The brain to gut pathway: a possible route of prion transmission

Objective The intestine is recognised to play a key role in the transmission of prion diseases. These diseases are associated with pathological isoforms (PrPSc) of the normal cellular prion protein (PrPC) and can be transmitted between individuals or arise spontaneously. The brain, as the primary site of prion replication, could provide infectious prions to peripheral tissues. Here, we examine whether the brain is a source of intestinal prion accumulation. Methods Following intracerebral inoculation with human origin prions the ileums of BalbC mice with clinical prion disease were assessed by Western immunoblot and immunohistochemical analysis for the presence of PrPSc and the survival of enteric glial cells (EGCs) and specific neuronal subpopulations in the myenteric and submucosal plexus. Results PrPSc was detected in the ileum of 13/13 mice following intracerebral inoculation with prions and 0/4 saline-inoculated mice. PrPSc was localised at detectable levels in the Peyer's patches of infected mice. Investigation of neuronal subpopulations revealed a significant decrease in neurofilament reactive neurons (11 +/- 8%, p<0.05, n=5) compared with saline-inoculated mice (23 +/- 5%, n=3). Neuronal nitric oxide synthase (nNOS) and tyrosine hydroxylase reactive neurons were decreased in some (2 of 4 and 1 of 3, respectively) but not all prion-infected mice, whereas calretinin and vasoactive intestinal peptide reactive neurons were unaffected. EGCs were highly distorted in circumscribed ganglia of the myenteric plexus. In areas of glial derangement, the neurons showed undefined outlines and faint cytoplasmic immuoreactivity for the pan-neuronal marker Hu and loss of nNOS reactivity. Conclusions The present work shows that PrPSc can be transmitted from the brain to the intestine. This causes pathological changes in enteric glia and neurons. We conclude that PrPSc of brain origin finds a substrate in the naturally occurring PrPC of EGCs and neurons. This results in a reservoir of PrPSc in the intestine, which may represent a source of prion disease transmission through surgical procedures and environmental contamination.