DOI: https://doi.org/10.21203/rs.3.rs-1576931/v2
The aim of our work is to summarize the current state of knowledge on gut microbiota changes in children and adolescents with mental illnesses. To our knowledge, this is the first review comparing gut microbiota changes in various mental disorders in children and adolescents.
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 42 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, major depressive disorder and tic disorders were found. The main findings of this research are discussed in our review, focusing on the association between the gut microbiota and behavioural manifestations.
To conclude, the gut microbiota in children and adolescents with mental disorders is evidently different from that in controls. Most pronounced changes are seen in children with autism spectrum disorders. These changes might be associated with often present gastrointestinal manifestations but, in general, also play a pathogenetic role in behavioural disorders. Based on research findings, we assume that there is a perspective of gut microbiota correction to improve clinical symptoms in psychiatry.
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, the 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 mental disorders in children and adolescents.
Multiple signaling pathways of bidirectional communication between the gut and the brain have already been described. Therefore, from the current state of knowledge, we can assume that gut dysbiosis may lead to an elevated risk of developing mental health 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 cesarean section), type of feeding of the newborn (breastfeeding or formula feeding), type of introduced solid food, use of antibiotics, probiotics and other drugs and supplements by mother or child. Furthermore, host genetics, dietary habits, gut physiology, hygiene level, stress, and physical activity influence the gut microbiota [1-6]. At the age of 3 years, the gut microbiota seems to be stabilized and resembles the composition of microbiota in an adult [6].
Remarkably, the human brain also develops intensively during the first years of life, and it seems that different environmental factors, including gut bacteria and their metabolites, influence its developmental milestones [7]. As reported in animal experiments, bacterial metabolites may cause morphological changes in different brain structures [8]. Research has proven an impact on neurogenesis, BDNF levels, neurotransmitters (NTs) and NT precursors and their receptors [9]. Furthermore, some bacteria were found to stimulate the production of proinflammatory bacterial metabolites, modulate the immune system, change the activation of the HPA axis and vagal signaling and influence blood-brain barrier (BBB) formation [7, 10, 11].
Furthermore, short-chain fatty acids (SCFAs), particularly acetate, butyrate, and propionate, important products of bacterial fermentation in the large intestine, have various neuroactive properties. They are known to take part in neurotransmitter synthesis and release, mitochondrial and immune functions, and gastrointestinal physiology [12].
Gut bacteria can also produce NTs or can stimulate their production in the host organism, as summarized by several authors [13-15]. It is still not clear whether most of the NTs produced in the gut can cross the BBB, although, for example, circulating tryptophan influences serotonin synthesis in the brain after crossing the BBB [12]. Several animal studies using germ-free (GF) mice found lower serum levels of serotonin (5-HT), dopamine, and GABA and altered metabolite and precursor levels in the gut lumen and urine [8].
The aim of our work is to summarize the current knowledge about gut bacterial composition changes in children and adolescents with psychiatric disorders. First, we provide an overview of studies published before October 2021, as well as their most important characteristics. Second, we discuss the main results separately according to diagnosis. Finally, we point out methodological limitations and emphasize the necessity of further investigations to obtain more comparable data, which will help to better elucidate possible links between gut bacteria and behavior.
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 speach disorder OR tic OR Tourrette) AND (children OR child) NOT (mouse OR mice OR pigs OR zebrafish OR animal OR rat) in October 2021. From 629 articles, publications in English presenting original data comparing the composition of gut microbiota in child psychiatric patients with gut microbiota in healthy children were selected. Because of the small number of eligible studies, we decided not to exclude studies that involved the participation of both children and adults. Case-control studies or studies comparing gut microbiota with the severity of the disease symptoms exclusively were excluded.
Forty-two papers fulfilled our inclusion criteria. Thirty-one studies included children with autism spectrum disorder (ASD). The other eleven studies involved participants with attention-deficit/hyperactivity disorder (ADHD) (#6), Rett syndrome (#1), anorexia nervosa (AN) (#2), major depressive disorder (MDD) (#1), and tic disorders (#1). The main characteristics of the included studies are summarized in Table 1.
Taken together, the gut microbiota of 3326 participants (2556 participants in ASD studies, 392 in ADHD, 65 in Rett syndrome, 67 in anorexia nervosa, 147 in depression and 99 in tic disorder studies) was evaluated. Healthy volunteers and neurotypical siblings served as the control groups. The trials were performed predominantly on males, except for anorexia nervosa and Rett syndrome studies, where only female participants were included.
