Ulcerative colitis is currently incurable
Genetic defects leading to a leaky gut are a key cause of the inflammatory disorder ulcerative colitis, UK research suggests.
The disorder causes ulceration of the rectum and the colon, but its exact cause has yet to be pinned down.
The latest study links the condition to four genes which all play a role in keeping the intestine lining healthy.
The Nature Genetics study is based on an analysis of the genes of 12,700 people.
It is twice as large as any previous study - giving the results far greater robustness.
Symptoms are intermittent
Symptoms of mild attacks include diarrhoea, tiredness, nausea, abdominal pain and poor appetite
Symptoms of severe attacks include severe diarrhoea many times a day, passing of blood and mucus, fever, abdominal pain and swelling, and weight loss
Ulcerative colitis is a life-long, incurable condition, which can cause diarrhoea, fever, abdominal pain and swelling and weight loss. It affects approximately one in 1,000 people.
The researchers, from the UK IBD Genetics Consortium and the Wellcome Trust Case Control Consortium, compared the genomes of 4,700 people with the condition, with those of 8,000 healthy people.
Their work highlighted variants in three regions of the genome which appeared to increase the risk of the condition.
In particular, they zeroed in on four genes - LAMB1, CDH1, CDH3 and HNF4A - which keep the epithelium - the lining of the intestine - working.
The genes affect the seals at the junctions between the cells of the epithelium.
The gut contains a huge number of bacteria which play a key role in the digestive process, and in keeping the gut healthy.
However, defects in the epithelium can allow these bacteria to leak into the wall of the intestine, where they can trigger an immune reaction, leading to prolonged inflammation.
Many experts believe this is one of the causes of ulcerative colitis - and the latest research provides hard evidence of a genetic basis to the theory.
Researcher Dr Miles Parkes, Consultant Gastroenterologist at Addenbrooke's Hospital, Cambridge, said: "We have long suspected that genetic defects in the epithelial barrier are important in ulcerative colitis.
"This large scale genetic study provides the first robust genetic evidence that this is the case."
Professor Chris Mathew, from King's College London, who also worked on the study, said: "This is very significant as most treatments to date are based on damping down immune response.
"In fact, our data suggests there may be mileage in trying to tighten up the mucosal barrier as well."
One of the genes highlighted by the research, CDH1, has also been implicated in the spread of colon cancer, suggesting their may be a genetic link between the two conditions.
Sir Mark Walport, director of the Wellcome Trust, said the study strongly suggested genetic inheritance was to blame for some people's vulnerability to ulcerative colitis.
"Although it is a long way from this discovery to developing new treatments for inflammatory bowel disease, new approaches to the treatment and prevention of chronic diseases require new insights into their causes."
Richard Driscoll, Director of the National Association for Colitis and Crohn's Disease, welcomed the research.
He said: "Every increase in knowledge moves us closer to the time when identifying a person's genes may enable them and their doctor to make decisions on treatment with a more certain understanding of how their disease is likely to develop over time."