TYPE Review

PUBLISHED 24 July 2023

DOI 10.3389/fcimb.2023.1238005

Psychobiotics and fecal

OPEN ACCESS microbial transplantation for
EDITED BY
Leena Malayil,
University of Maryland, United States
autism and attention-deficit/
REVIEWED BY
Robert Fultz,
hyperactivity disorder:
Brightseed, United States
Eugenia Bezirtzoglou,
Democritus University of Thrace, Greece
microbiome modulation and
*CORRESPONDENCE
Hyun-Kyung Park
therapeutic mechanisms
neopark@hanyang.ac.kr
†
These authors have contributed Min-jin Kwak 1†, Seung Hyun Kim 2†, Hoo Hugo Kim 3,
equally to this work and share
first authorship Rahul Tanpure 3, Johanna Inhyang Kim 4,5, Byong-Hun Jeon 3
RECEIVED 10 June 2023 and Hyun-Kyung Park 2,5*
ACCEPTED 30 June 2023 1
Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Science,
PUBLISHED 24 July 2023
Seoul National University, Seoul, Republic of Korea, 2 Department of Pediatrics, Hanyang University
CITATION College of Medicine, Seoul, Republic of Korea, 3 Department of Earth Resources and Environmental
Kwak M-j, Kim SH, Kim HH, Tanpure R, Engineering, Hanyang University, Seoul, Republic of Korea, 4 Department of Psychiatry, Hanyang
Kim JI, Jeon B-H and Park H-K (2023) University Medical Center, Seoul, Republic of Korea, 5 Clinical Research Institute of Developmental
Psychobiotics and fecal microbial Medicine, Hanyang University Hospital, Seoul, Republic of Korea
transplantation for autism and attention-
deficit/hyperactivity disorder: microbiome
modulation and therapeutic mechanisms.
Front. Cell. Infect. Microbiol. 13:1238005.
doi: 10.3389/fcimb.2023.1238005 Dysbiosis of the gut microbiome is thought to be the developmental origins of
COPYRIGHT
the host’s health and disease through the microbiota-gut-brain (MGB) axis: such
© 2023 Kwak, Kim, Kim, Tanpure, Kim, Jeon as immune-mediated, metabolic, neurodegenerative, and neurodevelopmental
and Park. This is an open-access article
diseases. Autism spectrum disorder (ASD) and attention-deficit/hyperactivity
distributed under the terms of the Creative
Commons Attribution License (CC BY). The disorder (ADHD) are common neurodevelopmental disorders, and growing
use, distribution or reproduction in other evidence indicates the contribution of the gut microbiome changes and
forums is permitted, provided the original
author(s) and the copyright owner(s) are imbalances to these conditions, pointing to the importance of considering the
credited and that the original publication in MGB axis in their treatment. This review summarizes the general knowledge of
this journal is cited, in accordance with
gut microbial colonization and development in early life and its role in the
accepted academic practice. No use,
distribution or reproduction is permitted pathogenesis of ASD/ADHD, highlighting a promising therapeutic approach for
which does not comply with these terms. ASD/ADHD through modulation of the gut microbiome using psychobiotics
(probiotics that positively affect neurological function and can be applied for the
treatment of psychiatric diseases) and fecal microbial transplantation (FMT).

KEYWORDS

autism spectrum disorder, attention-deficit/hyperactivity disorder, psychobiotics, fecal

microbial transplantation, gut microbiome

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Kwak et al. 10.3389/fcimb.2023.1238005

1 Introduction including genetic, environmental, and perinatal damage-associated

factors (Kalenik et al., 2021). ASD and ADHD are highly comorbid,
Two childhood-onset neurodevelopmental disorders that have where 20-50% children with ADHD meet the criteria for ASD and
been linked to gut microbial dysbiosis are autism spectrum disorder 30-80% of ASD meet the criteria for ADHD (Rommelse et al., 2010).
(ASD) and attention-deficit/hyperactivity disorder (ADHD) High co-occurrence rate challenges differential diagnosis and also
(Prosperi et al., 2022). ASD and ADHD are highly prevalent, worsens symptom severity and prognosis (Zhou et al., 2023). Based
commonly co-occur with each other, and share overlapping on this high comorbidity, extensive research has been conducted on
symptoms (Bundgaard-Nielsen et al., 2023). Both have been the overlapping genetic factors and shared biological underpinnings
found to be related to environmental exposures in early life, like of ASD and ADHD (Liu et al., 2020).
endocrine disrupting chemicals (EDC), and EDCs have been Here, we reviewed the literature on the influence of psychobiotics
suggested to induce microbiota changes through the gut-brain- and fecal microbial transplantation (FMT) on the gut microbiome
microbiota axis conferring susceptibility to neurodevelopmental and behaviors/gastrointestinal (GI) symptoms related to ASD and
disorders (Ramı́rez et al., 2022). In the early twenty-first century, ADHD, and the relationship between neurodevelopmental disorders
many papers highlighted the connection between the brain and gut. and psychobiotics has received considerable attention in recent years.
The term “psychobiotics”, defined as the probiotic bacteria-derived There is a bidirectional interaction in the microbiota-gut-brain
molecules exerting psychological potential to support mental health (MGB) axis, and its modulation exerts beneficial effects on brain
by targeting microbial interventions, was newly coined in 2013. The activity and behavior as potential treatments (Bundgaard-Nielsen
therapeutic potential of psychobiotics ranges from mood changes et al., 2020). In light of these considerations, the gut-brain axis is an
and anxiety to neurodegenerative diseases and neurodevelopmental attractive target for developing novel therapeutics, such as the use of
disorders (Sharma et al., 2021). probiotics, for neurodevelopmental disorders (Sarkar et al., 2016).
ASD is characterized by impairments in behavioral domains such The main subject of our review is the commonly known gut
as social communication, restricted interests, and repetitive behavior. microbiome in ASD and ADHD individuals, and its impact on the
Although the high heritability of ASD suggests that genetics is a key symptoms of these neurodevelopmental disorders. And we will also
factor in its pathogenesis (Tick et al., 2016). Gene-environment discuss the theoretical basis of the correlations and the therapeutic
interactions have also been reported to be substantially involved, possibility of psychobiotics and FMT on neurodevelopmental
with estimates that more than 50% of neurobiology is driven by non- disorders (Figure 1).
heritable factors (Cheroni et al., 2020). ADHD is defined as a To the best of our knowledge, no systematic review of
neurodevelopmental disorder, and it is described by hyperactivity, randomized controlled trials (RCTs) has been conducted so far,
inattention, and excessive impulsiveness. The pathogenesis of ADHD and there are relatively few clinical studies identifying the
is complex, and representative factors have been investigated therapeutic effects of psychobiotics and FMT on ASD and

