by Wayne Persky
Founder and President of the Microscopic Colitis Foundation
New research recently published by the doctors at the Royal Free Hospital claims to be a significant discovery in understanding (and potentially treating) inflammatory bowel disease (IBD), and possibly other autoimmune diseases (Royal Free NHS London Foundation Trust, 2024, June 5; Stankey, et al., 2024).1 So let's take a closer look.
The ETS2 gene drives inflammation in the intestines through its role as a central regulator of inflammatory responses in macrophages, a type of immune cell that plays a critical role in the body's immune defense and inflammation processes.
The research led to the following key findings and their implications:
Key findings
- The researchers identified a section of DNA known as an enhancer, located in a non-coding region (often referred to as a "gene desert"), which is active only in macrophages, a type of immune cell prevalent in IBD. This enhancer boosts the expression of the ETS2 gene, which is now recognized as a central regulator of inflammatory responses in macrophages. Higher levels of ETS2 are associated with increased inflammation and tissue damage, particularly in the gastrointestinal tract, leading to the chronic symptoms observed in IBD patients.
- The study confirmed that existing drugs, particularly MEK inhibitors, which are used for non-inflammatory conditions, can reduce ETS2 activity and thereby lower inflammation in IBD. However, these drugs are not currently suitable for long-term use due to side effects. The research team is now exploring ways to deliver these inhibitors directly to macrophages, which theoretically could offer a safer and more effective treatment option for IBD and potentially other autoimmune diseases.
- The findings suggest that overproduction of ETS2 is not only a major driver of IBD but may also be implicated in other autoimmune conditions linked to the same genetic region on chromosome 21 (chr21q22), such as ankylosing spondylitis and primary sclerosing cholangitis. This discovery provides a new target for developing drugs that inhibit the ETS2 pathway, potentially offering relief to millions of people suffering from various inflammatory diseases, if successful.
The intestines contain tissue-specific macrophages.
The research appears to focus on these intestinal macrophages. Basically, the researchers propose inhibiting intestinal macrophage activity in order to suppress intestinal inflammation. But intestinal macrophages did not evolve to cause the development of IBD. They're there to maintain gut health and immune balance.
Intestinal macrophages continuously monitor the gut for pathogens and harmful microbes. Unlike other macrophages, intestinal macrophages are less inflammatory, and they promote tolerance to the vast number of harmless bacteria in the gut while still defending against pathogens. And one of their most important functions is to help in maintaining the integrity of the intestinal barrier by clearing dead cells and debris without causing inflammation. In other words, intestinal macrophages are critical in balancing the gut's immune responses and ensuring a stable environment in the intestines.
Intestinal macrophages continuously monitor the gut for pathogens and harmful microbes. Unlike other macrophages, intestinal macrophages are less inflammatory, and they promote tolerance to the vast number of harmless bacteria in the gut while still defending against pathogens. And one of their most important functions is to help in maintaining the integrity of the intestinal barrier by clearing dead cells and debris without causing inflammation. In other words, intestinal macrophages are critical in balancing the gut's immune responses and ensuring a stable environment in the intestines.
Deactivating intestinal macrophages would impose significant risks.
While deactivating intestinal macrophages could lead to significant problems, such as a higher risk of infections, a disrupted balance between immune response and tolerance, and loss of integrity of the gut lining (leaky gut), the goal of this project, ideally, is not to deactivate intestinal macrophages, but to inhibit their overactivity associated with IBD. If this goal can be successfully accomplished, intestinal macrophages will still be able to perform their normal functions without the elevated activity level that leads to the inflammation associated with active IBD.
What are the takeaways?
Utilizing this discovery to develop safe and effective ETS2 inhibitors might hold the potential to provide much more effective autoimmune disease treatments, but of course there are never any guarantees regarding the outcome of medical research projects. Early opinions of discoveries such as this are almost always overly optimistic. Translating this discovery into the development of more effective treatment options for IBD, and other autoimmune diseases, is not a slam dunk. That work remains to be done (if, indeed, it can be done).
But if these research goals can be met, and a safe, effective treatment successfully developed, it will indeed revolutionize the treatment of IBD and probably numerous other autoimmune diseases. Of course in actual practice, such fine tuning of control in a drug treatment is seldom achieved, and the result is reduced effectiveness and unwanted side effects.
But if these research goals can be met, and a safe, effective treatment successfully developed, it will indeed revolutionize the treatment of IBD and probably numerous other autoimmune diseases. Of course in actual practice, such fine tuning of control in a drug treatment is seldom achieved, and the result is reduced effectiveness and unwanted side effects.
References
1. Royal Free NHS London Foundation Trust. (2024, June 5). Major cause of inflammatory disease revealed. NHS, Retrieved from https://www.royalfree.nhs.uk/news/major-cause-inflammatory-disease-revealed
