Researchers have unraveled new clues to help explain why a particular genetic mutation is more common in people with Crohn's disease.
Around 260 genes are associated with an increased risk of the inflammatory bowel disorder, although there is no single genetic mutation which triggers its onset.
Environmental factors, such as air pollution or infections, and lifestyle factors such as smoking and diet, are also known to play a part.
However, a mutation in a gene known as PTGER4 is more frequently found in people with Crohn's disease and, until now, scientists were unsure why.
Dr. Gwo-Tzer Ho, a consultant gastroenterologist and researcher at Edinburgh University's Centre for Inflammation Research, said the autoimmune disorder is like "a big jigsaw puzzle".
He added: "It's is not like Cystic Fibrosis where there's a single disease-causing variant so that you can identify the patient by the mutation.
"Even healthy people within the population will carry changes in this gene, but we do find that people with Crohn's disease have a slightly higher frequency.
"Of the 260 genes there are associated with Crohn's disease, this is the third strongest based on a statistical association.
"So we know that it's very closely linked to Crohn's disease but previously we didn't know how it works."
Edinburgh was previously identified as a world hotspot for inflammatory bowel disease (IBD), an umbrella term for ulcerative colitis, which only affects the colon, and Crohn's disease, which can affect any part of the digestive system.
Around one in 125 people in the capital suffer from IBD, but this is predicted to rise to one in 98 by 2029. The prevalence is believed to be similar across Scotland as a whole.
Characterized by symptoms including fatigue, abdominal pain, and severe diarrhea, Crohn's is caused when the body's immune system mistakenly attacks the lining of the digestive tract leading the gut to become inflamed.
The study, led by Dr. Chengcan Yao, a biomedical scientist, in collaboration with Dr. Ho, sheds light for the first time on the role played in this by the PTGER4 gene.
They were able to demonstrate that the gene influences a prostaglandin - a type of fatty chemical which normally protects the gut and other organs - called PGE2.
Instead, it disrupts the gut microbiota - the bacteria needed to keep the digestive system healthy - and this reduces the function of an immune cell called the regulatory T cell, which normally suppresses other immune cells to prevent autoimmune disorders.
This results in intestinal inflammation as the gut comes under attack.
However, when mice in the study were given non-steroidal anti-inflammatory drugs to block PGE2, this was shown to increase the level of beneficial microbes in their gut, promoting the regulatory T cells, and limiting intestinal inflammation.
The team now hopes to progress the research using immune cells collected from human Crohn's patients to develop a new therapy that can block PGE2.
This would be a breakthrough in the treatment of the disease, which currently relies on medications that suppress the immune system itself and often cause unpleasant side effects.
Many Crohn's patients have also had to shield themselves during the pandemic as these drugs leave them more vulnerable to infections such as Covid.
Dr. Ho said: "We will grow these cells in a dish and then interfere with the signaling pathways and relate that back to the genetics of the patients to see what we could block.
"What's really interesting is that there are already drugs out there, like aspirin, that can interfere with this pathway, but it's a slightly complex picture because sometimes aspirin can also make Crohn's disease worse.
"But we hope to move into the next phase, looking at human cells, later on, this year."
The study is published in the journal, Science Advances.
Matt Birnholz, MDPeer