Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that primarily
includes social impairment and repetitive stereotypic behaviors that typically
develop by age 3 and persist into adulthood [1]. These
are the core abnormal symptoms in individuals with ASD. In addition, there are
several abnormal behaviors, including sensory-motor abnormalities, speech delay, and
gastrointestinal (GI) symptoms [2]
[3]. According to the results of the Center for Disease
Control and Prevention (CDC) Autism Developmental Disabilities Surveillance Survey,
the prevalence of ASD is 1/54, which is higher than 1/59 [4]. In addition, the prevalence in males is 3–4
times higher than in females [5]. The disease may be
associated with multiple factors, including genetic factors as well as some
non-genetic factors [6]
[7]
[8]. Genetic factors are mainly caused by
chromosomal abnormalities. Environmental factors were mainly related to pregnancy
stress, diet, and perinatal exposure to drugs or heavy metals [9]
[10]
[11]
[12]
[13]. In addition, individuals with autism are not only
susceptible to illness, but also have difficulty obtaining the same level of
education and full-time employment as their peers, or even living independently
[14]. There is no doubt that the burden on
families, schools, health care systems, and individuals is substantial and ongoing
[15]. Therefore, addressing autism is of great
importance to schools, families, and society.
The intersection of microbiology and neuroscience has given rise to the new concept
of the gut-brain axis. Subsequently, gut-brain axis is a bidirectional communication
system between the brain and the nerves of the gut [16]. It controls the bidirectional communication between the gut and the
brain, which in turn affects brain function. Neural signals can influence gut
function and alter the composition of the gut microbiome (GM), while the GM can
signal the brain through different pathways, including immune and vagal activation,
microbial metabolite, peptide and neurotransmitter production [17]. GM affects various neurological disorders by
affecting the vagus, neuroendocrine and immune connections with the brain [18]
[19]. Dysfunction of
this axis can lead to many neuropsychiatric disorders such as Alzheimer’s
disease; Parkinson’s disease; and autism [20]
[21]. Previous studies have shown that
the relative abundance of GM in patients with ASD changes with the development of
gastrointestinal disorders, such as diarrhea, constipation and exchange
diarrhea/constipation, compared to normal subjects [22]
[23]. Transplantation of gut microbes
from ASD patients into germ-free mice was found to exhibit autistic-like behavior
[24]. Similarly, social impairment in mouse models
of ASD was well ameliorated by supplementation with Lactobacillus Reuteri
[25]. These findings strongly suggest a close
relationship between GM and ASD. At the same time, recent research findings also
provide favorable evidence for the treatment of ASD by improving the GM [26].
Exercise induces physiological and biochemical reactions in all tissues and organs
of
the body through energy expenditure in skeletal muscle, resulting in a combination
of effects, including improved metabolism, neuromuscular and contractile function,
and rebalancing of electrolytes [27]. In recent years,
the effects of exercise on the microbiota have become a focus of interest and have
been extensively studied. The positive effects of exercise are mainly associated
with changed GM diversity and a balanced relationship between beneficial and
pathogenic bacterial communities [28]. For example,
increasing the diversity of Lactobacillus, Bifidobacterium,
Blautia, and reducing the diversity of Clostridium and
Enterococus through exercise will help maintain a healthier intestinal
environment [29]. Lactobacillus plays an
important role in the production of bacteriocin, bile hydrolase, and phosphoketolase
pathway, and is closely related to the urogenital system of healthy women [30]
[31]. Metabolites of
Bifidobacterium can regulate the system, restore intestinal mucosal
barrier and regulate oxidative stress reaction [32]
[33]. Clostridium plays an
indispensable role in the body, but it can produce toxins and propionate. Excessive
Clostridium is related to disease [34]
[35]. An experimental animal study found that exercise
played a causal role in regulating GM benefits for health by colonizing microbiota
from exercising mice along with microbiota from sedentary mouse controls in
germ-free mice [36]. Not only in animals, but also in
humans. Exercise can regulate GM in a beneficial way [37]
[38]. This can be found in the GM study
of athletes [39]. Exercise as an intervention leads to
changes in their GM [29]
[40]. This change may be due to the close relationship between exercise
and oxidative stress leading to alterations in GM [41]. GM plays an important role in regulating body metabolism and immune
system development [42].
