Germs that do a body good: bacteria might someday keep the doctor away. (Cover Story).

After several straight months of persistent diarrhea, a New York woman was exhausted, uncomfortable, and frustrated. She also was out thousands of dollars that she'd spent on drugs and hospital bills. The problem had begun while she was being treated with intravenous antibiotics for an infection that caused inflammation in her colon. In healthy people, pathogens like the Clostridium difficile bacteria responsible for the woman's diarrhea are held in check by harmless intestinal microorganisms, poetically referred to as flora. By killing off these benign bugs, antibiotics often upset the balance of the gut ecosystem and leave it open to novel invaders or nasty, normally latent microbes.

Dorothy Ogden (not her real name) learned the hard way that antibiotic-associated diarrhea can persist in some people long after they've beaten their original infection and stopped taking antibiotics. No treatment for the diarrhea gave Ogden more than temporary respite, she says, until she agreed to undergo an unorthodox procedure at Montefiore Medical Center in New York.

Lawrence J. Brandt, a gastroenterologist at Montefiore, reseeded Ogden's colon with some of her husband's fecal matter--replete with a normal array of thriving microorganisms. By replacing the flora that Ogden had lost to antibiotics, Brandt revived the natural microbial competition.

Using good bacteria to obstruct bad ones--a strategy known as bacterial interference--is one application of so-called probiotics, a field with growing medical promise. The name suggests a twist on antibiotics, which kill disease-causing microbes. Some probiotic bacteria de their work by competing for resources and space with pathogens inside the body and, in effect, elbowing the bad bugs out of the way.

Others secrete byproducts that are toxic to a disease-causing microbe but harmless to people, trigger the host's immune system to gird itself for battle against hostile bacteria, promote other responses in the host that stymie pathogens, or use several mechanisms at once, says Gregor Reid, a microbiologist at the University of Western Ontario in London, Ontario.

Many folks, however, find the idea of receiving bacterial transfusions to prevent or treat illness rather hard to take, especially when it requires a distasteful treatment. "A lot of people don't like this procedure and won't do it," Ogden, now 72, recalls Brandt telling her before he described the fecal colonoscopy that he was recommending. Brandt mixed samples of the husband's stool in saline solution and deposited globules of it every 10 centimeters along her colon. The application extended from Ogden's anus to her cecum, about 150 centimeters away, which is as far into the intestinal tract as a colonoscope can reach.

The infusion seemed to restore the proper bacterial balance, and Ogden's symptoms disappeared immediately, Brandt reported in November 2000. It was the first time that Brandt--or anyone, as far as he knows--had attempted the procedure, although simpler fecal enemas had worked in several dozen earlier cases.

EDIBLE GERMS Although Ogden's therapy was novel, the use of probiotics isn't altogether new. Folk remedies since the beginning of recorded history have ascribed antidiarrheal effects to dairy foods, such as cheeses and yogurt. It turns out that their active component is live bacteria.

While gaps remain in understanding the mechanisms by which probiotics work, scientists have made great strides in the past 20 years in determining how natural bacteria can be added to foods to serve as protective agents. The most notable was the isolation from the intestine of a healthy person in 1983 of a strain of lactobacillus rhamnosus dubbed lactobacillus GG, says Sherwood L. Gorbach of Tufts University School of Medicine in Boston. When that particular bacterium establishes itself in the human gut, it reduces the incidence and severity of intestinal infections.

Lactobacillus GG belongs to the group that includes the microbes that turn milk into cheeses and yogurts. Other lactobacilli live naturally within the human body--for example, in the gut and the vagina.

Because some lactobacilli occur naturally in dairy products, scientists have used those foods as the main vehicle for introducing probiotics into the human body. To inhibit intestinal infections in consumers, producers, especially in Europe, have fortified some commercial yogurts with live cultures of bacteria after pasteurization.

According to Gorbach, research has so far proved the benefits of probiotics in food for at least two health problems. In the first case, probiotics to prevent or ease antibiotic-associated diarrhea, at least in eases that are less intractable than Ogden's. In the second, introduced bacteria combat acute diarrhea and intestinal inflammation by countering rotaviruses that typically affect children.

