Understanding the causes of tummy (abdominal) pain in Crohn’s and Colitis

What this research looked at

Tummy pain, sometimes referred to as abdominal pain, is common in people with Crohn’s or Colitis. It can greatly reduce quality of life, whether that’s making it harder to sleep well, needing to take time off work or school, or being in constant pain. Tummy pain is a symptom that has an impact both during a flare-up and when symptoms are well controlled. In people with Crohn’s or Colitis, pain is likely to be triggered by mediators released from the diseased bowel. These mediators activate the pain-sensing nerves in the gut, resulting in the feeling of pain.

Dr Bulmer’s research team previously found that the activation of pain-sensing nerves is greatest in people with Crohn’s or Colitis who report the highest levels of abdominal pain. This research project focused on finding out which mediators are most responsible for activating these pain-sensing nerves.

Dr Bulmer’s team found that one mediator, an enzyme called matrix metalloproteinase 12 (MMP-12), can activate pain-sensing nerves. It’s already known that MMP-12 is released from the bowel of people with Crohn’s and Colitis. The researchers explored how MMP-12 and other matrix metalloproteinases (MMPs) activate nerves. By doing this they hoped to better understand what causes tummy pain in people with Crohn’s or Colitis.

What the researchers found 

The researchers think that blocking MMPs will reduce pain by preventing ulcer formation and inflammation. They also think that it will stop the direct activation of pain-sensing nerves. The effects of MMPs on pain-sensing nerves were shown to be driven by a receptor called protease-activated receptor-1 (PAR1).

What the researchers think this might mean for people with Crohn’s and Colitis

By understanding how different MMPs can cause abdominal pain, the researchers hope this will lead to new treatments. Medicines that block MMPs, called MMP inhibitors, could be effective treatments of abdominal pain. The researchers hope that the findings from this project could support the development of MMP inhibitors for the treatment of abdominal pain for people living with Inflammatory Bowel Disease.

Developing new, effective treatments for abdominal pain could increase the quality of life for people living with Crohn’s and Colitis who experience pain.

Scientific publications

Bhebhe CN, Higham JP, Gupta RA, Raine T, Bulmer DC. KV7 but not dual small and intermediate KCa channel openers inhibit the activation of colonic afferents by noxious stimuli. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2023 Nov 1;325(5):G436-45. https://doi.org/10.1152/ajpgi.00141.2023

Higham JP, Bhebhe CN, Gupta RA, Tranter MM, Barakat FM, Dogra H, Bab N, Wozniak E, Barker KH, Wilson CH, Mein CA, Raine T, Cox JJ, Wood JN, Croft NM, Wright PD, Bulmer DC. Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease. Pain. 2024 Jul 1;165(7):1592-604. https://doi.org/10.1097/j.pain.0000000000003159

Chakrabarti S, Hore Z, Pattison LA, Lalnunhlimi S, Bhebhe CN, Callejo G, Bulmer DC, Taams LS, Denk F, Smith ES. Sensitization of knee-innervating sensory neurons by tumor necrosis factor-α-activated fibroblast-like synoviocytes: an in vitro, coculture model of inflammatory pain. Pain. 2020 Sep 1;161(9):2129-41. https://doi.org/10.1097/j.pain.0000000000001890

Pattison LA, Cloake A, Chakrabarti S, Hilton H, Rickman RH, Higham JP, Meng MY, Paine LW, Dannawi M, Qiu L, Ritoux A, Bulmer DC, Callejo G, Smith ESJ. Digging deeper into pain: an ethological behavior assay correlating well-being in mice with human pain experience. Pain. 2022 May 13:10-97. https://doi.org/10.1097/j.pain.0000000000003190

Higham JP, Bhebhe CN, Gupta RA, Tranter MM, Barakat FM, Dogra H, Bab N, Wozniak E, Barker KH, Wilson CH, Mein CA, Raine T, Cox JJ, Wood JN, Croft NM, Wright PD, Bulmer DC. AT1 receptors mediate the stimulatory effect of angiotensin ii on nociceptive neurons. DDW 2022 San Diego.

Charity Bebhe, James Higham1, Paul Wright, David Bulmer. Matrix metalloproteinases stimulate nociceptors via protease activated receptor 1 (PAR1) activation. World Congress on Pain 2022 Toronto

R Gupta, J Higham, T Raine, P Wright, D Bulmer. MMP12 stimulates colonic afferents, and nociceptors through the activation of PAR1. ECCO 2024 Berlin

Who lead this research: Dr David Bulmer, University of Cambridge 
Our funding: £69,978 
Duration: 3 years 
Official title of application: Matrix metalloproteinases, critical mediators of visceral nociception in inflammatory bowel disease