Researchers Link Gallstone Formation to the Safety Mechanism of the Body

In a recent study, researchers have discovered the mechanism that caused gall stone formation in the body. The findings from the research are published in the Immunity journal.

A team of researchers from the Universitätsklinikum Erlangen, Germany discovered that the neutrophils play a key role in the formation of gall stones. Neutrophils are white blood cells with a sticky meshwork of DNA and proteins, they act as a binder that sticks together calcium and cholesterol crystals during gallstone formation.

The researchers successfully limited the formation and growth of these so-called neutrophil extracellular traps (NETs) in mice and hope to emulate the same effect in humans.

The lead author of the study, an immunologist at Universitätsklinikum Erlangen, Martin Herrmann said; “Neutrophils have long been considered the first line of defense against infection and have been shown to generate NETs that entangle and kill pathogens,” He explained; “Here, we provide additional evidence for the double-edged-sword nature of these NETs by showing that they play an important role in the assembly and growth of gallstones. Targeting neutrophils and NET formation may become an attractive instrument to prevent gallstones in high-risk populations.”

These stone-like massive crystals form in a pear-shaped organ called the gallbladder. Gallstones may vary in size from as small as a grain of sand to as large as a golf ball. The gallbladder aids in the emulsification of fats by releasing bile through the bile ducts entering the small intestine where fat breakdown takes place.

It is believed that in most cases gallstones appear like a silent disease without any visible symptoms. Symptoms surface later on when the problem is severe and may include abdominal pain, nausea, and vomiting.

In the U.S, most adults are victims of gallstone, which is commonly removed by surgery. The medication for gallstones is available but it’s more time consuming, may take months or years to break all the gallstones and irregular use can make it ineffective.

The process involving the formation of gallstones is not exactly understood by the scientists which are hindering the development of new medication for its removal. It has been known for centuries, the precipitation of cholesterol and calcium salts in the bile is essential for gallstone formation. But unfortunately, what leads the calcium salts and cholesterol crystals to bind with one another which ultimately causes the production and growth of a gallstone was unknown.

Herrmann, with a co-first author Luis Muñoz of Universitätsklinikum Erlangen, working with their team extracted and examined biliary sludge from human patients receiving stents.

They discovered clusters of DNA in addition to the sturdy activity of neutrophils elastase on the surfaces of larger human gallstones, enabling the break-down of proteins into simpler molecules. These molecules reveal the mesh-like structures expelled by neutrophils, NETs give protection against infections but may lead to autoimmune or inflammatory disorders within the body.

The researchers by using human neutrophils cultured cholesterol crystals thus examined the release of DNA from neutrophil cells.

To examine the role of NETs in gallstone formation and development, the research team attached the gallstones to rotating and shaking gadgets and spun them in the presence or absence of neutrophil suspensions.

Gallstones rapidly attracted DNA clusters and the enzyme of their surface in the presence of neutrophil suspension. Further experimentation showed the aggregation of cholesterol and calcium salts by the NETs, the DNA clusters forming a coating around the calcium crystals leading to the formation of larger gallstones.

To enlighten the functions of NETs and neutrophils in the formation of gallstone, the researchers fed mice a high cholesterol diet which helped in the development of gallstones. The study showed the size of gallstones becomes smaller and also fewer in number, in mice with genetic defects that ceased NET formation or whose diets were supplemented with protein arginine deiminase 4 inhibitors (PAD4) which inhibits the NETs production.

PAD4 inhibiting compounds are also recognized as a beta-blocker called metoprolol, which hinders the migration of neutrophils thus effectively used for lowering blood pressure and a medicament for chest pain, as well as for ceasing the growth of pre-existing gallstones.

Muñoz said; “The possibility of stopping these processes with new PAD4 inhibitors or with metoprolol—an established beta-blocker—may introduce new therapeutic strategies that avoid surgery,” he explained; “However, human studies are required to establish new therapies for gallstone disease. Hopefully, we can convince pharmaceutical companies to perform a clinical study with inhibitors of NET formation or NET aggregation.”

The findings from the study are promising as they provide a new direction for the world of medicine to try and treat gallstones. Hopefully, in the future, a surgery-free technique can be employed for their removal and control.

Adeena Tariq

Adeena's professional life has been mostly in hospital management, while studying international business in college. Of course, she now covers topics for us in health.

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