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.
Highlights
Prion diseases, or transmissible spongiform encephalopathies, are typically sub-acute neurodegenerative diseases that affect humans and a number of captive and freeranging animal species
Irrespective of the microbiological status of the mice, the average severity and distribution of the spongiform pathology within the brains of the clinically affected mice after IC or IP injection with prions were similar (Fig. 2b, c, respectively). These data clearly show that the absence of the commensal microbiota in germ-free mice did not affect the accumulation of PrPd in the brain or the development of spongiform pathology at the clinical stage of disease
Microglial activation is a prominent feature of central nervous system (CNS) prion disease [4, 10], but whether the commensal gut microbiota influence the progression of CNS
Summary
Transmissible spongiform encephalopathies, are typically sub-acute neurodegenerative diseases that affect humans and a number of captive and freeranging animal species. Systemic administration of inflammatory stimuli such as bacterial lipopolysaccharide (LPS) during CNS prion disease can switch the microglial phenotype to one with a more proinflammatory bias, leading to exacerbated neuropathology [16, 17]. Consistent with this hypothesis, prion disease is delayed in mice deficient in CD14 (a component of the LPS receptor) and is accompanied by enhanced expression of anti-inflammatory cytokines such as IL-10 [18]
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