Gut Microbiota Profiles in Children and Adolescents with Psychiatric Disorders

The aim of our work is to summarize the current state of knowledge on gut microbiota differences in children and adolescents with psychiatric disorders. To find the relevant articles, the PubMed, Web of Science, and Google Scholar databases were searched. Articles in English presenting original data and comparing the composition of gut microbiota in child psychiatric patients with gut microbiota in healthy children and adolescents were selected. Finally, we identified 55 articles eligible for our purpose. The majority of patients with autism spectrum disorders (ASD) were investigated. A smaller number of studies evaluating the gut microbiota in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), Rett syndrome, anorexia nervosa, depressive disorder (DD), and tic disorders were found. The main findings of this research are discussed in our review, focusing on the age-related gut microbiota specificity for psychiatric disorders and the differences between individual diagnosis. To conclude, the gut microbiota in children and adolescents with psychiatric disorders is evidently different from that in controls. The most pronounced differences are seen in children with ASD, less in ADHD. Moreover, the changes are not identical to those in adult psychiatric patients, as Ruminococcus, Turicibacter, and Bilophila were increased in adults, and decreased in children with ASD, and Parabacteroides and Alistipes were more frequently represented in adults, but less frequently represented in children with depression. The available data suggest some genera have a different abundance in individual psychiatric disorders (e.g., Bilophila, Bifidobacterium, Clostridium, Coprococcus, Faecalibacterium, and Ruminococcus), suggesting their importance for the gut–brain axis. Other bacterial genera might be more important for the pathophysiology of specific disorder in children and adolescents, as Akkermansia and Desulfovibrio for ASD, or Romboutsia for DD. Based on the research findings, we assume that gut microbiota corrections have the potential to improve clinical symptoms in psychiatric patients.


Introduction
Studying the composition of gut microbiota in various medical conditions has extended to many different fields of medicine and science during the last two decades. First, gut microbiota was associated with somatic diseases. Later, an increasing number of articles describing a possible link between mental health conditions and gut dysbiosis were discussed. Unfortunately, there is still limited evidence of the contribution of gut dysbiosis to psychiatric disorders in children and adolescents.
Multiple signaling pathways of bidirectional communication between the gut and the brain have already been described [1]. Therefore, from the current state of knowledge, we can assume that gut dysbiosis may lead to an elevated risk of developing psychiatric disorders. Although some studies have provided evidence for the presence of bacterial DNA in human placenta and amniotic fluid, major bacterial colonization occurs at birth. The composition of the child gut microbiota depends on the delivery mode (vaginal or

Materials and Methods
Scientific databases (PubMed/MEDLINE, Web of Science, and Google Scholar) were searched using the key words: (gut bacteria OR microbiota OR intestinal microbiota OR microbiome) AND (obsessive OR OCD OR autism OR pervasive disorders OR ADHD OR hyperactivity OR schizophrenia OR psychotic disorder OR depression OR depressive OR anxiety OR addiction OR eating disorders OR anorexia OR bulimia OR neurodevelopmental disorders OR mental deficit OR behavior problem OR speech disorder OR tic OR Tourrette) AND (children OR child) NOT (mouse OR mice OR pigs OR zebrafish OR animal OR rat) in September 2022. From 734 results, the review articles and meta-analysis, book chapters, meeting abstracts, early access, and retracted articles and letters (#268) were eliminated. The remaining 466 articles were evaluated for our purposes and 41 articles met our inclusion criteria. Only articles in English presenting original data comparing the composition of gut microbiota in child and adolescent psychiatric patients (up to the age of twenty) with the gut microbiota in healthy children were included. We decided not to exclude the study where older participants were also included for the control group [17].
Taken together, the gut microbiota of 4826 participants (3630 participants in ASD studies, 472 in ADHD, 79 in Rett syndrome, 39 in anorexia nervosa, 458 in depression, and 148 in tic disorder studies) was evaluated. From 4826 participant, 2617 were patients, and 2199 healthy volunteers and neurotypical siblings served as a control group. In the study of Thapa et al. (2021), ten psychiatric patients formed the control group along with healthy participants [18]. The trials were performed predominantly on boys, except for anorexia nervosa and Rett syndrome study, where only girl participants were included.
