Feb. 3, 2004 Détente, and a good fence, can be far more effective than all-out assault in the age-old war between man and microbe, University of Chicago researchers report in the February issue of Gastroenterology. By injecting a protective coating into the intestines to pacify bacteria there instead of relying on antibiotics to kill them, the scientists were able to protect mice from otherwise lethal infections.
The protective coating, a high-molecular-weight polyethylene glycol, protected mice who had had major surgery from infection with Pseudomonas aeruginosa, a virulent pathogen that quickly kills 100 percent of untreated mice. A Pseudomonas infection is one of the most lethal complications for patients after major surgery.
"If you can't beat them -- and you can't -- then you want to indulge them," says John Alverdy, M.D., associate professor of surgery at the University of Chicago and director of the study. "An unhappy parasite is programmed to kill the host and move on. So we decided to look for ways to gratify them, to please these powerful microbes and keep them content."
Pseudomonas aeruginosa is common, found in the intestines of about three percent of healthy people. It is also a frequent cause of hospital-acquired infections, especially after major surgery. In the bowel, this germ can be harmless, or it can turn deadly, causing gut-derived sepsis.
"This is a disease of human progress," explains Alverdy. When people are severely ill "we put them in intensive care, where almost every thing we do alarms these bacterial passengers."
Suddenly nutrients no longer pass through the intestines but are dripped directly into the blood stream. The bowel decreases its activity, rendering it far less able to contain the toxic effects of certain strains of bacteria. At the same time, the intestine undergoes erosion of its protective mucus coating.
"Bacteria are smart enough to sense this change and re-program their strategy from peaceful coexistence to one in which harm to their host can occur," Alverdy adds.
Pseudomonas, Alverdy's team has found, detect an ill host's vulnerability by sensing chemicals that indicate stress. They respond like a rival nation -- unhappy with its own boundaries and discovering weakness in a neighbor -- by invading, boring their way through the bowel wall and into the blood stream.
"At this point, bacteria sense that the host is vulnerable and a liability to their survival," says Alverdy. Pseudomonas has tools that let it evade and even disable the host's immune system. It resists antibiotics and it secretes toxins similar to those used by diphtheria or anthrax.
"This is the most lethal of the opportunistic pathogens," he adds. "Patients with widespread Pseudomonas infection can die in a matter of days."
A coating with a high molecular weight polymer however, can form a surrogate bioshield, much like the intestine's own mucus, and stop this whole process before it begins, essentially putting the bacteria at ease.
It prevents the chemical signals of stress from reaching the bacteria and triggering the virulent response. It also serves as a buffer between the bowel wall and the microbes, preventing them from attaching, the first step to crossing the barrier.
The researchers tested the approach by performing major surgery on mice, then introducing Pseudomonas into the bowel, a model that kills all the mice within two days.
One treatment with PEG 15-20, injected into the bowel at the time of infection, however, completely protected the mice. A solution taken my mouth four to eight hours after infection also protected all treated mice.
PEG 15-20 seems to have no adverse effects on the mice and had no effect on bacterial growth or viability. A lighter weight PEG, commonly used as an intestinal cleansing agent (Golytely, PEG-3.35) did not protect mice, although it did have a slight protective effect in the test tube.
Refinement of this approach, say the authors, could prevent hospital infections without using antibiotics.
Grants from the National Institutes of Health, the Packard Foundation and the National Science Foundation supported this work.
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