Immunologist Mark Sundrud of Scripps Research, PhD, finds a new direction for Crohn’s disease research in the interaction of bile acids and T cells in the small intestine. Photo credit: Scott Wiseman for Scripps Research
People with Crohn’s disease are usually treated with strong anti-inflammatory drugs that work throughout the body, not just the digestive tract, and cause potentially unintended and often serious side effects. New research from the lab of Mark Sundrud, Ph.D., at Scripps Research, Florida, suggests that a more targeted approach to treatment is possible.
Crohn’s disease is caused by chronic inflammation in the digestive tract, often in the small intestine. More than half a million people in the United States are living with the disease, which can be debilitating and requires repeated surgery to remove irreversibly damaged intestinal tissue.
Sundrud’s team wrote in Nature on April 7th that certain immune cells in the small intestine have developed a molecular sensing mechanism to protect themselves from the toxic effects of high concentrations of bile acids. This sensory mechanism can be manipulated with small drug-like molecules, and the treatment reduces small bowel inflammation in mice.
“It seems that these immune cells, so-called T effector cells, have learned to protect themselves from bile acids,” says Sundrud. “These T cells use an entire network of genes to safely interact with bile acids in the small intestine. This pathway can lead to malfunction in at least some people with Crohn’s disease.”
Bile acids are made in the liver and released during a meal to aid digestion and absorption of fats and fat-soluble vitamins. They are actively recaptured at the end of the small intestine in an area known as the ileum, where they pass through layers of tissue that contain the intestinal’s dense network of immune cells, and finally get back into the bloodstream to return to the liver.
Since these are detergents, bile acids can cause toxicity and inflammation if the system is out of whack. Thanks to a complicated signaling system, the whole process continues to hum. Receptors in the nucleus of liver cells and intestinal barrier cells recognize the presence of bile acid and instruct the liver to stop producing bile acid if there is too much or to produce more if there is not enough to digest a large steak dinner, for example.
Given how harmful bile acids can be to cells, scientists have wondered how immune cells that live in or visit the small intestine tolerate their presence in the first place. Sundrud’s team previously reported that a gene called MDR1, also known as ABCB1, is activated when an important subset of immune cells circulating in the blood called CD4 + T cells enter the small intestine. There, MDR1 acts in transitory T cells to suppress bile acid toxicity and small intestinal inflammation.
In the new study, Sundrud’s team uses an advanced genetic screening approach to find out how T cells perceive and respond to bile acids in the small intestine to increase MDR1 activity.
“The fundamental discovery that T cells spend so much time and energy preventing bile acid-induced stress and inflammation opens up entirely new concepts for the way we think about and treat Crohn’s disease,” says Sundrud. “It’s like looking for treasure in the wrong place, and this work gives us a new map that shows where X marks the spot.”
T cells contain a receptor molecule in their core known as CAR, which stands for constitutive androstane receptor. CAR works in the small intestine and promotes the expression of MDR1. It also plays a role in activating an essential anti-inflammatory gene, IL-10, the team found.
“When we treated mice with drug-like small molecules that activate CAR, the result was localized detoxification of bile acids and a reduction in inflammation,” says Sundrud.
According to Sundrud, researching the therapeutic potential of CAR activation requires caution and creativity, as CAR is also critical to the breakdown and elimination of other substances in the liver, including many drugs.
Ultimately, the Crohn’s disease therapy emerging from this work could be something that activates CAR locally in small intestine T cells, or something that targets another gene that is similarly used to promote safe communication between small intestine T cells -Cells and bile acids is responsible. ” Says Sundrud.
It was also interesting that the bile acid inflammation feedback system in the colon worked somewhat differently together with gut microbiome factors. While the intestinal flora had a greater impact on the development and function of T cells in the large intestine, it was the core receptor CAR that had a greater impact on inflammation in the small intestine.
Inflammation plays both a positive and a negative role in the body. It can damage tissue, but it also suppresses cancer growth and fights infections. Current anti-inflammatory treatments shut it down systemically throughout the body. This could potentially have serious consequences, such as: B. the reduction of infection resistance or the release of the brakes in cancer. Targeting inflammatory disease treatment only to the affected tissue would be preferable if possible, he says.
“The 50 million or so people in the US who have an autoimmune disease or a chronic inflammatory disease receive the same medical treatment,” says Sundrud. “The holy grail would be to develop drug approaches to treat inflammation in only certain tissues, leaving the rest of the immune cells in your body untouched and able to fight off cancer and microbial infections.”
In some cases of Crohn’s disease, a dysfunctional gene may be to blame
Mei Lan Chen et al., CAR controls the adaptation of T cells to bile acids in the small intestine, Nature (2021). DOI: 10.1038 / s41586-021-03421-6 Provided by the Scripps Research Institute
Quote: Crohn’s disease can be caused by an immune signal failure (2021, April 7th), accessed on April 7th, 2021 from https://medicalxpress.com/news/2021-04-crohn-disease-immune-failure.html has been
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