The effectiveness of exercise in improving autism has been widely demonstrated [43]. So, are changes in GM in patients with ASD an
important mediator between exercise to improve GM and exercise to improve behavior?
It is worth exploring. However, the effect of exercise on the autism microbiome has
been little studied. In this review, we will collate GM changes in individuals with
autism, exercise-induced GM changes, and the possible relationships between these
changes. Furthermore, the effect of exercise intervention on autism was analyzed
from the perspective of GM changes.
Autism gut microbiota abnormalities
The relationship between microorganisms and autism is becoming increasingly
apparent. Various intestinal problems in ASD have become co-morbid, including:
abdominal pain, diarrhea, and constipation, the incidence of which has been
confirmed by retrospective and prospective studies ranging from 9% to
84% [44]. Bolte first suggested in 1998
that GM may have an association with the onset of autism [45]. Currently, many studies have confirmed that
people with ASD have different GM compared to normal people [46]
[47]. This
includes not only human but also mouse ASD models such as knockout models,
Sodium Valproate (VPA) models, etc. [48]
[49]. An interesting study found that mice exhibited
ASD-like behavior after feces from ASD patients and normal humans were colonized
into a germ-free (GF) mouse model [24]. Research
has identified that GM can access pathways that control neuronal differentiation
and survival through neurotrophins and their receptors, it can influence the
fate of neurons in different regions of the brain, which in turn affects
neurodevelopment and health [50]. Thus, there may
be a strong relationship between GM and ASD. The gut bacteria mainly include six
major phyla of Firmicutes, Bacteroidetes, Proteobacteria,
Actinomycetes, Verrucomicrobia and Fusobacteria, with
Bacteroidetes and Firmicutes as the dominant ones [51]. We organized and classified the collected
studies on ASD and GM. We use the keywords ASD, autism, intestinal flora, and
gut microbiota etc. to search in PubMed, web of science, and google school
databases. The studies included in the table are human studies, excluding animal
experiments and review articles.
Proteobacteria phyla
In Proteobacteria phyla, Sutterella is a gram-negative
non-phage that grows in a microaerobic environment or under anaerobic
conditions; it is resistant to bile acids, and regulates mucosal metabolism
and intestinal epithelial integrity [52]
[53]. The relationship between Sutterella
and gastrointestinal symptoms in ASD has been explored in studies [54]. Several studies have demonstrated that the
relative abundance of Sutterella is significantly elevated in
patients with ASD [23]
[52]
[54]
[55]. However, the opposite result was also found [56]
[57].
Coprococcus, is a Gram-positive anaerobic bacterium. In the current
study, Coprococcus is equally controversial, but there is a trend
towards a decrease in the relative abundance of Coprococcus relative
to normal human ASD patients [58]
[59]
[60].
Development of the present Clostridium perfringens with a role in
regulating host 5-hydroxytryptamine(5-HT) biosynthesis and release [61]. And by regulating the changes in 5-HT, it
led to the rescue of social impairment in the mouse model of autism [62]. Whether this is related to the abnormality
of this flora makes it worthwhile to continue to think deeply about the
study.
Bacteroidetes phyla
Bacteroides, Corynebacterium and Prevotella belong to
Bacteroidetes phyla. The trend in the relative abundance of
Bacteroides in ASD patients in the current study was elevated
[56]
[63]
[64]
[65]
[66]. Bacteroides are
polymorphic, non-spore producing Gram-negative anaerobic bacteria with the
ability to digest dietary fiber and polysaccharides. In the genus
Bacteroides, Bacteroides uniformis has effects on brain
reward responses, amelioration of binge eating, and reduction of
anxiety-like behavior. These effects were mediated, at least in part, by
changes in voxel nucleus dopamine, 5-HT and norepinephrine levels and
changes in prefrontal cortex and intestinal dopamine D1 and D2 receptor
expression [67]. In contrast, the reduced
relative abundance of Prevotella in ASD patients showed a decreasing
trend [58]
[59]
[63]
[68]. Prevotella is a beneficial bacterium and determines
the distribution of the intestinal microbiota in a key genus with
physiological importance. It may also be associated with intestinal
inflammation [69]
[70]. In one study, it was found that women with high
Prevotella caused their negatively valences images to be higher
[71]. Corynebacterium is a serious
pathogen in humans or animals, a gram-positive bacterium with an irregular
shape and varying thickness [72]. It has been
found that its relative abundance showed an increasing trend in ASD patients
[65].