FIGURE 1
Action mechanisms by which psychobiotics and fecal microbial transplantation exert the potential therapeutic effect on ASD and ADHD.
Abbreviations: g-aminobutyric acid (GABA), short-chain fatty acids (SCFAs).

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Kwak et al. 10.3389/fcimb.2023.1238005

ADHD. Therefore, we thoroughly summarized the latest reports on later-life health (Stiemsma and Michels, 2018; Niemarkt et al., 2019;
potential therapeutic mechanisms and promising perspectives, in Korpela et al., 2020).
addition to observed changes in the gut microbiome composition
and metabolites. Moreover, this review presents directions for
future treatments that could be employed to directly manipulate 2.2 Gut-brain axis and bidirectional
gut microbiota during early life stages in humans to prevent the communication
development of such diseases.
The past 15 years have seen the emergence of the microbiota as one
of the critical regulators of gut-brain function through a complex
2 Role of gut microbiome axis network of signaling pathways, which has led to the appreciation of the
importance of a distinct MGB axis (Cryan et al., 2019). There are
2.1 Early-life gut microbial colonization various bidirectional communicating pathways between the gut
and development microbiome and the brain, which include vagus nerve (VN),
immunity with tryptophan metabolism, endocrine system, and
Human microbial colonization begins in the fetus and enteric nervous system (ENS) with diverse bacterial byproducts, such
continues to develop and modulate species abundance for as peptidoglycans, short-chain fatty acids (SCFAs), and branched-chain
approximately three years until the gut microbiome becomes amino acids (Jena et al., 2020).
adult-like (Figure 2A) (Arrieta et al., 2014; Senn et al., 2020). Bidirectional communication between the microbiota and the
There is increasing evidence that the gut microbiota and its host through the gut-brain axis is an essential pathway for accessing
byproducts could play pivotal functions in the immune system the synergetic mechanism to modulate the host brain and behavior
maturation, development, and behavior of the host throughout the (Dinan and Cryan, 2017; Ronan et al., 2021). Studies to identify and
life cycle (Erkosar et al., 2013). examine the MGB axis have used different yet complementary
Microbiota development follows typical timely changes and the microbiota interventions, including germ-free rodents, antibiotic-
interplay between the gut microbiome and the rest of the human induced depletion, prebiotic/probiotic supplementation,
body that have been analyzed through metagenomics studies and gastrointestinal infection, and FMT (Cryan et al., 2019). Top-
recent strain-level profiling (Bäckhed et al., 2015; Selma-Royo et al., down signaling influences the motor, sensory, and secretory
2020). Especially microbial colonization of the newborn period is a functions of the gastrointestinal tract via the efferent fibers of the
critical process that affects long-term neurological outcomes and VN. Bottom-up communication affects the function of the brain,

FIGURE 2
(A) Microbial colonization and development from birth to child. (B) Various environmental factors could induce gut dysbiosis and result in the
pathogenesis of necrotizing enterocolitis, late onset sepsis, neurodevelopmental disorders, diarrhea, atopic disease, and type I diabetes.

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Kwak et al. 10.3389/fcimb.2023.1238005