The age range of participants varied depending on the diagnosis (see Table 1).
In the reviewed studies, stool samples were used for analysis. The majority of samples were stored at −80 • C within 24 h. Storage at −20 • C was reported in two earlier published studies, and in five cases, this information was not provided or was unclear. In one case, a microbial preservation solution was used and samples were subsequently stored at room temperature [19]. 16S rRNA sequencing was used to evaluate gut bacterial composition in most cases. As seen in Table 1, the diagnostic tools used to evaluate patients and healthy controls differed according to diagnosis.
Previous research proved that the composition of the gut microbiota varies according to weight, diet, drugs, and comorbid diseases. About one-third of the studies in our review reported the body mass index (BMI) of participants. In approximately half of the studies, the authors evaluated diet habits; nevertheless, the methods of evaluation were often not reported or unclear. Thirty-two studies included information about gastrointestinal (GI) symptoms in their participants. In two studies, participants with GI symptoms were excluded. In forty-six cases, patients using antibiotics (ATB) or pre/probiotics before sample collection were excluded. For detailed information, see Table 1.
Differences in gut bacterial phyla and genera in psychiatric patients compared with healthy controls are summarized in Tables 2 and 3, respectively. Only statistically significant results and reported nonsignificant differences are shown. The findings are discussed in detail below.

Gut Bacterial Profiles in Children with Autism Spectrum Disorder
Autism spectrum disorder is a lifelong neurodevelopmental disorder. Stereotyped and repetitive behavioral patterns, and a deficiency in communication and social interaction are its core symptoms [20]. The most frequent cooccurring mental health conditions in autism are ADHD, sleep-wake disorders, anxiety and depressive disorders, conduct disorders, bipolar disorders, schizophrenia, and obsessive-compulsive disorder (OCD) [21]. Furthermore, food selectivity, eating disorders, and gastrointestinal symptoms are frequently reported [22,23]. When compared with typically developing children, ASD patients are estimated to have a fivefold increased risk of developing a feeding problem (i.e., picky eating and severe food selectivity) and an approximately threefold increased risk of developing GI symptoms (e.g., diarrhea, constipation, abdominal pain/discomfort, bloating, or soiling) [22][23][24]. Many GI symptoms may remain undiscovered and be presented by more pronounced problematic behavioral manifestations (aggressivity, disrupted behavior, or self-injury) [24]. Even though the etiology of disturbed eating and GI symptoms in ASD patients remains unclear, these findings support the theory of dysbiosis in ASD patients.
As shown in Table 2, a number of studies reported significant differences in the abundance of specific bacterial phyla in ASD patients in comparison to healthy controls. However, consistent results were not obtained. Six studies revealed a decreased Bacteroidetes/Firmicutes ratio in ASD [30,34,41,49,54,62]. Contradictory findings were reported by the same number of authors [36,38,40,52,53,57], and in four other studies, no significant differences were observed [28,37,39,64]. A similar number of studies reported decreased, increased, or no specific difference in the abundance of Bacteroidetes, Firmicutes, and Actinobacteria. For Fusobacteria and Verrucomicrobia, mostly no specific differences were found. In most cases, levels of Proteobacteria were found to be increased or without specific differences (see Table 2). Only one out of thirteen studies bringing information about Proteobacteria reported decreased levels of this bacterial phylum [40]. However, while no statistically significant differences were found in nearly all other psychiatric diagnoses studied, ASD was clearly associated with gut microbiota differences at the phylum level.
Although many of the reviewed studies found differences in genera abundance in children with and without ASD, no consistent findings were observed for different bacterial genera except for Dialister and Phasolarctobacterium genera, which were found to be reduced in ASD patients in most of the reported cases (see Table 3). Higher abundances of Bacteroides, Parabacteroides, Lactobacillus, and Clostridium, and reduced abundances of Bifidobacterium, Dialister, Faecalibacterium, Streptococcus, and Veillonella were among the most frequently discussed findings. Lower amounts of Prevotella or certain Prevotella species in ASD patients were found in several studies [25,30,31,37]. In contrast, some authors found the opposite [33,40,42,55,57].
