How does IBD operate within the immune system?
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 peopleTrusted Source 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.
Can IBD be reduced with existing drugs?
“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.
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