Scientists discover major new cause of inflammatory bowel disease

• New research has elucidated how a previously identified area of ​​the genome contributes to the development of a number of autoimmune or inflammatory diseases, including inflammatory bowel disease (IBD).

• Discovering this genetic mechanism could help identify already existing drugs that could be used to treat inflammatory bowel disease (IBD).

• Some experts say additional studies in IBD patients are needed to confirm whether these drugs have the desired effect.

Scientists at the Francis Crick Institute in London have identified a genetic mechanism underlying the development of inflammatory bowel disease (IBD) and other autoimmune or inflammatory diseases and identified existing drugs that could target this pathway.

Previous genome-wide association studies of IBD and some other inflammatory and autoimmune diseases have identified variants on a region of the genome as being linked to these conditions. The role they played in these diseases was unclear because this part of the genome was a “genetic desert” that contained non-coding regions of DNA. There, they found a section of DNA that increases the number of proteins produced by neighboring genes; this activator was only translated in macrophages, an immune cell with significant function in IBD.

This essentially increased the volume of a gene called ETS2, a gene quite distant from this section of DNA, which scientists have discovered is essential for almost all inflammatory functions of macrophages, including several that directly contribute to tissue damage in IBD. An increased amount of ETS2 macrophage activity made them resemble inflammatory cells in IBD patients.

The results were published in the journal Nature.

There is no drug that directly blocks ETS2but researchers found that MEK inhibitors – drugs that can be used to treat cancer – targeted other parts of this pathway and reduced inflammation in macrophages and intestinal samples from IBD patients.

This development could help identify drugs and drug targets to treat IBD, which has historically proven difficult.

How do IBD work within the immune system?

Irritable bowel disease (IBD), which includes ulcerative colitis or Crohn’s disease, causes inflammation of the digestive tract, leading to a range of symptoms including pain, diarrhea and, more rarely, constipation, weight loss and problems with nutrient absorption. An estimated 6 million people worldwide have IBD, and the Centers for Disease Control and Prevention says about 3 million people in the United States have it. The root cause has not been identified, but a recent study suggests a link between genetics, diet and the gut microbiota that could lead to the development of IBD.

Only about 10% of drugs intended to treat these inflammatory or autoimmune diseases that enter clinical development are fully approved for treatment, which the researchers in this article say reflects a poor understanding of how these diseases work. . This motivated their research, which aimed to explore how genetic pathways might contribute to these diseases.

Ruslan Medzhitov, PhD, an excellent professor of immunobiology at the Yale School of Medicine, said Medical news today that the researchers’ findings represent very important advances in identifying and targeting genetic variants that can cause IBD and other medical problems.

“Studies that look for genetic associations with a particular disease often find signals (genomic variants) that do not correspond to any specific gene. It is therefore very difficult to understand the impact of these variants on the development of the disease. In this case, such a genetic variant was mapped to a region of part of the human genome where a long stretch of DNA is devoid of genes (the so-called “genetic desert”),” Medzhitov said .

Şebnem Ünlüişler, a genetic engineer at the London Regenerative Institute, said Medical news today that if the research represents a step forward in understanding how inflammatory or autoimmune diseases work, a broader test of the results must be carried out.

“The study highlights the important role of ETS2 gene in mediating inflammation in macrophages, particularly in the context of inflammatory bowel disease (IBD). By identifying a specific activator within a genetic desert that regulates ETS2the research provides a better understanding of how genetic variations can contribute to chronic inflammatory diseases,” said Ünlüişler.

“A potential flaw is that the study experiments were primarily performed in controlled laboratories, which might not fully replicate the complex environment of a living organism. More diverse and larger samples could help confirm the results,” she added.

Can IBD be reduced with existing medications?

“IBD is a complex disease, in which many genes contribute to varying degrees. This particular pathway may be relevant for a subset of IBD patients,” Medzhitov said. “But a broader implication is that the approaches used here can be applied to other cases where genetic variants have an unknown mechanistic link to disease (and not just IBD).”

Ünlüişler said that with wider application of the researchers’ findings, the ability to attack autoimmune diseases could be significantly increased. But she warned that the delicate nature of these diseases – and their pathways in the body – can complicate treatments.

“If these findings apply broadly, they could lead to new treatments targeting ETS2, potentially reducing inflammation more effectively and with fewer side effects than current treatments.” However, precisely targeting ETS2 could prove difficult and requires careful development to avoid unintended effects on other bodily functions,” she said.

View original article on Medical News Today