Several studies have also focused on searching for links between gut dysbiosis and autism severity. Finegold et al. (2010) found significantly higher amounts of several Desulfovibrio species and Bacteroides vulgatus in children with severe autism than in children with mild autism [35]. Tomova et al. (2015) also described a strong correlation between Desulfovibrio abundance and the severity of autism. The authors also found an increased level of Clostridium cluster I, but this finding did not reach statistical significance [62]. Other studies revealed higher Firmicutes abundance in severe ASD cases compared with mild autism cases [53] and elevated unidentified Lachnospiraceae, unidentified Erysipelotrichaceae, and decreased Faecalibacterium strains in children with severe ASD [39]. A weak correlation between Bacteroides spp. With the total score on the Social Responsiveness Scale (SRS) was described, but there was no significant correlation between Bacteroides spp. and Bifidobacterium spp. with the five subscales of the SRS [54]. A correlation between alpha diversity and the abundances of Bacteroides, Faecalibacterium, and Oscillospira and the Childhood Autism Rating Scale (CARS) total score was observed [32]. The opposite was found in the study of Xie et al. (2022) [56].
Several studies have looked for correlations between gut dysbiosis and GI symptoms in ASD children due to the high frequency of GI disorders in this population. GI symptoms in autistic children were associated with higher levels of Clostridium histolyticum (Clostridia cluster I and II) [59] or a lower amount of Faecalibacterium prausnitzii [25]. In the latter study, the authors linked this finding to an increased risk of gut inflammation [25]. However, in another study, levels of Faecalibacterium prausnitzii were found to be significantly higher in ASD patients, while levels of B. longum were decreased [36]. No difference in the abun-dance of Faecalibacterium prausnitzii was found by two other authors [55,61]. Furthermore, Strati et al. (2017) described a positive correlation between Eischerichia/Shigella and Clostridium cluster XVIII and GI symptoms in ASD children [49], while Rose et al. (2018) found increased Bacteriodaceae, Lachnospiraceae, Ruminococcaceae, and Prevotellaceae in ASD children with GI symptoms when compared with healthy children with GI symptoms. However, the authors did not reveal the same difference between autistic and healthy children, both without GI symptoms [63]. Chloroplast taxa were also found to be increased in autistic children. An even more pronounced difference was seen in the ASD with functional GI disorders (FGID) group compared with the ASD without FGID and neurotypical siblings. The authors discussed the possible link to chia seed consumption in these patients [48]. In the constipated ASD group, decreased bacterial species belonging to the genera Bacteroides, Prevotella, Phascolarctobacterium, and Paraprevotella and enriched Fusobacterium, Barnesiella, Coprobacter, and Actinomycetaceae were reported [27,30]. The SCFAs synthetizing genus Roseburia was proposed as a biomarker of an ASD patient with GI symptoms and this led to a question whether SCFAs producing bacteria preserve gut microbiota ecology [33]. On the other hand, significantly increased Ruminococcus in the ASD group without GI symptoms, according to the authors, corroborate the role of this bacterial genus in the improvement of the GI status of patients [33]. In contrast, Gondalia et al. (2012) failed to find any significant difference between gut bacteria in ASD patients and healthy controls, or differences in gut bacteria composition when comparing autistic children with and without GI dysfunction. Similarly, the authors found no link between microbiota composition and autism symptom severity [47]. It is worth mentioning that, in this study, stool samples were stored at −20 • C before analysis, which might have influenced the results. Another study revealed similar differences in the gut microbiota in "picky eaters" in both ASD and healthy children, and thus, the authors propose that certain differences in gut bacteria are associated with eating habits [65]. Interestingly, in the same study, other bacteria were found to be characteristic of the gut microbiota in children with ASD compared to controls [65]. In the recently published study of Wong et al. (2022), the abundances of genera Fusicatenibacter, Dialister, and Phasolarctobacterium were different in the ASD group with GI symptoms when compared with ASD, as well as healthy participants, both without GI symptoms [34]. Moreover, in the last-mentioned study, enriched Turicibacter was observed in the ASD group with GI symptoms. Based on previous knowledge, authors propose the role of Turicibacter in the pathophysiology of GI symptoms [34].