Phylum Firmicutes
Faecalibacterium
[73],
Lactobacillus
[ [23]
[65]
[74],
Runminococcus
[56], Clostridium
[
[56]
[75], Roseburia
[76] belong
to Firmicutes phylum shows an increased trends in the gut of ASD
patients. The relative abundance of Streptococcus and Blautia
was reversed [64]
[73]
[76]. After four weeks of
administration of Faecalibacterium prausnitzii to rats, behavior,
growth status, SCFA produced, plasma cytokines, endocrinology, and bone
density were assessed. Faecalibacterium prausnitzii was found to
reverse the effects of chronic unpredictable mild stress in rats [77]. For the genus Lactobacillus,
Lactobacillus reuteri could improve social impairment in autism
model rats, while cutting the vagus nerve revealed that social impairment
could not be improved. So it was found that Lactobacillus reuteri
affected dopaminergic (DA) neurons through the vagus nerve to release
oxytocin and thus improve autism social impairment [25]. The abnormalities of Ruminococcus may be related to
respiratory or skin allergies [75].
Clostridium is one of the largest genera of prokaryotes,
consisting of about 200 different species of bacteria, which are associated
with intestinal diseases, such as severe diarrhea [78]
[79]. Roseburia consists
of specific Gram-positive anaerobic bacteria that produces short-chain fatty
acids that affect colonic activity and may be associated with obesity,
neurological disorders, etc. [80]. Even its
relative abundance has been explored as a biomarker for ASD [76]. In the genus Roseburia,
Roseburia intestinalis treatment reduced depression-like behavior
in rats, and experiments on neuronal cells showed that Roseburia
intestinalis treatment reduced the expression of interleukin- 6 (IL-6),
interleukin- 7(IL-7) and 5-HT in serum and brain tissue [81].
Actinobacteria phyla
In Actinobacteria phyla, Bifidobacterium is a genus of
Gram-positive anaerobic bacteria that promotes health by fermenting complex
polysaccharides to regulate host function [82]
[83]. It has good
anti-inflammatory and immunomodulatory effects and even reported that
Bifidobacterium bifidum is associated with the production of
Gamma-aminobutyric acid (GABA) [84]
[85]. This further links Bifidobacterium
to ASD, where most of the existing studies found reduced abundance of
Bifidobacterium in patients with ASD [23]
[63]
[64]
[86]
[87]
[88]
[89], Zhou found the opposite trend [57]. Bifidobacterium longum in the genus
Bifidobacterium is anxiolytic by means of the vagus nerve but
does not involve intestinal immune regulation or nerve cell production of
brain-derived neurotrophic factor (BDNF). There is a close relationship
between BDNF and ASD, and it was even once used as a biomarker for ASD
patients [90]. Whether abnormalities of
Bifidobacterium in ASD patients are associated with abnormalities
of their BDNF deserves to be studied further. Since Bifidobacterium
longum reduces the excitability of intestinal neurons, it may send
signals to the central nervous system by activating the vagal pathway at the
level of the enteric nervous system [91].
However, many studies have elaborated changes in ASD Bifidobacteria,
and the mechanisms between its effects on brain mechanisms and ASD deserve
further exploration.
