Microorganisms can be found almost anywhere, including in and on the human body. The collection of microorganisms associated with a certain location is called a microbiota, with its collective genetic material referred to as the microbiome. The largest population of microorganisms on the human body resides in the gastrointestinal tract; thus, it is not surprising that the most investigated human microbiome is the human gut microbiome. On average, the gut hosts microbes from more than 60 genera and contains more cells than the human body. The human gut microbiome has been shown to influence many aspects of host health, including more recently the brain. Several modes of interaction between the gut and the brain have been discovered, including via the synthesis of metabolites and neurotransmitters, activation of the vagus nerve, and activation of the immune system. A growing body of work is implicating the microbiome in a variety of psychological processes and neuropsychiatric disorders. These include mood and anxiety disorders, neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, and even neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Moreover, it is probable that most psychotropic medications have an impact on the microbiome. Here, an overview will be provided for the bidirectional role of the microbiome in brain health, age-associated cognitive decline, and neurological and psychiatric disorders. Furthermore, a primer on the common microbiological and bioinformatics techniques used to interrogate the microbiome will be provided. This review is meant to equip the reader with a primer to this exciting research area that is permeating all areas of biological psychiatry research.

The impact of diet on the microbiota composition and the role of diet in supporting optimal mental health have received much attention in the last decade. However, whether whole dietary approaches can exert psychobiotic effects is largely understudied. Thus, we investigated the influence of a psychobiotic diet (high in prebiotic and fermented foods) on the microbial profile and function as well as on mental health outcomes in a healthy human population. Forty-five adults were randomized into either a psychobiotic (n = 24) or control (n = 21) diet for 4 weeks. Fecal microbiota composition and function was characterized using shotgun sequencing. Stress, overall health and diet were assessed using validated questionnaires. Metabolic profiling of plasma, urine and fecal samples was performed. Intervention with a psychobiotic diet resulted in reductions of perceived stress (32% in diet vs. 17% in control group), but not between groups. Similarly, biological marker of stress were not affected. Additionally, higher adherence to the diet resulted in stronger decreases in perceived stress. While the dietary intervention elicited only subtle changes in microbial composition and function, significant changes in the level of 40 specific fecal lipids and urinary tryptophan metabolites were observed. Lastly, microbial volatility was linked to greater changes in perceived stress scores in those on the psychobiotic diet. These results highlight that dietary approaches can be used to reduce perceived stress in a human cohort. Using microbiota-targeted diets to positively modulate gut-brain communication holds possibilities for the reduction of stress and stress-associated disorders, but additional research is warranted to investigate underlying mechanisms, including the role of the microbiota.

Gut microbiota are suspected to affect brain functions and behavior as well as lowering inflammation status. Therefore, an effect on depression has already been suggested by recent research. The aim of this randomized double-blind controlled trial was to evaluate the effect of probiotic treatment in depressed individuals. Within inpatient care, 82 currently depressed individuals were randomly assigned to either receive a multistrain probiotic plus biotin treatment or biotin plus placebo for 28 days. Clinical symptoms as well as gut microbiome were analyzed at the begin of the study, after one and after four weeks. After 16S rRNA analysis, microbiome samples were bioinformatically explored using QIIME, SPSS, R and Piphillin. Both groups improved significantly regarding psychiatric symptoms. Ruminococcus gauvreauii and Coprococcus 3 were more abundant and β-diversity was higher in the probiotics group after 28 days. KEGG-analysis showed elevated inflammation-regulatory and metabolic pathways in the intervention group. The elevated abundance of potentially beneficial bacteria after probiotic treatment allows speculations on the functionality of probiotic treatment in depressed individuals. Furthermore, the finding of upregulated vitamin B6 and B7 synthesis underlines the connection between the quality of diet, gut microbiota and mental health through the regulation of metabolic functions, anti-inflammatory and anti-apoptotic properties. Concluding, four-week probiotic plus biotin supplementation, in inpatient individuals with a major depressive disorder diagnosis, showed an overall beneficial effect of clinical treatment. However, probiotic intervention compared to placebo only differed in microbial diversity profile, not in clinical outcome measures.

The microbiome-gut-brain axis plays a role in anxiety, the stress response and social development, and is of growing interest in neuropsychiatric conditions. The gut microbiota shows compositional alterations in a variety of psychiatric disorders including depression, generalised anxiety disorder (GAD), autism spectrum disorder (ASD) and schizophrenia but studies investigating the gut microbiome in social anxiety disorder (SAD) are very limited. Using whole-genome shotgun analysis of 49 faecal samples (31 cases and 18 sex- and age-matched controls), we analysed compositional and functional differences in the gut microbiome of patients with SAD in comparison to healthy controls. Overall microbiota composition, as measured by beta-diversity, was found to be different between the SAD and control groups and several taxonomic differences were seen at a genus- and species-level. The relative abundance of the generaAnaeromassillibacillusandGordonibacterwere elevated in SAD, whileParasuterellawas enriched in healthy controls. At a species-level, Anaeromassilibacillus sp An250was found to be more abundant in SAD patients whileParasutterella excrementihominiswas higher in controls. No differences were seen in alpha diversity. In relation to functional differences, the gut metabolic module ‘aspartate degradation I’ was elevated in SAD patients. In conclusion, the gut microbiome of patients with SAD differs in composition and function to that of healthy controls. Larger, longitudinal studies are warranted to validate these preliminary results and explore the clinical implications of these microbiome changes.

The microbiota–gut–brain axis has been shown to play an important role in the stress response, but previous work has focused primarily on the role of the bacteriome. The gut virome constitutes a major portion of the microbiome, with bacteriophages having the potential to remodel bacteriome structure and activity. Here we use a mouse model of chronic social stress, and employ 16S rRNA and whole metagenomic sequencing on faecal pellets to determine how the virome is modulated by and contributes to the effects of stress. We found that chronic stress led to behavioural, immune and bacteriome alterations in mice that were associated with changes in the bacteriophage classCaudoviricetesand unassigned viral taxa. To determine whether these changes were causally related to stress-associated behavioural or physiological outcomes, we conducted a faecal virome transplant from mice before stress and autochthonously transferred it to mice undergoing chronic social stress. The transfer of the faecal virome protected against stress-associated behaviour sequelae and restored stress-induced changes in select circulating immune cell populations, cytokine release, bacteriome alterations and gene expression in the amygdala. These data provide evidence that the virome plays a role in the modulation of the microbiota–gut–brain axis during stress, indicating that these viral populations should be considered when designing future microbiome-directed therapies.