Neuroinflammation and neuroimmune abnormalities have been established in ASD as key factors in its development and maintenance [66]. In some of the reviewed studies, the levels of proinflammatory cytokines and markers of intestinal permeability were concurrently investigated. Although not statistically significant, levels of fecal TNFα were increased in children with autism, and a strong correlation between TNFα levels and GI symptoms was found [62], but, significantly increased levels of TNFα were also described [19,26]. Likewise, higher levels of TGFß were observed [19,26,44], as well as an increase in levels of IL-2 and IL-4 [19]. IL-4 was found to be negatively correlated with the CARS total score [19]. Furthermore, higher levels of serum IL-10, neurotensin peptide, and Sortilin1 (SORT-1), and increased fecal high-mobility group box protein 1 (HMGB1), were found in ASD patients [26]. HMGB1 is a multifunctional nuclear protein that can be released from cells in response to tissue damage or inflammation. A high level of circulating HMGB1 has been found in various autoimmune and inflammatory diseases, and fecal HMGB1 has been previously proposed as a biomarker of intestinal mucosal inflammation [67,68]. The amount of HMGB1 significantly correlated with the occurrence and severity of GI symptoms in ASD patients and was then proposed by authors as a biomarker to detect GI symptoms in these patients [26]. Levels of fecal calprotectin, another marker of intestinal inflammation, were previously found to be higher in ASD patients, and these results correlated with ASD symptomatology [69]. However, no significant differences in the levels of fecal calprotectin, serum IgA levels, or erythrocyte sedimentation rate between ASD patients and healthy children, as well as constipated and nonconstipated subjects in both groups, were found in another study [49]. Similarly, no significant differences of sIgA levels, but significant increase of zonulin and lysozyme was observed in the study of Vernocchi et al. (2022) [33]. In contrast, Adams et al. (2011) revealed a lower level of lysozyme, but this study failed to find significant differences in other possible markers of inflammation, such as lactoferrin, white blood cells, mucus, and secretory IgA [60]. Increased concentrations of IL-5, IL-15, and IL-17, and elevated markers of intestinal permeability zonulin-encoding genes, were associated with GI symptoms in ASD [63]. These findings suggest that children with ASD have disturbed immune signaling and intestinal permeability, and are consistent with previous findings about the relationship between enhanced gastrointestinal inflammation and GI symptoms in ASD [70], except for the study of Yitik Tonkaz et al. (2022), where authors did not support the role of gut bacteria in the etiology of ASD [64].
SCFAs (short-chain fatty acids), such as butyric, propionic, acetic, and valeric acids, are the main end-products of bacterial fermentation in the gut, and are also considered possible factors contributing to ASD symptoms. The main producers of butyrate belong to the Firmicutes families Ruminococcaceae (e.g., Faecalibacterium prausnitzii), Lachnospiraceae (e.g., Roseburia spp., Eubacterium rectale, Coprococcus spp.), Erysipelotrichaceae, and Clostridiaceae [71,72]. Propionate is produced by species of Bacteroidetes (e.g., Bacteroides spp., Veillonella spp., or Blautia spp.), while Akkermansia municiphila produces both propionate and acetate and Bifidobacterium spp. produce acetate and lactate [71,72]. SCFAs' influence on gut motility, mucus production, integrity of gut epithelium, and anti-inflammatory effects have already been proven [14]. In the brain, SCFAs help to maintain the blood-brain barrier (BBB) integrity and, after crossing the BBB, act as neuroactive molecules. They have a proven anti-inflammatory effect and an effect on the maturation of microglia, but the precise mechanism remains to be elucidated [14]. Moreover, SCFAs have an impact on appetite and energetic homeostasis in the hypothalamus, influence the sleep cycle, stimulate the expression of BDNF and nerve growth factor (NGF), neurogenesis and neuronal proliferation, and help the growth of progenitor neurons. Butyrate stimulates growth hormone secretion in the hypophysis and promotes consolidation of memory [14]. SCFAs can influence the level of NT and neurotrophic factors [10,14]. It seems that the beneficial impact of SCFAs on health also depends on their concentration in organisms [73]. Negative effect of high levels of SCFAs was also observed [74].
