Systems Interactions Between the Microbiome, Brain and Behavior
Elaine Hsiao, University of California, Los Angeles
In line with the staggering finding that our bodies are comprised of 10 times more microbial cells than human eukaryotic cells, that contribute 360 times more genes than does the human genome1, it is now known that the resident microbes that make up “us” play important roles in several biological processes2. In addition to the understanding that the microbiota affects immunity3, metabolism4 and gastrointestinal (GI) integrity5, there is increasing evidence that indigenous microbes fundamentally regulate the development and function of the nervous system6. Germ-free mice, which are raised in the absence of microbial colonization, exhibit abnormalities in several complex behaviors, including social interaction7, anxiety-like behavior8-10 and emotional behavior11,12. Furthermore, altering the microbiota in conventionally-colonized animals modulates the activity of enteric neurons as well as afferent vagus nerves that extend from the intestinal epithelium directly into the brainstem13. Transcriptomic profiling reveals a key role for the microbiota in regulating global gene expression in the striatum, hippocampus and cerebellum, including genes mapping to synaptic long-term potentiation, steroid hormone metabolism and cAMP-mediated signaling pathways8. In addition, manipulating the gut microbiota alters brain levels of neurotrophic factors8,10,14 and neurotransmitter receptors, including those for dopamine8, GABA11 and glutamine15 signaling. Such long-range interactions between the microbiota and brain support the ability of microbe-based therapies to treat symptoms of multiple sclerosis16,17, depression11 and autism18 in mice, and the reported efficacy of probiotics in impacting resting brain activity19 and treating emotional symptoms of chronic fatigue syndrome20 and psychological distress21 in humans. Overall, that commensal microbes have the remarkable capacity to modulate neural activity and behavior suggests that elucidating the mechanistic bases for microbiota-nervous system interactions will provide novel insights into brain development and function, and potentially uncover tractable strategies for treating complex nervous system disorders.