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How ROS loss leads to inflammatory bowel disease

Reactive oxygen species, or ROS, get a bad rap. The volatile byproducts of chemical reactions with oxygen, they’re well-known markers of inflammation. Their build-up can damage DNA, RNA and proteins in the cell.

But the compounds are critical to some biological functions such as maintaining the health of the lining in the gut, where a ROS imbalance can lead to conditions like inflammatory bowel disease, or IBD. Now, scientists at Mount Sinai have characterized the mechanism by which ROS exert their protective effects, opening the door to new IBD treatments. The results of their work were published Oct. 3 in the journal Gut.

“While it’s clear that regulation of oxygen and reactive oxygen species plays a crucial role in chronic diseases generally, and IBD in particular, this study provides a major advance in defining the key role of oxygen species in maintaining a healthy epithelial barrier for IBD,” Judy Cho, MD, senior author, said in a press release.

The researchers built upon previous studies showing that loss-of-function mutations in a gene called NOX1 resulted in a ROS deficiency, which had been linked to IBD development. They also hypothesized that tumor necrosis factor alpha, or TNF-alpha—an inflammatory compound that IBD drugs inhibit—might be playing a role as well.    

The scientists started by analyzing ROS levels and NOX1 gene expression profiles in intestinal cells from mice and human patients with and without ulcerative colitis, a subtype of the IBD. As expected, the loss-of-function mutation in NOS led to a decline in ROS, which was driven by lower levels of transcription factors that are key to the compounds’ production.  

But that wasn’t all. In the presence of TNF-alpha, the loss of ROS also led to a pathological increase in the number of intestinal stem cells differentiating into microfold cells, or M cells, which recruit immune molecules to the gut and promote inflammation. The immune induction slowed when the cells were treated with ROS.

It’s too soon to tell whether directly treating patients with ROS could work as a therapy for patients with IBD. Still, there are few if any existing therapies that target the intestinal cells themselves, the scientists noted. If borne out in future research, their findings could lead to an attractive new treatment pathway.

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