The Microbiome in Child and Adolescent Psychiatry
Abstract
Abstract: Recent research has increasingly emphasized the function of the microbiome in human health. The gut microbiome is essential for digesting food and seems to play a vital role in mental health as well. This review briefly overviews the gut microbiome and its interplay with the central nervous system. We then summarize some of the latest findings on the possible role of the microbiome in psychiatric disorders in children and adolescents. In particular, we focus on autism spectrum disorder, attention-deficit/hyperactivity disorder, anorexia nervosa, bipolar disorder, and major depressive disorder. Although the role of microbiota in mental development and health still needs to be researched intensively, it has become increasingly apparent that the impact of microbiota must be considered to better understand psychiatric disorders.
Zusammenfassung: Die Forschung der letzten Jahrzehnte machte die Funktion des Mikrobioms für die menschliche Gesundheit immer deutlicher. Das Darmmikrobiom ist dabei nicht nur wichtig für die Verarbeitung von Lebensmitteln, sondern scheint auch eine entscheidende Rolle für die psychische Gesundheit zu spielen. In diesem Review geben wir einen kurzen Überblick über das Darmmikrobiom und sein Zusammenspiel mit dem zentralen Nervensystem. Anschließend fassen wir einige der neuesten Befunde zur möglichen Rolle des Mikrobioms bei psychiatrischen Erkrankungen bei Kindern und Jugendlichen zusammen. Hier konzentrieren wir uns auf Autismus-Spektrum-Störungen, Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen, Anorexia nervosa, bipolare Störungen und depressive Störungen. Obwovhl die Rolle des Mikrobioms für die mentale Entwicklung und Gesundheit noch intensiv erforscht werden muss, wird deutlich, dass beim Verständnis psychiatrischer Erkrankungen der Einfluss des Mikrobioms berücksichtigt werden sollte.
Introduction
Our understanding of microorganisms has evolved considerably since their discovery in the 17th century. Initially, and only after having been recognized as ubiquitous “little animals” by Antonie van Leeuwenhoek (Smit & Heniger, 1975), did Koch postulate in 1890 that certain bacteria may cause certain diseases (Koch, 1877). During the 100 years that followed, bacteria and other microorganisms were considered pathogens in the context of human health. This is not surprising because only a few bacteria and other microorganisms are culturable under laboratory conditions. Only recently have advancements in sequencing technology, methods, and analysis made it possible to detect microorganisms independently of their culturability. Over the past decades, large-scale research projects, like the human microbiome project (Turnbaugh et al., 2007) and other studies (Sender et al., 2016), have yielded new insights into the variety of the human microbiome and its complex interplay with the human body. Today, we know that the various interactions between microbes and their hosts can be commensalistic, mutualistic, or pathogenic, and that nearly every part of the human body has its own specific microbial flora contributing to human health. Furthermore, microbiota plays an important role during all stages of human development, from newborn to old age (Wilmanski et al., 2021). Examples of body parts colonized by bacteria are the lungs, skin, vagina, eyes, placenta, ears, mouth, and nasal cavities (Integrative HMP (iHMP) Research Network Consortium, 2012, 2019), while the gut is the most populated (Qin et al., 2010). It is beyond the scope of this review to cover all publications or factors that may have influenced the summarized results. In this review, we therefore focus on a few selected publications.
The Gut Microbiome
The gut is not only important for digesting and processing food, with 100 trillion microorganisms it also harbors most of the human microbiota (Thursby & Juge, 2017). The gastrointestinal microbiota is a diverse mix of viruses, bacteria, archaea, and fungi (Lindon et al., 2018). The number and diversity of microorganisms increase continuously from the stomach to the colon (Tojo et al., 2014). The formation of the gut microbiota begins early in life and is influenced by many factors like mode of delivery, type of feeding (breast milk or formula), and the weaning period (Ottman et al., 2012). Since early childhood, each individual carries a unique gut microbial community that is involved in digestion, nutrient uptake, mucosal stability, immunomodulation, and pathogen defense (Hardy et al., 2013; Zheng, D. et al., 2020). More specifically, the gut commensals are involved in the synthesis of vitamins (e.g., B and K), fermentation of indigestible carbohydrates and fibers, thus providing the host with short-chain fatty acids (e.g., butyrate) as well as in the metabolism of bile acids and sterols (Cummings & Macfarlane, 1997; O’Hara & Shanahan, 2006). Once established, the individual microbial profile remains relatively stable over time but can be temporarily disturbed by living habits, diets, and antibiotic/drug intake (Patangia et al., 2022; Rinninella et al., 2019a). While one individual’s microbiota remains comparatively consistent over time, microbial profiles differ between individuals because of variations in body mass index, lifestyle, cultural nutrition, exercise, etc. Recent research on this topic indicates that there is no single optimal gut microbiota but rather an individual healthy microbiota, which is important to preserve. The six main phyla of bacteria in the mammalian gut, including Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Fusobacteria collectively constitute approximately 90% of the total microbial population (Eckburg et al., 2005). Besides acute infections, which rapidly alter the host’s constitution and microbiome, dysbiosis has been linked not only with intestinal disorders (inflammatory bowel diseases [IBD], ulcerative colitis [CU]) but also various extraintestinal diseases (e.g., asthma, allergies) as well as metabolic (diabetes) and neurological disorders (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder).
