In experiments with laboratory mice, a team of American, Canadian and Italian researchers have discovered a cause and potential treatment for painful colitis and other forms of inflammatory bowel disease.
The often painful conditions can arise from the action of one of the body's signaling chemicals, a peptide called substance P, released by sensory nerves in the intestines and known to be involved in other inflammations.
The scientists had earlier determined that bowel inflammation restricts production of an enzyme that would otherwise break down substance P. In the current study, they found that colitis was up to five times worse if mice lacked 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 because substance P doesn't break down and so continues to cause colitis. The finding also shows that breaking this cycle - either by administering the NEP enzyme or blocking 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 a similar role in humans as they do in the mice, then drugs already in the pipeline could prove effective against colitis, said Nigel Bunnett, PhD, professor of surgery and physiology at the University of California, San Francisco and designer of the study The research results are published in the current issue (Sept. 26) of the Proceedings of the National Academy of Sciences (PNAS).
Inflammations of the pancreas and skin also appear to be aggravated and controlled by the NEP/substance P cycle, Bunnett said, and these too may be treatable 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 conventional anti-inflammatory therapies, and these patients may be particularly prone to the 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 normally degrade substance P. They found that NEP knockout mice had twice as much substance P in the intestinal wall than normal mice. The NEP-deficient mice also showed a four-fold greater "leakage" of proteins and immune cells from the blood into the wall of the colon, which may predispose the animals to develop inflammation, the scientists reported.
The researchers were able to counter both the more severe colitis and this abnormal leakage by giving the mice either a genetically engineered form of NEP or a drug to interfere with the action of substance P activity (a "substance P receptor 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 bowel disease at any time and the treatments are sometimes inadequate or too burdened by side effects.
Sergio Sturiale, MD, research fellow at the University of Messina, Italy, is first author of the PNAS paper, based on research he did at McMaster University with Collins and colleagues.
Co-authors on the paper, along with Suriale, Collins and Bunnett, are Giovanni Barbara, MD, assistant professor at the University of Bologna; Bosheng Qiu, MD, a postdoctoral fellow at McMaster.
Other researchers include Michela Figini, PhD, postdoctoral fellow, and Pierangelo Geppetti, MD, professor, both at the University of Ferrara; Norma Gerard, PhD, and Craig Gerard, MD, at Harvard Medical School; and Eileen Grady, PhD, assistant professor of surgery at UC San Francisco.
The research was funded by the National Institutes of Health, the Crohn's and Colitis Foundation of America, and NATO.
Journal
Proceedings of the National Academy of Sciences