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IBD: Scientists find major cause that drives excessive inflammation

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6 months ago

June 14, 2024

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IBD: Scientists find major cause that drives excessive inflammation

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Scientists have discovered the genetic mechanism underpinning inflammatory bowel disease. Maria Korneeva/Getty Images

New research has elucidated how an already identified area of the genome contributes to the development of a number of autoimmune or inflammatory diseases, including inflammatory bowel disease (IBD).
The discovery of this genetic mechanism could help identify drugs that already exist that could be used to treat inflammatory bowel disease (IBD).
Some experts say further studies in patients with IBD are needed to confirm if these medications have the intended effect.

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

Previous genome-wide association studies into IBD, and some other inflammatory and autoimmune diseases, had identified variants on a region of the genome as being linked to these conditions. The role they played in these diseases was unclear as this part of the genome was a “gene desert” which contained non-coding regions of DNA. There, they found a section of DNA that enhances the number of proteins that nearby genes make; this enhancer was translated only in macrophages, an immune cell with significant function in IBD.

It essentially raised the volume on a gene called ETS2, a gene quite a long way away from this section of DNA, which scientists found was essential for almost all inflammatory functions in macrophages, including several that directly contribute to tissue damage in IBD. An increased amount of ETS2 activity in macrophages made them resemble inflammatory cells in patients with IBD.

The findings were published in the journal Nature.

There are no drugs that directly block ETS2, but the researchers found that MEK inhibitors — drugs that can be used to treat cancer — targetted other parts of this pathway and reduced inflammation in macrophages and gut samples from patients with IBD.

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

Irritable bowel disease (IBD), which includes ulcerative colitis or Crohn’s disease, causes inflammation in the digestive tract, leading to a range of symptoms including pain, diarrhea, and less commonly constipation, weight loss, and problems absorbing nutrients. An estimated 6 million people worldwide have IBD, and the Centers for Disease Control and Prevention say that there are about 3 million people in the U.S. who have it. The root cause has not been identified, but a recent study suggests a connection between genetics, diet, and gut microbiota that could lead to developing IBD.

Only about 10% of the drugs to treat such inflammatory or autoimmune diseases that enter the clinical development stage become fully approved for treatment, which the researchers for this paper say reflects a poor understanding of how these diseases work. This prompted their research, which was intended to explore how genetic pathways could contribute to these diseases.

Ruslan Medzhitov, PhD, sterling professor of immunobiology at the Yale School of Medicine, told Medical News Today that the researchers’ findings represent very important advances in the identification and targeting of genetic variants that can cause IBD and other medical issues.

“Studies that look for genetic associations with a particular disease often find signals (genomic variants) that do not match any specific genes. This makes it very hard to figure out how these variants impact on the disease development. In this case, such a genetic variant was mapped to a region of a part of the human genome where a long stretch of DNA is devoid of genes (so-called ‘Gene Desert’),” Medzhitov said.

“In this study, researchers were able to discover that this genetic variant, known to be associated with an increased risk of inflammatory bowel disease (IBD), affected a piece of DNA that controlled the expression of a gene (called ETS2) located far away from the variant. This is the first major finding — connecting an ‘anonymous’ mutation to a specific gene. Secondly, they demonstrated that elevated expression of ETS2 in macrophages promotes their inflammatory functions, which would explain how it contributes to IBD development.”
— Ruslan Medzhitov, PhD

Şebnem Ünlüişler, genetic engineer at the London Regenerative Institute, told Medical News Today that while the research is a step forward to understanding how inflammatory or autoimmune diseases operate, a broader test of the findings needs to be performed.

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

“One potential flaw is that the study’s experiments were mostly done in controlled lab settings, which might not fully replicate the complex environment in a living organism. More diverse and larger sample sizes could help confirm the findings,” she added.

“IBD is a complex disease, with many genes making contributions to different 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 unknown mechanistic connection to a disease (and not just IBD).”

Ünlüişler said that with more expansive application of the researchers’ findings, the ability to attack autoimmune diseases could be greatly increased. But she cautioned that the delicate nature of such diseases — and their pathways in the body — can complicate treatments.

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