Phylum Verrucomicrobia
Finally, there is the phylum Verrucomicrobia Akkermansia, an oval
Gram-negative anaerobic bacterium whose function is mainly to improve the
metabolic function and immune response of the host. In patients with ASD the
same was found to produce changes in its relative abundance compared to the
normal group [92]. Zurita found that the
relative abundance of Akkermansia was increased in patients with ASD
compared to normal subjects, but the opposite was true in Maria [60]
[93]. It was
found that Akkermansia muciniphila in the genus Akkermansia
affects the 5-HT system in the colon and hippocampus of mice, causing them
to produce more 5-HT [94]. There may be a
relationship between this and the development of autism, pending subsequent
studies to be conducted.
This shows a controversial trend in many of the current studies on the GM of
patients with ASD. However, these studies all indicated significant
differences in GM in ASD patients compared to normal subjects. (insert [Table 1])
Table 1 ASD abnormal gut microbiota.
|
Author
|
Sample
|
methods
|
groups
|
Outcomes (Genus) Rising relative abundance
|
Outcomes (Genus) Decrease in relative abundance
|
|
Kang [58]
|
Feces
|
16 S rDNA
|
ASD:20
|
|
Prevotella, Coprococcus, Unclassified Veillonellaceae
|
|
HC:20
|
|
Zhang [55]
|
Feces
|
16 S rRNA
|
ASD:35
|
Sutterella
|
Streptococcus, Veillonella
|
|
HC:6
|
|
Luna [56]
|
Rectal biopsy
|
16 S rDNA
|
ASD-FGID:14
|
Clostridia, Clostridium, Lachnoclostridium,
Runminococcus
|
Flavonifracto, Sutterella, Dorea, Blautia
|
|
NT-FGID:15
|
|
NT:6
|
|
Zhou [57]
|
Feces
|
16 S rDNA
|
ASD:143
|
|
Sutterella, Prevotella, Bacteroides
|
|
HC:143
|
|
Finegold [64]
|
Feces
|
16 S rDNA
|
ASD:33
|
Desulfovibrio, Bacteroides
|
Bfidobacterium,
|
|
NS:7
|
|
NT:8
|
|
Kang [59]
|
Feces
|
16 S rRNA
|
ASD:21
|
|
Feacalibacterium, Prausnitzii, Haemophilus
Parainfluenzae
|
|
HC:23
|
|
Pulikkan [68]
|
Feces
|
16 S rRNA
|
ASD:20 HC:20
|
Lactobacillus, Megasphaera, Mitsuokella
|
|
|
Strati [65]
|
Feces
|
16 S rRNA
|
ASD:40
|
Alistipes, Bilophila, Dialister, Parabacteroides,
Veillonella
|
Collinsella, Corynebacterium, Dorea, Lactobacillus,
|
|
HC:40
|
|
Tomova [74]
|
Feces
|
16 S rRNA
|
ASD:10
|
Lactobacillus, Desulfovibrio
|
|
|
NS:9
|
|
HC:10
|
|
Julio [66]
|
Feces
|
16 S rRNA
|
ASD:52
|
Bacillus, Butyrivibrio, Enterococcus, Hespellia,
Prevotella
|
|
|
(ANMR:32
|
|
AMR:20)
|
|
HC:57
|
|
María [93]
|
Feces
|
16 S rRNA
|
ASD:25
|
Bacteroides, Akkermansia, Coprococcus, Ruminococcus
|
|
|
HC:35
|
|
Inoue [73]
|
Feces
|
16 S rRNA
|
ASD:6
|
Faecalibacterium
|
Blautia
|
|
HC:6
|
|
Maria [60]
|
Feace
|
16 S rRNA
|
PDD-NOS:10
|
Dorea, Clostridia, Desulfovibrio, Sutterella,
Bacteroides
|
Faecalibacterium, Coprococcus, Akkermansia,
Streptococcus
|
|
16 S rDNA
|
ASD:10
|
|
HC:10
|
ASD: autism spectrum disorder; HC: healthy contral; ASD-FGID: autism
spectrum disorder-children with functional gastrointestinal
disorders; NT-FGID: neurotypical-children with functional
gastrointestinal disorders; NT: neurotypical; AMNR:ASD by no mental
regression; AMR: ASD by mental regression; PDD-NOS: Pervasive
Developmental Disorder Not Otherwise Specified; NS: non-autistic
siblings.
