Perspective

Is It Time for a Metagenomic Basis of Therapeutics?

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Science  08 Jun 2012:
Vol. 336, Issue 6086, pp. 1253-1255
DOI: 10.1126/science.1224396

Abstract

The trillions of microbes associated with the human body are a key part of a comprehensive view of pharmacology. A mechanistic understanding of how the gut microbiota directly and indirectly affects drug metabolism is beginning to emerge.

The human microbiota, the vast number of microbes that live within and upon us, is an important but largely underexplored component of therapeutics, prompting efforts to complement pharmacological studies with detailed analyses of our microbial communities. Recent studies suggest that opportunities to develop new diagnostics and treatments may arise through a mechanistic understanding of our resident microbial communities’ abilities to extend human metabolism and an exploration of their impacts on human health and predisposition to disease. Indeed, our emerging view of the human microbiome—the aggregate genomes of our microbiota and the diverse metabolic activities that they encode—has the potential to revolutionize the way we view modern therapeutics.

The past century has provided a wealth of information in the field of pharmacology, elucidating the rates of absorption, distribution, metabolism, and excretion for hundreds of xenobiotics (compounds foreign to a living organism, including therapeutic drugs, antibiotics, and diet-derived bioactive compounds) (1). Combining knowledge of environmental risk factors and human genetics has further advanced our understanding of the basis for interindividual variations in drug bioavailability, toxicity, and efficacy (2). However, the existing clinical and genetic biomarkers often fail to explain a large part of the variation in patient response; for example, even in the case of the well-studied anticoagulant warfarin, up to 50% of the variation is still unexplained (2).

A neglected but critical component of xenobiotic metabolism is the influence of the trillions of microorganisms inhabiting our gastrointestinal tract. In addition to merely expanding the set of human-associated enzymes that can directly modify xenobiotics (there are more than 30 known drugs for which this contribution likely plays an important role) (3), members of the gut microbiota can also influence xenobiotic metabolism by altering host gene expression (4) and producing compounds that interfere with metabolism outside of the gut (Fig. 1) (5). Importantly, these interactions are reciprocal, as exposure to xenobiotics, especially antibiotics, can affect the structure of our indigenous microbial communities (6, 7).

The discovery of antibiotics changed the way we have viewed infectious disease over the past century, yet we are just beginning to assess the unintended collateral damage that antibiotics often impart on the symbiotic microorganisms living in our gastrointestinal tract (8). Repeated exposure to broad-spectrum antibiotics can dramatically alter the composition of human gut microbial communities, which can persist for long periods of time (6, 7). Antibiotic exposure has also been linked to marked changes in the metabolic output of the intestinal tract; for example, almost 88% of the ~2000 detectable metabolites derived from fecal samples were present in altered amounts after antibiotic treatment in mice (9). The functional consequences of such shifts are not always obvious; however, it is clear that antibiotic treatment can render individuals more susceptible to infection (10). This is exemplified by Clostridium difficile, a microbe that can cause severe diarrheal illness with potentially life-threatening complications following a reduction in diversity of the gut microbiota after antibiotic treatment (11).

Fig. 1

A microbial view of xenobiotic metabolism. The gut microbiota interacts with xenobiotics directly by catalyzing various biotransformations. In turn, many xenobiotics inhibit microbial growth or cause cell damage. Indirect interactions have also been described, including microbial effects on the expression and activity of components of host xenobiotic metabolism.

Although we are still in the early stages of investigating the impact of xenobiotics on the composition and function of gut microbial communities, we know even less about how the microbes living in the gut influence the metabolism of therapeutic drugs. A review of the pharmacological literature from the past few decades reveals several cases in which a particular biotransformation (the chemical alteration of a compound by an organism) is suspected to result directly from a reaction carried out by gut microbes (3). Typically, these studies involve either monitoring drug metabolism during the ex vivo incubation of fecal samples with a given drug or observing that antibiotic pretreatment abolishes the biotransformation, presumably due to the widespread depletion of the gut microbiota.

