The last decade has witnessed a growing appreciation of the fundamental role played by an early assembly of a diverse and balanced gut microbiota and its subsequent maintenance for future health of the host. Gut microbiota is currently viewed as a key regulator of a fluent bidirectional dialogue between the gut and the brain (gut-brain axis). A number of preclinical studies have suggested that the microbiota and its genome (microbiome) may play a key role in neurodevelopmental and neurodegenerative disorders. Furthermore, alterations in the gut microbiota composition in humans have also been linked to a variety of neuropsychiatric conditions, including depression, autism and Parkinson’s disease. However, it is not yet clear whether these changes in the microbiome are causally related to such diseases or are secondary effects thereof. In this respect, recent studies in animals have indicated that gut microbiota transplantation can transfer a behavioral phenotype, suggesting that the gut microbiota may be a modifiable factor modulating the development or pathogenesis of neuropsychiatric conditions. Further studies are warranted to establish whether or not the findings of preclinical animal experiments can be generalized to humans. Moreover, although different communication routes between the microbiota and brain have been identified, further studies must elucidate all the underlying mechanisms involved. Such research is expected to contribute to the design of strategies to modulate the gut microbiota and its functions with a view to improving mental health, and thus provide opportunities to improve the management of psychiatric diseases. Here, we review the evidence supporting a role of the gut microbiota in neuropsychiatric disorders and the state of the art regarding the mechanisms underlying its contribution to mental illness and health. We also consider the stages of life where the gut microbiota is more susceptible to the effects of environmental stressors, and the possible microbiota-targeted intervention strategies that could improve health status and prevent psychiatric disorders in the near future.

Research into the influence of human genetics on numerous conditions, including neuropsychiatric disorders, has been underway for many years; however, the etiology of most of these conditions has yet to be unraveled. As in other multifactorial conditions, there is considerable discordance in the development of neuropsychiatric disorders between monozygotic twins, indicating that non-genetic factors are also involved[1,2]. Nowadays we know that both the human genome and the genome of the gut microbiota (microbiome) are essential for maintaining health, since the latter also plays a crucial role in regulating important aspects of host physiology, including brain development and function[3,4]. Indeed, different studies have reported that gut microbiota is able to shape brain physiology and thus behavior through the gut-microbiota-brain axis and have suggested gut microbiota as a key trigger factor in the development of many neuropsychiatric conditions[5]. Most of the neuropsychiatric disorders are considered as multifactorial disorders prompted by certain environmental factors in genetically susceptible individuals. However, there is a need of further work to elucidate the exact complex gene-environment interactions and gut microbiota alterations that precede the onset of the different neuropsychiatric diseases and their manifestations in order to decipher the etiology of the neuropsychiatric disorders.

It is noteworthy that the microbiota is more “medically” accessible and modifiable than the human genome. This fact provides a promising opportunity for preventing or treating neuropsychiatric conditions[6]. In this respect, studies in animal models, where the intestinal microbiota can easily be manipulated, have shed light on how the microbiota may be involved in the development of certain mental diseases. In fact, different communication routes between the microbiota and brain have already been identified[7] although further studies are required to elucidate the underlying mechanisms. Various studies also indicate that the activity of the gut microbiota can modify the host epigenome impacting on gene expression[8]; furthermore, epigenetic mechanisms are involved in neurogenesis, neuronal plasticity, learning and memory, and in disorders such as depression, addiction, schizophrenia and cognitive dysfunction[3]. Consequently, it has been suggested that gut microbiota may be involved in the pathogenesis and risk of developing neuropsychiatric disorders through epigenetic modifications, which are highly dynamic and reversible[3]. Thus, it is tempting to speculate that modulating the microbiota and its metabolic products will enable us to modulate the epigenome and, thereby, prevent or treat mental illness. In this respect, metabolites produced by the microbiota from fiber fermentation are known to inhibit histone deacetylases (HDACs) and reduce inflammation through epigenetic modifications[9].

Currently it is well accepted that our gut microbiota is critical for brain processes such as myelination, neurogenesis and microglial activation and can effectively modulate behavior and influence psychological processes such as mood and cognition[10]. Indeed, very recently gut microbiota have been shown essential for the maintenance of microglia in a healthy functional state[11], which is necessary for the prevention of neurodevelopmental and neurodegenerative disorders[12].