especially the amygdala and hypothalamus, via the afferent roles in the production of substances, such as SCFAs, which are
vagal fibers. reported to have diverse neurobiological correlations in the context
of the MGB axis, and 4-ethylphenylsulfate, which is a dietary
tyrosine metabolite that is considered to induce ADS-like
3 Neurodevelopmental disorders and behavior among many others (Hsiao et al., 2013; Dalile et al.,
gut microbiome 2019). In an experiment with genetically engineered mice,
maternal interleukin-17a secreted by Th17 cells was observed to
3.1 Gut dysbiosis in neurodevelopmental induce behavioral and cortical issues in their offspring, suggesting a
disorders possible role for the cytokine receptor interleukin-17a in the
modulation of ASD (Choi et al., 2016).
Dysbiosis may play a role in the etiology and development of
neurodevelopment disorders (Nagpal and Cryan, 2021). Earlier
reports confirmed that the index of gut microbial a-diversity of 3.3 ADHD and gut microbiome
1-year-old children showed a close correlation with cognitive
functions at 2-year-old (Carlson et al., 2018). Furthermore, ADHD is a common childhood-onset neurodevelopmental
additional human studies have suggested that the first year of life disorder that persists into adulthood, with a worldwide prevalence
is the most authoritative period in human cognitive development of 5% (Polanczyk et al., 2007). ADHD is distinguished by symptom
(Figure 2B). These results indicate that the occurrence risk of domains of inattention, hyperactivity, and/or impulsivity. Although
diseases might be increased during fetal development and early some children might not reach the threshold of full diagnosis,
life stages. ADHD traits are continuously distributed throughout the
population (Brikell et al., 2021). ADHD is a complex genetic
disorder with a high heritability rate of 76%; however, this
3.2 ASD and gut microbiome estimate encompasses gene by environment interaction and such
interactions may account for much of the etiology of ADHD
In general, ASD patients frequently coincidently have various (Faraone and Larsson, 2019). Diverse environmental factors,
gastrointestinal disorders, and it might be due to the tight including perinatal factors (prematurity, low birth weight) and
association between gut microbial disturbances and mental psychosocial determinants (adoption, child neglect), have been
health. Moreover, these connections in ASD individuals have reported as reasonable factors to ADHD.
suggested increased gut permeability, called “leaky gut”. If gut However, there are few reports on the role of the gut
permeability arose, the gut barrier allows to cross the bacterial microbiome in ADHD patients. A recent systematic review found
metabolites into animal’s body, and it could negatively affect that all six included studies had distinct taxon findings between
neurodevelopment during early childhood through the gut-brain patients with ADHD and healthy controls. However, results varied
axis. Fowlie and colleagues demonstrated that psychobiotics between studies, and there was minimal consensus on which
treatment in ASD patients has a potential to relieve ASD bacterial taxa correlated most with ADHD (Sukmajaya et al., 2021).
symptoms by modulation of the gut microbiome (Fowlie In the case of ADHD, there have been multiple attempts to find
et al., 2018). relationships between clinical features and differences of this
An important feature of ASD is its marked comorbidity with disorder and healthy samples based on the gut-brain axis concept.
gastrointestinal symptoms. A high rate of ASD patients, ranging A study that attempted to associate gut microbiota and plasma
from 9% to 90%, report comorbid gastrointestinal symptoms such cytokine levels with ADHD showed a higher abundance of three
as constipation, abdominal pain, diarrhea, gas, and vomiting genera (Agathobacter, Anaerostipes, and Lachnospira) and
(Vuong and Hsiao, 2017). Moreover, the observed GI decreased levels of TNF-a in the ADHD group compared with
disturbances were strongly correlated with ASD severity. These that of the control group (Wang et al., 2022). However, the studies
GI problems suggest that the intestine plays an important role in conducted so far have not been able to show clear relationships
ASD pathogenesis. Previous studies on microbiota composition in between microbial taxa and ADHD, compared to the relatively
patients with ASD have shown highly heterogeneous results more established ASD studies (Bundgaard-Nielsen et al., 2020).
between studies, but the majority of them have found that the Considering the relative paucity of scientific literature, more
overall microbiota composition of ASD cases is different from that research efforts to clarify the possible relationship between
of the controls (Bundgaard-Nielsen et al., 2020). However, no ADHD and the gut-brain axis are required.
specific bacteria are consistently associated with ASD diagnosis or
severity in the literature.
Specifically for ASD, the specific composition of microbial taxa 4 Psychobiotics: potential roles on
in the human gut, including Firmicutes/Bacteroidetes ratio, is MGB axis as treatment target
reported to differ between the control and patient groups, with
Fusobacteria and Verrucomicrobia abundances being lower in the Psychobiotics, next-generation probiotics (NGPs) for the brain,
patient group (De Angelis et al., 2013). Microbial taxa have specific are a special class of probiotics that positively affect neurological

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function and can be applied for the treatment of psychiatric diseases spectrum from stress alleviation to being an adjuvant in the
(Cheng et al., 2019). They are different from typical probiotics in treatment of diverse neuro-developmental and degenerative
their ability to affect the gut-brain axis by modulating microbial diseases (ADHD, ASD, Parkinson’s disease, and Alzheimer’s
composition, immune activation, VN signaling, and production of disease). Generally, conventional psychobiotic bacteria belong to
neuroactive metabolites, such as neurotransmitters, cytokines, the family Lactobacilli, and Bifidobacteria (Sharma et al., 2021).
SCFAs, and enteroendocrine hormones (Bermú dez-Humará n A summarized overview of clinical studies on the use of
et al., 2019; Kwak et al., 2021; Morais et al., 2021). Considering psychobiotics and FMT in individuals with ASD or ADHD is
this potential, psychobiotics have a wide-ranging application shown in Table 1.

TABLE 1 Treatment trials with psychobiotics and fecal microbial transportation in ASD and ADHD patients1.

Types Population Method Strain name Dose Main effects Reference

ASD symptoms
S. thermophilus, B. breve, 9.0 × 1011 CFU in 1st
↓
85 patients B. lungum, B. infantis, month
ASD Probiotics Inflammation, ↓ (Santocchi et al., 2020)
(3–6 years) L. acidophilus, L. plantarum, 4.5 × 1011 CFU in
Oxidative stress
L. paracasei, L. delbrueckii following
↓

3.0 × 1010 CFU BW < Improve

131 patients 30 kg intestine
ASD Probiotics L. plantarum PS128 (Mensi et al., 2021)
(4–11 years) 6.0 × 1010 CFU BW > ASD symptoms
30 kg ↓

ASD symptoms
35 patients 10 ↓
ASD Probiotics L. plantarum PS128 6.0 × 10 CFU (Kong et al., 2021)
(3–25 years) Veillonella, ↑
Streptococcus ↑

