Growing up in a Bubble: Using Germ-Free Animals to Assess the Influence of the Gut Microbiota on Brain and Behavior

Abstract

There is a growing recognition of the importance of the commensal intestinal microbiota in the development and later function of the central nervous system. Research using germ-free mice (mice raised without any exposure to microorganisms) has provided some of the most persuasive evidence for a role of these bacteria in gut-brain signalling. Key findings show that the microbiota is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition. Furthermore, the microbiota maintains central nervous system homeostasis by regulating immune function and blood brain barrier integrity. Studies have also found that the gut microbiota influences neurotransmitter, synaptic, and neurotrophic signalling systems and neurogenesis. The principle advantage of the germ-free mouse model is in proof-of-principle studies and that a complete microbiota or defined consortiums of bacteria can be introduced at various developmental time points. However, a germ-free upbringing can induce permanent neurodevelopmental deficits that may deem the model unsuitable for specific scientific queries that do not involve early-life microbial deficiency. As such, alternatives and complementary strategies to the germ-free model are warranted and include antibiotic treatment to create microbiota-deficient animals at distinct time points across the lifespan. Increasing our understanding of the impact of the gut microbiota on brain and behavior has the potential to inform novel management strategies for stress-related gastrointestinal and neuropsychiatric disorders.

Keywords: cognitive dysfunction; germ-free mouse; microbiota-gut-brain axis; social development; stress response.

Figure 1.

Germ-free (GF) mice as a tool to study the microbiota-gut-brain axis. GF mice are raised in isolation in a GF unit without any exposure to microorganisms. Gut-brain signalling is altered due to the lack of bacterial exposure throughout the lifetime. The microbiota is required for normal stress responsivity, anxiety-like behaviors, sociability, and cognition. Furthermore, the microbiota protects CNS homeostasis by regulating immune function and blood brain barrier (BBB) integrity.