Prion disease pathogenesis in the absence of the commensal microbiota

Abstract

Prion diseases are a unique group of transmissible, typically sub-acute, neurodegenerative disorders. During central nervous system (CNS) prion disease, the microglia become activated and are thought to provide a protective response by scavenging and clearing prions. The mammalian intestine is host to a large burden of commensal micro-organisms, especially bacteria, termed the microbiota. The commensal microbiota has beneficial effects on host health, including through the metabolism of essential nutrients, regulation of host development and protection against pathogens. The commensal gut microbiota also constitutively regulates the functional maturation of microglia in the CNS, and microglial function is impaired when it is absent in germ-free mice. In the current study, we determined whether the absence of the commensal gut microbiota might also affect prion disease pathogenesis. Our data clearly show that the absence of the commensal microbiota in germ-free mice did not affect prion disease duration or susceptibility after exposure to prions by intraperitoneal or intracerebral injection. Furthermore, the magnitude and distribution of the characteristic neuropathological hallmarks of terminal prion disease in the CNS, including the development of spongiform pathology, accumulation of prion disease-specific protein (PrP), astrogliosis and microglial activation, were similar in conventionally housed and germ-free mice. Thus, although the commensal gut microbiota constitutively promotes the maintenance of the microglia in the CNS under steady-state conditions in naïve mice, our data suggest that dramatic changes to the abundance or complexity of the commensal gut microbiota are unlikely to influence CNS prion disease pathogenesis.

The microbiota–microglia axis in central nervous system disorders

“…However, a more recent study by Bradford et al shows that the exposure to prions by intraperitoneal or intracerebral injection did not affect the susceptibility or survival of the GF compared to SPF mice. In addition, they report neither a difference in disease development, nor in the distribution and the magnitude of activation of microglia in the GF mice based on histological analyses (130). Given these findings, the role of the gut microbiota in prion diseases remains controversial ( Figure 1) and additional detailed investigations including gene expression analysis are required to characterize the microglial activation state and contribution to prion pathogenesis.…”

How microbiota shape microglial phenotypes and epigenetics

“…One hallmark of prion diseases such as Creutzfeldt‐Jacob disease in humans and scrapie in cattle are aggregations of misfolded prion disease‐specific PrP (PrP Sc ) that accumulate in affected tissues including the CNS causing spongiform pathology and concomitant microglia activation. No major changes in terms of pathology severity as well as microglial numbers and morphology were reported in mice lacking commensal microbiota compared to matched controls (Bradford, Tetlow, & Mabbott, ). However, C3H/LacDk mice lacking TLR4 were used in this study, the number of analyzed mice was rather low and the experiments were performed only once.…”

Modulation of Neuroinflammation by the Gut Microbiota in Prion and Prion-Like Diseases

“…Although a subsequent study by Wade et al (1986) revealed no difference in survival time between germ-free and controls mice inoculated intracerebrally with ME7 scrapie prions, a longer survival time was observed in germ-free but not in control mice after intraperitoneal inoculation [ 90 ]. In contrast, Bradford et al recently demonstrated that the absence of the commensal microbiota in germ-free mice did not affect prion disease duration or susceptibility after intraperitoneal or intracerebral injection of mouse-passaged 22C scrapie prions [ 91 ]. In addition, this study also found that the magnitude and distribution of the prion-characteristic neuropathological changes including spongiform degeneration and accumulation of PrP Sc as well as astrogliosis and microglial activation in the brain exhibited no differences between conventional and germ-free mice.…”

“…In addition, this study also found that the magnitude and distribution of the prion-characteristic neuropathological changes including spongiform degeneration and accumulation of PrP Sc as well as astrogliosis and microglial activation in the brain exhibited no differences between conventional and germ-free mice. It was concluded that dramatic changes to the abundance or complexity of the commensal gut microbiota are unlikely to influence prion disease pathogenesis [ 91 ]. The reasons behind the inconsistencies among above studies remain unclear.…”