The early assembly of a well-balanced microbiota composition and its subsequent maintenance is considered crucial for human health as perturbations negatively impact health and increase host susceptibility to a wide variety of diseases, including behavioral and neuropsychiatric disorders[3,4]. In this respect, three critical time windows have been proposed including infancy, adolescence and ageing, when the gut microbiota is more vulnerable to external influence[13]. Therefore, strategies aiming to target the gut microbiota might have a greater impact at those stages of life, i.e., newborn, adolescence and elderly populations.

Many factors, including human genetics, influence the gut microbiota composition; therefore the microbiota constitutes a highly dynamic ecosystem, with high inter-individual variability[14,15] and this indeed hampers the understanding of the role of gut microbiota in the etiology and progress of neuropsychiatric diseases.

Nowadays, each adult individual is believed to harbor a unique gut microbiota composition, as personal as a fingerprint, and certain early life events may be important contributors to the individual’s microbiota, including mode of delivery, type of feeding, medication, stress and infections[15]. The critical gut microbiota developmental period occurs in parallel to growth, maturation and sprouting of neurons in the young brain. In fact, childhood and adolescence represent the most dynamic and vulnerable periods for both gut microbiota composition and neuronal development[16]. Furthermore, although the symbiotic link between the host and the microbiota seems to be established early in life, the gut microbiota composition may still experience changes in adulthood despite its greater resilience to the effect of detrimental environmental factors. Likewise, it is also well recognized that ageing is associated with reduced microbial diversity and that healthy ageing correlates with a diverse microbiota[17]. Furthermore, research shows that as we age there is a decline in microbiota complexity parallel to a decrease in neuronal complexity and, altogether, those changes may lead to an increased risk of neurodegenerative disorders[18]. Nowadays, it is well recognized that the onset of most of the neuropsychiatric disease really often is close to a period where the gut microbiota is more unstable and, therefore, at risk of suffering microbiota alterations. Despite these findings, there is currently a need for longitudinal studies in humans to assess the impact of the gut microbiota dynamics on the maintenance or decline of neurocognitive function and to understand to what extent results in animal models can be generalized to humans[19].

In this review, first we summarize the current evidence for a role of the gut microbiota in brain development and function, and also summarize the state of the art on the different mechanisms involved. Thereafter, we provide an update on research into specific neuropsychiatric disorders. We also refer to the different stages of gut microbiota development and maturation, identifying the periods where the gut microbiota is more unstable and, therefore, at greater risk of suffering microbiota alterations due to exposure to stressors. Lastly, we briefly highlight different microbiome intervention strategies that might be implemented to improve the management of psychiatric diseases.

To investigate the role of the gut microbiota in the gut-brain axis, numerous approaches have been taken using animal models, including the study of microbiota deficient animals, known as germ-free (GF) mice, and of animals treated with antibiotics or with specific bacterial species. Such studies have provided new insights into how the microbiota is involved in regulating brain development and function (Table 1)[20,21].

Recently, different studies using GF mice have demonstrated that animals completely lacking microbiota have impaired social behavior, as well as other types of behaviors such as anxiety and stress response[22-24]. Furthermore, it has been observed that certain behaviors induced by the absence of gut microbiota correlate with neurochemical changes in the brain[24]. Said studies have also shown crucial changes in multiple neurotransmitters and their receptors in different brain regions of GF mice. Moreover, the ability to transfer behavioral traits using fecal microbiota transplantation has also been demonstrated, suggesting that some microbiota changes could be rather a cause than a consequence of behavioral alterations[25].

Recent data obtained using GF animals have shown that neurogenesis, a process that plays a critical role in modulating learning and memory, is also regulated by the microbiome[26]. Furthermore, the gut microbiota is reported to modulate structural and functional changes in the amygdala, a critical brain area for social and fear-related behaviors, which are associated with a variety of neuropsychiatric disorders[27].

Another aspect of neurodevelopment shown to be critically regulated by the microbiome is prefrontal cortical myelination[28]. A recent study also showed that depletion of the gut microbiota as of early adolescence in mice alters their behavior and significantly reduces brain-derived neurotrophic factor (BDNF), oxytocin and vasopressin expression in the adult brain[21].