The Gut-Brain Axis
First hints of an interaction of the gut with the brain were discovered in the early 20th century. A report from 1910 in the British Journal of Psychiatry stated the successful treatment of melancholia with lactic acid bacillus (Phillips, 1910). And the 1908 Nobel Prize winner, Metchnikoff, was convinced that fermented milk has beneficial effects for autointoxication, which, aside from other symptoms, included fatigue and melancholia (Bested et al., 2013). Around the same time, Pavlov conducted his work in classical conditioning, clearly demonstrating a gut-brain interaction of dogs in response to sensory signals (The Nobel Prize in Physiology or Medicine 1904). The gut-brain interaction aroused new interest in 2004 when experiments with germ-free mice showed abnormal behavior (Sudo et al., 2004).
Today, the gut-brain axis is considered the bidirectional signaling between the gastrointestinal tract (GI) and the central nervous system (CNS). Specifically, the gut-brain axis includes the central nervous system, neuroendocrine system, neuroimmune systems, the hypothalamic-pituitary-adrenal axis (HPA axis), the sympathetic and parasympathetic arms of the autonomic nervous system, the enteric nervous system, and the vagus nerve. Current research suggests that the inhabitants of the gut – the gastrointestinal microbiota – are of special importance, too, since the microbiota contributes to the signaling by providing biologically active microbial molecules and metabolites. Members of the gut bacterial community are capable of producing neurotransmitters like dopamine, norepinephrine, serotonin, GABA as well as their precursors, tyrosine, tryptophan, and phenylalanine (Lyte, 2016; Strandwitz, 2018).
Not only are these neurotransmitters produced by bacteria, they also influence the composition of the gut microbial community by acting as growth factors. For example, the presence of norepinephrine increases the growth of Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Shigella sonnei, and Staphylococcus aureus (O’Donnell et al., 2006). Furthermore, pathogenic E. coli O157:H7 (EHEC) not only exhibits an increased growth rate in the presence of norepinephrine but also increased motility, biofilm formation, and virulence (Bansal et al., 2007). The interplay between bacterial species is well balanced in a healthy microbial community. Changes in the community composition have a huge impact on available metabolites and therefore on the interaction with the host metabolism and CNS. Some metabolites might affect the host directly, like bacterially derived choline, which can cross the blood-brain barrier via a choline transporter (Allen & Lockman, 2003). Other neurotransmitters might work indirectly via the vagus nerve. A study demonstrated that the injection of Lactobacillus rhamnosus into mice resulted in a reduction in depressive and anxiety-like behavior as well as alterations in the vagus nerve and cerebral GABA-ergic activity. Those effects were not seen in vagotomized mice (Bravo et al., 2011). This interaction of the gut microbiota and its metabolites with the CNS is called the microbiota-gut-brain axis (MGB) (Martin et al., 2018). Studies with animal models have indicated the role of the microbiota in neurogenesis, myelination, and microglia activation (Liu et al., 2016). As in dysbiosis, disturbances in the microbiota lead to changes in the bidirectional relationship between microbiota and the nervous system and are associated with several psychiatric and neurological disorders. Of particular importance might be neurodevelopmental windows and early-life disturbances, which may result in psychiatric disorders later on (Borre et al., 2014).
