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Crohn’s disease may be caused by a failure of immune signals

The study reveals how T cells in the small intestine respond to bile acids, and provides a topical treatment direction for the cause of chronic disease.

Jupiter, Florida – People with Crohn’s disease are usually treated with powerful anti-inflammatory drugs that work throughout the body, not just in the digestive system, creating the potential for unintended, often dangerous, side effects. New research from Mark Sundrod, Ph.D., at Scripps Research, Florida, suggests the possibility of a more targeted treatment approach.

Crohn’s disease develops from chronic inflammation of the digestive tract, often the small intestine. More than half a million people in the United States live with the disease, which can be debilitating and require frequent surgeries to irreversibly remove damaged intestinal tissue.

Writing in the journal Temperate nature On April 7, Sundrud’s team discovered that some immune cells in the small intestine had developed a molecular sensing mechanism to protect themselves from the toxic effects of elevated bile acid concentrations there. They found that this sensory mechanism could be manipulated with small drug-like molecules, and the treatment reduced inflammation of the small intestine in mice.

“It appears that these immune cells, called effector T cells, have learned how to protect themselves from bile acids,” says Sundrod. These T cells use a whole network of genes to safely interact with bile acids in the small intestine. “This pathway may be impaired in at least some individuals with Crohn’s disease.”

Bile acids are made in the liver and released during a meal to aid in the digestion and absorption of fats and fat-soluble vitamins. It is actively picked up at the end of the small intestine, in an area called the ileum, where it passes through layers of tissue containing a dense network of intestinal immune body cells, and eventually enters the bloodstream to return to the liver. ..

Because they are cleaners, bile acids can cause toxicity and inflammation if the system becomes unbalanced. The whole process is preserved throughout thanks to a complex signaling system. The receptors in the nuclei of both hepatocytes and intestinal barrier cells sense the presence of bile acid and tell the liver to back down from producing bile acid if there is too much, or to produce more if there isn’t enough to digest a large steak dinner, for example.

Given how much damage bile acids can do to cells, scientists have questioned how well immune cells that live or visit the small intestine could tolerate their presence at all. Sundrod’s team previously reported that a gene called MDR1, also known as ABCB1, is activated when an important subset of immune cells that circulate in the blood, called CD4 + T cells, make their way into the small intestine. There, MDR1 works in transient T cells to suppress bile acid toxicity and inflammation of the small intestine.

In the new study, Sundrud’s team is using an advanced genetic screening approach to uncover how T cells sense and respond to bile acids in the small intestine to increased MDR1 activity.

“The fundamental finding that T cells devote a lot of their time and energy to preventing bile acid stress and inflammation sheds light on entirely new concepts in how we think about and treat Crohn’s disease,” says Sundrod. “It’s as if we’re digging in the wrong place for treasure, and this work gives us a new map showing where an X is on the spot.”

T cells contain a receptor molecule in their nucleus known as CAR, short for formative androsten receptor. The team found that it works in the small intestine, boosts expression of MDR1, and also plays a role in activating the key anti-inflammatory gene, IL-10.

“When we treated mice with tiny, drug-like molecules that activate CAR, the result was topical detoxification of bile acids and reduced inflammation,” says Sundrod.

Sundrud says exploring the therapeutic potential for activating CAR will require caution and creativity, because CAR is also needed to break down and eliminate other substances in the liver, including many drugs.

“Ultimately, the treatment for Crohn’s disease that arises from this work could be something that activates CAR locally in small intestinal T cells, or something targeting another gene that is similarly responsible for promoting safe communication between intestinal T cells and bile acids,” Sundrod says.

Also interestingly, the team found that the bile acid inflammation feedback system worked somewhat differently in the colon in coordination with the gut microbiome factors. While the intestinal flora had a greater effect on T cell development and function in the colon, it was the CAR nuclear receptor that had the greatest effect on the inflammation of the small intestine.

Inflammation plays a positive and negative role in the body. It can damage tissue, but it prevents cancer growth and fights infection. Current anti-inflammatory treatments shut off it systemically, throughout the body. This can have dire consequences, such as reducing infection resistance or reducing cancer suppression. He says directing treatment for inflammatory diseases only to affected tissues would be better whenever possible.

“The nearly 50 million people living in the United States with some type of autoimmune disease or chronic inflammation are all treated the same way, medically,” says Sundrod. “The holy grail will be to come up with therapeutic methods to treat inflammation in specific tissues only and leave the rest of the immune cells in your body untouched, capable of fighting cancer and microbial infections.”

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