bloodstream (Argou-Cardozo and Zeidan-
Chulia, 2018). Lower ratios of Clostridium clusters have been observed in vegetarians and vegans versus
omnivores (Rinninella et al., 2019). Additionally, certain metabolites derived from the activity of
Clostridium, such as short-chain fatty acids (SCFAs), are produced through the fermentation of dietary

Figure 5. Reported increase/decrease in abundance of gut operational taxonomic units in youth with ASD following prebiotic (black),
probiotic (red), or synbiotic (green) supplementation (A) across included interventional systematic reviews (n = 16) and (B) after
overlap bias was minimized (n = 6).
fibre. SCFAs play a critical role in maintaining the proper functioning of the gut immune system by
modulating gene expression. SCFAs promote gut health through increasing epithelial cell turnover and
their use as sources of energy for intestinal cells (Xing et al., 2020). Imbalances in SCFA concentrations
can disrupt gut homeostasis and potentially trigger peripheral inflammation. Additionally, SCFAs can
reach the brain through the bloodstream, where they influence its development by modulating the
production of neurotransmitters, for example, serotonin and dopamine (Srikantha and Mohajeri, 2019).
Bifidobacterium are considered to be beneficial bacteria whose presence is consistent with a greater
adherence to Mediterranean diets and lower adherence to high fat intakes similar to those seen in
Western diets (Rinninella et al., 2019). Evidence from animal studies suggests that certain species of
Bifidobacterium have a positive effect on the hypothalamic–pituitary–adrenal axis by lowering dopa-
mine and adrenaline and may also have an anti-inflammatory effect on the gastrointestinal tract (Moya-
Pérez et al., 2017). Bifidobacterium also has the capability to produce gamma-aminobutyric acid, an
important inhibitory neurotransmitter that is closely associated with the metabolism of glutamate, the
primary excitatory neurotransmitter in the brain (Perna et al., 2019).
While the full analysis may exaggerate the importance of certain species, the sensitivity analysis may
potentially underestimate the importance of certain species. OTU signals remaining after the sensitivity
analysis indicate a lower abundance of beneficial bacteria and higher levels of harmful bacteria in ASD
youth contributing to gut dysbiosis, characterized by an imbalance or altered composition of OTUs. For
example, weak but consistent increased abundance of OTUs remained for harmful bacteria in ASD
youth such as Candida, which releases ammonia and toxins (Reichelt and Knivsberg, 2009), Dorea which
promotes inflammation (Schirmer et al., 2016), Bacteroides, which produces propionic acid-neurotoxic
SFCA (Abdelli et al., 2019), and SCFA producers such as Roseburia. Moreover, weak but consistently