Microbiome and Mental Health in Children and Adolescents
Because of the vast increase in our knowledge in recent years, we have a clearer view of the bidirectional interactions between the gut microbiome and mental health. Furthermore, several studies showed that the microbiome composition differs between individuals with mental health conditions and healthy individuals. In this unsystematic review, we summarize some of the latest findings in selected disorders in child and adolescent psychiatry, with a focus on autism spectrum disorder, attention-deficit/hyperactivity disorder, bipolar disorders, depression, and eating disorders.
Autism Spectrum Disorder
According to ICD-11, autism spectrum disorder (ASD) is defined as a fundamental impairment of social interaction and communication as well as the presence of restricted or repetitive behaviors (World Health Organization, 2018). ASD results from early, altered brain development and neural reorganization (Choi & An, 2021; Courchesne et al., 2019). Ten years ago, global prevalence rates for ASD were estimated to be below 1% (Elsabbagh et al., 2012); however, probably because of public health efforts and improvements in the health system, ASD has become more recognized, and prevalence rates have increased worldwide to 2.8%, with varying prevalence among different regions (Chiarotti & Venerosi, 2020; Graf et al., 2017)). Many studies have proposed a possible link between ASD and multiple environmental as well as genetic risk factors. Still, the specific pathogenesis is yet unknown (Hu et al., 2020). While ASD itself is assumed to be a chronic condition, psychotherapeutic and community-care interventions can improve psychosocial functioning (AWMF, 2021).
Beyond this, an increasing number of studies link ASD symptom severity to nutrition or digestive functioning (Andreo-Martínez et al., 2022; Song et al., 2022). It is known, for example, that many patients with ASD also suffer from GI problems (Kedem et al., 2020)(Kedem et al., 2020). GI problems, on the other hand, are often associated with an alteration in the gut microbiome (Nouvenne et al., 2018). Postnatal risk factors like nonbreastfeeding, antibiotic intake, and newborn diet are associated with ASD. Those factors likewise have an impact on the gut microbiota. Regarding factors that influence the microbiome, ASD is associated with a less-diverse diet as well as reduced microbial alpha diversity and loose stool consistency (Yap et al., 2021). In the past few years, many studies have dealt with a possible correlation between gut microbiota and symptoms of ASD. Although the results are ambiguous and did not provide evidence of causality, they do emphasize a potential association. While several studies have shown no difference in alpha diversity between ASD and healthy controls (Pulikkan et al., 2018; Son et al., 2015; Zhang et al., 2018), others have shown an increase (Cao et al., 2021; De Angelis et al., 2013) or a decrease in alpha diversity measures (Kang et al., 2013; Yap et al., 2021). Regarding the differences on the taxonomic level concerning bacteria mentioned in more than one study, different studies have found a significant decrease in Bifidobacterium spp. (Coretti et al., 2018; De Angelis et al., 2013; Finegold et al., 2010; Grimaldi et al., 2018). Among those studies, Coretti et al. examined very young children (2-4 years) with ASD and found a highly reduced presence of Bifidobacterium, indicating a very early shift in colonization by beneficial gut species. Likewise, some studies reported an increase in adverse bacterial strains like Faecalibacterium (Coretti et al., 2018; De Angelis et al., 2013; Inoue et al., 2016) (Coretti et al., 2018; De Angelis et al., 2013; Inoue et al., 2016), Clostridium (Cao et al., 2021; De Angelis et al., 2013; Finegold et al., 2010; Strati et al., 2017), and an increase in the Bacteroidetes/Firmicutes ratio (Strati et al., 2017; Tomova et al., 2015; Williams et al., 2011).
Some interventions in the gut microbiota produced promising results regarding the development and symptoms of ASD. For example, perinatal probiotic treatment reduced the risk of getting ASD (Pärtty et al., 2015). Even more intriguing were fecal transplantation experiments with mice. Gut microbiota from typically developing (TD) as well as ASD individuals were transferred to germ-free mice. Those mice enterically inoculated with the microbiota from ASD individuals developed hallmark autistic behavior (Sharon et al., 2019). On the other hand, other studies showed that individuals with ASD benefit from a fecal transplantation from a healthy donor. The study subjects showed significant improvements in GI symptoms, autism-related symptoms, and gut microbiota composition (Kang et al., 2019).
