New way to treat CDI and other common hospital-acquired infection

The right image shows abundant S-nitrosylation (green) in human colitis compared with much less found in the left image of a normal colon. (Credit: UCLA/University of Texas Medical Branch at Galveston)

Researchers at the David Geffen School of Medicine at UCLA and the University of Texas Medical Branch at Galveston have discovered a molecular process by which the body can defend against the effects of Clostridium difficile infection (CDI), pointing the way to a promising new approach for treating an intestinal disease that has become more common, more severe and harder to cure in recent years.

In the U.S., several million people are infected each year, approximately double the incidence of a decade ago, mainly due to the emergence of a new, highly virulent strain of the bacteria that causes CDI.

As a result of the study findings, published in the Aug. 21 online edition of the journal Nature Medicine, the researchers are preparing to launch clinical trials using their discovery as a new CDI therapeutic approach.

The team also included researchers from Case Western Reserve University, Tufts University and the Commonwealth Medical College.

CDI is a bacterial infection that can cause diarrhea and more serious intestinal conditions, such as colitis, the inflammation of the colon. In the most severe cases, CDI can be fatal. It is most commonly acquired in hospitals by patients, particularly the elderly, who are being treated with antibiotics for another infection.

Currently, one of two potent antibiotics is used to treat the infection, but up to 20 percent of patients experience a relapse and a return of symptoms within a few weeks.

"We are treating a disease caused by antibiotics with yet another antibiotic, which creates the conditions for re-infection from the same bacteria," said study co-author Dr. Charalabos Pothoulakis, director of UCLA's Inflammatory Bowel Disease Center and a professor of medicine in the division of digestive diseases. "Identification of new treatment modalities to treat this infection would be a major advance."

Clostridium difficile causes diarrhea and colitis by releasing two potent toxins into the gut lumen that bind to intestinal epithelial cells, initiating an inflammatory response. These toxins are released only when the Clostridium difficile bacteria are multiplying. When antibiotics are used to treat another infection, it changes the bacterial landscape in the gut and, in the process, may kill bacteria that under normal conditions would compete with Clostridium difficile for energy. Scientists believe this may be what provides the opportunity for Clostridium difficile to grow and release its toxins.

The UCLA and University of Texas researchers found in laboratory studies that upon infection with Clostridium difficile, human cells in the gut are capable of releasing molecules that will neutralize these toxins, rendering them harmless. In animal studies, the researchers showed that using a drug to induce this process, known as protein s-nitrosylation, inhibited Clostridium difficile toxins from destroying intestinal cells. Forthcoming clinical trials will test this approach in humans.

"Our study suggests a novel therapeutic approach for treating Clostridium difficile infection by exploiting a newly discovered defense mechanism that has evolved in humans to inactivate microbial toxins," said Tor C. Savidge, an associate professor in the division of gastroenterology and hepatology at the University of Texas Medical Branch at Galveston and the paper's lead author.

Along with its potential to provide a much-needed new approach to treating CDI, the discovery could be applied to developing new treatments for other forms of diarrhea, as well as non-diarrheal diseases caused by bacteria.

Study details machinery of immune protection against colitis and inflammatory diseases

Study details machinery of immune protection against colitis and inflammatory diseases ScienceBlog.com

Scientists report a protein made by a gene already associated with a handful of human inflammatory immune diseases plays a pivotal role in protecting the intestinal tract from colitis.

St. Jude Children's Research Hospital investigators led the research, which points to possible new strategies for combating colitis. Colitis is a chronic inflammatory disease associated with colon damage, resulting in abdominal pain, bleeding and other symptoms.

The work also expands the link between the Nlrp3 protein and Crohn's disease, said Thirumala-Devi Kanneganti, Ph.D., assistant member of the St. Jude Department of Immunology and the paper's senior author.

Md. Hasan Zaki, Ph.D., a St. Jude postdoctoral fellow, is first author of the study, which appears in the March 18 online edition of the journal Immunity.

