Gutbrain axis: how the microbiome infl uences anxiety and depression Jane A. Foster and Karen-Anne McVey Neufeld Department of Psychiatry and Behavioural Neurosciences, McMaster University, at St. Josephs Healthcare, 50 Charlton Ave. E, T3308, Hamilton, ON, L8N 4A6, Canada Within the fi rst few days of life, humans are colonized by commensal intestinal microbiota. Here, we review re- cent fi ndings showing that microbiota are important in normal healthy brain function. We also discuss the rela- tion between stress and microbiota, and how alterations in microbiota infl uence stress-related behaviors. New studies show that bacteria, including commensal, probi- otic, and pathogenic bacteria, in the gastrointestinal (GI) tract can activate neural pathways and central nervous system (CNS) signaling systems. Ongoing and future animal and clinical studies aimed at understanding the microbiotagutbrain axis may provide novel approaches for prevention and treatment of mental ill- ness, including anxiety and depression. Introduction The human intestine harbors nearly 100 trillion bacteria that are essential for health 1. These organisms make critical contributions to metabolism by helping to break down complex polysaccharides that are ingested as part of the diet and they are critical to the normal development of the immune system. Recent studies reveal the impor- tance of gut microbiota to the function of the CNS 26. Bidirectional communication between the brain and the gut has long been recognized. Established pathways of communication include the autonomic nervous system (ANS), the enteric nervous system (ENS), the neuroen- docrine system, and the immune system. Recently, there has been a rethinking of how the CNS and periphery communicate, largely due to a growing body of experi- mental data from animal studies focused on the micro- biome (see Glossary). Neuroscientists are now taking notice of these novel reports that highlight the bottom- up infl uence of microbes themselves, with several stud- ies showing that commensal bacteria are important to CNS function. In this review, we discuss current experimental data on how gut microbiota infl uence the brain. Based on recent discoveries, we suggest that gut microbiota are an impor- tant player in how the body infl uences the brain, contribute to normal healthy homeostasis, and infl uence risk of dis- ease, including anxiety and mood disorders (Figure 1). Although much of this work is preclinical, we also review the limited work in the clinical arena to date. Overview of the microbiome Early postnatal life in mammals represents a period of bacterial colonization. Resident or commensal microbiota colonize the mammalian gut shortly after birth and remain there throughout life. In humans, the lower intestine con- tains 10141015bacteria, that is, there are 10100 times more bacteria in the gut than eukaryotic cells in the human body (1013) 1,7,8. The presence of commensal microbiota is critical to immune function, nutrient processing, and other aspects of host physiology 913. As we discuss here, microbiota are also important in the function of the CNS. To understand effectively the role of commensal micro- biota in health and disease, we must be able to describe the complex ecology of the microbiome. Recently developed molecular and metagenomic tools have allowed research- ers to better understand the structure and function of the microbial gut community. Several bacterial phyla are represented in the gut, and commensals exhibit consider- able diversity, with as many as 1000 distinct bacterial species involved 1416. The two most prominent phyla are Firmicutes and Bacteroides, accounting for at least 70 75% of the microbiome 1517. Proteobacteria, Actinobac- teria, Fusobacteria, and Verrucomicrobia are also present but in reduced numbers 15. The dynamic nature and the diversity of the microbiome determined to date extends far beyond what researchers expected. We are only beginning to understand how the diversity and distribution of these Review Glossary Bacterial colonization: naturally occurring bacterial colonization of infants (human) or pups (rodents) begins at birth and continues through postnatal life. Experimentally, mice lacking microbiota (GF mice) can be colonized by removal from the gnotobiotic rearing conditions, followed by exposure to microbiota (often exposure to mouse feces); these mice are referred to as conventionalized mice. Bacterial phyla: several bacteria phyla are represented in the intestinal microbiome, including Firmicutes, Bacteroides, Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia. Recent metagenomic population studies have attempted to classify different profiles of bacterial phyla across groups of humans that are referred to as enterotypes. Commensal intestinal microbiota: the human intestine is home to nearly 100 trillion microbes. The relation between these microbes and their host begins at bi