The age range of child participants varied depending on the diagnosis (see Table 1). Due to the small number of published articles, we decided not to exclude studies that involved both children and young adults. Adult patients were included in one AN study, two ADHD studies, and the MDD and Rett syndrome study [16-20].
In the reviewed studies, stool samples were used for analysis. The majority of samples were stored at -80°C for 24 hours. Storage at -20°C was reported in two earlier published studies, and in four cases, this information was not provided or was unclear. 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. Less than one-third of the studies in our review reported the body weight index (BMI) of participants. In approximately half of the studies, the authors evaluated diet habits; nevertheless, the methods of evaluation were not reported or unclear. Twenty-five studies included information about gastrointestinal (GI) symptoms in their participants. In two studies, participants with GI symptoms were excluded. In thirty-seven cases, patients using antibiotics (ATB) or pre/probiotics before sample collection were excluded. For detailed information, see Table 1.
Changes in gut bacterial phyla and genera in psychiatric patients are summarized in Table 2 and Table 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 manifesting as strongly disturbed behavior. Stereotyped and repetitive behavioral patterns, a deficiency in communication and social interaction, are its core symptoms [21]. 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) [22]. Furthermore, selective eating patterns and gastrointestinal symptoms are frequently reported. 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) [23-25]. Many GI symptoms may remain undiscovered and be presented by more pronounced problematic behavioral manifestations (aggressivity, disrupted behavior, or self-injury) [25]. 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.
Several researchers suggest that changes in microbial diversity may be associated with autistic symptoms, but the results from thirty-one reviewed studies are not consistent. Lower alpha diversity in ASD patients was described in seven studies [26-32], while in nine cases, higher alpha diversity was found [33-41]. Another nine studies did not reveal any significant differences in alpha diversity between ASD patients and healthy controls [42-50]. In the rest of the studies, information about alpha diversity changes was not provided [51-56]. Differences in beta diversity were described in ten studies [26, 28, 29, 32, 36, 37, 39, 44, 47, 49].
As shown in Table 2, a number of studies reported significant changes in the abundance of specific bacterial phyla in ASD patients in comparison to healthy controls. However, consistent results were not obtained. Five studies revealed a decreased Bacteroidetes/Firmicutes ratio in ASD [31, 39, 44, 49, 55]. Contradictory findings were reported by the same number of authors [34, 36, 38, 47, 48], and in three other studies, no significant changes were observed [29, 35, 37]. A similar number of studies reported decreased, increased, or no specific changes in the abundance of Bacteroidetes, Firmicutes and Actinobacteria. For Fusobacteria and Verrucomicrobia, mostly no specific changes were found. In most cases, levels of Proteobacteria were found to be increased or without specific changes (see Table 2). Only one of thirteen studies bringing information about Proteobacteria reported decreased levels of this bacterial phylum [38]. However, while no statistically significant differences were found in nearly all other psychiatric diagnoses studied, ASD was clearly associated with gut microbiota changes 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 the Dialister genus, which was found to be reduced in ASD patients in most of the reviewed studies (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 [26, 31, 32, 35]. In contrast, some authors found the opposite [38, 40, 50].
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 [33]. Tomova et al. also described a strong correlation between Desulfovibrio abundance and the severity of autism. The authors also found an increased level of Clostridia claster I, but this finding did not reach statistical significance [55]. Other studies revealed higher Firmicutes abundance in severe ASD cases than in mild autism cases [48] and elevated unidentified Lachnospiraceae, unidentified Erysipelotrichaceae and decreased Faecalibacterium strains in children with severe ASD [37]. Weak correlation between Bacteroides spp. with total score on Social Responsiveness Scale (SRS) was described, but there was no significant correlation between Bacteroides spp. and Bifidobacterium spp. with the 5 subscales of the SRS [49].
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 C. histolyticum (Clostridium claster I and II) [52] or a lower amount of Faecalibacterium prausnitzii [26]. In the latter study, the authors linked this finding to an increased risk of gut inflammation [26]. However, in another study, levels of F. prausnitzii were found to be significantly higher in ASD patients, while levels of B. longum were decreased [34]. No difference in the abundance of F. prausnitzii was found by two other authors [50, 54]. Furthermore, Strati et al. described a positive correlation between Eischerichia/Shigella and Clostridium claster XVIII and GI symptoms in ASD children [44], while Rose et al. 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 [56]. 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 [43]. 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 [28, 31]. In contrast, Gondalia et al. (2012) failed to find any significant difference between gut bacteria in ASD 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 [42]. 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 changes in the gut microbiota in “picky eaters” in both ASD and healthy children, and thus, the authors propose that certain changes in gut bacteria are associated with eating habits [57]. Interestingly, in the same study, other bacteria were found to be characteristic of the gut microbiota of children with ASD compared to controls.