80 patients ASD symptoms

ASD Probiotics L. plantarum PS128 3.0 × 1010 CFU (Liu et al., 2019)
(7–15 years) ↓

ASD symptoms
22 patients 9 ↓ (Kałużna-Czapliń ska and
ASD Probiotics L. acidophilus 5.0 × 10 CFU
(4–10 years) Urinary Błaszczyk, 2012)
arabinitol ↓

ASD symptoms
↓
Gut symptoms
30 patients B. longum, L. rhamnosus,
ASD Probiotics 5.0 × 108 CFU ↓ (Shaaban et al., 2018)
(5–9 years) L. acidophilus
Bifidobacterium
↑
Lactobacillus ↑

9.0 × 1010 CFU in

B. breve, B. longum, B. infantis,
Bifido. ASD symptoms
L. acidophilus, L. plantarum,
1 patient 8.0 × 1010 CFU in ↓
ASD Probiotics L. paracasei, L. bulgaricus, (Grossi et al., 2016)
(12 years) Lacto. Gut symptoms
L. delbrueckii, S. thermophilus,
2.0 × 1011 CFU in ↓
S. salivarius
Strepto.

Behavior
41 patients improved
ASD Prebiotics Galactooligosaccharide 1.8 g for 6 months (Grimaldi et al., 2018)
(4–11 years) Bifidobacterium
↑

Behavior
8 patients B. infantis 2.0 × 1011 CFU improved
ASD Synbiotics (Sanctuary et al., 2019)
(2–11 years) Bovine colostrum 5.0– 10.0 g/day Gut symptoms
↓

L. casei, L. plantarum, Behavior

13 patients L. acidophilus, L. delbrueckii 1.8 × 106 – 3.2 × 106 improved
ASD Probiotics (Arnold et al., 2019)
(3–12 years) B. lungum, B. infantis, B. breve, CFU Gut symptoms
S. thermophilus ↓

61 patients L. fermentum, L. plantarum, Behavior

ASD Probiotics 1.0 × 1010 CFU (Guidetti et al., 2022)
(2–16 years) L. salivarius DSM 22 improved

(Continued)

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TABLE 1 Continued

Types Population Method Strain name Dose Main effects Reference

Gut symptoms
↓

Standardized human
18 children ASD symptoms
ASD FMT gut microbiota (Hamilton, Weingarden 2.5 × 1012 cells/day (Kang et al., 2017)
(7–17 years) ↓
et al., 2012)

ASD symptoms
Standardized human
18 children ↓
ASD FMT gut microbiota (Hamilton, Weingarden 2.5 × 1012 cells/day (Kang et al., 2019)
(7–17 years) Improved
et al., 2012)
behavior

ASD symptoms
Standardized human
40 children 12 ↓
ASD FMT gut microbiota (Hamilton, Weingarden 2.5 × 10 cells/day (Li et al., 2021)
(3–17 years) Improved
et al., 2012)
behavior

132 infants ADHD

ADHD Probiotics L. rhamnosus GG 1.0 × 1010 CFU (Pärtty et al., 2015)
(2–13 years) symptom ↓

Improve QoL
35 patients
ADHD Probiotics L. rhamnosus GG 1.0 × 1010 CFU Improve (Kumperscak et al., 2020)
(4–17 years)
cytokines

ADHD
30 patients
ADHD Probiotics B. bifidum Bf-688 5.0 × 109 CFU symptom ↓ (Wang et al., 2022)
(4–16 years)
Weight gain ↑

L. mesenteroides, L. paracasei,
66 patients 4.0 × 1011 CFU ADHD
ADHD Synbiotics L. plantarum (Skott et al., 2020)
(5–55 years) 2.5 g of prebiotics symptom ↓
B-glucan, inulin, pectin, starch

B. subtilis, B. bifidum, B. breve,

B. infantis, B. longum,
38 patients ADHD
ADHD Probiotics L. acidophilus, L. delbrueckii, 2.0 × 109 CFU (Ghanaatgar et al., 2022)
(6–12 years) symptom ↓
L. casei, L. plantarum L. lactis,
L. salivarius, S. thermophiles

ADHD
symptoms ↓
34 patients L. reuteri, L. acidophilus,
ADHD Probiotics 8.0 × 109 CFU Inflammation ↓ (Sepehrmanesh et al., 2021)
(8–12 years) L. fermentum, B. bifidum
Oxidative stress
↓

ADHD
1 patient symptom ↓
ADHD FMT Healthy doner’s microbiota Not applicable (Hooi et al., 2022)
(22 years) F. prausnitzii ↑
B. longum ↓
1
Abbreviations: autism spectrum disorders (ASD), attention deficit/hyperactivity disorder (ADHD), fecal microbial transplantation (FMT).

