Blocking gut danger signals as a target for Inflammatory Bowel Disease treatment

What this research looked at

In people with Crohn’s or Colitis, damaged gut cells release danger signals. One of these danger signals is called mitochondrial DNA. This is genetic material that leaks out from the ‘batteries’ that power the cell (the mitochondria) when they are damaged. Mitochondrial DNA is very similar to DNA from bacteria. Immune cells can confuse mitochondrial DNA with bacterial DNA, and react to it. This can drive gut inflammation.

The researchers wanted to find out:

• Whether mitochondrial DNA from people with active Crohn’s or Colitis triggered a greater inflammatory response than mitochondrial DNA from people with Crohn’s or Colitis in remission or from people without Crohn’s or Colitis
• Whether blocking the sensor in immune cells that detects mitochondrial DNA could be helpful
• Whether any medicines might be able to block the inflammatory response to mitochondrial DNA

What the researchers found

The researchers confirmed that levels of mitochondrial DNA in blood samples were higher in people with Crohn’s or Colitis with active disease than in those who were in remission. They also found that mitochondrial DNA from damaged gut cells gets broken down into very short strands. They proved that these short strands activated immune cells in lab tests.

They found that a sensor called STING on specialised immune cells detects these short fragments of mitochondrial DNA. This makes the immune cells send chemical signals that trigger an inflammatory response. The researchers found that levels of these chemicals were higher in biopsy samples from people with active Crohn’s or Colitis than from people with Crohn’s or Colitis in remission or people without Crohn’s or Colitis. This shows that the STING pathway is important in driving gut inflammation and could be a possible target for new medicines.

What the researchers think this could mean for people with Crohn’s or Colitis

The researchers think that a test to measure levels of short strands of mitochondrial DNA could be a useful way to monitor gut inflammation in people with Crohn’s or Colitis. They are looking into this in more detail in a clinical trial called MUSIC. They are also working with researchers at Heriot-Watt University to develop a faster way to test mitochondrial DNA levels.

They also hope that, in the future, they might be able to develop a medicine that blocks the STING pathway. They think this could have the potential to reduce inflammation in people with high levels of mitochondrial DNA. They are planning to test this theory in the lab to see if they can find any possible drug targets.

Scientific publications

• Ho GT, Theiss AL. Mitochondria and inflammatory bowel diseases: Toward a stratified therapeutic intervention. Annual Review of Physiology 2022; 84: 435–459. Available at: https://www.annualreviews.org/doi/abs/10.1146/annurev-physiol-060821-083306
• Ho GT, Cartwright JA, Thompson EJ, Bain CC, Rossi AG. Resolution of inflammation and gut repair in IBD: Translational steps towards complete mucosal Inflammatory Bowel Disease 2020; 26(8): 1131–1143. Available at: https://academic.oup.com/ibdjournal/article/26/8/1131/5813958
• Porter RJ, Kalla R, Ho GT. Ulcerative colitis: Recent advances in the understanding of disease pathogenesis. F1000 Research 2020; 9: F1000 Faculty Rev-294. Available at: https://f1000research.com/articles/9-294/v1

Who is leading this research: Dr Gwo-Tzer Ho, Centre for Inflammation Research, University of Edinburgh
Our funding:  £118,767
Duration: 2 years
Official title of application: Blocking gut danger signals as treatment for inflammatory bowel disease