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Microbial bliss: Meet the bugs in your gut!
POSTED 30 APRIL 2009

Probiotics: The flip side of germ theory?

The surging interest in taking probiotics -- beneficial bacteria that live in our intestines -- represents an about-face for medicine, which for centuries has battled bacteria. Not that we deny the benefits of the germ theory of disease, which in the 1800s blamed infectious diseases on microscopic organisms. "Germ theory revolutionized public health, and we managed to wipe a number of diseases off the top 10 list," says Gary Huffnagle of the University of Michigan, "but the problem is that we went too far and tried to get rid of all bacteria. The bottom line is that an incredibly small percentage of microbes cause disease. In our effort to eliminate contact with the microbial world, to be healthy, we ended up doing the opposite. The number of infectious diseases went down, but the incidence of inflammatory diseases went up."

A male runner in a blue shirt leads the marathon, the other runners out of focus behind him
In Australia, probiotics halved the number of days lost to illness among serious runners.

These diseases, including allergies, asthma and various inflammations of the gastrointestinal tract, "can't be due to a genetic change in us," Huffnagle points out. The change was "too quick, so it must be that something has happened in our environment."

Although the increasing use of antibiotics has spawned an intense problem with antibiotic-resistant bacteria, it has another consequence: antibiotics can leave the GI tract largely empty of bacteria, ripe for invasion. Many invaders are decay-resistant bacterial spores, but others may be ones that normally lurk in small numbers in the intestine, and do not cause a problem unless the microbial community is destroyed by antibiotics.

Running in place

Let's begin looking at new data on the role of probiotics in preventing or treating disease with a recent study from Australia. Twenty runners took pills for a month, stopped for a month, and then took pills for another month. Neither the runners nor the researchers knew which pills contained placebo and which contained the probiotic bacterium lactobacillus fermentum VRI 003.

When the runners, who trained an average of 60 miles a week, were tested on a treadmill, the probiotics produced no benefit.

But check the report on sick days: the runners were sick a total of 30 days while taking probiotics, and 72 days while taking the sham pills. "We saw a substantial reduction in the number of days of respiratory illness with the probiotic group having less than half the illness of the placebo group," says David Pyne of the Department of Physiology at the Australian Institute of Sport. "This was a nice clinical finding and the most important in a practical sense for health care professionals, athletes and coaches. The severity of illness was also much lower in runners taking probiotic supplements. Taken together these findings provide preliminary evidence on the clinical benefits of probiotics."

Pyne said the probiotics might be working through several mechanisms. "Probiotics work by improving the intestinal microbial balance between the so-called 'good' and 'bad' bacteria, modulating certain immune functions by down-regulating inflammatory cytokines (proteins) or inducing regulatory mechanisms."

Flaring up

Most studies of probiotics focus on the GI tract. A recent analysis (see #3 in the bibliography) suggested that probiotics can reduce the symptoms of irritable bowel syndrome. According to the NIH, the syndrome may afflict 20 percent of American adults with abdominal pain, constipation and diarrhea. Irritable bowel can become severe enough to prevent work or travel, but it does not lead to worse disease.

Researchers are finding a more conclusive benefit in "pouchitis," an inflammation that can follow bowel-removal surgery (colectomy) to treat ulcerative colitis, a mysterious condition that can destroy the colon (large intestine).

When surgeons remove the colon, they may create a small pouch to store feces, making life a lot easier after surgery. But up to half of the patients will develop inflammation of the mucosal lining[VBY1] in the pouch.

The condition is peculiar, says Vincent Young, an infectious disease specialist at the University of Michigan. "Although ulcerative colitis occurs only in the colon, they don't have a colon anymore. The pouch is made up of small intestine tissue that has never been affected by inflammation."

However, the bacteria in the pouch resemble normal residents of the colon, and several clinical trials show that probiotics can reduce the pouchitis symptoms. "This is one of the best examples of the use probiotics to prevent or treat disease," says Young.

Unfortunately, probiotics are less effective in experiments with ulcerative colitis (the disease that necessitated colectomy) and Crohn's disease, the other type of inflammatory bowel disease. "The results are much more sketchy, but the studies are small, the patients are mixed," says Young. "There is a suggestion that it can work, but the evidence is not as good as for pouchitis."

Taking on a most difficult job...

Probiotics are also gaining credibility with antibiotic-associated diarrhea, caused by bacteria that occupy an empty intestinal tract after antibiotic treatment. One focus of attention is Clostridium difficile (C. difficile), a tough-to treat infection that often follows the use of antibiotics. Hospitalized C. difficile patients had a 17 percent death rate in one study (see #4 in the bibliography).