4.1 Therapeutic mechanisms/effects 4.1.1 Shift of gut dysbiosis toward eubiosis

on ASD 4.1.1.1 Affecting the gut microbiome population
One study found reduced D-arabinitol levels, a metabolite of
Gut dysbiosis in ASD has been reported in numerous studies Candida species, in the urine of children with ASD after probiotic
(Kho and Lal, 2018). Patients with ASD possess significantly supplementation (Shaw et al., 1995). This result suggests that
altered gut microbiota, resulting in GI symptoms. When probiotics may prevent gastrointestinal colonization by Candida
dysbiosis occurs in disorders such as irritable bowel disease species. In another study, the levels of Bifidobacterium (known as
and ASD, the psychobiotics would help the gut microbiota beneficial bacteria, such as Lactobacillus species) were significantly
return to normal levels and have positive effects on psychiatric lower in the stool of children with ASD (Shaaban et al., 2018). After
diseases. Consequently, various studies demonstrated that the probiotic supplementation, there was a significant increase in the
use of psychobiotics for ASD individuals suffering from GI colony counts of Bifidobacterium and Lactobacillus with significant
disorders would be a supplementary therapeutic method improvement in the severity of ASD and gastrointestinal symptoms.
(Zheng Y et al., 2020). A study in 2015 reported the effect of mixed probiotic

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administration on gut microbiota composition in children with plantarum, L. acidophilus, and L. paracacei) attenuated the
ASD (Tomova et al., 2015). The abundance of Clostridia and inflammatory responses in a VPA-induced rodent ASD model. In
Desulfovibrio and Bacteroidetes/Firmicutes ratio were related to particular, this study also showed that psychobiotic treatment
the severity of ASD and gastrointestinal symptoms. After decreased serum pro-inflammatory cytokine, IL-6 levels, and
probiotics treatment, the amount of Firmicutes significantly increased anti-inflammatory cytokine, IL-10 levels, with the
decreased, which resulted in an increase in the Bacteroidetes/ improved status of diverse behavior tests including social
Firmicutes ratio to a level similar to that observed in healthy interaction, anxiety, and repetitive behaviors (Adıgüzel et al.,
children, Bifidobacterium increased, and Desulfovibrio decreased 2022). Alonazi also demonstrated that dietary psychobiotic
significantly. Moreover, a study of a mixture of Lactobacillus spp. supplementation could reduce levels of various serum
and Bifidobacterium spp. in two different rodent ASD models inflammatory cytokines, such as IL-1b, IL-8, IL-10, and IFN-g, in
indicated that a probiotic mixture could improve social behavioral an ASD rat model induced by a neurotoxic dose of propionic acid
symptoms by modulating the gut microbial population (Mintá l (Alonazi et al., 2022).
et al., 2022).
4.1.3 Neural pathway and chemical signaling
4.1.2 Anti-inflammation and immunomodulation 4.1.3.1 Changing microbial signals (neuroendocrine
4.1.2.1 Psychobiotics as immunomodulators signaling)
Psychobiotics have a potential to not only reconstruct the gut The gut microbiota influences the brain directly through neural
barrier function by resisting harmful bacteria, but also exert an pathways, including the VN and ENS. The VN connects the ENS
immunomodulatory effect by reducing circulating hormones and and CNS and it could be activated by cytokines, which could be
pro-inflammatory cytokines in serum. The gut microbiota has been modulated by bacteria, and byproducts from bacteria including
demonstrated to serve as a regulator of intestinal, systemic, and endotoxins and peptides. In particular, the neuropeptide could be
CNS resident immune cell function (Zheng D et al., 2020). Gut sensed by receptors associated with dendritic cells in the gut, which
microbiota can communicate with the CNS by regulating intestinal could transfer the signals to the brain (Perez-Burgos et al., 2013).
and peripheral immune cells and peripheral immune responses via Psychobiotics modulate CNS-related behaviors through the VN
circulating cytokines (Arrieta and Finlay, 2012). pathway and the physiological response of various metabolites,
including SCFAs, enteroendocrine hormones, cytokines, and
4.1.2.2 Psychobiotics reduce inflammation neurotransmitters (Bravo et al., 2011; Dinan et al., 2014; Sgritta
Any peripheral inflammatory event induces VN to cause the et al., 2019).
suppression of the release of proinflammatory cytokines from
intestinal macrophages (Daliri et al., 2016). Probiotics reduce gut 4.1.3.2 Hormones and metabolic changes
inflammation through various mechanisms, such as reducing The levels of oxytocin and DHEA-S, which have been
inflammatory cytokines and other immunomodulatory effects. For considered to be etiologies of ASD, were significantly lower in the
example, anti-inflammatory cytokines (IL-4 and IL-10) and plasma of children with ASD in a clinical study, and there was a
proinflammatory cytokines (TNF-a, IL-1b, IL-2, IL-6, IL-8, IL-12, trend towards a correlation between decreased DHEA-S levels and a
IL-17, and IL-18) are significantly changed by Lactobacillus lower Bacteroidetes/Firmicutes ratio which increased after probiotic
rhamnosus GG (LGG) (Miyazawa et al., 2015; Cicenia et al., 2016; implementation (Tomova et al., 2015). According to Grimaldi,
Fong et al., 2016; Wang et al., 2016; Aoki-Yoshida et al., 2017; increases in butyrate production, potentially positively affecting
Clarke, 2018; Cai et al., 2019). ASD, were detected in children with ASD following exclusion
diets (Nankova et al., 2014; Grimaldi et al., 2018). Additionally,
4.1.2.3 Inflammatory cytokines change in ASD lower levels of amino acids (isoleucine, leucine, valine, alanine, and
In clinical studies, Tomova et al. found that TNF-a levels were glutamine) and lactate were detected in the B-GOS group. The
strongly correlated with GI symptoms and showed a trend toward presence of amino acids in feces is associated with problems in gut
correlation with ASD severity (Tomova et al., 2015). Probiotic barrier function (Marchesi et al., 2007).
supplementation significantly decreased TNF-a levels in the feces
of children with ASD. Similar to this study, Sanctuary demonstrated 4.1.3.3 Gut microbiome modulation and
that psychobiotic supplementation could reduce the intracellular GABA metabolism
expression of certain cytokines in CD4+ T cells (Sanctuary et al., A study of psychobiotics in a rodent ASD model, which was
2019). The frequency of CD4+/IL-13+ T cells was significantly induced by oral propionic acid ingestion, proposed that
lower after the treatment. Lactobacillus bulgaricus and Bifidobacterium infantis could
ameliorate glutamate excitotoxicity, a major autistic feature in this
4.1.2.4 Animal studies on the anti-inflammatory effects model. The therapeutic effect of these psychobiotics might be due to
of psychobiotics the reduction of oxidative stress, restoration of the depleted GABA
Adıgüzel et al. demonstrated that dietary treatment with signaling pathway, and upregulation of the GABA receptor’s gene
multispecies probiotics formulations (Sptreptococcus thermophilus, expression (Bin-Khattaf et al., 2022). Ingestion of Lactobacillus
Bifidobacterium breve, B. animalis, Lactobacillus helveticus, L. rhamnosus could connect bidirectional communication of the