Attention-Deficit/Hyperactivity Disorder
Another neurodevelopmental disorder, attention-deficit/hyperactivity disorder (ADHD), is characterized by the core symptoms of inattention, hyperactivity, and/or impulsiveness (World Health Organization, 2018). About 3–5% of youths worldwide meet the diagnostic criteria of ADHD (Polanczyk et al., 2007; Polanczyk et al., 2015); it is more common in males than in females (Willcutt, 2012). ADHD is caused by genetically based alterations in the structure and function of fronto-striatal brain regions. With high effect sizes, stimulants such as methylphenidate or amphetamine can reduce symptom severity by increasing the availability of dopamine or noradrenaline in fronto-striatal brain circuits (Arnsten, 2006; Posner et al., 2020; Rubia et al., 2014). While a balanced combination of stimulants and behavioral therapy is considered to be the first-line treatment (AWMF, 2017), studies have also revealed that healthy dietary patterns (vegetables, fruits, legumes, and fish) can significantly decrease symptom severity (Shareghfarid et al., 2020; Sonuga-Barke et al., 2013) (Shareghfarid et al., 2020; Sonuga-Barke et al., 2013).
Host microbiome interactions have been shown to influence hormones and neurotransmitter levels relevant in ADHD pathogenesis (Bull-Larsen & Mohajeri, 2019; Wan et al., 2020). The dopaminergic system plays an important role in the context of ADHD, including cognitive, emotional, and behavioral aspects (Cortese, 2012; Posner et al., 2020). Therefore, theories about the neurobiology of ADHD mainly focus on the dysfunction of noradrenergic and dopaminergic pathways; the serotonergic and cholinergic pathways are also of interest (Tripp & Wickens, 2009). Aarts et al. (2017) found that microbiota differing between patients with ADHD and controls (i.e., increase in Bifidobacterium) may be involved in altered reward anticipation responses; they found no differences in alpha and beta diversity. Those researchers were the first to show that the gut microbiome has the genetic capability to influence the dopaminergic metabolic pathway in patients with ADHD. A recent study complements their finding by showing that the gut microbiota contributes to dopamine bioavailability through key bacterial players like Prevotella, Bacteroides, Lactobacillus, Bifidobacterium, Clostridium, Enterococcus, and Ruminococcus (Hamamah et al., 2022).
Jiang et al. (2018) also found differences in microbial compositions upon comparing treatment-naive ADHD children with healthy controls. While they found no differences in alpha and beta diversity between the two groups, one species (Faecalibacterium [Ruminococcaceae family]) was significantly decreased in the ADHD samples. Levels of Faecalibacterium were furthermore negatively associated with parental reports of ADHD symptoms. Low levels of Faecalibacterium have also been associated with atopic diseases like asthma, eczema, and allergic rhinitis (Penders et al., 2007). Atopic diseases, on the other hand, are associated with ADHD (Schans et al., 2017; Tsai et al., 2013). In a small study, Prehn-Kristensen et al. (2018) found a decreased alpha diversity in patients with ADHD and Neisseria as a potentially associated bacterium, whereby levels of hyperactivity significantly correlated with a change in alpha diversity. In another small study in children with ADHD, the supplementation of micronutrient resulted in a decrease in the abundance of species from the genus Bifidobacterium (Stevens et al., 2019). Interestingly, a recent meta-analysis by Wang et al. (2020) found increased alpha diversity and significantly increased Sutterella stercoricanis in the ADHD group. In all these studies, regional habits such as diet must be considered. Howard et al. (2011) showed that the Western diet is associated with a prevalence of ADHD. As diet is known to also have an impact on the microbiome, other studies investigated the potential role of the interplay between diet and the gut microbial community in ADHD-related behavior (Szopinska-Tokov et al., 2020; Wang et al., 2020).
Constant dysbiosis driven by immune dysfunction and pathogen exposure may contribute to hyperactivity in ADHD patients (Ming et al., 2018). There have been attempts to regulate the gut microbiota with probiotic treatment. In a small, longitudinally randomized control study with perinatal probiotic intervention, Pärtty et al. (2015) showed that children treated with probiotics were less likely to be diagnosed with ADHD. In line with this is also the study from Kumperscak et al. (2020), which showed that children and adolescents with ADHD treated with Lactobacillus rhamnosus GG reported better health-related quality of life. But psychometric tests conducted by parents and teachers – and differences in the levels of inflammatory cytokines – have shown ambiguous results. Nevertheless, interventions to improve the gut microbiota in patients with ADHD may be promising and useful.
