Excessive three-stranded RNA-DNA structures (called R-loops) can cause inflammatory bowel disease

What is it about?

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestines, including Crohn's disease and ulcerative colitis. Despite its prevalence, the exact cause of IBD has remained elusive, making effective treatment a challenge. Here we discovered that oxidative stress causes excessive build-up of nucleic acid R-loops, which are three-stranded RNA-DNA structure, in intestinal epithelial cells. This build-up happens because a protein called TDP-43 moves from the cell's nucleus to its cytoplasm, where it shouldn't normally be. The excess R-loops then trigger inflammation in the intestines by causing a type of cell death called necroptosis. This process is initiated by the depletion of NAD+, an essential molecule for cell survival and function. Furthermore, we discovered that supplementing with a molecule called NAD+ and its precursor NMN can reduce inflammation in the colon. This suggests that NMN could be a promising treatment for IBD.

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Photo by julien Tromeur on Unsplash

Photo by julien Tromeur on Unsplash

Why is it important?

Our findings show that oxidative stress-induced excessive nucleic acid R-loops trigger intestinal inflammation by initiating a type of cell death called necroptosis in epithelial cells, and provide proof-of-principle that NMN is a viable therapeutic approach for IBD.

Perspectives