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gut-brain axis, and it could regulate emotional behaviors by 4.2.1.3 Synthesis of serotonin beyond BBB
controlling the GABA receptor expression in the VN (Bravo Serotonin also plays a role in ADHD pathogenesis, however, it
et al., 2011). In 2018, the specific bacterial species of ASD were affects brain function not directly, but via the nervous system
identified in Shank3 knock-out mice, and this study suggested that (Banerjee and Nandagopal, 2015; Hou et al., 2018). On the other
oral Lactobacillus reuteri ingestion could decrease repetitive hand, gut microbiota directly act a biological role on the brain by
behaviors by up-regulation of the g-aminobutyric acid (GABA)- modulation tryptophan’s peripheral availability because tryptophan
related metabolism (Tabouy et al., 2018). can cross the BBB and affect serotonin synthesis in CNS (Richard
et al., 2009; Schwarcz and Stone, 2017).

4.2 Therapeutic mechanisms/effects 4.2.1.4 GABAergic system and GABA production

on ADHD A recent experimental study has demonstrated that
Lactobacillus rhamnosus regulates, via the VN, emotional
The etiology of ADHD is multifactorial. However, emerging behavior and the central GABAergic system, which is also
research has shown the involvement of modulation in the gut associated with neuropsychiatric disorders (Enticott et al., 2010).
microbiome and its promising effect on the clinical course of According to Pärtty, the early supplementation of Lactobacillus
ADHD (Kalenik et al., 2021). In general, the effect of probiotic rhamnosus GG decreases the risk of developing ADHD, and Liang-
supplementation could act in both direct and indirect ways on Jen Wang suggested that oral probiotic Bifidobacterium bifidum
ADHD, and ADHD-suffering children have higher GI severity (Bf-688) improves the clinical symptoms of ADHD. In addition,
index grade than healthy children (Ming et al., 2018). These GI food supplement treatments containing Lactobacillus acidophilus
symptoms can be relieved by adjustment of the gut microbial and Bifidobacterium improve the self-control and attention of
community via probiotic administration, however, Rianda’s children with ADHD (Pärtty et al., 2015; Wang et al., 2022).
randomized trial demonstrated that only one out of seven studies These results are thought to be due to the role of Lactobacillus
showed a positive effect of probiotics on cognitive function (Rianda and Bifidobacterium as producers of GABA, which is known to
et al., 2019). decrease in patients with ADHD (Yunes et al., 2016).

4.2.1 Neurotransmitters and metabolites 4.2.2 Intermediate substances and metabolites

4.2.1.1 Microbiome producing neurotransmitters 4.2.2.1 Vagus nerve
Bacteria can synthesize and respond to hormones and The VN is the longest cranial nerve in the body, and it delivers
neurotransmitters. Lactobacillus species produce acetylcholine and electronic signals from the body (lungs, liver, heart, GI tract) to the
GABA, Bifidobacterium species produce GABA, Escherichia brain through sensory fibers. And this connection administers the GI
produces norepinephrine, serotonin, and dopamine, Streptococcus tract’s function via the metabolites from intestinal microorganisms.
and Enterococcus produce serotonin, and Bacillus species produce The VN is involved in functions such as mood control, immune
norepinephrine and dopamine (Galland, 2014). Other bacterial response, and GI tract function via intestinal permeability and enteric
strains (Lactococcus lactis subsp. cremoris, L. lactis subsp. lactis, reflex and influences the hypothalamic-pituitary-adrenal axis. Vagal
Lactobacillus plantarum, Streptococcus thermophilus, Escherichia afferent fibers sense microbiota signals indirectly through the diffusion
coli, Morganella morganii, Klebsiella pneumoniae, and Hafnia of bacterial compounds, metabolites, or other cells located in the
alvei) produce serotonin (O’Mahony et al., 2015). epithelium that relay luminal signals (Del Toro-Barbosa et al., 2020).
The gut microbiome has the capacity to modulate the host’s emotional
4.2.1.2 Positive effects on dopaminergic and and behavioral responses by acting on vagal afferents.
noradrenergic system
Various studies have suggested the dopamine hypothesis, which 4.2.2.2 Short-chain fatty acids
indicates that the enteric neurotransmitter release by nutrient Various host physiological metabolism could be regulated by
intake could affect brain health and responses. And Bacillus, one SCFAs, in particular, gut barrier integrity, immune defense system,
of the representative bacteria to modulate the dopaminergic system, and lipid metabolism could be the major target of the SCFA. (Dalile
is known for its ability to produce dopamine and noradrenaline et al., 2019). Moreover, SCFAs might directly influence neural function
directly in the GI tract (Satti et al., 2023). Dysregulated by reinforcing BBB integrity, modulating neurotransmission,
dopaminergic and noradrenergic neurotransmission has been influencing the levels of neurotrophic factors, and promoting
widely implicated in the pathophysiology of ADHD, and memory consolidation. Increased evidence suggests a potential key
dopamine and norepinephrine play essential roles in behavioral, role for SCFAs in gut-brain axis signaling (Silva et al., 2020). The
cognitive, and affective functions (Del Campo et al., 2011). In a ADHD group showed significantly lower concentrations of fecal acetate
study using patients with ADHD, Bifidobacterium was increased in and butyrate than the control group, and various bacterial strains
patients with ADHD, which was linked with the enzyme involved in (Bifidobacteria, L. salivarius, L. agilis, L. acidophilus, LGG, B. longum, B
the dopamine precursor (phenylalanine) synthesis (Aarts bifdum, and L. gasseri) are known to increase SCFAs production
et al., 2017) (LeBlanc et al., 2017; Jung et al., 2022).