Lower total SCFA levels in stool samples of children with autism were reported in two studies [42,60], while higher levels were reported in another study [54]. Furthermore, lower fecal acetate and butyrate [27,60] and lower propionate in autistic patients were described [60]. According to the latter mentioned authors, these results were strongly associated with GI symptoms and autism severity [60]. Faecal valerate was found to be higher in ASD [27]. Moreover, the gut microbiota was positively correlated with SCFAs. At the family level, Acidobacteria and Actinomycetaceae were correlated with valeric acid, while Streptococcaceae, Peptostreptococcaceae, Lactobacillaceae, Clostridiaceae_I, Family_XIII, and Leuconostocaceae had a positive correlation with butyrate. Streptococcaceae were highly correlated with propionic acid, and Desulfovibrionaceae were correlated with propionic as well as acetic acid [27]. Other studies have found higher concentrations of butyrate [36,50], acetate, and propionate [50] in children with autism, as well as higher abundance and higher effect of enzymes involved in butyrate production [36]. Berding and Donovan (2018) associated these findings with specific dietary patterns [50]. In the study by Carissimi et al. (2019), a lower abundance of E. coli was found. The authors suggested that elevated propionate in ASD patients might also be explained by its reduced degradation as a consequence of the E. coli drop, in addition to the enhanced production by Clostridia [26]. However, no significant differences in the levels of acetate, propionate, and butyrate, and no differences in relative concentrations of SCFAs, were described [25,54]. Although many studies suggest the possible role of SCFAs in ASD manifestations, more research is required to prove this possibility.

Gut Bacterial Profiles in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with the prevalence of approximately 7% among children and adolescents [75]. It is mainly characterized by symptoms of inattention, motor hyperactivity, and impulsivity [76]. ADHD is highly heritable, but several environmental factors, including gut bacteria, are believed to play a role in its development. To date, little is known about the composition of the gut microbiota, specifically in children and adolescents with ADHD. We evaluated seven studies that involved children and adolescents up the age of 20 years, but, for now, these studies did not bring any consistent conclusions.
Alpha diversity of intestinal microbiota between the ADHD and control groups did not differ significantly in five studies [17,[77][78][79][80]. One study reported decreased alpha diversity in ADHD patients, and moreover, this result negatively correlated with hyperactivity symptoms [81]. However, it must be noted that, in this study, all patients were taking methylphenidate for more than one year, and this medication was discontinued only 48 h prior to sample collection, which might have influenced the results [82]. Wang and colleagues (2020) revealed the higher diversity indexes (Shannon and Chao) in ADHD [6]. In terms of beta diversity, only two studies described significant differences at the bacterial phylum level. More abundant Actinobacteria, less abundant Firmicutes [17], and increased Fusobacteria were observed in the ADHD group [6]. The remaining four studies failed to find differences in the abundance of dominant bacterial phyla (see Table 2).
A lower abundance of Faecalibacterium was negatively associated with the total Conners' Parent Rating Scale (CPRS) score and the hyperactivity index score [78]. Wan and colleagues (2020) hypothesized that Faecalibacterium dysregulation may cause changes in inflammatory cytokine levels, and therefore participate in ADHD pathogenesis [77]. Lower plasma TNFα levels in ADHD patients vs. healthy controls were found in one study [80], but no association between other cytokine levels and ADHD were observed [80]. An earlier published study described a significant increase in Eggerthella, Alistipes, Odoribacter, Parabacteroides, and Bifidobacterium, while the latter was associated with significantly enhanced predicted biosynthesis potential of a dopamine precursor (phenylalanine) in the gut microbiome of ADHD patients, which was linked to altered reward anticipation responses in the brain, a neural hallmark of ADHD [17]. Abnormal levels of Odoribacter and Enterococcus were previously associated with dysregulated neurotransmitter production [83,84]. Therefore, these bacteria may play a potential role in the development of ADHD [77]. Furthermore, differences in certain species of Bacteroides, Sutterella, and Neisseria in the ADHD group might, according to the authors, serve as possible biomarkers for ADHD, since these species were correlated with ADHD symptoms, such as hyperactivity and impulsivity [6,81].

Gut Bacterial Profiles in Children with Rett Syndrome
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene [85]. This condition predominantly affects females and is associated with intellectual disability and early neurological regression that severely affects motor, cognitive, and communication skills, leading to psychomotor delay and autistic features [86]. Moreover, 90% of patients suffer from gastrointestinal and nutritional problems that pose a significant medical burden for their caregivers [87], and in the context of gut microbiota research, dysbiosis may be one of the causes contributing to GI difficulties.
