Finding ways to stop fibrosis in Crohn’s

2018

2018


By understanding the mechanisms that drive fibrosis we will be able to find targets for better treatments for strictures.

Prof Andrew Silver and Prof James Lindsay
Barts and the London School of Medicine

What is this research looking at? 

Ongoing (chronic) inflammation in Crohn’s Disease can cause tissue damage and scarring in the bowel. This is known as fibrosis. Fibrosis can lead to strictures (narrowing) and blockage of the bowel. 1 in 3 people with Crohn’s will develop strictures – and may experience pain and vomiting due to a blockage. No current treatment can reverse or cure fibrosis. Strictures caused by fibrosis are the main reason for surgery in people with Crohn’s. Surgery is associated with a higher risk of unemployment and a poorer quality of life due to disease recurrence. New treatments are urgently needed to prevent or reverse fibrosis in Crohn’s.

The factors that drive fibrosis in the bowel are complicated and not fully understood. Fibrosis involves cells in the bowel wall called fibroblasts. Fibroblasts make collagen – collagen encourages fibrosis and causes strictures. Understanding how fibrosis and bowel blockage happens in Crohn’s will help researchers discover new treatments. In this study, the researchers were interested in an important chemical change in fibroblasts in people with Crohn’s. When this change goes wrong in other diseases, it causes inflammation and fibrosis, which can be treated using medicines.

The researchers had already shown that valproic acid – used to treat other conditions such as epilepsy – has an effect on this chemical change. It stops the formation of collagen. Testing whether existing medicines, like valproic acid, can treat fibrosis in Crohn’s is cheaper and faster than discovering new medicines.

What did the researchers find?

The researchers found that a protein called TGFβ1|1 (also known as HIC-5) plays an important role in fibrosis in the gut in Crohn’s. TGFβ1|1 is increased in Crohn’s patients with strictures and it’s expressed by fibroblasts in the gut, which drive stricture development.

The researchers took fibroblasts from the gut tissue of people with Crohn’s. They treated the fibroblasts with valproic acid in the lab to understand how it reduces collagen production.

Valproic acid reduced TGFβ1|1 and reduced collagen production in gut fibroblasts in the lab. The researchers also found that by blocking TGFβ1|1 in fibroblasts from people with Crohn’s they could reduce collagen production. Blocking TGF-beta1|1 selectively with medicines like valproic acid should be investigated further as a potential new treatment for strictures in people with Crohn’s.

What do researchers think this could mean for people with Crohn's or Colitis? 

There are no specific treatments that prevent or reverse fibrosis in Crohn’s. Valproic acid is a safe and inexpensive medicine. If proven to reduce or reverse fibrosis in high quality clinical trials, medicines like valproic acid will have a major impact on people’s quality of life and ability to work.
     

Who is leading this research:  Professors Andrew Silver and James Lindsay, Blizard Institute, Barts and The London School of Medicine & Dentistry 
Our Funding: £73,573 
Duration: 12 months 
Official title of application: Restoration of histone acetylation levels and reduction of collagen expression via inhibition of HIC-5: a new strategy to limit fibrosis in Crohn’s Disease