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Kwak et al. 10.3389/fcimb.2023.1238005

4.2.3 Immune pathway and anti-inflammation the healthy group. Especially, the FMT response significantly
4.2.3.1 Anti-inflammatory effects of probiotics reduces the abundance of Eubacterium coprostanoligenes (Li et al.,
Lactobacillus rhamnosus GG is known to strengthen the gut 2021). These data also indicated that decrement in the population of
permeability barrier by fortifying intestinal tight junctions, mucin Eubacterium coprostanoligenes by FMT might be a curative
layer thickness, and antigen-specific immunoglobulin A production technique for ASD symptoms and behaviors.
(Asano et al., 2012). In particular, L. rhamnosus GG administrated
participants showed a significant decrease in the serum levels of the 5.1.2 Modulating neurotransmitters
pro-inflammatory cytokines (IL-6, IL-12 p70, and TNF-a). 5.1.2.1 FMT alters the serum levels of neurotransmitters
(Kumperscak et al., 2020). Unlike probiotics, FMT refers to the transfer of the full spectrum of
gut microbial communities containing more than 1,000 bacterial strains,
and it might be more effective than psychobiotics in aspects of
5 FMT: rebuilding gut microecology physiological regulation in the nervous system, endocrine system, and
host behavior (Chen et al., 2022). In recent studies, FMT could exhibit a
The definition of FMT is the transfer technique of a healthy donor’s recovery effect on the serum levels of serotonin, GABA, and DA in the
fecal specimen to the GI tract of a recipient patient to reestablish the ASD cohort, which means that FMT might be an effective technique in
normal gut microbiome. This technique has been focused in recent years regulating neurotransmitters via the MGB axis (Li et al., 2021). Moreover,
because of the technical advances in metagenomics sequencing and the FMT in the ASD cohort could decrease GABA and serotonin in serum,
growing understanding of its function. FMT has been demonstrated to but the dopamine level was increased by FMT. It could be assumed that
be able to reconstruct a normally functioning microbial community, FMT may be an efficient approach to modulate neurotransmitter
making it an accepted therapy with biological plausibility. Considering secretion for regulation of the central nerve via the MGB axis.
the effect of FMT on the reorganization of gut microbiota, it is considered
to have the potential for the treatment of neurodevelopmental diseases 5.1.3 Regulating immune responses
such as ASD through the interaction of the MGB axis. It is necessary to 5.1.3.1 Chemokines and microbiome
determine the optimal composition of the microbiome to be used for Alterations in the gut microbiota composition after FMT could
FMT by clarifying the structure or functional profile of the microbes significantly improve behavioral impairments and regulate immune
associated with improved clinical outcomes (Zhuang et al., 2019). responses in ASD. Chen and colleagues demonstrated that treatment
Bacterial diversity and health-associated functions, such as colonization using FMT with in vitro cultured healthy donor’s intestinal microbiota
resistance, can be restored using FMT. In addition to bioactive had a positive effect on ASD symptoms in mouse ASD model (Chen
compounds, FMT is also a source of microbes, such as phages. These et al., 2020). They observed amelioration of anxiety actions and
components come together in a symbiotic community, allowing better repetitive performance with lower serum levels of metabolites, such
colonization of the GI tract (Goldenberg et al., 2018). In terms of the gut as GRO-a and MIP-1a, and a conversely higher level of MCP-3,
microbiota, FMT is considered an untargeted intervention. RANTES, and Eotaxin. Additionally, family or genus levels of S24-7,
Clostridiaceae, Prevotella, and Candidatus Arthromitus were key
microbial taxa in FMT treatment, and serum levels of chemokines
5.1 Therapeutic mechanisms and their were related to the relative abundance of these taxa.
effects on ASD
5.1.3.2 Original donor vs in vitro cultured
5.1.1 Altering gut ecosystem In this study, both original donor microbiota transplantation
5.1.1.1 Bacterial diversity and cultured microbiota transplantation improved behavioral
FMT could serve as a protective treatment for reconstructing the abnormalities and chemokine disorders in an ASD mouse model
gut microbiota at both the phylum and genus levels and has a and were effective in the modification of several key differential taxa
therapeutic effect on ASD symptoms and gastrointestinal disorders in the gut microbial composition (Chen et al., 2020). These results
(Li et al., 2021). A modified FMT protocol for children with ASD, of cultured microbiota transplantation suggest the possibility of
termed microbiota transfer therapy, appears to be a promising using “donor-free FMT” and regulating the donor gut microbiota
approach to alter the gut microbiome and improve GI and structure before transplantation during in vitro culture. The batch
behavioral symptoms of ASD (Kang et al., 2017; Kang et al., 2019). methods are fast, easy, and repeatable culturing techniques.
This protocol improved GI and ASD symptoms, and the microbiome
persisted for two years after treatment, suggesting a long-term impact.
Important changes in the gut microbiota at the end of treatment were 5.2 Therapeutic mechanisms/effects on
observed during follow-ups, including significant increases in bacterial ADHD
diversity and relative abundance of Bifidobacteria and Prevotella.
5.2.1 Neuroprotective effects of the
5.1.1.2 Engraftment of the donor microbiome transplanted microbiome
Li et al. showed that the gut microbial population of ASD A case report provides preliminary evidence regarding the use of
children was altered by FMT with donor microbiota toward that of FMT in a patient with C. difficile infection and ADHD. The authors