One study published to date involved children and adolescents with RTT exclusively [88]. Alpha diversity was decreased and beta diversity differed significantly between patients and healthy controls [88]. At the phylum level, an increase in Actinobacteria and a decrease in Bacteroides and Bacteroides/Firmicutes ratios were observed. Multiple bacterial genera were found to be different from healthy controls (see Table 3). Especially, a decrease in Prevotella and Faecalibacterium, which supports the hypothesis of the proinflammatory status of the gut microbiota in Rett syndrome.

Gut Bacterial Profiles in Children and Adolescents with Anorexia Nervosa
Anorexia nervosa (AN) is a severe psychiatric disorder with a high mortality rate and, in many cases, a life-long course. The prevalence of AN in Europe and the U.S.A. varies between 0.9% and 4% [89,90]. AN is characterized by a restrictive diet and low body weight. Excessive physical activity, purging, and the misuse of various drugs are frequent compensatory mechanisms that lead to subsequent weight loss [91]. Disturbed body image and enormous fear of weight gain complicate the treatment [91]. Many somatic, hormonal, and psychiatric comorbidities worsen its prognosis [89].
Little is known about the relationship between gut dysbiosis and adolescent AN. To date, only one study has investigated the gut microbiota in adolescents with anorexia nervosa exclusively [92]. This study described differences in beta diversity, but not in alpha diversity, of AN patients [92]. At the genus level, an increase in Anaerostipes and a reduction in Romboutsia were observed [92].
It seems that the abundance of different bacteria changes in the course of anorexia treatment. Alpha diversity and the abundance of Firmicutes phyla increased after weight recovery, while Bacteroidetes decreased. Furthermore, increasing levels of Fusicatenibacter, Lachnospiraceae, Ruminococcaceae, and Faecalibacterium, and a decrease in levels of Bacteroides, were observed in AN patients at discharge from the hospital when compared with findings at admission. However, Romboutsia and unclassified Enterobacteriaceae remained decreased [92]. In this study, the potential influence of bacteria on the duration of treatment was also evaluated. The authors found that a higher abundance of unclassified Lachnospiraceae was associated with a shorter duration of treatment, and they linked this finding with the anti-inflammatory effect of Lachnospiraceae [92].

Gut Bacterial Profiles in Adolescents with Depression
Major depressive disorder (MDD) is a serious public health problem with an increasing prevalence and a wide range of adverse consequences. Epidemiological studies estimate the lifetime prevalence at 11%, with a significant increase across adolescence, and a markedly greater increase in women than in men [93].
Several studies examining the role of intestinal microbiota in adult depression have already been published, while three of them evaluated its potential role in adolescent depression [18,94,95]. There are no consistent findings about alpha and beta diversity differences between patients with depression and healthy controls in these studies. Thapa et al. (2021) failed to find statistically significant differences in the abundance of the main bacterial phyla and genera in MDD patients [18]. In contrast, two other articles brought the evidence of several differences in gut bacteria between patients and healthy controls [94,95]. Among 26 significantly increased bacterial genera, Ling et al. (2022) identified eight bacterial taxa to be the biomarkers of childhood depression (Prevotella, Bifidobacterium, Eischerichia/Shigella, Agathobacter, Gemmiger, Streptococcus, Collinsella, and Klebsiella) from which Streptococcus was the best predictor for MDD in children [94]. Bacteroides and Faecalibacterium as the antiinflammatory genera were found to be decreased in patients with depression, and Faecalibacterium was negatively correlated with levels of pro-inflammatory cytokines [94]. Previously published studies on adult depression found negative correlation between the abundance of Bacteroides and Faecalibacterium and the severity of depressive symptoms [96,97]. How-ever, inconsistently with these findings, Zhou et al. (2022) described enriched populations of Bacteroides in children with depression [95]. Enriched Eischerichia/Shigella and unclassi-fied_f_Enterobacteriaceae were positively correlated with anxiety and depressive scores in the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) [95]. Likewise, the abundances of Faecalibacterium and Bacteroides were similar between the patients and the healthy control group in the study of Thapa et al. (2021) [18]. These authors also showed that neither MDD nor selective serotonin reuptake inhibitors (SSRIs) use were associated with differences in gut bacterial composition in older adolescents [18]. A study performed on healthy children indicated that psychosocial stress might modulate the composition of the gut microbiota, and the authors suggested evaluating parasympathetic activity in future research [98].

