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Novel Targeted Treatment Approach in Crohn’s Disease

Crohn’s disease is a type of inflammatory bowel disease (IBD) that causes inflammation of the digestive tract. Anti-inflammatory medications can greatly reduce its signs and symptoms and even bring about long-term remission and healing of inflammation. However, medications do not just target the digestive tract; they can affect the entire body creating the potential for unintended side effects. Using a mouse model, researchers led by Mark Sundrud, PhD, associate professor, department of immunology and microbiology at Scripps Research, Florida, now suggest a more targeted treatment approach.

Their findings are described in the journal Nature in a paper titled, “CAR directs T cell adaptation to bile acids in the small intestine.”

“Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine,” wrote the researchers. “As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn’s disease-like small bowel inflammation. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine.”

The researchers discovered that certain immune cells in the small intestine have learned how to protect themselves from the effects of high bile acid concentrations by using a molecular sensing mechanism to protect themselves.

“It seems that these immune cells, called T effector cells, have learned how to protect themselves from bile acids,” Sundrud explained. “These T cells utilize an entire network of genes to interact safely with bile acids in the small intestine. This pathway may malfunction in at least some individuals with Crohn’s disease.”

Because they are detergents, bile acids can cause toxicity and inflammation if the system becomes unbalanced. The whole process is kept humming along thanks to an intricate signaling system. Receptors in the nucleus of both liver cells and intestinal barrier cells sense the presence of bile acid and tell the liver to back off on bile acid production if there’s too much, or to produce more if there aren’t enough to digest a big steak dinner, for example.

Sundrud’s team previously reported how a gene called MDR1 becomes activated when 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, the researchers used an advanced genetic screening approach to uncover how T cells use their sensing mechanism to increase MDR1 activity.

“Activation of CAR [constitutive androstane receptor] induced large-scale transcriptional reprogramming in Teff cells that infiltrated the siLP, but not the colon,” wrote the researchers. “CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1/ or Rag2/ mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation.”

Sundrud stated that the findings 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. “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,” he said.

When the researchers treated mice with drug-like small molecules that activate CAR, the result was localized detoxification of bile acids and reduction of inflammation.

“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,” Sundrud said.

The researchers also discovered that the bile acid-inflammation feedback system worked differently in the colon in concert with gut microbiome factors. While gut flora had more influence on T cell development and function in the colon, it was the nuclear receptor CAR that had more influence on inflammation in the small intestine.

“The roughly 50 million people living in the United States with some sort of autoimmune or chronic inflammatory disease are all treated the same, medically,” Sundrud said. “The holy grail would be to come up with druggable approaches to treat inflammation in only specific tissues and leave the rest of the immune cells in your body untouched, and able to fend off cancer and microbial infections.”

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