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Kwak et al. 10.3389/fcimb.2023.1238005

suggested that gut microbiome modulation, particularly the gain or loss microbiome to improve the GI and behavioral symptoms of patients
of specific microbial species and pathways involving the metabolism of with ASD or ADHD. Development of the gut microbiome in early life
SCFAs, tryptophan, and GABA, may merit further exploration as a plays an important role in the overall well-being of humans.
potential therapeutic strategy for ADHD (Hooi et al., 2022). Among Numerous studies have demonstrated that early alterations in the
bacteria engrafted through FMT, F. prausnitzii may reduce gut microbiome are closely related to neurodevelopmental disorders,
neuroinflammation and alleviate ADHD symptoms. F. prausnitzii such as ASD and ADHD. Nevertheless, the ambiguous and equivocal
exhibits anti-inflammatory effects by increasing anti-inflammatory evidence of clinical studies makes it difficult to believe the therapeutic
cytokines and decreasing inflammatory cytokines that promote method targeting the MGB axis. To better understand the role of the
neuroinflammation and development of ADHD. L. ruminis possesses gut microbiome in heterogeneous and complex ASD/ADHD
genes contributing to the pentose phosphate pathway, which pathogenesis, double-blind, randomized, controlled trials and
contributes to SCFA production. Engraftment of Lactobacillus genus treatments tailored to individual characteristics and the host
may exert neuroprotection by producing anti-inflammatory SCFAs. microbiome are recommended. In particular, the process of
(Basen and Kurrer, 2021). intestinal microbiota colonization and establishment in the early
stage of life is crucially affected by maternal conditions/diseases, mode
of delivery, and exposure to antibiotics. Therefore, future studies are
6 Future perspectives and needed to determine more accurate therapeutic targets in immune,
concluding remarks metabolic, endocrine, and neural pathways by mechanism validation
through culturomics experiments of mainly modulated microbial
Although the application of pre- and probiotics as psychobiotics populations and metabolomic analysis of the mother’s skin, vagina,
remains promising, it is feasible that the effect of psychobiotics will gut microbiota, and infant gut environments.
be decreased over time due to the significant influence of
environmental reasons occurred in child development (Grimaldi
et al., 2018). Further studies should be needed to address the drug Author contributions
administration timing, the effect of different strain combinations,
safety, and efficacy of probiotics. Furthermore, the novel therapeutic All authors researched the data for this article, made substantial
functions of the psychobiotics and commensal bacteria will be contributions to discussions of the content, wrote the article, and
investigated in synthetic biology fields (Bin-Khattaf et al., 2022). reviewed and/or edited the manuscript prior to submission.
For example, Korpela proposed that oral-fecal transplantation with
diluted fecal samples from the maternal gut microbiome could
restore normal gut microbiota in Cesarean-born infants (Korpela Funding
et al., 2020). Furthermore, a study demonstrated that using E. coli
native to the target murine host to knock-in specific functions and This research was supported by the research fund of Hanyang
apply them back to the host enabled the perpetual engraftment of University MEB (Global Center for Developmental Disorders, HY-
transgenic bacteria in the intestine, which was demonstrated until 201900000003070) and the National Research Foundation of Korea
the transformation stage of human borne E. coli (Asano et al., 2012). (NRF) funded by the Ministry of Science and ICT (RS-2023-
As such, various studies have focused on fortifying the modulating 00219983).
effects on the gut microbiome via adjustment at the molecular level.
The use of probiotics is feasible in children, and short-term
supplementation has been shown to be safe. However, the long-term Conflict of interest
effects of repeated applications on the gut microbiome and the safety
concerns of treatment are unknown. The actual efficacy of FMT has The authors declare that the research was conducted in the
been proved by various studies using diverse animal models. However, absence of any commercial or financial relationships that could be
Safety is the most important aspect in the FMT study because most construed as a potential conflict of interest.
ASD patients are children. In previous studies, the oral ingestion of
human fecal suspensions was considered an unpleasant experience for
patients and might cause side effects, including extra ingestion with Publisher’s note
acid inhibitors. As it has been known that a colon-release capsule
coated with acid-resistant hydroxypropyl cellulose is the best All claims expressed in this article are solely those of the authors
formulation for patients (Kang et al., 2019). and do not necessarily represent those of their affiliated organizations,
This review summarizes the current knowledge on the positive or those of the publisher, the editors and the reviewers. Any product
effects and potential pathways of promising therapeutic interventions, that may be evaluated in this article, or claim that may be made by its
including psychobiotic supplementation and modulation of the gut manufacturer, is not guaranteed or endorsed by the publisher.

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Kwak et al. 10.3389/fcimb.2023.1238005

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