The classical examples of direct microbial biotransformations often consist of either the activation or inactivation of a parent compound. An example of the former comes from the anti-inflammatory drug sulfasalazine, which is used to treat rheumatoid arthritis and inflammatory bowel disease. Sulfasalazine is subject to metabolism by microbial azoreductases that split the drug into two halves: 5-aminosalicylic acid, which is pharmacologically active, and sulfapyridine, which is thought to cause the undesirable side effects associated with this drug (3). The role of the individual bacterial species involved and the molecular mechanisms underlying the biotransformation are largely uncharacterized. Conversely, the cardioactive drug digoxin is susceptible to almost complete inactivation through the reduction of a single double bond in the lactone ring of this compound. A common member of the gut microbiota, Eggerthella lenta, can carry out this reduction reaction in isolation (12). Activation of a drug by the gut microbiota can be undesirable if the reaction occurs in an unintended body site. This is the case for levodopa, an orally administered drug used to treat Parkinson’s disease by ameliorating a dopamine imbalance. Levodopa can cross the blood-brain barrier, after which it depends on a host-catalyzed decarboxylation reaction to convert it to dopamine in the central nervous system (CNS). However, the gut microbiota can also perform this biotransformation (3); having this modification take place in the gut prevents dopamine from reaching the CNS, potentially contributing to the variability in patient responses to levodopa treatment. An integral part of translating these observations into practical recommendations that improve drug efficacy will be identifying which particular microbes, or microbial consortia, carry out the relevant biotransformations and unraveling the underlying molecular mechanisms.

Our capacity to metabolize therapeutic drugs is also affected indirectly by the gut microbiota. Microbes can secrete metabolites that act as substrates for host enzymes essential to process a given drug, thus titrating away their activity. By diminishing the host’s capacity to metabolize drugs, the gut microbiota may indirectly affect the desired pharmacological action, potentially prolonging the time spent in circulation or increasing toxicity. This was recently demonstrated by monitoring pre- and postdose metabolite profiles in human participants who were given the drug acetaminophen. A microbial compound, p-cresol, was abundant in the predose metabolite profiles of individuals who did not fully metabolize acetaminophen (5). Because the excretion of both p-cresol and acetaminophen depends on the same O-sulfonation conjugation reaction in the liver, the results suggest that p-cresol–producing members of the gut microbiota can indirectly inhibit the metabolism of this widely used xenobiotic.

The gut microbiome also affects the metabolism of diet-derived bioactive compounds. A metabolomics screen of human plasma revealed that the phosphatidylcholine metabolites choline, trimethylamine N-oxide, and betaine serve as predictive biomarkers for the development of cardiovascular disease (13). In this same study, germ-free mice revealed that the gut microbiota is directly involved in producing these metabolites and that suppression of the gut microbiota (via antibiotic treatment) can prevent choline-induced atherosclerosis. These findings highlight the critical role of the gut microbiota in extending our own metabolism through modifying the micronutrient component of our diet and also serve as a notable example of how the composition of commensal microbial communities can directly affect disease.

Can the efficacy of a therapeutic agent be improved through a mechanistic understanding of how the indigenous microbiota interact with the compound? Administered as a prodrug, the chemotherapeutic agent irinotecan becomes activated by enzymes in serum and tissue, where it inhibits topoisomerase I (an enzyme that regulates the structure and replication of DNA) in rapidly growing tumor cells. Before excretion, the drug is converted in the liver to a nontoxic metabolite; however, bacterial enzymes (β-glucuronidases) can reactivate this metabolite after it is released back into the intestine, resulting in severe diarrhea that often prevents further increases in dosage. Although the administration of broad-spectrum antimicrobials prevents this undesirable biotransformation of irinotecan, this approach also leaves individuals susceptible to other serious complications. A recent study addressed this issue by harnessing a chemical screen to identify compounds that specifically inhibit bacterial β-glucuronidase (14). Remarkably, the administration of irinotecan with a β-glucuronidase inhibitor alleviated the negative side effects in mice.

Advances in DNA sequencing, cell sorting, mass spectrometry, microfluidics, and computational biology are contributing an array of new tools to the study of human-associated microbial communities. These approaches could lead to the first metagenomic basis of therapeutics that merges the vast knowledge of pharmacology with a quantitative understanding of key environmental risk factors and their interactions with our human and microbial genomes. To complete this picture, it is important to move beyond largely DNA sequencing–based association studies toward a mechanistic understanding of how members of the gut microbiota, either in isolation or through mutualistic interactions with each other, can transform each compound. This will require multiple complementary top-down and bottom-up approaches, including detailed in vitro analyses of culturable microbes; studies in germ-free and intentionally colonized animal models; metagenomic surveys of patients before, during, and after treatment; and large-scale clinical trials. These types of studies will likely lead to new microbial therapeutic targets, noninvasive biomarkers for drug toxicity or efficacy, and a broader understanding of the short- and long-term impact of xenobiotics on host and microbial physiology. Furthermore, the detailed study of pharmaceutically active compounds may be a tractable first step toward understanding the fundamental rules that govern the immense phylogenetic and metabolic diversity of our microbial partners and how they influence our predisposition to and recovery from disease.

References and Notes

  1. Acknowledgments: H.J.H. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (MFE-112991). P.J.T. is supported by a grant from the NIH (P50 GM068763).
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