Exercise changes gut microbiota
Exercise: An effective tool
The World Health Organization (WHO) recommends physical activity at certain
doses to improve physical fitness and quality of life [95]. This shows that exercise is a tool to be
active and stay healthy. Research has identified a potential external effect
of exercise on the ability to alter gut biodiversity by promoting GM
diversity [96]. The change of microbiotas by
exercise should first be reflected in athletes, who are groups that have
undergone regular exercise training, and the change of their GMs is
important evidence to reflect the effect of exercise on GM. For example,
analysis of the GM of professional cyclists, rugby players, marathon
runners, and skiers revealed significant changes in their GM [97]
[98]
[99]. The relative abundance of
Prevotella in marathon runners, skiers and competitive cyclists
produced a significant upward trend [37]
[97]
[99]. The
relative abundance of Bacteroides, Ruminococcus and
Akkermansia also changed significantly among the athletes. These
changes may be the result of the athlete’s long-term athletic
training, and the changes do not just respond to the athlete. The relative
abundance of GM can also be altered by active regular physical activity, as
has been demonstrated in experiments with animals and in humans [29]
[40]
[100]. However, because the changes caused by
exercise are affected by individual metabolic status, this factor must be
considered in future research.
Exercise changes the relative abundance of gut microbiota
The effect of exercise on the improvement of GM is significant, and according to
the length of the exercise cycle can be simply divided into short-term and
long-term exercise. Both short-term and long-term exercise can improve the
composition of the GM. Immediate post-half marathon (21.1 km) testing of
20 runners revealed significant alterations in the Actinobacteria phylum
of the athletic participants [101]. Changes in the
relative abundance of GM were also reflected after a single cycling session
[102]. The test results 72 hours after
exercise showed more significant changes compared to 48 hours. Moreover,
regular physical activity in the medium to long term can also have an impact on
the GM, which we will summarize below from a genus perspective ([Table 2]) .
Table 2 Exercise improves gut microbiota.
|
Author
|
Sample
|
Groups
|
Method
|
Plan
|
Outcomes (Genus) Rising relative abundance
|
Outcomes (Genus) Decrease in relative abundance
|
|
Morita [106]
|
Feace
|
AE:17
|
16SrRNA
|
AE: 1 h of brisk walking; intensity≥3MET
|
AE: Bacteroides
|
AE:Clostridium subcluster XIVa
|
|
TM:12 pre-post test
|
TM: weekly 1 h for 12 weeks
|
|
Zhao [101]
|
Feace
|
HG:20 pre-post test
|
16SrRNA
|
half marathon
|
Ezakiella, Romboutsia
|
Coprococcus, Ruminococcus
|
|
Motiani [108]
|
Feace
|
SIT:13
|
16SrRNA
|
2 weeks 6 times
|
Veillonella, Lachnospira
|
Blautia, Clostridium
|
|
MICT:13 Pre-post test
|
SIT: Wingate protocol
|
|
MICT:40–60 min 60%VO2peak
|
|
Mariangela [109]
|
Feace
|
HG:40 pre-post test
|
16srRNA
|
running 1 km at maximum speed
|
Romboutsia, Blautia
|
Ruminiclostridium, Clostridium
|
|
Rocío [110]
|
Feace
|
OE:25
|
16srRNA
|
Oe:12 weeks 24 times strength and endurance training
|
OE VS OC:Blautia, Dialister, Roseburia, Flavobacteriia
|
OE VS OC : Bacteroides Gammaproteobacteria,
|
|
OC:14 pre-post test
|
|
Flavobacterium
|
|
Faecalibacterium
|
|
Clostridium
|
|
Allen [40]
|
Feace
|
LG:18
|
16SrRNA
|
6 weeks exercise 60%–75% of HR 30 to
60 min
|
Faecalibacterium
|
Bacteroides
|
|
OG:14 pre-post test
|
Roseburia
|
|
Faecalibacterium
|
|
Lachnospira
|
|
Eveliina [112]
|
Feace
|
HG:19 pre-post test
|
16SrRNA
|
6 weeks 3 times/week
|
Streptococcus
|
Odoribacter
|
|
1–2 week 40 min
|
Bifidobacteriaceae
|
|
3–4 week 50 min
|
Akkermansia
|
|
5–6 week 60 min
|
|
AE: aerobic exercise training; TM: trunk muscle training; HG: healthy
group; SIT: sprint interval; MICI: moderate-intensity continuous
training; OE: obesity exercise group; OC: obesity control; LG: lean
group; OG: obesity group.