Gut Bacterial Profiles in Children with Tic Disorders
Tic disorder (TD) is another neurodevelopmental condition, including provisional and chronic motor or vocal tic disorders and Tourette syndrome. Many of these patients suffer from comorbid psychiatric conditions, such as ADHD, obsessive-compulsive disorder, or depression, which may have an impact on patients' daily functioning [99,100]. Etiology is not fully known, but both genetic and environmental factors may play a role in pathogenesis [101].
Two studies published to date did not find the differences in alpha diversity of patient samples in comparison with HC [102,103]. Significant differences in beta diversity were found in the study of Wang et al. (2022) [102]. Xi et al. (2021) revealed higher abundances of certain bacterial species, such as Bacteroides plebeius and Ruminococcus lactaris, and lower abundances of Prevotella stercorea and Streptococcus lutetiensis in TD patients [103]. The authors also found correlations between tic severity and the abundance of Klebsiella pneumoniae, Akkermansia muciniphila, Bacteroides spp., Bifidobacterium spp., and Eubacterium spp. Moreover, study data indicate that treatment with dopamine receptor antagonists result in changes in the gut bacterial community [103]. In the other study, a significant reduction in Bifidobacterium genus was found in TD patients [102]. Authors suggest its possible role in TD by affecting the release of neurotransmitters, and speculate about the possible use of Bifidobacterium to treat mild or moderate symptoms of tic disorders. In the same study, a significant increase in Prevotella and Odoribacter was revealed in children with TD [102]. Prevotella is believed to have a pro-inflammatory effect [104], and increased inflammatory factors were found in TD [105]. Increased Odoribacter was also found in neuropsychiatric diseases such as pediatric acute onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) [83], and thus, this finding may likewise suggest the relationship with the etiopathogenesis of tic disorders [102].

Discussion and Conclusions
The intestinal microbiota is comprised of a population of microorganisms more numerous than host cells, with several functions responsible for physiological processes in the entire human body. Furthermore, the gut-microbiota-brain axis displays a bidirectional communication that involves several main pathways along which interaction occurs. Disturbances of this communication in the form of dysbiosis are associated with various diseases, including psychiatric disorders, such as ASD, ADHD, depression, Rett syndrome, AN, and TD.
Although patients diagnosed with psychiatric disorders have been shown to suffer from GI symptoms such as constipation, diarrhea, reflux, vomiting, or abdominal pain, a conclusive link between these symptoms and disorders is yet to be drawn. Nevertheless, recently, a mounting number of investigations of gut microbiota in patients with psychiatric disorders suggest its important role for mental health. This study is focused on children and adolescents because the gut microbiota changes with age [2] and any differences in compared groups could be age-specific. For example, the Firmicutes/Bacteroidetes ratio has been shown to increase with age [106]. Comparing the gut microbiota in the groups targeted here, we found some common and some different characteristics in children compared with adults. In depression, Faecalibacterium had decreased abundance in adults [107], and in children [94], and Streptococcus genera were increased in both groups [94,108]. Parabacteroides and Alistipes had increased levels in adults [109], but decreased levels in children [94,95], while Lactobacillus and Eggerthella were elevated in adults but not changed in children [109].
For ASD, the science dedicates attention mostly to children, but very few articles about microbiota in ASD adults show similar decreases of Fusobacteria phyla abundance in both groups [110]. Interestingly, this was the only change found in adults compared to numerous changes in children's microbiota. At the genera level, the level of Fusobacterium was shown to be decreased in both children and adults, contrarily to the abundance of some Clostridium strains, Bacteroides, and Desulfovibrio, which was increased in both. Ruminococcus, Turicibacter, and Bilophila were more abundant in adults, and less abundant in children [34,35,49,50,110,111].