21
decreased abundance of OTUs remained for beneficial bacteria in ASD youth such as Coprococcus, which
are necessary for carbohydrate digestion and fermentation (Kovatcheva-Datchary et al., 2015), and
Dialister, which are known to assist with the maintenance of the normal gastrointestinal tract function
(Taylor et al., 2020).
The inconsistent findings regarding specific OTUs and their association with ASD symptoms may be
attributed to several factors. Firstly, the high degree of natural variability observed in the composition of
the gut microbiome across different populations can contribute to divergent results. Each individual’s
gut microbiome is influenced by numerous factors, including genetics, environment, and lifestyle,
leading to significant variation (Vandeputte et al., 2021). Secondly, the heterogeneity of the ASD
phenotype, characterized by variations in symptom severity and presentation, may also influence the
composition of the gut microbiome and obscure clear associations with specific OTUs. One potential
explanation for ASD-related gut dysbiosis is that children and youth with ASD have been noted to have
lower vegetable intake compared with neurotypical youth. This discrepancy in vegetable consumption
has been attributed to selective eating patterns and sensory disturbances commonly experienced by
children with ASD (Emond et al., 2010; Siddiqi et al., 2019). The complex nature of ASD and the diverse
symptoms experienced by individuals with ASD make it challenging to establish consistent relationships
between specific OTUs and ASD symptoms (Jacob et al., 2019). Lastly, the variability in the age of
subjects included in studies examining the gut microbiome in relation to ASD could contribute to the
inconsistent findings. The gut microbiome undergoes developmental changes during childhood, and
differences in age among study participants could influence the composition and functioning of the
microbiome (Ronan et al., 2021). These factors collectively emphasize the complexity of studying the gut
microbiome in relation to ASD and highlight the need for further research that takes these variables into
account to provide more conclusive insights.
Weak signals also indicate the presence of gut dysbiosis in ADHD youth. The sensitivity analysis
conducted for ADHD revealed an elevated level of replication of primary study findings in multiple
reviews, which further highlights the limited primary research available in this area. Therefore, caution
should be exercised when interpreting these findings. Only one review reported an increased abundance
of OTUs belonging to the Bacteroides and Prevotella genus in youth with ADHD. Bacteroides metabolize
polysaccharides and oligosaccharides, providing nutrition and vitamins to the host and other intestinal
microbial residents. However, when dietary habits include the consumption of high animal protein
foods, which promote the growth of Bacteroides, it may lead to a relative decrease in other bacterial taxa,
creating an imbalance in the microbial community (Desai et al., 2016; Rinninella et al., 2019). One review
also reported decreased relative abundance of beneficial OTUs belonging to the Faecalibacterium genus
which produce butyric acid, bioactive peptides, and other anti-inflammatory substances with immuno-
modulatory effects, consistent with a diet low in dietary fibre, fruit, and vegetables (Quévrain et al., 2016,
Zou et al., 2021). While these weak signals suggest gut dysbiosis in ADHD youth, it is important to note
that the current understanding is based on a limited number of reviews and their findings should be
interpreted with caution. Additionally, the complexity of ADHD, which involves various genetic,
environmental, and neurological factors, further complicates the interpretation of the results.
Interventions for ASD consistently demonstrated improvements in ASD symptoms across all reviews
that evaluated biotic supplements. This trend persisted even after conducting the sensitivity analysis to
account for potential overlap. These findings provide support for the hypothesis that the gut–brain axis,
which involves bidirectional communication between the gut and the brain, plays a role in the
manifestation of ASD. Among the reviews of interventions for ASD, the sensitivity analysis unveiled
a high degree of overlap among primary studies, indicative of a reduced volume of primary research
available. Therefore, when interpreting the findings, it is essential to consider the implications of
minimizing the results due to overlap. Specifically, probiotic supplementation promoted a healthier
state of the gut microbiota, known as gut eubiosis, as consistently reported in the reviewed studies.
Enhanced gut microbiome eubiosis was characterized by an increase in the abundance of beneficial
bacteria, such as Lactobacillus and Enterococcus, and a decrease in the abundance of detrimental bacteria,
including clusters of Clostridium. Among this early evidence, a consistent link between enhanced gut

