What causes gallstones? Immune cells set a trap

What causes gallstones? This question has plagued the more than 20 million people who have or will have gallstones. Gallstones are hardened crystals that form in the gallbladder or bile ducts. They contain cholesterol, bilirubin, or a combination of the 2 along with other components.

Gallstones are extremely painful and often require removal of the gallbladder in severe cases. But this is not an ideal situation, though one can live a relatively normal life without their gallbladder. Be that as it may, you want to avoid removing it.

There are many modifiable risk factors to address that reduce the risk of gallstones. These risk factors include:

  • Obesity
  • Type 2 diabetes
  • Metabolic Syndrome
  • Non-alcoholic fatty liver disease(NAFLD)
  • Low HDL/High Triglycerides
  • Western diet (Highly processed)
  • Being sedentary

As you can see, it’s the standard offenders as with most chronic disease. But a new study gives us a glimpse into how the process unfolds. Hopefully, this brings us an answer as to what causes gallstones.

The gallbladder and bile

Before we go over the study, let’s cover how we make bile what the gallbladder has to do with it. We produce bile in our liver out of cholesterol, phospholipids, bile acids, and bile pigments. We use bile to emulsify fats, which makes them easier to digest. Bile also promotes motility and acts as an antimicrobial, helping maintain a healthy microbiome.

Once in the liver, bile goes to the gallbladder for storage. When we eat and food enters our duodenum, the gallbladder contracts and release bile in to it. We also release bile directly from the liver, but most bile comes from gallbladder contraction.

Bile then makes its way through the small intestine helping us emulsify and absorb fats and fat soluble vitamins. When it reaches the end of the small intestine, or ileum, it gets recycled back to the liver and stored in the gallbladder.

Bile circulates multiple times for a single meal, something called enterohepatic circulation.

Neutrophil trap causes gallstones
Image courtesy of knowyourmeme.com

So what causes gallstones?

In a study published last week, researchers investigated how gallstones are formed. We already know the first part of the process. The gallbladder keeps bile pretty soluble due to acidification. But when it becomes overwhelmed, crystals form from calcium salts and cholesterol.

But this isn’t enough to cause gallstones. In order to proceed to gallstones, these crystals must get larger. To do this, something must act as a glue to hold the crystals together. Until now, we had no idea what acted as the glue.

The immune system as a cause of gallstones

To no one’s surprise, the immune system plays a starring role. Immune cells called neutrophils normally protect us from infections. They patrol our body looking to start a fight with any bad guys they encounter. When they encounter bacteria, they engulf them or secrete proteins that kill them

They also have another strategy: NETs. Neutrophils trap pathogens with something called neutrophil extracellular traps, or NETs. They essentially cast these NETs to wall off intruders and digest them outside of the cell. This blocks the pathogen from damaging tissues and digests it without harming healthy tissues.

As it turns out, NETs are the glue that binds crystals together. When neutrophils encounter crystals, they cast out their NETs and bind the crystals together, forming gallstones.

Gallstones and other chronic conditions

NETs are an important player in the immune system but cause problems under the wrong conditions. Chronic inflammation “confuses” neutrophils and increases their numbers. This can also cause them to cast their NETs in error. Thus, NETs are a bridge between gallstones and other chronic conditions.

The fibers neutrophils make NETs with are made of neutrophil DNA. Not a big deal when you have acute inflammation to remove something like Candida abicans. But when inflammation moves from acute to chronic the risk for an autoimmune condition increases. NETs are elevated in lupus, IBD, psoriasis, rheumatoid arthritis, and other autoimmune conditions.

And autoimmune conditions aren’t the only problem. NETS set the stage for Ovarian Cancer to metastisize and travel elsewhere in the body. Blocking NETs prevents metastasis.

NETs are also elevated in Hashimoto’s thyroiditis. And it’s interesting to point out that people with gallstones have a doubled risk of auotimmune thyroid disease. In most of these conditions, neutrophils from patients are more prone to forming NETs than healthy controls.

Finally, the chronic hyperglycemic state in Type 2 diabetes causes neutrophils to cast their NETs all the time. Ironically, this is one of the reasons why Type 2 diabetes are more prone to infection. Their immune system is too busy fighting their own body to fight off an infection.

Seems like a good reason why they’re also more prone to autoimmune disease.


Just what causes gallstones? We know what gallstones are made of and how the process starts. But the glue that holds gallstones together has eluded scientists for quite sometime. New research implicates neutrophil extracellular traps(NETs) as that glue.

NETS are also prevalent in Type 2 diabetes, which I’ve covered as one of the worst things you can have going on. Some of the more nasty symptoms of Type 2 diabetes may come from excess NET formation. Additionally, NET formation is increased in a number of autoimmune conditions.

To decrease NET formation, managing blood glucose levels is probably the most important thing you can do. Addressing circadian disruption also goes a long way in decreasing the risk of gallstones. I cover that in a blog you can find here.

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