Last year scientists at drug giant Pfizer noticed something peculiar. Rats in a routine study were excreting unusually low levels of a metabolite in their urine called hippuric acid. It was a metabolic oddity that could throw off further laboratory results. So the scientists dug deeper. The rats had been reared at the same facility in Raleigh, N.C., as another group. The metabolite levels should have all been the same. But curiously, the rats in question had been bred in one particular room. Further investigation turned up an unlikely culprit--the rats carried a unique composition of gut microorganisms that had altered their metabolism.
"That was really a surprise," remarks Lora C. Robosky, principal scientist at Pfizer. Robosky is part of a team at the company investigating how spectroscopy and pattern-recognition software could analyze metabolites in body fluids--called metabonomics--to better select drug compounds. Along the way, the technology has revealed a factor often overlooked as a source of individual responses to drugs--gut microflora.
Scientists have long speculated that gut bacteria play a role in human health. But the microbes--passed from mother to infant via feeding and physical contact--are uniquely adapted to the gut and are not easily studied outside of it. "Remarkably, the first paper that enumerated human gut microbiota was published just a few months ago," says Jeffrey I. Gordon, director of the Center for Genome Sciences at Washington University in St. Louis. Through genomic sequencing, the paper, by Paul B. Eckburg and his colleagues at Stanford University, estimates at least 400 species in our gut. Each species exists in different strains, multiplying the variation. In humans, microorganisms in the distal intestines may liberate at least 20 percent of calories by breaking down sugars into more digestible forms.
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Scientists have only just begun to elucidate how these mysterious bugs influence health. Two years ago, for example, David G. Binion of the Medical College of Wisconsin showed that the sodium butyrate produced by gut microorganisms could inhibit blood vessel growth in the intestine by blocking COX-2--an enzyme implicated in many inflammatory disorders (and the target of drugs such as Vioxx). Other studies have shown that specific strains of Escherichia coli can metabolize dimethylarsine, a derivative of arsenic, to produce potentially toxic compounds, which may underlie the carcinogenicity of arsenic in the gut. Bacteria may also free therapeutic compounds in foods such as soy. And people who pack on pounds easily might be suffering from especially thrifty gut bacteria that are contributing to obesity, Gordon and some scientists hypothesize.
Although Pfizer scientists did not investigate their unusual rats' ability to metabolize drugs, the discovery may partly explain why data from presumably identical animals sometimes conflict, Robosky says. What is more, investigators have shown that gut microbes affect drug metabolism, she adds. How significantly, however, remains unknown.
Jeremy K. Nicholson, a pioneer of metabonomics research at Imperial College London, has no doubt that bacteria substantially affect the way the body responds to drugs. "What determines metabolism is largely environmental: how stressed you are, what gut microbes you've got--that turns out to be incredibly important," he argues. For example, many species produce compounds that switch on detoxification enzymes in the liver, and certain microbial metabolites are necessary players in human metabolic pathways.
The microflora may even influence some drugs that turn toxic in a minority of people, such as Vioxx with its cardiovascular complications, Nicholson speculates. But most efforts to identify individual variation focus on genes rather than gene-environment interaction, Nicholson points out, which is likely to be more important.
To take his research further, Nicholson has been collaborating with several companies, including Pfizer and Bristol-Myers Squibb, to develop metabonomic technology that identifies metabolite patterns to predict both a drug compound's toxicity and the biochemical pathways involved. But Nicholson says he and others are working toward a broader ideal: to statistically integrate data from all the "omics" disciplines, such as proteomics and transcriptomics, for a complete picture of a drug's physiological effects.