microbiome eubiosis and positive outcomes in ASD supports the notion that targeting the gut micro-
biota through biotic supplements may hold therapeutic potential for individuals with ASD.
The effect of prebiotic, probiotic, and synbiotic supplementation on Bifidobacterium demonstrated
inconsistent findings in interventional reviews before and after overlap minimization (Figure 5A,B). This
highlights the need for additional research to provide a more comprehensive understanding of the
impact of biotic supplementation on Bifidobacterium and to address the lack of evidence.
This umbrella review identified a significant issue of primary study overlap in the systematic evidence
gathered so far. A significant amount of overlap was found in the primary studies included in
observational systematic reviews and interventional reviews. Approximately 54% of primary studies
in the observational reviews and 64% of primary studies in the interventional reviews were reported in
two or more reviews. This overlapping inclusion of studies can introduce a high to very high level of bias
when reviewing the systematic evidence. This bias was demonstrated in the sensitivity analysis, which
revealed exaggerated reporting of OTUs in the included studies. Moreover, the review found that a
considerable proportion (56%) of the observational and interventional reviews had low or critically low
methodological quality. This was due to several factors, including missing details about excluded primary
studies, failure to provide a registered a priori protocol, and inadequate use of comprehensive search
strategies. These methodological shortcomings may limit the reliability and generalizability of the
findings and underscore the importance of following rigorous systematic review protocols.
This umbrella review also highlights a significant issue of reporting inconsistency within the literature
regarding the gut microbiota of children and adolescents with mental health disorders. Although all
studies reported relative taxon abundances, very few report diversity measures such as richness, which is
crucial in understanding the gut microbiome’s complexity. Diversity, richness, and evenness are all vital
concepts that provide a more comprehensive understanding of the gut microbiome. A greater diversity of
bacteria in the gut is generally considered to be more beneficial than a less diverse microbiome (Young
and Schmidt, 2008). Therefore, the lack of diversity reporting in the literature is a significant gap that
needs to be addressed to better understand the relationship between the gut microbiome and mental
health disorders in children and adolescents. Additionally, the compositional nature of sequence datasets
may also contribute to the conflicting findings, as an increase in the relative abundance of a taxon can
occur even if its absolute abundance decreases (Gloor et al., 2017). This could lead to confounding
findings from many of the included reviews, possibly providing an explanation for the inconsistent
results observed in different studies.
This umbrella review has several strengths. Firstly, the search and review process was rigorous, and
the broad search strategy resulted in a large number of records being captured without limiting the search
by date or country of publication. Secondly, this review addressed the issue of primary study overlap,
which is a known source of bias in umbrella reviews. By minimizing overlap, the review was able to
provide a more comprehensive and unbiased synthesis of the available evidence. Additionally, the
inclusion of both observational and interventional reviews allowed for a comprehensive assessment of
the literature on the gut microbiome and mental health disorders among youth.
Despite these strengths, some limitations should be considered when interpreting the results. Due to a
high degree of heterogeneity, we were unable to conduct a meta-analysis. Caution should be exercised
when interpreting findings related to OTUs, as the significance of certain OTUs may be overstated due to
primary study overlap, while the importance of others may remain unclear or ambiguous. Additionally,
due to the limitations inherent in a high-level overview, we were unable to delve into the specifics of
individual treatments and their direct effects on the gut microbiome and mental health. However, our
study contributes by synthesizing and presenting a broader perspective on the overall trends and
implications of biotic treatments on mental health. Also, we did not report OTUs that exhibited no
associations or lack of efficacy with the disorders under investigation to maintain clarity and avoid
presenting conflicting or inconclusive information. It is important to note that the research field on this
topic is still in its early stages, and as more studies emerge, this will improve. Additionally, the current
review may under-represent research conducted in a language other than English, as our inclusion
criteria led to the exclusion of seven non-English reviews. Finally, although this review focused on

