Study reveals possibility of new drug therapy
A targeted treatment for people with Crohn’s disease could soon be available, according to new research.
Crohn’s is an inflammatory bowel disease which can affect any part of the gut, from the mouth to the anus.
Patients are typically treated with powerful anti-inflammatory medications that act throughout the body, not just in the digestive tract, creating the potential for unintended, and often serious, side-effects.
Writing in the April 2021 edition of the journal Nature, Sundrud et al said they found that certain immune cells in the small intestine have evolved a molecular sensing mechanism to protect themselves from the toxic effects of high bile acid concentrations in the small intestine.
This sensory mechanism can be manipulated with small drug-like molecules, and the treatment had reduced small bowel inflammation in mice.
“It seems that these immune cells, called T effector cells, have learned how to protect themselves from bile acids,” said lead researcher Mark Sundrud – Associate Professor, Department of Immunology and Microbiology, at Scripps Research in Florida.
“These T cells utilise an entire network of genes to interact safely with bile acids in the small intestine,” he added.
“This pathway may malfunction in at least some individuals with Crohn’s disease.”
Sundrud et al previously reported that a gene called MDR1, also known as ABCB1, is activated when an important subset of immune cells that circulate in blood, called CD4+ T cells, make their way into the small intestine.
There, MDR1 acts in transitory T cells to suppress bile acid toxicity and small bowel inflammation.
In the new study, Sundrud’s team uses an advanced genetic screening approach to uncover how T cells sense and respond to bile acids in the small intestine to increase MDR1 activity.
“The basic discovery that T cells dedicate so much of their time and energy to preventing bile acid-driven stress and inflammation highlights completely new concepts in how we think about and treat Crohn’s disease,” Sundrud said.
“It’s like we’ve been digging in the wrong spot for treasure, and this work gives us a new map showing where X marks the spot.”
The T cells contain a receptor molecule in their nucleus known as the constitutive androstane receptor (CAR).
Acting in the small intestine, CAR promotes expression of MDR1, and also plays a role in activating an essential anti-inflammatory gene, IL-10, researchers noted.
“When we treated mice with drug-like small molecules that activate CAR, the result was localised detoxification of bile acids and reduction of inflammation,” Sundrud explained.
Sundrud said that exploring the therapeutic potential of CAR activation required caution and creativity, because CAR was also critical for breaking down and eliminating other substances in the liver, including many medicines.
“Ultimately, the Crohn’s disease therapy that emerges from this work could be something that activates CAR locally in small intestinal T cells, or something that targets another gene that is similarly responsible for promoting the safe communication between small intestinal T cells and bile acids,” he added.