Regular exercise as an effective means of improving GM has been well validated in
experiments using exercise as an intervention. This is reflected not only in
human studies, but also in animal studies. In Proteobacteria phyla, Karl
Found that the relative abundance of Sutterella after military training
was lower than that before training [103]. This is
a microbiota associated with intestinal verification by inhibiting the secretion
of immunoglobulin A [104]. For Prevotella,
exercise increased the relative abundance of Prevotella compared to
resting controls with lower BMI, which was also reflected in the animal model
[28]
[37]. Lower
levels of Bacteroides/Prevotella were also found in the
mouse model of diabetic exercise compared to the sedentary mice [100]. Apparently, exercise is associated with an
increase in the metabolic pathways associated with Prevotella in the GM,
and exercise leads to a higher relative abundance of Prevotella in the
gut [105]. In contrast, the relative abundance of
bacteriophages did not vary as consistently [40]
[106].
Regarding Firmicutes phyla, studies have shown that movement can
independently reduce the relative abundance of Lactobacillus,
Clostridium and Actinobacteria
[[100]
[107]
[108]
[109]. While the relative abundance
of Ruminococcus, Roseburia and Streptococcus was increased
by exercise [37]
[39]
[40]
[101]
[103]
[109]
[110]
[111]. These findings are relatively consistent.
In Actinobacteria phyla, Eveliina found that the relative abundance of
Bifidobacteria was elevated after exercise by using exercise as an
intervention [112]. This was also found in animals
[100]. Roseburia is a genus of
Actinobacteria whose relative abundance can be increased by motor
intervention [110].
Finally, in Verrucomicrobia, Akkermansia as a typical colony was
found to have elevated its relative abundance after an exercise intervention
[112]. This was achieved through six weeks of
aerobic exercise.
Potential mechanism by which exercise influences gut microbiota
GM of athletes showed a relative increase in amino acid synthesis and
carbohydrate utilization. There is a relative increase in fecal metabolites such
as: short-chain fatty acid (SCFA), acetate, propionate and butyrate produced by
microorganisms [98]. However, athletes show a more
diverse gut microbiome, but not all of these changes are necessarily beneficial.
Exercise may affect the integrity of the gut mucus layer, which plays an
important role in preventing microbial adhesion to the gut epithelium and is an
important substrate for certain mucosa-associated bacteria [39]. The effects of exercise on the gut can also
reduce intestinal blood flow by more than 50%, with significant
intestinal ischemia occurring within 10 minutes of high-intensity
exercise [113]. Exercise can reduce blood flow to
the gut by more than 50%, especially within 10 minutes of
high-intensity exercise when significant intestinal ischemia can occur [113]. Heat stress and ischemia induced by exercise
may temporarily cause more direct contact between the microbes in the intestinal
lumen and mucosa, thereby potentially affecting the GM. Of course, these changes
may also be the enterohepatic circulation of bile acids. Compared with sedentary
hypercholesterolemia mice, hypercholesterolemia mice showed increased bile acid
secretion and increased fecal bile acid output after 12 weeks of roller exercise
[113]. Bile acids are effective regulators of
the structure of the gut microbial community, and the absence of these molecules
is related to the significant changes in the gut microbial community [114].
In summary, it has been found that exercise has the effect of improving GM
through exercise intervention, which has been well demonstrated in both animal
and human experiments. However, due to the instability of external factors such
as environment, diet, stress and other conditions, it is difficult to make the
human experiments more precise. Also, there is no clear reference for the
intensity, frequency, and duration of exercise to improve GM through exercise
intervention, and we expect that subsequent studies can explore the indexes of
exercise to improve GM more systematically.
