> > Gut reaction: What's going on deep inside critically ill patients?

A bacteria's drive to survive may suggest ways to help seriously ill patients survive too.

Like many doctors, John C. Alverdy, associate professor of surgery, recalls a critically ill patient who died in his care. In Alverdy's case, the patient was someone he encountered during his residency at the Michael Reese Hospital in Chicago in the mid-1980s. The 11-year-old boy, whose leukemia was in remission, had the classic symptoms of infection: "spiking" a fever every day, rapid heart rate, and sepsis, an inflammatory reaction to bacteria spreading toxins throughout the body. But the microbe causing the infection eluded doctors' efforts to identify it. Repeated blood and urinary cultures came back negative, and CAT scans failed to reveal a focus of infection anywhere in his body.

"What can you do? You've taken pictures from head to toe, cultured everything culturable, and you still can't identify the offending microbe. Yet infection is clinically suspected, and powerful antibiotics are usually administered," says Alverdy, now director of the Surgical Critical Care Unit at the U of C Medical Center. "Maybe there are unusual circumstances at work."

Among intensive-care patients in whom infection is suspected on clinical grounds, as many as 50 percent have no identifiable source. Alverdy has set about reconstructing the circumstances that cause sepsis, currently blamed for the deaths of 1,400 patients each day worldwide, making it the No. 1 killer in intensive-care units (ICUs). A wiry guy with a shiny pate and rectangular eyeglasses, the surgeon focuses on the one place in the body that's full of bacteria-the gut. With a $1.1 million grant from the National Institutes of Health, Alverdy is showing that Pseudomonas aeruginosa, a bacterium commonly found in the intestinal tract of critically ill humans, can mount the equivalent of "guerrilla warfare" if its survival is threatened. And he believes he's found a way to inhibit-or at least make peace with-the bacteria in what he calls a classic evolutionary struggle to survive.

Why would a bacterium that can naturally live in our intestinal tracts want to kill us? Because artificial support systems in the ICU create what Alverdy calls a "historically unprecedented" situation, forcing a bacterium to resort to unique tactics to gain nutrition and survive.

"Bacteria may use systems analogous to smell, taste, and feel to assess the body's response to injury and to gauge whether survival is likely." For example, Pseudomonas has virulence genes activated by high levels of the stress hormone norepinephrine, which the body produces after major surgery. The norepinephrine tells the bacterium that the host is under extreme duress, which may mean death is imminent for colonizing bacteria too. But since a dead host also may mean immediate access to months and years of food in the form of decaying tissue, "it's in their best interest to kill you," to temporarily stave off their own demise.

The ICU isn't helping the situation by feeding patients "chemically defined foodstuff" intravenously or directly into the intestines. When humans are healthy, says Alverdy, they treat their intestinal microbes to a predictable environment and a constant food supply, sending the by-products of digestion and vital nutrients down to their intestines for the microbes to eat. But IVs and chemically defined food deprive the bacteria of their customary nutrients. After a long stay in the ICU, the bacteria in a patient's gut get hungry.

Meanwhile, another "unusual" circumstance may be prompting bacteria to increase their potential for harm. It's possible, says Alverdy, that the ICU environment itself inadvertently creates a situation in which powerful bacteria such as Pseudomonas flourish. Large doses of antibiotics, steroids, and antacids upset the balance of microbial "flora" in patients' digestive tracts, he says, "wiping out the good organisms and letting pathogens like Pseudomonas multiply."

Alverdy cites recent research demonstrating that Pseudomonas, like other bacteria, efficiently monitors its environment, communicating along a "quorum-sensing signalling system"-a cell-to-cell game of postman in which the chemical homoserine lactone gets produced and absorbed down a line of organisms, enabling the bacteria to track population density. A "critical mass"-about 105 organisms, speculates Alverdy, perhaps hiding out in the pouch-like cecum of the large intestine-is necessary before the bacteria mount a toxic offensive. Alverdy's lab has shown that if Pseudomonas achieves a critical mass while on red alert from norepinephrine, it expresses the gene PA-I, which then allows the organism to penetrate the intestinal walls with adhesins-little "molecular syringes" that deliver shots of toxins into the host's cells.

On the light box in Alverdy's office hangs a series of transparent "blots" showing Pseudomonas before and during PA-I expression. The blots look like inked fingerprints-some light, others dark and heavy. In fact, the blots come from the stool of mice in which Alverdy simulated the hostile environment of a critically ill patient's gut. He performed major surgery on the mice, removing 30 percent of their livers. After putting the animals on a 48-hour water-only diet to simulate a postoperative state, he injected a critical mass of Pseudomonas into the animals' ceca and regularly swabbed their intestinal linings. As the bacteria's quorum-sensing system began producing and absorbing homoserine lactone molecules and the PA-I genes were expressed, the blots got progressively darker. In 90 percent of the mice, the PA-I attack was lethal.

Alverdy describes such gene expression as guerrilla warfare because it doesn't follow conventional thinking on how bacteria kill their hosts. "Ask any infectious-disease specialist, and they'll tell you that most bacteria kill their host by disseminating through the body, eventually causing bloodstream infection. An area of the body gets infected, it gets inflamed and full of pus, the bacteria and its toxins become bloodborne, and the patient dies because their immune system is overwhelmed." But Alverdy argues that bacteria whose survival is threatened have nothing to gain by going up against the immune system. Instead, he believes they use extension appendages such as adhesins to feed directly off the intestinal host cells. "If this resource is threatened, they are capable of delivering toxic shots en masse to undo the host.

"The most amazing thing is that this can occur without clinical detection. The bacteria use subterfuge to kill, without necessarily invading the bloodstream." It isn't yet clear how, but Pseudomonas is able to touch the intestinal wall and stimulate the opening of natural "garage doors"-gaps in the intestinal lining that let nutrients in and, in theory, keep toxins out. The doors open, and the appendages shoot their toxins into the cells. Evidence suggests that bacteria can accomplish the sneak attack by secreting immune-suppressing substances to camouflage themselves from host recognition.

Alverdy proposes two ways for ICU physicians to prevent a potentially lethal attack in the gut. Routinely blotting the intestinal linings of critically ill patients would tell physicians when bacteria are reaching critical mass. With the NIH grant, Alverdy is studying a natural sugar that could be used to blanket bacteria and prevent them from poking cells with their toxic needles.

A second way to fight the microbial guerrillas is simple: insert food into the bowels of critically ill patients in a form that the microbes can eat. Says Alverdy, "All these bacteria want is a normal environment and a healthy host." It's a small price for peace.-S.A.S.

 

---