Very recently it has been demonstrated that the maturation and activation of microglia, the macrophages of the brain crucial for maintaining brain tissue homeostasis, are also regulated by the gut microbiota[11]. The same study demonstrated that treatment with microbial-produced short-chain fatty acids (SCFAs) could rescue microglial function impaired in GF animals[11]. In addition, various studies have shown that probiotic administration to healthy rats and mice can alter behavior, achieving a reduction in anxiety-like and depressive-like behaviors and thus highlighting the beneficial effects of probiotics on stress-related behaviors[6]. All these findings indicate that probiotics may have broader therapeutic applications than previously considered, particularly in the area of anxiety and depression[6].

Recent studies have provided insights into the possible pathways and mechanisms that connect the microbiota to the brain. In fact, recent evidence largely suggests that there are several mechanisms by which microbiota may modulate brain development, function and behavior including immune (cytokines), endocrine (cortisol) and neural (vagus and enteric nervous system) pathways (Figure 1). Likewise, different mechanism have been identified by which also brain can influence the gut microbiota composition[7]. Results of animal studies show that stress and emotions cause the brain to influence the microbial composition of the gut through the release of hormones or neurotransmitters, which influence gut physiology and alter the habitat of the microbiota, resulting in preferential growth of certain communities. Indeed, host stress hormones such as noradrenaline might influence bacterial gene expression or signaling between bacteria, and this might change the microbial composition and activity of the microbiota. In addition, the microbiota has a substantial impact on the metabolomics profile of the host. It is important to highlight that a large array of crucial molecules with neuroactive functions is produced by microbes[7]. Nowadays it is clear that certain bacteria are strain-specifically able to produce different essential neurotransmitters and specific neuromodulators. Indeed, several neurotransmitters such as gamma-aminobutyric acid (GABA), serotonin, catecholamines and acetylcholine are produced by bacteria, some of which are inhabitants of the human gut. Indeed, researchers report that Lactobacillus spp. and Bifidobacterium spp. produce GABA[29]; Escherichia spp., Bacillus spp. and Saccharomyces spp. produce noradrenalin; Candida spp., Streptococcus spp., Escherichia spp. and Enterococcus spp. produce serotonin; Bacillus spp. produce dopamine; and Lactobacillus spp. produce acetylcholine[6]. Neurotransmitters secreted from bacteria in the intestinal lumen may induce epithelial cells to release molecules that, in turn, have the ability to modulate neural signaling within the enteric nervous system and subsequently control brain function and behavior. Various bacterial strains have also been shown to mediate behavioral effects via the vagus nerve in some animal studies although vagotomy does not seem to mediate all microbiota-mediated effects on brain function and behavior[30].

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Figure 1 Schematic representation of the mechanisms involved in the relationship between microbiota and brain development and function: Cytokine balance and microglia activation (immune pathway), cortisol (endocrine pathway) and vagus and enteric nervous system (neural pathway). The axis plays an important role in homeostasis and has been linked to several disorders. Altered gut microbiota composition enhances the risk of neurodevelopmental and neurodegenerative disorders possibly from microbiota-derived products such as small chain fatty acids and neurotransmitters. HPA: Hypothalamic-pituitary-adrenal.

Tryptophan is an essential amino acid precursor to many biologically active molecules, including the neurotransmitter serotonin and metabolites of the kynurenine pathway. Only around 5% of systemic tryptophan is metabolized into serotonin and the rest is metabolized along the kynurenine pathway. This depends on the expression of two enzymes, indoleamine 2,3-dioxygenase, which is found in all tissues, and tryptophan 2,3-dioxygenase, which is localized within the liver. The activity of both enzymes is strongly controlled by inflammatory mediators such as cytokines and corticosteroids. The increased activation of these two enzymes could induce serotonin depletion and depressive mood. Furthermore, the downstream metabolites of the kynurenine pathway are neuroactive metabolites, which can also modulate neurotransmission. In addition, the oral ingestion of Bifidobacterium infantis led to increased levels of the serotonin precursor, tryptophan, in the plasma of rats, suggesting that this specific strain may be a potential antidepressant. Other studies have also demonstrated the effect of the gut microbiota on the levels of other metabolites related with tryptophan metabolism[31].