Bipolar Disorder
Bipolar and related disorders (BD) are episodic mood disorders defined by the occurrence of manic or hypomanic episodes/symptoms that typically alternate with depressive episodes/symptoms (World Health Organization, 2018). Compared to adults (3.1%), the prevalence rates of bipolar spectrum disorder are lower (1.8%) in the pediatric population (Cichoń et al., 2020; McIntyre et al., 2020; Teh et al., 2020). Ultrarapid and ultracycling mood changes are more common in children than adolescents and adults, making it more challenging to identify BD correctly in children (Post & Grunze, 2021). Based on a high genetic vulnerability (heritability of 70-90%), exposure to stress leads to recurring affective episodes (McIntyre et al., 2020). The recommended treatment of BD in children and adolescents involves psychosocial interventions in combination with psychopharmacotherapy (AWMF, 2020). Interestingly, dietary approaches can have a positive impact on BD symptomatology. Gabriel et al. (2022) found this in a systematic review of 33 observational trials (15 on fatty acids, 9 on micronutrients, 5 on specific foods, 4 on macro- and micronutrients).
Studies have demonstrated that individuals with BD show chronic inflammation, as shown by disturbances in plasma cytokines, soluble cytokine receptors, chemokines, acute phase reactants, and T-cell activation (Jones et al., 2021). Inflammation may further be the cause or consequence of changes in the gut microbial community. Alterations in the gut microbiota occurred among patients who suffer from episodes of mania as well as depression. Levels of the bacteria Escherichia coli and Bifidum adolescentis were higher in patients with manic episodes, while patients with depressive symptoms showed elevated levels of Stercoris (Huang et al., 2019). A study including unaffected first-degree relatives revealed that Flavonifractor occurred significantly more often in patients with BD than in their unaffected relatives or the other healthy controls; this may also be associated with smoking habits and female gender (Coello et al., 2019). Evans et al. (2017) reported a possible link between the gut microbiota and BD symptoms. Comparing the gut microbiota of BD-affected individuals with healthy controls, these researchers found decreased levels of Faecalibacterium in the BD group, while the abundance was also negatively correlated with self-reported symptoms of depression severity. These findings were consistent with the study by Painold et al. (2019), who found Ruminococcaceae and Faecalibacterium to be less abundant in BD. Furthermore, Painold and colleagues identified bacterial strains associated with inflammatory status, serum lipids, tryptophan, depressive symptoms, oxidative stress, anthropometrics, and metabolic syndrome. Interestingly, they also found a negative correlation between microbial alpha-diversity and illness duration. A more diverse microbiota is usually correlated with gut and overall health and well-being (Rinninella et al., 2019b). Since the overall importance of a healthy gut microbiome is undeniable, approaches to modifying the gut microbiota in individuals with BD are understandable. A pilot study investigating the effect of a 3-month probiotic supplementation on euthymic BD-affected individuals showed significant improvement in performance regarding attention and psychomotor processing speed but also improved executive function (Reininghaus et al., 2020). Especially regarding manic episodes, Dickerson et al. (2018) showed that the number of rehospitalizations decreased significantly after probiotic treatment with Lactobacillus rhamnosus strain GG. The preventive effect increased in individuals with elevated levels of systemic inflammation at baseline. As a side note, Bharwani et al. (2021) tested whether or not treatment with infliximab affects the microbiota of BD patients but found no impacts at any level.
Major Depressive Disorder
With a prevalence rate of 2.6%, major depressive disorder (MDD) is a common mental health condition in children and adolescents (Polanczyk et al., 2015). Throughout maturation, the prevalence rises to reach adult levels by the midteens (Hankin et al., 2015), which is largely accounted for by an increase in prevalence for girls (Salk et al., 2017). However, MDD symptoms display age-dependent patterns (varying from irritation or aggressive behavior in younger to classically depressed mood in older children). As a result, MDD is often overlooked in childhood (Lagges & Dunn, 2003). The etiology is multifactorial, since several biological, psychological, and environmental risks have been proven to cause or at least increase MDD symptoms (Selph & McDonagh, 2019). Psychotherapy is recommended as the first-line treatment in children and adolescents; antidepressants may be administered concomitantly if indicated (AWMF, 2013). Besides these well-established treatment approaches, further studies suggest that diet could play an important role in the treatment and prevention of childhood depression (Khalid et al., 2016).
