A Major Cause of Inflammatory Bowel Disease Uncovered

18th June 2024

By Samantha Weetman, Science Writer.

Inflammatory Bowel Disease (IBD) encompasses a group of disorders, primarily Crohn’s disease and ulcerative colitis, that cause chronic inflammation in the digestive tract. Affecting millions globally, the exact causes of these debilitating diseases have remained elusive, despite extensive research efforts. However, recent scientific advancements have provided new insights into the underlying causes of IBD, offering hope for more effective treatments and improved management strategies[1]. In this blog post, we explore the latest groundbreaking research that identifies a major cause of IBD and its implications for future therapies.

Incidence and History of IBD

IBD is a significant global health issue; since its initial identification in the early 20th century incidence rates have been rising, particularly in Western countries[2], [3], [4]. According to recent studies, over half a million people in the UK are living with IBD[5] and global estimations exceed 6.8 million[2]. Crohn’s disease and ulcerative colitis, the two primary types of IBD, lead to severe gastrointestinal inflammation, causing symptoms like abdominal pain, diarrhoea, and weight loss. These diseases often require lifelong management, impacting patients’ daily lives and mental health.

For some more background on the relationship between the gut and the brain, take a look at our previous blog – The Gut-Brain Axis: the two-way street of physical and mental health.

The quest to understand IBD has spanned decades, involving genetic, environmental, and immunological studies. Researchers have long suspected a complex interplay of these factors in disease onset and progression, but pinpointing specific causes has been challenging. The increasing prevalence highlights the urgency for innovative research and better understanding of the disease mechanisms.

A Breakthrough: Uncovering the Biological Pathway of IBD

A groundbreaking study published in Nature has identified a major genetic contributor to IBD, marking a pivotal moment in the field of gastroenterology. Through investigating an intergenic region on chromosome 21q22 (chr21q22), the international team of scientists uncovered an enhancer that interacts with the promotor of ETS2. This subsequently led to the identification of ETS2 as the causal gene of IBD when upregulated[1].

Key Discoveries in IBD biology

The study revealed several critical findings about the disease mechanism and the enhancer at the associated locus on chr21q22:

1.Enhancer-Promoter Interaction: The chr21q22 enhancer interacts with the promoter of the ETS2 gene, which is approximately 290 kb away. This interaction is crucial for the regulation of ETS2 expression during inflammation.

2.Identification of ETS2: Through promoter-capture Hi-C and expression quantitative trait locus (eQTL) analysis, ETS2 was identified as the primary gene influenced by this enhancer. Its expression was significantly elevated in monocytes and macrophages from individuals carrying the IBD risk haplotype.

3.CRISPR-Cas9 Validation: Using CRISPR-Cas9 to delete the chr21q22 enhancer, researchers observed a marked reduction in ETS2 expression, confirming the enhancer’s role in regulating this gene.

4.Inflammatory Response: ETS2 has an essential role in inflammation. The elevated expression of ETS2 in response to inflammatory stimuli highlights its importance in macrophage-mediated inflammation, a key process in IBD pathogenesis.

Implications for IBD Treatment

The identification of ETS2’s role in IBD introduces exciting implications for treatment strategies. By targeting ETS2 or the chr21q22 enhancer, researchers propose a novel approach to modulate gene expression and curb inflammation associated with IBD. Their findings show the potential of MEK (mitogen activated protein kinase) inhibitors in reducing ETS2 expression and dampening inflammatory responses, suggesting a promising avenue for repurposing these drugs.

In order to avoid MEK inhibitor toxicity, the drug could be selectively delivered via the suggested method of antibody-drug conjugates to macrophages directly. This repurposing could expedite the development of new therapies, leveraging existing treatments’ safety profiles. Furthermore, the study encourages exploration into other small molecules and biologics that target the ETS2 pathway. Overall, the identification of the ETS2 enhancer as a therapeutic target marks a significant step toward innovative treatments that address the genetic underpinnings of IBD and improve patient outcomes.

A Hopeful Future

The discovery of the ETS2 enhancer as a key factor in IBD offers a beacon of hope for developing more effective and targeted treatments. This breakthrough not only unveils new therapeutic targets but also highlights the significance of non-coding genetic associations, and the untapped opportunities to resolve disease biology through genome-wide association studies (GWASs). This study has revitalised the pursuit of innovative solutions for IBD patients, paving the way for treatments that could significantly enhance the quality of life for millions affected by IBD.

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References

[1]      C. T. Stankey et al., ‘A disease-associated gene desert directs macrophage inflammation through ETS2’, Nature, vol. 630, no. 8016, pp. 447–456, Jun. 2024, doi: 10.1038/s41586-024-07501-1.

[2]      S. Alatab et al., ‘The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017’, The Lancet Gastroenterology & Hepatology, vol. 5, no. 1, pp. 17–30, Jan. 2020, doi: 10.1016/S2468-1253(19)30333-4.

[3]      R. Wang, Z. Li, S. Liu, and D. Zhang, ‘Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019’, BMJ Open, vol. 13, no. 3, p. e065186, Mar. 2023, doi: 10.1136/bmjopen-2022-065186.

[4]      G. P. Caviglia et al., ‘Epidemiology of Inflammatory Bowel Diseases: A Population Study in a Healthcare District of North-West Italy’, J Clin Med, vol. 12, no. 2, p. 641, Jan. 2023, doi: 10.3390/jcm12020641.

[5]      K. Freeman, R. Ryan, N. Parsons, S. Taylor-Phillips, B. H. Willis, and A. Clarke, ‘The incidence and prevalence of inflammatory bowel disease in UK primary care: a retrospective cohort study of the IQVIA Medical Research Database’, BMC Gastroenterology, vol. 21, no. 1, p. 139, Mar. 2021, doi: 10.1186/s12876-021-01716-6.