Prion disease pathogenesis and microbiota: how answering one question unveils many more

Credit: Dawn Hudson via

Professor Neil Mabbott and his group at the Roslin Institute have contradicted data that was originally published more than 20 years ago by showing that the progression of the prion diseases is not influenced by the composition of the mammalian microbiota.

The prion diseases are a group of progressive neurodegenerative diseases that affect humans and animals. These diseases are characterised by the accumulation and aggregation of abnormally shaped host-specific proteins called prion proteins. Once the proteins infiltrate the central nervous system (CNS) – in other words the brain – the result is extensive neurodegeneration.

One of the first signs of this type of neurodegeneration is the build-up of prion proteins and the activation of microglia. Microglia, the main inflammatory cell type found in the brain, respond to pathogens and brain injury by becoming activated. Once activated, microglia travel to the site of injury or infection where they destroy the invading pathogens and other dead brain cells in order to protect the brain from disease.

The mammalian digestive tract houses a diverse ecological community of microorganisms, known as the commensal microbiota. The microbiota-host relationship provides a range of beneficial effects to host health including the development and regulation of the immune system. Alterations to the gut microbiota have been shown to contribute to the pathogenesis of different disorders including anxiety, depression and neurodegenerative diseases. Until recently, it was thought that the commensal microbiota also played a role in prion disease pathogenesis, but new research suggests that this is not the case.

The communication system known as the gut-brain axis integrates hormonal, neural and immunological signaling between the gut and the brain. In this way, the brain is able to influence the gut and vice versa. In 2015, exciting data suggested that the commensal microbiota is able to maintain normal function of microglia in the brains of mice under normal physiological conditions. This data also showed that microglial development was compromised in germ-free mice (i.e. mice without commensal microbiota). This data also suggested a role for the microbiota in microglial development and function and therefore a possible role in prion disease pathogenesis. However, this role remained unclear until recently.

In a study published last month, scientists from the University of Edinburgh showed that prion disease progression and susceptibility is not influenced by the gut microbiota as was previously thought. They did this by injecting normal and germ-free mice with a small amount of brain tissue from mice terminally infected with a prion disease known as scrapie. Both groups of mice were then monitored regularly to see when and if they would develop the clinical signs of terminal scrapie prion disease. Scientists confirmed the prion disease diagnosis by histopathology which involved the examination of brain tissue from these mice under a microscope in order to study the manifestation of the disease. These fascinating findings contradict data which was published more than 20 years ago and leaves us wondering what role, if any, the microbiota actually plays in prion disease pathogenesis. This is another case in which answering one scientific question reveals a host of even more intriguing questions regarding the complex microbiota-host relationship and disease progression.


This article was written by Zandile Nare and edited by Bonnie Nicholson.

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