Review
Gut–brain axis: how the microbiome influences anxiety and depression

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Within the first few days of life, humans are colonized by commensal intestinal microbiota. Here, we review recent findings showing that microbiota are important in normal healthy brain function. We also discuss the relation between stress and microbiota, and how alterations in microbiota influence stress-related behaviors. New studies show that bacteria, including commensal, probiotic, 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 microbiota–gut–brain axis may provide novel approaches for prevention and treatment of mental illness, 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 importance of gut microbiota to the function of the CNS 2, 3, 4, 5, 6. 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 neuroendocrine 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 experimental data from animal studies focused on the microbiome (see Glossary). Neuroscientists are now taking notice of these novel reports that highlight the ‘bottom-up’ influence of microbes themselves, with several studies showing that commensal bacteria are important to CNS function.

In this review, we discuss current experimental data on how gut microbiota influence the brain. Based on recent discoveries, we suggest that gut microbiota are an important player in how the body influences the brain, contribute to normal healthy homeostasis, and influence risk of disease, 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.

Section snippets

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 contains 1014–1015 bacteria, that is, there are 10–100 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 9, 10,

Alterations in HPA function

Clinically, depressive episodes are associated with dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis [28] and resolution of depressive systems with normalization of the HPA axis 29, 30. A direct link between microbiota and HPA reactivity was established with the 2004 report that showed an exaggerated corticosterone (CORT) and adrenocorticotrophin (ACTH) response to restraint stress in germ-free (GF) mice when compared with conventionally house-specific pathogen-free (SPF) mice [5]

Gut–brain axis and behavior

Evidence gathered from experiments carried out in animals with altered commensal intestinal microbiota, whether GF mice, or conventionally housed animals either treated with probiotics and/or antibiotics or infected with pathogenic bacteria, all indicate that rodent behavioral responses are impacted when the bacterial status of the gut is manipulated. Genetic differences across strains influence behavior and, therefore, it is important to note that work studying the role of microbiota in

Clinical evidence of probiotic use for mood and anxiety symptoms to date

Although the use of probiotics in animal studies has consistently shown an impact on anxiety- and depressive-like behaviors, there is little published work concerning the effects of probiotics on depression or anxiety symptoms in humans. In the limited work that does exist, however, there is evidence that probiotics have similar antidepressive and anxiolytic effects as those observed in preclinical studies. In a double-blind, placebo-controlled, randomized parallel group clinical trial, healthy

Gut–brain axis and neurochemistry

Bidirectional communication between gut microbiota and components of the gut–brain axis influence normal homeostasis and may contribute to risk of disease through alterations in GI, CNS, ANS, and immune systems (Figure 1). A critical question facing neuroscientists is whether changes in behavior mediated by microbiota are a result of long-term changes in central signaling systems. To date, investigators have provided evidence that both neuroplasticity-related systems and neurotransmitter

Concluding remarks

Significant progress has been made over the past decade in recognizing the importance of gut microbiota to brain function. Key findings show that stress influences the composition of the gut microbiota and that bidirectional communication between microbiota and the CNS influences stress reactivity. Several studies have shown that microbiota influence behavior and that immune challenges that influence anxiety- and depressive-like behaviors are associated with alterations in microbiota. Emerging

Acknowledgments

Operating funds from the National Science and Engineering Research Council of Canada (NSERC, to J.A.F.), and equipment funds from Canadian Foundation for Innovation (to J.A.F.) contributed to this project. Graduate stipend support (to K.A.N.) was provided by Ontario Graduate Scholarship and Ontario Graduate Scholarship in Science and Technology.

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

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