Since animal models are widely used for studying and understanding psychiatric disorders in humans, it is also important to point out that some genera with increased abundance in individuals with ASD, specifically, Bilophila, Clostridium, Dorea, and Lactobacillus, revealed the same changes in mouse models of autism. Other genera with decreased abundance in autistic individuals, e.g., Blautia, show the same picture in animals, as reported in a recent review [112]. Many other differences in gut microbiota were found exclusively in humans (e.g., Alistipes, Ruminococcus) or exclusively in animal models (e.g., Asaccharobacter) [112].
Most of the articles included in our review comparing the gut microbiota of children and adolescents with different psychiatric disorders at the phyla level, found significant differences of bacterial abundance in ASD, sometimes in ADHD, and a few available studies about MDD, RTT, AN, and TD barely found any difference. Although the abundance of some bacterial phyla had contradictory changes in ASD patients, Proteobacteria was increased in almost all studies (except one) and Verrucomicrobia was decreased. This suggests the significant role of gut microbiota for ASD, supported also by changed alpha and beta diversity, which was not reported for ADHD and other disorders. In collected studies, some genera were observed to be more frequently represented in ASD as Bacillus, Clostridiales, and Klebsiella, and others as Actinomyces, Bifidobacterium, Bilophila, Eischerichia, Faecalibacterium, Flavonifractor, Phascolarctobacterium, Veillonella and Weissella were found to be less frequently represented. From these studies, it can be summarized that Bifidobacteriales, Clostridiales, Faecalibacterium, and Ruminococcaceae are associated with ADHD, as evidenced by an increase in Clostridiales, Enterococcus, Bifidobacterium, Odoribacter, and Ruminococcaceae, and a reduction in Faecalibacterium, Haemophilus, Prevotella, and Lactobacillus.
Taken together with up-to-date data, some genera are suggested to be important for the entire gut-brain axis, as they show similar changes in abundance in various psychiatric disorders (e.g., Bilophila, Bifidobacterium, Clostridium, Coprococcus, Faecalibacterium, and Ruminococcus). Other bacterial genera could be more important for a specific disorder in children and adolescents, such as Akkermansia and Desulfovibrio for ASD, or Romboutsia for MDD, and might be candidates as triggers or etiological agents of these disorders.
Although different studies found similar changes of some strains in a specific disorder, the abundance of other strains is inconsistent along the different studies. The reason behind this could be the limitations applied to studies and their interpretation, including: geographical, cultural, dietary, and demographic variability within the study populations, intake of medications, and methodological alterations. Furthermore, different disorders are age typical for different age groups. In spite of this, evidence suggests the microbiota-gutbrain axis' involvement in psychiatric disorders and very complex relations between the brain and the microbiota.
Many external and environmental factors play a role in the manifestation of psychiatric disorders, and many factors shape the composition of gut microbiota, which makes research in this field very demanding. As this review demonstrated, numerous studies revealed that gut microbiota in children and adolescents with psychiatric disorders differ from that in the healthy population. Namely, studies on ASD, ADHD, Rett syndrome, AN, depression, and tic disorders have been performed to date. Current research aims to determine which gut microbiota differences are associated with concurrent symptoms and which might be connected to the pathophysiology of specific behavioral manifestations. However, independently of that, modulation of gut microbiota might be a feasible way to at least alleviate symptoms of various diseases, including psychiatric disorders, especially in children and adolescents.
Possible modification of gut bacterial composition using specific probiotics, prebiotics, or fecal microbiota transplantations for health improvement has been of great interest in recent years. Although the use of gut microbiota modulation is in perspective, the current state of knowledge is far from conclusive because of the research complexity and various limitations. For conclusions that will lead to clear recommendations, a higher number of study participants is required. Accordingly, geographical location and corresponding diet, and the use of various psychotropic drugs and nutritional supplements must also be considered. An age-related bacterial signature needs to be identified and taken into account. Therefore, our review focused on child patients with psychiatric disorders. In addition, microbial species other than bacteria, such as viruses, fungi, or protozoa, both in the lumen of the intestine and in the mucosa and other body environments (saliva, urine, or buccal mucosa), as well as microbial metabolites, should also be investigated to determine their impact on behavioral manifestations in psychiatric patients. Longitudinal studies should be conducted in the future to better understand the relationship between gut microbiota alterations and human behavior.

Conflicts of Interest:
The authors declare no conflict of interest.