Researchers have discovered a mechanism that drives inflammation in IBD. The discovery may lead to better diagnosis and treatment of two of the most common types of bowel disorders - Crohn’s disease and ulcerative colitis.
Inflammatory bowel disease (IBD), an umbrella term used to describe disorders that trigger chronic inflammation in the digestive tract, remains a clinical puzzle. Current treatments are not effective for all individuals with IBD and many even stop working with time. However, regardless of their different responses to treatment, those living with IBD share a common problem: inflammation in the gastrointestinal tract.
Most recently, researchers have discovered a mechanism that drives inflammation in IBD. The discovery may lead to better diagnosis and treatment of two of the most common types of bowel disorders - Crohn’s disease and ulcerative colitis (UC).
Opening ‘Pandora’s box’
Researchers at Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, in collaboration with researchers at Technion-Israel Institute of Technology in Haifa, Israel, have identified a protein that drives inflammation in the gastrointestinal tract. “Scientists have long known that proteins associated with inflammation can also be linked with IBD. In fact, a U.S. Food and Drug Administration (FDA)–approved clinical diagnosis for IBD relies on some of these proteins. Yet, the cause for the intestinal inflammation remained unknown. Our study has found this mystery player to be a protein that is part of the cell’s protein homeostasis system, RNF5” said Yu Fujita, first author of the paper and postdoctoral fellow at the laboratory of Ze’ev A. Ronai, lead investigator of the study and a professor in the NCI-designated Cancer Center at Sanford Burnham Prebys.
More specifically, Prof. Ronai and his fellow colleagues found that RNF5 regulates the activity of S100A8, a pro-inflammatory protein.
At the start of their investigation, about 10 years ago, the researchers created mice that lacked RNF5. “To our great surprise, these mice did not appear to have any significant traits. We even called them ‘the boring mice’” said Prof. Ronai. The mice had limited symptoms of inflammation in their gastrointestinal tracts, but enough to keep an eye on.
It was that baseline inflammation that led Prof. Ronai and fellow colleagues to wonder what would happen if they prompted more inflammation in the gastrointestinal tracts of the mice. They decided to expose the mice to an inflammation-inducing agent by the name of dextran sodium sulfate and sure enough, they noticed that the mice developed severe IBD. “This certain level of inflammation caught our attention. When we gave the mice inflammatory agents in their drinking water, those who had a lack of the RNF5 gene had very serious inflammation, diarrhea — basically, all of the characteristics of IBD. The fact that almost 50 percent of the mice died as a result of this very minor inflammatory agent indicated that this protein is very important in preventing IBD” said Prof. Ronai.
The researchers also analyzed the role of S100A8, which has already been linked to several inflammatory conditions and is used as a biomarker to diagnosis IBD. They found that RNF5, which is abundant in the cells that line the gastrointestinal tract, keeps S100A8 stable and its absence unleashes the inflammatory power of S100A8. On the contrary, when the researchers used neutralizing antibodies to inactivate S100A8 in the blood of mice, the severe IBD symptoms disappeared. “Our findings indicate that RNF5 is the lock that keeps a key inflammatory protein under control” said Prof. Ronai.
Confirming the results in human samples
To confirm their findings, Prof. Ronai and his fellow colleagues analyzed tissue samples taken from the intestines of 19 individuals with UC and compared the results with tests performed on healthy tissue.
The results revealed that low levels of RNF5 and high levels of S100A8 were associated with disease severity, reinforcing the findings from the RNF5-deleted mice. Prof. Ronai then went on to suggest that IBD may respond to drugs that either regulate RNF5 or deactivate S100A8. “RNF5 also appears to be a potential predictor of disease severity, and could be used as a diagnostic marker” he said.
Avoiding unnecessary treatment
A common type of IBD treatment are TNF inhibitors – drugs used to help stop inflammation. However, TNF inhibitors are not effective for all individuals with IBD and predicting who will benefit from them is important, seeing as how they present severe, unwanted side effects.
In order to determine whether there was an association between RNF5 and response to treatment with TNF inhibitors, Dr. Ronai and his fellow colleagues analyzed the level of RNF5 and the level of S100A8 in patients that either responded or did not respond to treatment with TNF inhibitors. They found that those who did not respond to the treatment had low levels of RNF5. “This finding indicates RNF5 could help predict which IBD patients will respond to anti-TNF therapy. Measuring RNF5 might be a useful biomarker that helps IBD patients and doctors avoid unnecessary treatments” said Prof. Ronai.
An urgent need for new IBD treatments
According to the Centers for Disease Control and Prevention (CDC), over 3 million adults in the United States are living with IBD. Symptoms of IBD include diarrhea, rectal bleeding, abdominal pain and cramping, as well as a sudden and pressing need to use the restroom. All of these symptoms cause pain and discomfort – urging a need for new IBD treatments.
The recent findings have helped to solve a large part of the mystery involving the underlying driving mechanism of IBD. Now, these findings can hopefully lead to more targeted treatments down the line. “Nearly every day I work with IBD patients who are struggling to keep their disease under control. Better treatments that work for more patients are urgently needed. Although early, this study points to several promising targets that could lead to more personalized medicines or new diagnostics for IBD, a subject for future independent investigations” said William Jeffery Sandborn, director of the Inflammatory Bowel Disease Center at UC San Diego Health, who was not affiliated with the study.
Moving forward, Prof. Ronai stated that there are a number of directions he and his research team could be headed. One would likely be to understand what could be the best agent to tackle the pro-inflammatory S100A8 protein. Prof. Ronai also added that their findings could have ramifications beyond IBD, such as a better understanding of effective approaches to treating cancer. “We are trying to understand the manifestation of our findings when it comes to cancer and the reason for why the current immunotherapies that are abundantly given to cancer patients — when effective — are also causing inflammatory disorders” he concluded.