Gut May Hold Key to Infectious Brain Diseases

Specialized cells in the lining of the gut may provide a key to preventing an infectious brain disease caused by misfolded proteins.

We can easily imagine white blood cells attacking foreign germs in the bloodstream. While your immune system is literally everywhere in your body, it has special duties in the areas where germs have an opening, such as through the mouth, nose, skin, eyes, or via the genitals.

A new study examines how the body and immune system use special cells—called microfold, or M cells—to ferry microbes and infectious agents deeper into the gut after being eaten with food.

Published in the journal PLOS Pathogens, the new study from a team at the University of Edinburgh wanted to find out more about how infectious diseases get into the body through the gut after ingestion. From the gut, these infectious germs which cause prion diseases infiltrate the brain, ultimately causing death.

In human brain tissue, the arrow points to a lesion caused by Creutzfeldt-Jakob disease.

What Are Prion Diseases & How Do They Get to the Brain?

The term prion disease may not be familiar to you, but if you have heard of Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (often called "mad cow disease"), or chronic wasting disease, then you are in prion disease territory.

Prion diseases are a group of related diseases that effect humans, cattle, and hoofed ruminant mammals with antlers, like deer, elk, and moose. In the US, hunters are urged to use caution processing or consuming deer from areas where chronic wasting disease is found. Sheep are effected by a similar disease called scrapie. All of these diseases are called transmissible spongiform encephalopathies (TSEs).

Normal prion proteins are found throughout the body, especially the brain. Abnormal prions are introduced to the body by eating infected food, medical contamination, or through genetic inheritance. Pathogenic prions target normal prion proteins and cause abnormal folding and dysfunction.

These spreading clumps of abnormally folded proteins lead to brain damage that impairs motor ability and memory, causes personality changes and dementia, and ultimately leads to death. While there are tests to support a diagnosis, there is currently no cure for prion disease.

Prion diseases are devastating, fatal conditions that usually make their way into the body through contaminated meat or through pasturing and animal-to-animal conditions. When consumed, prions travel to the gut, where they mingle with M cells. With the role of transferring microbes from the gut across the intestinal barrier, M Cells are an important player in body defense.

The thin mucousal tissue that lines the gut is called the epithelium. The epithelium, in its many cell forms, is located throughout the body, including the lungs, reproductive organs, heart, and digestive and respiratory tract and skin. M cells live in the epithelium, or lining, of the intestine. They are particularly concentrated in areas called Peyer's patches.

Peyer's patches are named for Hans Conrad Peyer, a Swiss anatomist who lived in the 17th century. Lining the epithelium of the small intestine, Peyer's patches are sections of lymph nodules. Located throughout the body, lymph nodes filter, sequester, and destroy, harmful or infectious substances circulating in lymph fluid formed throughout the body.

The team of researchers from the University of Edinburgh made insights into how dangerous prions are able to pass from the gut, and into the body, where they cause damage to the brain.

Using prions from the disease scrapie, mice studies were conducted that illustrate one route of prion disease into the body—via M cells. Their findings include:

• M cells are key mediators to the entry of prion diseases into the body. In mice with no M cells, uptake of the prion disease was blocked.
• The higher the number of M cells, the greater the transmission of prions into Peyer's patches. After replicating themselves by folding normal prion proteins in the lymph nodes of Peyer's patches, the prions disseminate into the body. In the study, the authors note, "M cells could be considered as the gatekeepers of oral prion infection whose density directly limits or enhances disease susceptibility."
• The route of prions through M cells appears essential to the infection. In other areas where prions might enter the body, different players from the immune system, like macrophages, identify the abnormally-folded proteins and consume them.
• The structure and fast transit times of M cells may be the reason prions can pass into the Peyer's patches undetected. Other studies referenced by this research indicate low levels of prions are detectable in the bloodstream (which means they've transitioned through the gut epithelial cells already) "within minutes of oral exposure." While speed serves the efficient uptake of nutrients to fuel our bodies, it also appears to facilitate transmission of deadly disease.

Importantly, the scientists identify factors that might increase vulnerability to infection with prion diseases. Those criteria include:

• Being young: Young adults have more M cells than older adults, thereby increasing the likelihood of uptake of the disease-causing prions.
• Immune compromise: Individuals already suffering from inflammation caused by infection, like Salmonella, could be at higher risk.
• Being older: Immune function declines with age, so our bodies are less able to fight off infections.

"Our next step is to understand how the prions exploit these cells to infect the gut," study researcher Neil Mabbott, of the University of Edinburgh, said in a press release. "If we can design treatments to block the uptake of prions by M cells, this may provide a novel method to prevent prion infections in humans and animals."

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