23
alterations of gut microbiota, other research has shown that the gut–brain axis links numerous peripheral
intestinal functions to brain centres through a wide range of processes and pathways, potentially in a
bidirectional manner (Arneth, 2018).
To further advance our understanding of the relationship between the gut microbiome and mental
health disorders among children and adolescents, future studies should consider several important
methodological improvements. Researchers should consider using amplicon sequence variants (ASVs)
in study analyses. ASVs allow for better comparisons across different studies and enable the identifi-
cation of rare taxa that would otherwise be lost in OTU-based analyses (Amir et al., 2017; Chiarello et al.,
2022). This is because OTUs can vary according to the dataset, as they rely on (and are sensitive to)
clustering of sequences, while ASVs will be consistent and are not impacted by the dataset. Future
research accounting for lifestyle factors and other drivers of microbiome composition such as antibiotic
use is needed to determine whether putative variations in the microbiome are mechanistically important
or simply non-specific correlates of psychiatric disorders. Research examining potential mechanisms of
action is also needed, whereby the pathways by which the gut microbiome may influence mental health
can be more clearly elucidated. Although studies using 16S analysis can provide data on species, the
resolution is too limited for this purpose, given dramatic differences in gene complements even across
strains of the same species. Thus, future studies should also incorporate more mechanistic approaches
such as metagenomics, metatranscriptomics, and metabolomics. These technologies can provide a
deeper understanding of the functional potential of the microbiome and identify specific pathways
and metabolites that may be involved in mediating the relationship between the gut microbiome and
mental health. Accordingly, future research should consider metabolomic changes over microbiome
changes, whereby researchers can identify specific metabolites that are influenced by alterations in the
gut microbiota composition or activity. These changes can be associated with various health conditions,
including metabolic disorders, inflammatory bowel diseases, mental health disorders, and more.
Understanding these metabolomic alterations could potentially provide valuable information about
the mechanistic links between gut microbiota and host health, facilitating the development of targeted
interventions or therapeutic approaches. Finally, standardization of intervention approach and report-
ing is needed to compare results more accurately across clinical trials.
Conclusion
The research investigating the connection between the gut microbiome and mental health disorders in
children and adolescents is expanding, with the majority of studies focusing primarily on ASD. A smaller
proportion of studies examined the relationship between the gut microbiome and ADHD. However,
there is still a significant gap in our understanding of the gut microbiome’s role in other common and
debilitating mental health disorders such as depression, anxiety disorders, OCD, and bipolar disorder.
Further research in these areas is crucial to gain a better understanding of the potential involvement of
the gut microbiome in the development and treatment of these disorders.
In relation to ASD, this umbrella review reveals a consistent pattern across multiple reviews,
indicating associations between an increased abundance of detrimental bacteria and a decreased
abundance of beneficial bacteria. Although the body of review literature on interventions targeting
the gut microbiome in ASD is relatively smaller, emerging evidence suggests that the use of biotic
supplements can promote gut microbiome eubiosis, leading to positive impacts on ASD symptoms.
These findings support the need for further investigation into the role of biotic supplementation in the
management of ASD. Furthermore, considering the diverse array of clinical and microbial phenotypes
found in individuals with ASD and the specificity of emerging therapies in targeting specific traits and
microbial populations, it is increasingly apparent that a personalized treatment approach should be
adopted to effectively address the unique requirements of each patient.
To inform the development of more targeted and effective prebiotic interventions, future research
should also consider potential mediators and moderators of the gut microbiome–ASD relationship,

including the mechanisms through which the gut microbiome may contribute to ASD development and
the factors that may modulate this relationship. Finally, this review highlights the need for the
development of consensus reporting guidelines for a core set of gut microbiome outcome measures,
which will be essential for comparing results across studies and informing future research efforts in this
field.
Supplementary material. The supplementary material for this article can be found at https://doi.org/10.1017/gmb.2023.16.
Author contribution. Conceptualization: D.J.K., K.R., T.Z., S.C.C.; Funding acquisition: D.J.K., S.C.C.; Methodology: D.J.K.,
S.C.C.; Supervision: D.J.K., S.C.C.; Writing – review & editing: D.J.K., K.R., T.Z., A.S., C.Z., J.P., K.M., P.S., S.C.C.; Data curation:
K.R., T.Z., A.N.S., C.Z., K.M., S.C.C.; Formal analysis: K.R., A.S., A.N.S., C.Z., J.P., P.S.; Writing – original draft: K.R., A.S.,
A.N.S., S.C.C.; Visualization: A.S., S.C.C.; Project administration: S.C.C.
Disclosure statement. The authors declare none.
Funding. This work was supported by the SickKids Hospital Precision Child & Youth Mental Health Research Initiative.
Research transparency and reproducibility. Reasonable requests for data can be made to Daphne J. Korczak, 1145 Burton
Wing, Department of Psychiatry, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; Tel
416 813–6936; Fax 416–813-5236; email [email protected].
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Cite this article: Romano K, Shah AN, Schumacher A, Zasowski C, Zhang T, Bradley-Ridout G, Merriman K, Parkinson J,
Szatmari P, Campisi SC and Korczak DJ 2023. The gut microbiome in children with mood, anxiety, and neurodevelopmental
disorders: An umbrella review. Gut Microbiome, 4, e18, 1–27. https://doi.org/10.1017/gmb.2023.16