Effect of diet on exercise mediated intestinal intervention
Diet is an important factor influencing and shaping GM [115]. A study confirmed that exercise and diet orthogonal changes GM
[116]. Furthermore, some also discussed the
effects of dietary intake and supplements on the GM of athletes [96]
[117]. The
influence of diet and exercise is also closely related to people’s
health [118]. As the result, diet also plays an
important role in the process of changing GM through exercise. A study was
carried out on the changes of GM of elite race walkers who had undergone
intensive training under different dietary patterns. The diet of high fat and
low carbohydrate increased the relative abundance of athletes’
intestinal Bacteroides and Dorea and the relative abundance of
Faecalibacterium. In the baseline group, the GM was dominated by
Prevotella or Bacteroides
[119].
Protein supplementation will also affect the GM of endurance athletes. For
cross-country runners, high protein supplement increases the abundance of their
Bacteroidetes phylum, and reduces the existence of health-related
groups, including the relative abundance of Roseburia, Blautia,
and Bifidobacterium longum
[120]. These
changes have a negative impact on the GM. The study of beneficial effects of
nominal exercise on GM diversity under the intervention of extreme diet of
football players provides evidence, but also shows that this relationship is
complex and related to the accompanying extreme diet [37]. Some researchers even think that some differences or changes in
GM seem to be related to exercise, but it may be mainly due to differences or
changes in dietary intake, especially plants and carbohydrates, rather than
exercise itself [117]. However, the relationship
between diet and exercise on GM is very close. Therefore, it is necessary to
study the relationship between GM and exercise to control and regulate the
dietary intake of participants.
Potential mechanism of exercise on ASD gut microbiota
Gut-brain axis is a two-way communication system between brain and enteric nerve
[16]. Nerve signals can affect intestinal
function and change the composition of GM, while GM can send signals to the
brain through different ways, including immune and vagus nerve activation,
production of microbial metabolites, peptides, and neurotransmitters [17]. Intestinal microorganisms contact the brain by
affecting vagus nerve, intestinal nerve, etc., thus affecting various
neurological diseases [18]. The dysfunction of
this axis can lead to many neuropsychiatric diseases, such as autism and
Parkinson’s disease. This provides a new perspective for the
pathogenesis and treatment of autism, has good guiding value, and may become a
potential new target for clinical treatment of autism.
Currently, there are few studies examining the effects of exercise on the
improvement of GM and its core symptoms in autism. However, by the above summary
we also found that the relative abundance of GM in ASD patients does differ from
normal individuals and that exercise does have an improving effect on the
relative abundance of GM ([Fig. 1]).
Fig. 1 Schematic outlining the abnormal gut microbiota (Genus) and
motility altered gut microbiota in autistic patients. The trending
counterpart microbiota of which was found. ? indicates an unclear,
↑ indicates an increase and ↓ signifies a decrease in
the relative process.
Bacteroides genus
Here, we have identified some abnormal flora in autistic patients through a
review. These microbiotas can be altered by movement. Firstly, we found that
the relative abundance of Bacteroides was significantly elevated in
many patients with ASD and many studies have found that exercise as an
intervention can reduce its relative abundance [37]
[40]
[57]
[93]. Studies have shown that
high levels of Bacteroides affect infants’ cognitive and
language skills, and it is also related to the production of GABA [121]
[122]
[123]. The higher levels of Bacteroides
in children with ASD may be related to the underlying mechanisms of certain
behaviors, which are worthy of further study. Reduced relative abundance of
Bacteroides can prevent pathogen invasion, reduce immune
function, and promote immunity [103].
Bifidobacterium genus
While Bifidobacterium has also been proven to be related to the
production of GABA [85]. The relative
abundance of Bifidobacterium in patients with ASD was found to be
reduced in many studies, while some experiments using exercise as an
intervention confirmed that exercise increased the relative abundance of
Bifidobacterium [
[64]
[100]. GABA is an amino acid neurotransmitter
that is an important heterogeneous neurotransmitter in the central system.