An increasing number of studies investigating the pathophysiology of depression direct their attention to the gut microbiome. These studies have successfully demonstrated a significant correlation between gut microbiota and mental well-being (Limbana et al., 2020). Subsequently, dysbiosis may affect mental health and lead to depressive symptoms. Studies focusing on the compositional differences between depressed and healthy individuals highlighted differences in the intestinal flora in patients with depression compared to healthy controls (Barandouzi et al., 2020; Jiang, H. et al., 2015). Regarding diversity and richness, the results are ambiguous, however. Three studies revealed contradicting results regarding the alpha diversity as measured by the Shannon index. While one study observed higher alpha diversity (Jiang, H. et al., 2015), another reported lower alpha diversity (Liu et al., 2016), and the third indicated no significant difference (Kelly et al., 2016). Studies with other alpha diversity estimators are also inconsistent (Chen et al., 2018; Kelly et al., 2016; Zheng, P. et al., 2016). Regarding beta diversity, however, Kelly et al. (2016) and Zheng et al. (2016) reported significant differences between patients with depression and healthy controls.
Anorexia Nervosa
As the most severe eating disorder, anorexia nervosa (AN) is characterized by significantly low body weight for the individual’s height, age, and developmental stage not resulting from another health condition or the unavailability of food (World Health Organization, 2018). With a peak onset in adolescence, up to 4% of females and up to 0.3% of males suffer from anorexia nervosa (Neale & Hudson, 2020; van Eeden et al., 2021). While genetic factors influence risk, psychosocial and interpersonal factors can trigger onset, and changes in neural networks can sustain the illness (Zipfel et al., 2015). Treatment approaches involve psychotherapy and nutrition management, while psychopharmacological treatment is meaningful only under certain conditions (AWMF, 2018) . Since nutrition is the central element of AN, its impact on digestion is obvious.
AN has a strong impact on the physical constitution of an affected person. It is easy to imagine that habits such as prolonged caloric restriction can affect the microbiota of the digestive tract. However, the results from studies comparing stool samples of patients with AN to those of healthy, normal-weight participants reported so far are heterogeneous. Several studies found a reduction in alpha diversity (Hanachi et al., 2019; Kleiman et al., 2015; Mörkl et al., 2019; Mörkl et al., 2017). Kleiman and colleagues (2015) investigated changes in stool microbiota during renourishment and found that patients with AN had lower alpha diversity than healthy controls at the time of admission and discharge as well as between the different timepoints within the AN group. Mörkl et al. (2017; 2019) and Hanachi et al. (2019) found a decrease in alpha diversity for AN compared to normal-weight persons. The study by Hanachi et al. (2019) also revealed that the severity of functional intestinal disorders (FIDs) strongly correlated with several specific genera (Peptostreptococcaceae family, Dialister, Robinsoniella, and Enterococcus). Likewise, other studies have also shown strong associations between bacterial genera and anorexic status. One study found Methanobrevibacter smithii at much higher levels in anorexic patients than in unaffected controls (Armougom et al., 2009)). This finding was confirmed by three other studies (Borgo et al., 2017; Mack et al., 2016; Million et al., 2013). Million et al. showed that M. smithii and B. animalis were negatively correlated with BMI, while Lactobacillus reuteri positively correlated with BMI (Million et al., 2013). On the other hand, Mack et al. (2016) found M. smithii in only 20% of the participants. However, when M. smithii was detected, the abundances were higher in AN before weight gain than in normal-weight participants. The same authors also found differences in the gut microbial composition between restrictive AN and binge-purging AN. In line with previous findings, Borgo et al. (2017) also found a significant increase in M. smithii and Enterobacteriaceae in AN compared to healthy controls. The authors simultaneously found a decrease in the genera Roseburia, Ruminococcus, and Clostridium. Furthermore, they found alterations in the short-chain fatty acids butyrate and propionate. Butyrate concentrations were inversely correlated with anxiety levels, whereas propionate directly correlated with the relative abundance of Roseburia inulinivorans and insulin levels (Borgo et al., 2017). Prochazkova et al. (2021) also investigated Intestinal microbiota and metabolites. They compared the composition and diversity between patients with AN (before and after renourishment) and healthy controls. The overrepresented OTUs they found in AN belonged to Alistipes, Clostridiales, Christensenellaceae, and Ruminococcaceae; OTUs belonging to Faecalibacterium, Agathobacter, Bacteroides, Blautia, and Lachnospira were underrepresented. Regarding the metabolites, patients had decreased levels of serotonin, GABA, dopamine, butyrate, and acetate, though the association with the microbiome