The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis

Prion diseases are a unique group of transmissible, chronic, neurodegenerative disorders. Following peripheral exposure (e.g. oral), prions often accumulate first within the secondary lymphoid tissues before they infect the central nervous system (CNS). Prion replication within secondary lymphoid tissues is crucial for the efficient spread of disease to the CNS. Once within the CNS, the responses of innate immune cells within it can have a significant influence on neurodegeneration and disease progression. Recently, there have been substantial advances in our understanding of how cross-talk between the host and the vast community of commensal microorganisms present at barrier surfaces such as the gut influences the development and regulation of the host's immune system. These effects are evident not only in the mucosal immune system in the gut, but also in the CNS. The actions of this microbial community (the microbiota) have many important beneficial effects on host health, from metabolism of nutrients and regulation of host development to protection from pathogen infection. However, the microbiota can also have detrimental effects in some circumstances. In this review we discuss the many and varied interactions between prions, the host and the gut microbiota. Particular emphasis is given to the ways by which changes to the composition of the commensal gut microbiota or congruent pathogen infection may influence prion disease pathogenesis and/or disease susceptibility. Understanding how these factors influence prion pathogenesis and disease susceptibility is important for assessing the risk to infection and the design of novel opportunities for therapeutic intervention.