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Gut Microbiome (2023), 4, e18, 1–26

The gut microbiome in children with mood, anxiety, and

(Received 24 April 2023; revised 07 September 2023; accepted 08 September 2023)

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

Inclusion and exclusion criteria

Study selection and data collection

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

Methodological quality evaluation

Taxonomic evidence synthesis

Sensitivity analysis: overlap minimization

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

Identification of studies via databases and registries

Records identified from Databases

Ovid Embase (n=892) Records removed before

Records screened Records excluded

Reports sought for retrieval Reports not retrieved

Review studies included in the

Figure 1. PRISMA flowchart.

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

intervention parameters (prebiotic or probiotic combination trialled, intervention duration). Review

Methodological quality assessment

Gut microbiome taxonomic evidence synthesis

Observational systematic reviews – ASD

Observational systematic reviews – ADHD

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

Review Biotic Duration/dosage Supplement Gut microbiome Mental health

Prebiotics– 6 weeks Galactooligosaccharide Increased Faecalibacterium • Improved anti-social behaviour (tool

Kaitlin Romano et al.

Probiotic 5 weeks B. infantis Not reported • Improved Aberrant Behavior Checklist

Probiotic 10 weeks Galactooligosaccharide Not reported • Improvements in anti-social behaviour

Review Biotic Duration/dosage Supplement Gut microbiome Mental health

Probiotic 2 months L. acidophilus Not reported • Improvement in concentration and

Kaitlin Romano et al.

Martinez-Gonzalez Probiotic 2 months L. plantarum Increased Lactobacillus, • No statistically significant effect on

Prebiotic 6 months Galactooligosaccharide Decreased Bifidobacterium • Improvements in anti-social behaviour

Probiotic 3 months B. longum, L. acidophilus, Increased Bifidobacterium • Improvements in severity of autism

Probiotic 12 months B. infantis Not reported • Reduced occurrence of aberrant

Review Biotic Duration/dosage Supplement Gut microbiome Mental health

Kaitlin Romano et al.

Prebiotic 8 weeks Galactooligosaccharide Increased Bifidobacterium • Improved ASD behaviour

Probiotic 3 weeks L. plantarum Decreased Clostridium • No major differences in behaviour

Probiotic 3 months 3 strains of Lactobacillus, Decreased Bifidobacteria • Decreased ASD severity

Probiotic 4 weeks L. plantarum Not reported • Improved opposition/defiance behav-

Review Biotic Duration/dosage Supplement Gut microbiome Mental health

Prebiotic 6 months Galactooligosaccharide Increased Lachnospiraceae • Improvements in anti-social behaviour

Probiotic 6 months L. plantarum Not reported • Increased level of shared attention,

Kaitlin Romano et al.

Probiotic 3 months B. longum, Not reported • Decrease in total and subdomain

Prebiotic 2–15 months Galactooligosaccharide Not reported • Decrease in autism behaviour

Prebiotic 6 weeks Galactooligosaccharide Not reported • Decrease in Autism Treatment

Probiotic 5 weeks Bifidobacterium Not reported • Decrease in autism behaviour checklist

Review Biotic Duration/dosage Supplement Gut microbiome Mental health

Prebiotics 21 days Galactooligosaccharide Not reported • Decreased attentional bias towards

Probiotic 84 days L. plantarum Not reported • Improvements in anxiety and stress

Interventional systematic reviews

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press

https://doi.org/10.1017/gmb.2023.16 Published online by Cambridge University Press