People with Crohn’s disease are usually treated with potent anti-inflammatory drugs that work throughout the body, not just the digestive tract, creating the potential for unwanted and often serious side effects. New research from the laboratory of dr. Mark Sundrud of Scripps Research in Florida suggests that a more targeted approach to treatment is also possible.
Crohn’s disease develops from chronic inflammation in the digestive tract, often in the small intestine. More than half a million people in the United States live with the disease, which can be debilitating and require repeated surgeries to remove irreversibly damaged intestinal tissue.
Writing in a magazine Nature On April 7, Sundrud’s team discovered that certain immune cells in the small intestine had developed a molecular sensory mechanism to protect themselves from the toxic effects of the high concentrations of bile acids there. This sensory mechanism can manipulate small drug-like molecules, and the treatment has reduced small bowel inflammation in mice.
These immune cells, called T effector cells, appear to have learned how to protect themselves from bile acids. These T cells use the entire network of genes to safely interact with bile acids in the small intestine. This time, failure can occur in at least some people with Crohn’s disease. “
Mark Sundrud, Ph.D., Scripps Research, Florida
Bile acids are formed in the liver and are released during meals to help digest and absorb fats and fat-soluble vitamins. They are actively recaptured at the end of the small intestine, in an area called the ileum, where they pass through layers of tissue that contain the body’s dense network of intestinal immune cells and eventually re-enter the bloodstream to return to the liver.
Being detergents, bile acids can cause toxicity and inflammation if the system becomes unbalanced. The whole process is constantly buzzing thanks to the complex signal system. Receptors in the nucleus of liver cells and intestinal barrier cells sense the presence of bile acid and tell the liver to give up bile acid production if there is too much, or to produce more if there is not enough to digest a large steak dinner, for example.
Given how much bile acids can potentially be harmful to cells, scientists have wondered how immune cells that live in the small intestine or visit the small intestine tolerate their presence at all. Sundrud’s team previously reported that a gene called MDR1, also known as ABCB1, is activated when an important subset of circulating immune cells, called CD4 + T cells, break into the small intestine. There, MDR1 acts in transient T cells by suppressing bile acid toxicity and small bowel inflammation.
In a new study, Sundrud’s team uses an advanced genetic screening approach to detect how T cells sense and respond to bile acids in the small intestine to increase MDR1 activity.
“The basic discovery that T cells devote so much of their time and energy to preventing stress and inflammation triggered by bile acids highlights completely new concepts in the way we think and treat Crohn’s disease,” says Sundrud. “It’s like we dug a treasure in the wrong place, and this paper gives us a new map that shows where X marks that place.”
T cells contain a receptor molecule in their nucleus known as CAR, short for constitutive androstan receptor. By acting in the small intestine, CAR promotes MDR1 expression and also plays a role in activating an essential anti-inflammatory gene, IL-10, the team found.
“When we treated the mice with small molecules similar to the drugs that activate CAR, the result was localized detoxification of bile acids and a reduction in inflammation,” says Sundrud.
Sundrud says exploring the therapeutic potential of CAR activation will require caution and creativity, as CAR is also crucial for the breakdown and removal of other substances in the liver, including many drugs.
“Ultimately, Crohn’s disease therapy resulting from this work could be something that locally activates CAR in small intestinal T cells or something that targets another gene that is similarly responsible for promoting secure communication between small intestinal T cells and bile acids,” he says. Sundrud.
It is also interesting that the team found that the bile acid and inflammation feedback system acted somewhat differently in the colon, along with intestinal microbiome factors. Although the intestinal flora had a greater impact on T cell development and function in the colon, the CAR nuclear receptor had a greater impact on inflammation in the small intestine.
Inflammation has both positive and negative roles in the body. It can damage tissue, but it also suppresses the growth of cancer and fights infections. Current anti-inflammatory treatments systemically rule it out throughout the body. This can have potentially serious consequences, such as reduced resistance to infections or facilitated cancer inhibition. He says it would be desirable to focus the treatment of inflammatory diseases only on the affected tissue whenever possible.
“Approximately 50 million people living in the U.S. with some type of autoimmune or chronic inflammatory disease are treated in the same medical way,” Sundrud says. “The Holy Grail should devise drugs that can be treated to treat inflammation only in certain tissues, leaving the rest of the immune cells in your body intact and capable of fighting cancer and microbial infections.”
Scripps Research Institute
Chen, ML, and others. (2021) CAR directs the adaptation of T cells to bile acids in the small intestine. Nature. doi.org/10.1038/s41586-021-03421-6.