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Sealing a Leaky Gut

Cedars-Sinai Investigators Have Discovered a Biological Mechanism That Could Lead to New Therapeutics for Inflammatory Bowel Disease

By studying the cells that line the intestines, Cedars-Sinai investigators have discovered a biological process that helps these cells repair themselves. The findings, published in the journal Cellular and Molecular Gastroenterology and Hepatology, illuminate what goes wrong in people with inflammatory bowel disease (IBD).

IBD is an autoimmune disorder primarily causing ulcerative colitis or Crohn’s disease. The immune system attacks healthy tissue in the gastrointestinal track, and can lead to severe diarrhea, malnutrition, dangerous blood clots, pancreatitis, and extensive and painful scarring.

“Almost all treatments for IBD target inflammation that occurs in this disease,” said Kathrin Michelsen, PhD, research assistant professor of Medicine and Biomedical Sciences in the F. Widjaja Foundation Inflammatory Bowel Disease Institute in the Department of Medicine at Cedars-Sinai, and senior author of the study. “We want to learn how to repair what we refer to as a ‘leaky gut,’ the damaged intestinal lining that also occurs in people with IBD.”

Scientists hypothesize that people with leaky guts are vulnerable to getting harmful substances, such as some types of bacteria, in their bloodstream.

This study by Michelsen and colleagues follows up on previous studies that investigated the function of a gene called tumor necrosis factor superfamily member 15, or TNFSF15. This is one of the first genes found to be associated with IBD.

TNFSF15 produces a protein called TL1A that is involved in intestinal inflammation. The investigators sought to know more about how the interactions between this protein and the intestinal lining might cause IBD symptoms. They focused on the TL1A receptor, a protein called death receptor 3, or DR3. Receptors are proteins that bind to molecules and aid in the communication between cells. DR3 binds to the surface of TL1A, for example.

To perform their study, the investigators observed laboratory mice carrying the TNFSF15 gene and mice not carrying it. They examined cells taken from the intestines of the mice and cultured them in a petri dish to see whether the cells expressed the gene. They also studied whether the collection of cells lining the intestines, known as the epithelial barrier, were damaged and how the cells could heal and grow again. 

Epithelial barrier cells are connected by proteins that keep the lining of the intestines tight. This prevents bacteria from getting into the lamina propria, the connective tissues that also line the intestines and that form part of the immune system. People with IBD typically have inflammation in the lamina propria, which is supposed to serve as a protective physical barrier in the body.  

The investigators discovered that mice that did not produce DR3 had less tightly bound epithelial cells. Their intestines were permeable enough to allow in bacteria that caused inflammation in the lamina propria.

The investigators also discovered that although laboratory mice that had inflammation in their intestines showed increased levels of TL1A, their epithelial cells did not show increased DR3 expression.

“These findings suggest that therapeutic approaches targeting TL1A rather than DR3 could reduce inflammation while preserving the repair mechanisms that DR3 is essential for in epithelial cells,” said Yosuke Shimodaira, PhD, first author of the study and a former investigator at Cedars-Sinai.

DR3, for example, contributes to the regeneration of the epithelial barrier, which is necessary for healing cell damage in the intestines caused by IBD.

“There are currently clinical trials that are studying drugs that target TL1A,” Michelsen said. “It's really important to elucidate all the potential mechanisms that could impact potential therapeutic efficiency and efficacy in those clinical trials.”

The investigators are continuing to study the effects of other genes associated with IBD.

Funding: The study was funded by the National Institutes of Health (award number DK056328) and the F. Widjaja Foundation.

Read more on the Cedars-Sinai Blog: Living a Life That Isn't Defined By IBD