Researchers demonstrated that in a mouse model of colitis, Nlrp3 plays a pivotal role in keeping the intestinal tract intact, thus preventing further damage that occurs if intestinal bacteria leak into the body.

Nlrp3 works by anchoring a large, multi-protein complex known as the Nlrp3 inflammasome where the messenger protein interleukin 18 (IL-18) is made. IL-18 belongs to a family of molecules known as cytokines, which shape the body's immune response.

In this study, researchers showed IL-18 produced by the Nlrp3 inflammasome helped mice maintain healthy colon by triggering production of more epithelial cells to compensate for those damaged or destroyed by colitis.

"This paper provides the basis for more effective, potentially disease-modifying approaches to treatment," Kanneganti said. She added that in this study, scientists showed the specific pathway activated in the epithelial cells lining the colon for IL-18 production.

Previous studies linked changes in the NLRP3 gene to several auto-inflammatory problems in which a person's immune system mistakenly attacks healthy tissue. The gene is part of the body's innate immune response. That is the branch of the immune system programmed to act immediately against infectious diseases and other threats.

"I believe if we target molecules that are part of the innate immune response we can find cures for many diseases, including cancer," Kanneganti said. She and her colleagues focused on Nlrp3 in colitis after reports that patients with Crohn's disease, another disorder characterised by chronic intestinal inflammation, had low levels of the protein.

In a series of experiments, scientists demonstrated that the Nlrp3 inflammasome not only helps protect against chemically induced colitis in mice, but also showed how and where in the body the protection occurred.

The researchers demonstrated that in response to colitis, the Nlrp3 inflammasome is activated in the epithelial cells lining the colon, where IL-18 can be produced.

Investigators also established that IL-18 is crucial for protecting the colon from colitis. In fact, researchers reported that injecting IL-18 into mice that lacked the molecule eased colitis symptoms.

The other authors of this study are Kelli Boyd, Peter Vogel and Michael Kastan (all St. Jude) and Mohamed Lamkanfi (Ghent University, Ghent, Belgium).

This research was supported in part by the National Institutes of Health, the National Cancer Institute and ALSAC.

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Does Aspirin Reduce the Chance of Colon Cancer

People with a genetic susceptibility to colon cancer could cut their chances of developing the disease in half by taking a daily dose of aspirin, researchers said Monday.

The finding might lead to other treatments by helping researchers understand how aspirin combats colon cancer, one of the top three cancers in rich countries.

Though aspirin has been used widely for years to treat minor aches and to alleviate fevers, it can irritate the stomach and intestines and cause major bleeding.

European researchers followed more than 1,000 people with Lynch syndrome, a genetic mutation that makes them vulnerable to cancers in the colon, rectum, stomach, brain, liver, womb and elsewhere. The syndrome accounts for about 5 percent of all colon cancers.

About half of the study participants were given 600 milligrams, or two aspirin pills daily, while the other half got placebo pills for about four years.

In the group that got aspirin, six people developed colon cancer, versus 16 in the group that got placebos. "We are delighted," said John Burn of Newcastle University in Britain, who led the study.

"All the more so because we stopped giving the aspirin after four years, yet the effect is continuing," he said in a statement.

Burn presented the study results Monday in Berlin at a joint meeting of the European Cancer Organisation and the European Society for Medical Oncology.

Experts said the finding would have no immediate impact on the general public.

"This doesn't mean that everyone should start taking aspirin if they're worried about bowel cancer," said Henry Snowcroft of Cancer Research United Kingdom.

"Aspirin can cause significant side effects if not used as directed by a doctor," Snowcroft said.

Previous studies have found patients who already have colon cancer and are being treated with chemotherapy and surgery may further reduce their risk of dying by up to 30 percent by taking aspirin. The cheap drug is also taken by millions of people worldwide to prevent heart attacks and strokes.