There are scholars who now believe that ASD results from an imbalance of
excitatory and heterogeneous neurotransmitters during development [124]. Glutamatergic and GABAergic dysfunction
and its impact on excitatory to inhibitory cortices is one current
hypothesis to explain the social and cognitive impairments in autism and
schizophrenia [125]. It was found
significantly higher GABA content in the Dorsolateral Prefrontal Cortex
(DLPFC) of ASD compared to the normality by hydrogen proton magnetic
resonance spectroscopy (1H-MRS) [126]. And is
the close relationship between Bifidobacterium and Bacteroides
and GABA related to these? Could the improved relative abundance of
Bifidobacterium and Bacteroides through exercise be a
pathway for exercise to alleviate symptoms in ASD patients? These can all be
discussed further in subsequent studies. Not only GABA, but
Bifidobacterium may also be associated with
5-Hydroxyindole-3-acetic acid(5-HIAA), 3,4-dihydroxyphenylacetic
acid(DOPAC), and tryptophan [127]. Changes in
all of these substances may be associated with neurological disorders.
Clostridium genus
Clostridium perfringens was significantly increased in most of the
studied patients with ASD compared to the normal group [56]
[60]
[75]. The intervention with exercise as the
means of intervention led to a decrease in their relative abundance [109]
[110].
Clostridium perfringens is a Gram-positive bacterium that has
also been extensively studied in ASD because of its production of exotoxins
and propionates [34]
[35]. A proportion of children with degenerative ASD develop
neurobehavioral symptoms and chronic diarrhea due to repeated antibiotic
administration, so it has been suggested that toxin-producing Clostridium
may be involved [109]. While Sandler treated
children with degenerative autism by administering oral vancomycin, an
antibiotic known to have anti-clostridial activity, for six weeks. Eight of
the 10 children studied showed significant improvement in neurobehavioral
symptoms (some even scored in the neurotypical range), as well as
improvement in gastrointestinal symptoms [128]. This also illustrates the close relationship between ASD and
Clostridium.
Blautia genus
Blautia, an anaerobic genus with probiotic properties, is widespread
in the feces and gut of mammals. It is significantly associated with host
physiological dysfunction. For example, obesity, diabetes, cancer, and
various inflammatory diseases [129]. We found
that the relative abundance of Blautia was decreased in many of the
ASD patients studied [64]
[76], and that the relative abundance could be
enhanced by some research exercises as an intervention [109]
[110]. This
genus has also been found to play a role in biotransformation and
interactions with other intestinal microorganisms [130]. However, the specific relationship between ASD patients and
the genus Blautia has not been clearly explained.
Akkermansia genus
Akkermansia muciniphila is a strictly anaerobic bacterium isolated
from human feces that uses mucin as its sole source of carbon and nitrogen
[131]. It is an oval-shaped bacterium,
strictly anaerobic, non-motile and Gram-negative. In patients with ASD, the
relative abundance of Akkermansia is controversial [60]
[93], while
its relative abundance is elevated by exercise interventions [112]. Akkermansia muciniphila maintains
host gut microbial homeostasis by converting mucins into beneficial
by-products [132]. The decrease in the
relative abundance of Akkermansia muciniphila is thought to be
associated with certain diseases. Most of them are metabolic disorders and
inflammatory diseases, including obesity, type 2 diabetes, inflammatory
bowel disease (IBD), autism, and atopic diseases [92]. In the future, it may be an important target for some
diseases.
Streptococcus genus
Streptococcus, another large group of common gram-positive cocci in
pyogenes, is widely distributed in the nasopharynx, gastrointestinal tract,
and so on in nature and the human body, and is mostly a normal microbiota.
Streptococcus showed a decreasing trend in relative abundance in
autistic patients [55]
[60], and exercise was an effective means of elevating its
relative abundance [112]. It has been reported
that it can cause life-threatening diseases such as meningitis and sepsis
[133]
[134].
There are many species of Streptococcus, mainly associated with
various inflammatory conditions, but current research has found little study
of the relationship with ASD.