MORE THAN A GUT FEELING While research has focused primarily on probiotics' effects on digestive tract health, some scientists recognize potential applications to the vagina, the respiratory tract, and other parts of the body where bacterial ecosystems also exist. This research is promising, if preliminary.

For example, studies by Sharon L. Hillier of Magee-Women's Hospital in Pittsburgh suggest that probiotics can help combat an infection called bacterial vaginosis, which is caused by anaerobic microbes that trigger a shift in vaginal flora. This infection affects about 1 in 10 U.S. women of reproductive age and sometimes causes itching, excessive vaginal discharge, and a fishy odor. It's been linked to elevated risk of HIV infection (SN: 9/5/98, p. 158) and complications with pregnancy.

Hillier developed a suppository that consists of a gel capsule that melts upon insertion into the vagina, dispersing a payload of probiotic lactobacilli that researchers isolated from the vaginas of healthy women. In an initial trial, the capsules proved effective at restoring depleted vaginal populations of lactobacilli. Hillier is currently overseeing a study of about 400 women that examines whether these vaginal suppositories will alleviate bacterial vaginosis.

Hillier draws a distinction between two types of probiotics. Some, including most bacteria being administered in food, interfere with pathogens but don't remain permanently in the body. Others rely on bacteria that are naturally present in the body, such as those in the vaginal suppositories and those that Brandt introduced into Ogden's colon.

Hillier says that replacing natural bacteria makes sense in parts of the body at constant risk of pathogenic invasion. For example, because beneficial flora in the reproductive tract play a role in resistance to disease, helping women reestablish lost populations of microbes would be a simple strategy for improving reproductive health.

Therapy that replaces depleted bacteria may also fight respiratory tract infections. Swedish researchers reported in the Jan. 27, 2001 British Medical Journal that they used a probiotic to reduce the recurrence of otitis media, an infection of the middle ear, among children prone to the ailment. Parents repeatedly sprayed a solution laced with alpha-streptococcus bacteria in the children's noses. Part of the normal flora of tubes that connect the upper nasal passage to the middle ear, alpha-streptococci kept the pathogens that cause otitis media from spreading up the nose and into the ear (SN: 2/3/01, p. 68).

PREEMPTIVE STRIKE Beyond using probiotics to replenish missing bacteria, clinicians are working to prevent pathogenic invasions of normally bacteria-free tissues that are, for one reason or another, at risk of infection. The strategy in these cases is to install harmless bacteria at the site before nasty ones invade.

Reid has experimented with using probiotic lactobacilli to prevent Staphylococcus aureus from colonizing animals' wound sites, where it can cause life-threatening infections. He and his colleagues at the University of Western Ontario simulated a surgical operation by implanting small pieces of silicone beneath the skin of laboratory rats. They simultaneously added S. aureus to the wounds.

Five of nine animals receiving just the implant developed S. aureus infections within 3 days. However, all nine rats that received large doses of one live Lactobacillus fermentum strain at the wound site during surgery remained free of the pathogen. In other tests, rats receiving lower doses showed progressively less protection, the researchers report in an upcoming issue of the Journal of Infectious Diseases.

Rolien H. Free of the University Hospital of Groningen in the Netherlands and her colleagues have used probiotics to guard prosthetic voice boxes--though only in beakers in the lab--from the films of dangerous bacteria and yeasts that tend to form on them. These silicone rubber devices enable people to speak after their cancerous larynx has been removed. An estimated 10,000 are in use in the Netherlands alone.

In a study in the October 2001 Annals of Otology, Rhinology, and Laryngology, Free's team reported that a probiotic strain of streptococci reduced bacterial growth on one prosthesis model by 53 percent and yeast growth by 33 percent. A second probiotic strain cut bacteria on another model by 19 percent and yeasts by 45 percent. Other tests suggest that the probiotics may be even more effective if drunk in a bacteria-rich saline solution rather than in dairy products.