Neuroinflammation and neuroimmune abnormalities have been established in ASD as key factors in its development and maintenance [58]. 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 [55]. Higher levels of serum TNFα, IL-10, TGFß, neurotensin peptide and Sortilin1 (SORT-1) and increased fecal high-mobility group box protein 1 (HMGB1) were found in ASD patients. The amount of HMGB1 significantly correlated with the occurrence and severity of GI symptoms in ASD patients and was proposed as a biomarker to detect GI symptoms [27]. Levels of fecal calprotectin, a marker of intestinal inflammation, were previously found to be higher in ASD patients, and these results correlated with ASD symptomatology [59]. 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 [44]. 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 [53]. 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 [56]. These findings suggest that children with ASD and concurrent GI symptoms have disturbed immune signaling and intestinal permeability.
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. Most SCFAs are produced by Bacteroides spp. a Clostridiae spp., and their influence on gut motility, mucus production, integrity of gut epithelium, and anti-inflammatory effects have already been proven. As reviewed by Silva et al. (2020), SCFAs also serve as an energy source for hepatocytes and regulate mitochondrial functions, influencing the production of neuroactive molecules such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) [12]. In the brain, SCFAs help to maintain 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. [12]. 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 [12]. SCFAs can influence the level of NT and neurotrophic factors [8, 12]. It seems that the beneficial impact of SCFAs on health depends on their concentration in organisms as well [60].
Lower total SCFA levels in stool samples of children with autism were reported in two studies [40, 53], while higher levels were reported in another study [49]. Furthermore, lower fecal acetate and butyrate [28, 53] and lower propionate in autistic patients were described [53]. According to the latter mentioned authors, these results were strongly associated with GI symptoms and autism severity [53]. Faecal valerate was found to be higher in ASD [28]. 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 [28]. Other studies have found higher concentrations of butyrate [34, 45], acetate, and propionate [45] in children with autism, as well as more abundant and higher functions of enzymes involved in butyrate production [34]. Berding and Donovan (2018) associated these findings with specific dietary patterns [45]. 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 [27]. However, no significant differences in the levels of acetate, propionate, and butyrate and no differences in relative concentrations of SCFAs were described [26, 49]. 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 a prevalence of approximately 7% among children and adolescents [61]. It is mainly characterized by symptoms of inattention, motor hyperactivity, and impulsivity. ADHD is highly inherited, 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 six studies that involved children and adolescents under the age of 18 years, but, for now, these studies did not bring any consistent conclusions.
Alpha diversity between the ADHD and control groups did not differ significantly in four studies [17, 18, 62, 63]. One study reported decreased alpha diversity in ADHD patients, and moreover, this result negatively correlated with hyperactivity symptoms [64]. 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 hours prior to sample collection, which might have influenced the results [65]. Wang and colleagues (2020) revealed a higher Shannon and Chao index and a reduced Simpson index in ADHD [3]. 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 [3]. The remaining four studies failed to find differences in the abundance of dominant bacterial phyla (see Table 2).
At the genus level, certain significant differences were found. Decreased levels of Faecalibacterium [62, 63], Haemophilus [18], Prevotella and Parabacteroides [64], Lachnoclostridium, Sutterella, Dialister [63] and Veillonella [62] were reported in the ADHD group. On the other hand, elevated amounts of Neisseria [64], Fusobacterium [3], Ruminococcaceae_UCG_004 [18], Enterococcus and Odoribacter [62] were observed. The genus Ruminococcaceae_UCG_004 was associated with inattention scores on the Conners Adult ADHD Rating Scales (CAARS) and Conners Teacher Rating Scale (CTRS) [18].
A lower abundance of Faecalibacterium was negatively associated with the total Conners’ Parent Rating Scale (CPRS) score and the hyperactivity index score [63]. Wan and colleagues (2020) hypothesized that Faecalibacterium dysregulation may cause changes in inflammatory cytokine levels and therefore participate in ADHD pathogenesis [62]. 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 [66, 67]. Therefore, these bacteria may have a potential role in the development of ADHD [62]. 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 [3, 64].
