The realization of the importance of the gut microbiota in health and disease has been one of the most exciting areas in biomedical research over the past 5 years. We are teeming with microrganisms in and on our body, having >150 times more microbial genes (the microbiome) than mammalian genes. Studies are revealing how variations in the composition of the gut microbiota influence all aspects of physiology, including brain function and even behavior. In terms of neuroscience and psychiatric disease the field is still very much in its infancy, but evidence is accumulating that it has a key role. Factors that shape the bacterial landscape include being born by Caesarian delivery, not being breastfed, environment, gestational age, host genetics, exposure to infections (both maternal and infant), and antibiotic usage. Moreover, stress, especially that in early life and prenatally, can have marked effects on microbiota composition (Borre et al, 2014).

A variety of strategies have been used to investigate the role of this so-called microbiota–gut–brain axis in health and disease. Germ-free mice (mice that never have been exposed to any bacteria) have been used to show that microbiota is crucial for hypothalamic–pituitary–adrenal axis function. Moreover, these mice have widespread neurodevelopmental changes in the brain, including alterations in monoaminergic neurotransmission and behavioral changes in anxiety (Foster and McVey Neufeld, 2013). More recently, we have shown that these mice also exhibit autism-like traits, such as deficits in sociability, social cognition, and increased repetitive behaviors (Desbonnet et al, 2014). Interestingly, as in autism and other neurodevelopmental disorders, these effects are much more pronounced in males than females. Moreover, studies in germ-free mice can be expanded to enable research on the ‘humanization’ of the gut microbiota, that is, transplanting faecal microbiota from specific human conditions or from animal models. Indeed, it has been shown that behavioral traits can be transplanted between strains of mice (Collins et al, 2013).

Administration of various potential probiotic strains in rodents or humans has also been shown to have beneficial effects in rodents. Major strain and species differences occur in terms of their ‘psychobiotic’ effects. Studies have shown that some Bifidobacteria and Lactobacilli species as well as Bacteroides fragilis can have positive effects on anxiety, depression, cognition, and autism-related behaviors (Hsiao et al, 2013). Prebiotics, nondigestible food ingredients that promotes the growth of beneficial gut microorganisms, are also being shown to affect brain BDNF levels. Human studies of prebiotics and probiotics have lagged behind to date, although there is interesting neuroimaging studies emerging clearly showing that such bacterial-based dietary interventions can affect brain function.

Finally, perturbation of the microbiota by administration of antimicrobial drugs can allow for a temporally controlled and more clinically relevant tool to assess the role of the gut microbiota on behavior. Antibiotics in adulthood and early-life can reverse both antipsychotic-induced obesity (Davey et al, 2013) and increase visceral pain (O'Mahony et al, 2014) responses, respectively. Further studies focused on the mechanisms on how these gut microbiota signal to the brain are now warranted. To date, it is clear that the vagus nerve, immune signaling, and the production of bioactive metabolites are strongly implicated in communication across the microbiota–gut–brain axis (Figure 1).

Figure 1
figure 1

Key pathways involved in microbiota–gut–brain signaling. There are many potential direct and indirect pathways exist through which the gut microbiota can modulate the gut–brain axis. They include endocrine (cortisol), immune (cytokines), and neural (vagus and enteric nervous system) pathways. The gut microbiota and probiotic agents can alter the levels of circulating cytokines, and this can have a marked effect on brain function. Both the vagus nerve and modulation of systemic tryptophan levels are strongly implicated in relaying the influence of the gut microbiota to the brain. In addition, short-chain fatty acids (SCFAs) are neuroactive bacterial metabolites of dietary fibers that can also modulate brain and behavior. Harnessing such pathways may provide a novel approach to treat various brain disorders.

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FUNDING AND DISCLOSURE

The authors are funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan in the form of a centre grant (Alimentary Pharmabiotic Centre Grant Number SFI/12/RC/2273); by the Health Research Board of Ireland (Grant Numbers HRA_POR/2011/23 and HRA_POR/2012/32) and received funding from the European Community's Seventh Framework Programme Grant MyNewGut under Grant Agreement No. FP7/2007–2013. The Centre has conducted studies in collaboration with several companies including GSK, Pfizer, Alimentary Health, Cremo, Suntory Wellness, Danone-Nutricia, Wyeth, and Mead Johnson. The authors thank Dr Roman Stilling for assistance with graphics.