Other important molecules, which are produced in the colon by microbial fermentation of dietary fiber, are SCFAs such as butyrate, acetate and propionate. SCFAs are known to have neuroactive properties; for instance, the administration of a high dose of propionate in rats induced a neuroinflammatory response and behavioral alterations related with neurodevelopmental disorders[32]. Propionate is also a common preservative in food products that has been demonstrated to exacerbate autism spectrum disorder symptomatology. Moreover, butyrate decreases depressive-like behavior with parallel changes in histone deacetylation and BDNF expression. SCFAs also regulate the gut immune system and this may have consequences on the central nervous system. As mentioned above, the maturation and activation of microglia is also regulated by the gut microbiota[11] and oral treatment with microbial produced SCFAs can rescue microglial function impaired in GF animals[11]. However, it is still unclear whether SCFAs produced in the gut can cross the blood-brain barrier.

It is currently well recognized that there are many changes in gene expression not caused by variations in sequence or genotype. Those changes are rather triggered by epigenetic modifications, such as methylation, acetylation or non-coding RNAs (ncRNAs), which modulate chromatin remodeling and the final translation of coding mRNA into proteins. Several types of epigenetic-modifying enzymes together with ncRNAs are involved in epigenetic regulation and have been demonstrated highly sensitive to environmental changes. Therefore, epigenetic modifications associated to many diseases have been recognized as possible pieces missing in the puzzle linking the human genome, environment and phenotype development[33]. Epigenetic mechanisms are currently known to be involved in neurogenesis, neuronal plasticity, learning and memory, and in disorders such as depression, addiction, schizophrenia and cognitive dysfunction[3,34]. Many of the environmental factors apparently playing a crucial role in the etiology of neuropsychiatric disorders might be related with the risk of developing the condition through epigenetic mechanisms.

Changes in histone modifications and DNA methylation have been found at the promoters of genes involved in neuropsychiatric conditions[3]. For instance, chromatin remodeling at the BDNF gene promoter has been associated with neuronal activity and stress and likely affects many more genes involved in brain function and behavior[35]. In fact, there is now a great deal of evidence for the role of epigenetic regulation in shaping brain function and behavior, even though the underlying molecular mechanisms by which epigenetics might be leading to the behavioral and biochemical alterations observed in neuropsychiatric disorders are still not well understood[36].

Gut microbiota has been shown to impact host gene expression by modulating epigenetic processes which are highly dynamic and reversible[33]. Therefore, it is tempting to speculate that modulating the microbiota will enable us to shape our epigenome in the near future. Indeed, the methylation levels of specific genes involved in metabolism and inflammatory responses have been associated with gut microbiota profiles[37]. Furthermore, various studies have described a link between microRNAs, a group of small ncRNAs, and microbiota[38]. Histone deacetylations by HDACs are also critical in epigenomic regulation and are related with condensed chromatin and, consequently, the inhibition of the gene expression. Indeed, SCFAs have the capacity to inhibit HDACs, thus activating the gene expression of previously deacetylated genes[33].

Aging is associated with profound epigenetic changes resulting in alterations in gene expression and also with a wide range of human disorders, including neurodegenerative diseases. Therefore, the reversibility of epigenetic changes that occur as a hallmark of aging offers exciting opportunities to treat age-related diseases[39].

So far many evidences derived from multiple studies performed in both animal models and humans have strongly suggested a link between gut microbiota and development and/or manifestation of different neuropsychiatric conditions (Table 2).

It is becoming evident that brain development and function are dependent on the diversity and structure of the gut microbiota and may, therefore, influence mental health. This hypothesis is based mainly on animal trials and a few observational human studies associating gut microbiota alterations with mental disorders, including depression, autism and PD. This notion has been further supported by recent transplantation experiments where the gut microbiota has been shown to transfer a behavioral phenotype or the disease features to the recipient animal, providing stronger evidence for a causal relationship. However, longitudinal studies in humans are still needed to investigate whether the gut microbiota changes in subjects with different neuropsychiatric disorder can contribute to disease onset and the role of other interacting factors such as the diet. So far various communication routes between the microbiota and brain have been identified, including immune, endocrine and neural pathways. Thus, interventions with pro and pre-biotics in animal models have shown that the microbiota could play a role in mental health by regulating inflammatory and endocrine secretions, synthetizing neuroactive compounds and interacting with the vagal nerve. Greater understanding of the precise underlying mechanisms is required to develop a clear rationale for conducting microbiota-based interventions in humans. In particular, inflammation seems to be a critical pathophysiological feature of mental disorders and, therefore, a potential target for microbiota-based interventions. Nonetheless, further knowledge is needed on how microbiota signals generated in the gut can impact on microglial activation and neuroinflammation.