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 [68]. 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 [69]. Moreover, 90% of patients suffer from gastrointestinal and nutritional problems that pose a significant medical burden for their caregivers [70], and in the context of gut microbiota research, dysbiosis may be one of the causes contributing to GI difficulties.
Only one study published to date involved children and adolescents with RTT along with young women [20]. Alpha diversity and beta diversity did not differ significantly between patients and healthy controls. However, the control group had a relatively more heterogeneous community composition. The mean relative abundance of bacterial taxa at the phylum, family and genus levels was not significantly different between RTT and controls, but an increase in Bacteroides, Parabacteroides and Clostridium XIVa and a decrease in Prevotella and Faecalibacterium were observed in patients with RTT [20]. These findings may support the hypothesis of the proinflammatory status of the gut microbiota in Rett syndrome.
Gut bacteria profiles in children and adolescents with anorexia nervosa
Anorexia nervosa (AN) is a severe mental disorder with a high mortality rate and, in many cases, a life-long course. The prevalence of AN in Europe and the USA varies between 0.9% and 4% [71, 72]. AN is characterized by disturbed eating patterns and low body weight. Excessive physical activity, purging, and misuse of various drugs are frequent compensatory mechanisms that lead to subsequent weight loss. Disturbed body image and enormous fear of weight gain complicate the treatment. Many somatic, hormonal, and psychiatric comorbidities worsen its prognosis.
To date, little is known about the relationship between gut dysbiosis and AN. To date, only two studies have investigated the gut microbiota in adolescents with anorexia nervosa. One study described differences in beta diversity but not in alpha diversity of AN patients [73]. At the genus level, an increase in Anaerostipes and a reduction in Romboutsia were observed [73]. In contrast, another study observed significantly lower alpha diversity in patients vs. healthy volunteers and lower levels of the Anaerostipes and Faecalibacterium genera [16].
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 [73]. 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 [73]. In contrast, Kleiman and colleagues (2015) did not prove changes in the alpha diversity of AN patients during inpatient recovery. Lower alpha diversity in AN was associated with depression symptoms and eating disorder psychopathology [16]. However, greater differences in the bacterial composition of samples between AN and HC groups were observed at admission than at discharge from hospital. Marked changes were observed, particularly among genera of the family Ruminococcaceae [16], which are associated with intestinal disorders and inflammation [74, 75].
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 females than in males [76].
Several studies examining the role of intestinal microbiota in adult depression have already been published, but we found only one study evaluating its potential role in adolescent depression. Even if the authors revealed that the diversity of bacteria tends to be lower in patients with MDD, these findings did not reach the level of statistical significance [19]. Likewise, no statistically significant differences were found in the abundance of the main bacterial phyla and genera (see Tab. 3). However, a tendency for a higher relative abundance of the phylum Actinobacteria and increased abundance of the Akkermansia genus in MDD patients were described. In contrast, the abundances of the genera Faecalibacterium and Bacteroides were similar between the two groups. The authors also showed that neither MDD nor SSRI use was associated with differences in gut bacterial composition in older adolescents [19]. 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 [77].
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 [78, 79]. Etiology is not fully known, but both genetic and environmental factors may play a role in pathogenesis [80].
The study of Xi et al. (2021), which is the only study published to date, did not reveal significant differences between alpha or beta diversity among children with TD [81]. Higher abundances of Bacteroides plebeius and Ruminococcus lactaris and lower abundances of Prevotella stercorea and Streptococcus lutetiensis were described in TD patients. 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 results in changes in the gut bacterial community [81].
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 changed gut microbiota in children and adolescents with mental disorders. 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 changes 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 transplantation 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, 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 mental 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.
Acknowledgments
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Funding
This work was supported by grants: Slovak research and development agency - APVV 20-0070 and APVV-20-0114, Scientific grant agency - VEGA 1/0062/21, VEGA 1/0068/21.
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The authors have no competing interests to declare that they are relevant to the content of this article.
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Authors’ Contributions
D.O. contributed to the design of the work, M.S. and A.T. conducted the literature review and wrote the draft of the manuscript. All authors have equally contributed to the critical revision of the manuscript and approval of the final version of the manuscript.
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Tables 1 to 3 are available in the Supplementary Files section.