The link with antibiotic treatment suggests that the balance of intestinal microbes plays a role in C. difficile, and Young says the gut bacteria are indeed simpler than what is normally seen in healthy individuals. In several studies, probiotics containing bacteria and yeast did rebalance the intestinal bacteria and treat C. difficile (see #5 and "New advances..." in the bibliography).

But instead of using a probiotic containing a few organisms at most, why not transfer the whole shebang of intestinal microbes? Why not use, in other words, a stool transplant, which may carry countless bacteria in their uncountable variety?

Because C. difficile patients have a disturbed set of microbes in their gut, "it would make sense that giving them stool would give back the missing diversity, even if we don't know [exactly] what is missing," says Young.

Stool transplants 'are the ultimate probiotic, and also the grossest.';

Meeting Mr. Yuk

A stool transplant is nothing short of disgusting: After a donor's feces are tested for viruses, bacteria and parasites, they are pumped through a nasal tube into the patient's intestine. In a 2003 experiment (see #6 in the bibliography), feces were transferred into 18 patients with untreatable C. difficile. Fifteen people were cured, two (who were in critical condition at the time of transplant) died. The 18th patient was cured by a subsequent course of antibiotics.

So are feces transplants an accepted treatment? "It's only been published a couple of times, but the result was fantastic," says Young. "It's been vetted in the literature, but it's not a standard treatment. How am I going to write a prescription? And you have to worry, if you are giving all this stuff, are potential pathogens in there?"

For the gross factor, feces transplants rank alongside two other uses of biology to cure wounds - using leeches to extract surplus blood and promote circulation, and using maggots to eat decaying flesh.

But we should not have too much fun with stool transplants. They were tried because C. difficile can kill, has become more common, and is now appearing in a new, improved, super-toxic strain. (For more on C. difficile, see #7 in the bibliography.)

I'm off the drugs. Who's home?

One scientific benefit of the increasing focus on probiotics is a better understanding of what lives in the intestines. When we are born, our intestines are sterile; bacterial colonization begins within days, largely from contact with the mother.

 In the antibiotic phase, the proportion of firmicutes decreases most; proteobacteria increase.
Courtesy Vincent Young and American Society for Microbiology, see Reproducible Community Dynamics....
Bacteria in the intestines of mice analyzed immediately ("antibiotic treated") and two weeks after ("recovery") antibiotic treatment. Control animal was not treated. Notice that the intestinal microbes more or less return to normal. Phyla are large-scale divisions of the living realm that comprise many species.

The C. difficile epidemic is another reason to wonder what happens when the GI tract is partly sterilized by antibiotics. To find out, Young treated some mice with an antibiotic, and found that a bacterium that is seen rarely in untreated animals was suddenly dominating the gut. Yet within two weeks after ceasing the antibiotic, Young says the animals "were pretty much back toward the original state, although there were some minor differences in composition that may or not be significant."

The pie chart of isolated animals? bacteria lacks the diversity and balance of the non-isolated
Courtesy Vincent Young and American Society for Microbiology, see Reproducible Community Dynamics....
The control animal shows a normal complement of intestinal bacteria. Animals in "donor recovery" were exposed to an untreated animal for one day after the antibiotic treatment ceased. Notice how their bacteria resemble those in the control animal? (Colors indicate presence of different classes of bacteria.)

However, other antibiotics caused long-lasting changes in the gut's bacterial community. To explore how those mice would reacquire gut bugs, Young added one untreated mouse to the group, and substantially restored the original intestinal diversity.

Because the bacteria are probably being passed around as the rodents eat each other's feces, Young says the experiment "gives credibility to the idea of using a complex mixture of probiotics. But maybe we can come up with better things than feces" (see #8 in the bibliography).

On the lookout for bugs

Beneficial microbes could also explain why farm people have low rates of asthma and allergy. This phenomenon was widely interpreted as showing how the immune system benefits from an occasional challenge from microbes.

1940 photo of a boy in overalls with a machete and a girl holding a sugar beet as big as her head
Photo: Nebraska, 1940, National Archives
What explains the lower rates of asthma and allergy among people who live on farms? Could it be exposure to dirt, mold, pollen and a variety of antigens, plus increased travel among beneficial bacteria?

But Huffnagle says traveling bacteria could be part of the explanation. "We know that large families have lower rates of inflammatory disease. Is it because you are wrestling with your sibling or eating off a fork that somebody else has used? Compare that to someone living in a city apartment, spending all the time at the computer, not interacting much. After a course of antibiotics, how do they recover their flora?"

At long last, a medical endorsement for elbow-bending! "We need a healthy flora flow," Huffnagle adds. "Maybe going out on a Friday night and having a beer, yelling, laughing, making an aerosol of microbes is a good thing. I raise this as a possibility. We do not know how we get" our complement of beneficial microbes.

So. Should we be taking probiotics? Which ones?
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Terry Devitt, editor; Nathan Hebert, project assistant; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive

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