remains unclear. This is also one of the rare studies that examined the mycobiome, even though the authors did not find any significant differences between AN and healthy controls and no correlations between fungal composition and the bacteria (Prochazkova et al., 2021). In a small pilot study concerning the metabolites, Speranza et al. (2018) also found significantly reduced butyrate and propionate fecal concentrations in restrictive patients with AN compared to controls, which aligns with the previously mentioned studies. Monteleone et al. (2021) further investigated the microbiome and metabolites differentiating restrictive and binge-purging AN. The authors identified several fecal metabolites differentiating between restrictive patients with AN, binge-purging patients with AN, and healthy controls. Both patient groups showed decreased alpha diversity compared to healthy controls. Comparison of the two patient groups with each other revealed that the relative abundances of Bifidobacterium, Bifidobacteriaceae, Bifidobacteriales, and Eubacteriacae significantly increased, while Odoribacter, Haemophilus, Pasteurellaceae, and Pasteurellales significantly decreased in patients with binge-purging AN. They also found that relationships of selected fecal metabolites with microbial families were more similar between AN and restrictive AN than with binge-purging AN. Another pilot study with adolescents showed that alpha diversity increases after short-term weight recovery with remaining differences in beta diversity. Reduced levels of Romboutsia and OTUs classified as Enterobacteriaceae at admission and discharge and increased levels of taxa belonging to Lachnospiraceae at discharge differed most between AN and healthy controls. The authors proposed that the taxa belonging to Lachnospiraceae could be predictors of clinical outcome, since they helped predict shorter inpatient treatment duration (Schulz et al., 2021). In recent years, the field of probiotic treatment has emerged in psychiatry, leading to numerous new studies, including one investigating the effects of probiotics in adolescents with AN (Gröbner et al., 2022).
Psychobiotics
Psychobiotics are specific probiotics, prebiotics, or symbiotics that impact the gut’s microbial composition to improve mental health (Dinan et al., 2013; Sarkar et al., 2016). The idea of probiotics is to improve the microbial community by adding certain bacterial strains. Because microbial communities consist of a fine-tuned network of beneficial and mutual effects between the bacterial strains, the positive effects result not from the strain itself but from its beneficial effects on the microbial ecosystem (Duran-Pinedo & Frias-Lopez, 2015). Prebiotics, in contrast, are nutrients thought to promote the growth of beneficial microbes, and symbiotics consist of a blend of both pro- and prebiotics. Even though psychobiotics represent an interesting approach, the evidence is still weak because of limited or poorly conducted studies (Kadosh et al., 2021).
Conclusion
As a key player in maintaining human development and health, the microbiota’s impact on the human brain should not be underestimated. In light of the many shifts in bacterial composition in the context of psychiatric disorders, the involvement of the microbiota is most likely. However, exactly how microbes contribute to disease outcomes should be the subject of further research. Further research should also consider that many psychiatric disorders have their onset in childhood or adolescence. Disturbances in early life microbiota development might play a role as much as acute dysbiosis. Also, the microbiota contributes to host homeostasis by providing several metabolites, including known neurotransmitters. Altering the levels of those neurotransmitters might directly influence host responses and contribute to gut-brain interactions. Furthermore, the microbiota plays an important role in digestive processes. Alterations in microbial composition may lead to alterations in nutrition uptake, which could secondarily influence the host physiology and mental status.
Although there is convincing evidence that the microbiota and psychiatric disorders are interrelated, age or habits, such as diet, smoking, drug intake, or sleep behavior (Redondo-Useros et al., 2020), may impact the gut bacteria’s composition. Similarly, concurrent medical conditions such as psychiatric comorbidities, somatic illness, or Medications need to be taken into account (Requena & Velasco, 2021). Therefore, one should always view study results in the context of the quality of the control for such influences. Nevertheless, this emerging area in treating psychiatric disorders with encouraging initial outcomes involves administering a combination of prebiotics and probiotics to the host to enhance the positive impacts on the gut microbiome and, consequently, the gut-brain axis. In-depth research in this field has the potential to improve clinical treatments, which could be particularly significant for exploring novel approaches in patients who may be resistant to conventional therapies. In summary, the microbiota should be regarded as a vital component of human well-being, particularly its role in mental health.
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