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Gut M Cells: The Gatekeepers of Oral Prion Infection

A recent study published online in PLOS Pathogens provides new insight on why some animals and humans might be more susceptible than others to prion diseases.
“[O]ur data demonstrate that factors such as pathogen infection, inflammation, and aging, which alter the abundance of M cells in the intestine, may be important risk factors which influence susceptibility to orally-acquired prion infections,” wrote David S. Donaldson, from The Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, United Kingdom, and colleagues.
Prion diseases are a rare group of fatal neurodegenerative disorders that can affect humans and animals; these diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and variant Creutzfeldt-Jakob disease (vCJD) in humans. In these diseases, abnormal, misfolded proteins—known as prions—accumulate in the tissues of infected individuals.
According to the authors, after animals or humans are orally infected with prions, these misfolded proteins accumulate and replicate within the gut-associated lymphoid tissues (GALT), including the Peyer’s patches of the small intestine, before the disease spreads to the brain.
Peyer’s patches contain specialized cells, known as M cells, which form part of the mucosal immune system, helping to protect mucosal surfaces against invading pathogens. During the initial immune response to certain pathogens, these M cells transport antigens from the gut, across the Peyer’s patches, to cells of the immune system.
Certain bacteria, such as Salmonella Typhimurium, can take advantage of this transport mechanism and use it to cross the Peyer’s patches and infect the host. “Independent studies suggest orally administered prions may similarly be transported by M cells into host tissues and that this transport may be important to establish host infection,” the authors said.
The researchers conducted a study using mice to investigate the role of M cells in the development of prion disease. They found that M cells are the key gatekeepers of prion disease development after a human or an animal is orally infected with prions. In particular, the density of M cells in the gut epithelium directly limits or enhances disease susceptibility, the authors noted.
In mice that lacked M cells, prion accumulation within Peyer’s patches and the subsequent spread of prion disease to the brain were blocked, emphasizing that M cells play an important role in transferring prions across the gut epithelium to establish infection. 
In contrast, however, the researchers found that mice that had more M cells in their gut were about ten times more susceptible to developing prion disease and had shortened disease duration and survival time.
According to the authors, these findings could help explain why most cases of clinical vCJD have involved young adults who typically have more M cells than older people have.
“Our data also raise the possibility that the density of M cells in the gut epithelium may similarly influence susceptibility to other important orally-acquired bacterial and viral pathogens which are considered to exploit M cells to infect the host,” the authors added.

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