Scientists Uncover Possible Cause Of Colitis

The often painful conditions can arise from the action of one of the body'ssignaling chemicals, a peptide called substance P, released by sensory nervesin the intestines and known to be involved in other inflammations.

The scientists had earlier determined that bowel inflammation restrictsproduction of an enzyme that would otherwise break down substance P. In thecurrent study, they found that colitis was up to five times worse if micelacked the enzyme, known as NEP. When they reintroduced NEP into these mice,the bowel inflammation subsided, they report.

Their study shows that loss of the NEP enzyme fuels inflammation becausesubstance P doesn't break down and so continues to cause colitis. The findingalso shows that breaking this cycle - either by administering the NEP enzyme orblocking substance P with a drug - can dramatically reduce the inflammation.

Substance P-blocking drugs are already under development to treat depression,asthma and other conditions. If studies show that NEP and substance P play asimilar role in humans as they do in the mice, then drugs already in thepipeline could prove effective against colitis, said Nigel Bunnett, PhD,professor of surgery and physiology at the University of California, SanFrancisco and designer of the study

The research results are published in the current issue (Sept. 26) of theProceedings of the National Academy of Sciences (PNAS).

Inflammations of the pancreas and skin also appear to be aggravated andcontrolled by the NEP/substance P cycle, Bunnett said, and these too may betreatable with substance P blockers.

Current first-line treatments for inflammatory bowel disease often have limited effect or carry serious side effects such as osteoporosis and mood shifts, said co-investigator Steven Collins, MD, professor of medicine and head of the division of gastroenterology at McMaster University in Ontario, Canada. Surgery can effectively treat some, but not all, cases.

For unknown reasons, some patients don't respond to conventionalanti-inflammatory therapies, and these patients may be particularly prone tothe nerve-related mechanisms of inflammation that was this study's focus,Collins said.

The researchers examined the mechanisms that control colitis by studying"knockout" mice that lacked the gene for NEP, and therefore could not normallydegrade substance P. They found that NEP knockout mice had twice as muchsubstance P in the intestinal wall than normal mice. The NEP-deficient micealso showed a four-fold greater "leakage" of proteins and immune cells fromthe blood into the wall of the colon, which may predispose the animals todevelop inflammation, the scientists reported.

The researchers were able to counter both the more severe colitis and thisabnormal leakage by giving the mice either a genetically engineered form of NEPor a drug to interfere with the action of substance P activity (a "substance Preceptor antagonist").

Colitis causes often severe abdominal pain and bloody diarrhea, Collins said.As many as one person in 2,000 suffers from some form of inflammatory boweldisease at any time and the treatments are sometimes inadequate or too burdenedby side effects.

Sergio Sturiale, MD, research fellow at the University of Messina, Italy, isfirst author of the PNAS paper, based on research he did at McMasterUniversity with Collins and colleagues.

Co-authors on the paper, along with Suriale, Collins and Bunnett, are GiovanniBarbara, MD, assistant professor at the University of Bologna; Bosheng Qiu,MD, a postdoctoral fellow at McMaster.

Other researchers include Michela Figini, PhD, postdoctoral fellow, andPierangelo Geppetti, MD, professor, both at the University of Ferrara; NormaGerard, PhD, and Craig Gerard, MD, at Harvard Medical School; and EileenGrady, PhD, assistant professor of surgery at UC San Francisco.

The research was funded by the National Institutes of Health, the Crohn's andColitis Foundation of America, and NATO.