Chapter 16 - Germ-Free Animals: A Key Tool in Unraveling How the Microbiota Affects the Brain and Behavior

Abstract

Numerous studies have implicated the gut microbiota in the development, function, and maintenance of brain health and behavior. Indeed, research utilizing germ-free animals (animals raised devoid of all microorganisms) has been instrumental in providing evidence supporting a role for gut microbes in gut–brain axis communication. Key findings have highlighted the role of the gut microbiota in a multitude of neurophysiological processes including neurogenesis, myelination, blood–brain barrier permeability, neuroplasticity, neurotransmission, microglial activation, and neuroinflammation. Further, the molecular mechanisms underlying germ-free behavior are being elucidated and implicate gut microbes in a myriad of complex behaviors including stress responsivity, anxiety-like behavior, sociability, and cognition. Though the germ-free mouse has been the model employed by most studies linking the gut microbiota to the brain, alternative models such as zebrafish, Drosophila, Caenorhabditis elegans, and the pig are also emerging, further advancing our mechanistic understanding of microbiota–gut–brain communication. The principal advantage of the germ-free model is in proof-of-principle studies, whereby researchers can selectively introduce a specific bacterium or consortium and investigate its mechanistic underpinnings during specific windows throughout the host's lifespan. However, a germ-free upbringing significantly influences neurodevelopmental outcomes that may deem them unsuitable for certain investigations. Further, limited translatability to humans is another key consideration in the use of germ-free models, highlighting the need for alternative and complementary strategies. Increasing our understanding of the impact of the gut microbiota on brain health and behavior using a variety of approaches will enable the development of novel therapeutics targeting disorders associated with perturbed microbiota–gut–brain axis signaling.