Another target for probiotic therapy is the bladder. Richard Hull of Baylor College of Medicine in Houston began a decade ago to use probiotics to prevent recurrent bladder infections. Unlike the gut or vagina, a healthy bladder doesn't contain microorganisms, which makes introducing bacteria to the organ a counterintuitive idea that's unpopular with some clinicians.

However, "the bladder is not sterile in our patient group," says Hull, who treats people with spinal-cord injuries that render them unable to urinate without a catheter. The catheter tube makes occasional infections almost inevitable, he says.

To protect a patient against such infections, Hull sends a small amount of solution containing an apparently harmless strain of Escherichia coli through the catheter and into the bladder. This inoculation won't fight an infection already in progress, but it does make it more difficult for new harmful bacteria to take hold, he says.

In the September 2001 Urology, Hull and his colleagues reported the results of a pilot trial in which they introduced probiotic E. coli into the bladders of 44 catheter-using patients with spinal injuries. In 30 of these patients, the E. coli inhabited the bladder for an average of more than a year. During that time, only two urinary tract infections occurred in the group. Before receiving the treatment, each of the 30 patients had experienced an average of nearly two infections per year. In the other 14 patients, the infused E. coli failed to colonize the bladder but caused no illness.

Only two Houston medical centers currently administer this unusual treatment. Hull intends to conduct a multicenter scientific trial if several health centers agree to test the procedure.

WHAT'S NEXT? Although a staunch advocate of food-based probiotics, Gorbach is wary of promoting other applications for bacteria because he says the safety and efficacy evidence is scanty. He is particularly concerned about the risks of therapies, such as Hull's, that introduce bacteria to normally sterile parts of the body. "I don't want to be a party to promoting putting [probiotics just] anywhere," says Gorbach.

Hull acknowledges that "a lot of the research in probiotics isn't very good science." There's often only anecdotal success stories and small-scale studies that have yet to be replicated. That's precisely why research on many possible uses for probiotics should forge ahead, he says.

Even ingestible probiotics, which offer relatively well-established benefits, face obstacles that limit the full exploitation of the therapeutic strategy. Part food, part drug, and part dietary supplement, probiotics fall in a regulatory gray area, says Gorbach. In the United States, food manufacturers can advertise that products contain live cultures, but packaging can't display health claims regarding specific ailments.

Reid says that this is appropriate in some cases because the strains that products contain aren't necessarily identical to those that research has shown to have healthful effects, making it uncertain whether the bacteria on supermarket shelves actually work as probiotics. On the other hand, he says, "it's a shame that strains that have been shown to have specific health benefits can't make [those] claims."

Despite regulatory uncertainties, research forges ahead. When a candidate for a probiotic isn't naturally available, progress may require engineering one, suggests Jeffrey D. Hillman of the University of Florida College of Dentistry in Gainesville. Streptococcus mutans, a bacterium that is commonly responsible for tooth decay, metabolizes lactic acid from sugars in food residues on the surface of teeth. That acid eats away at the minerals that make up the tooth, creating cavities. Hillman modified a strain of S. mutans so that it could no longer produce the offending acid.

He chose to work with a particularly aggressive strain that can often replace other bacteria already living on the teeth. Hillman figured that the engineered strain might take over the habitat that acid-producing strains normally dominate. In experiments with lab rats, the strategy worked, Hillman reported in an August supplement to Operative Dentistry.

Hillman hasn't tried the engineered probiotic in people, but he suggests that someday dentists will squirt solutions of the altered bacteria onto the teeth of children during a regular cleaning.

"In theory, a single application of our [modified] strain could give lifelong protection against tooth decay," he says.

That's a tall promise from the relatively immature field of probiotics. In the meantime, the approach faces a variety of obstacles, including a federal regulatory system that's never handled bacteria as therapeutics and prospective patients who balk at having living organisms put into their bodies. But with sufficient scientific research, probiotics might one day provide wholesome antidotes to a host of infections.