Pharmacometagenomics: Understanding microbial metabolism for precision medicine.
Written by Alexandra Mushegian
Research on the human microbiome has captured the public imagination. Data showing that gut bacteria could be involved in protection against everything from malnutrition to obesity to anxiety and sleep disorders has led to the hope that perhaps the answers to what ails us have literally been inside us all along. With this hope, however, have come calls for caution and moderation from a number of researchers. Many working in the microbiome field agree that reliably effective health interventions based on manipulating the microbiome are still far away. There is, however, at least one dimension of research into microbiome effects on health in which clinical applications might be close: using knowledge of microbial metabolism of drugs to personalize pharmacology.
Many effects of the microbiome on health involve complex interactions between multiple species of microbes,genetic factors of the host, and additional environmental or dietary factors. The emerging field of pharmacometagenomics, on the other hand, revolves around a relatively simple key insight: bacterial strains in the human microbiota can alter the chemical structures of drugs and other foreign compounds (xenobiotics), for the good or ill of the host. Dozens of drugs are known to be metabolized by gut bacteria. Perhaps the most well-characterized example is the cardiac drug digoxin, which has been known since the 1980s to be inactivated by certain strains of bacteria via reduction of its lactone ring resulting in decreased target affinity. The enzymes responsible for this effect have recently been identified and experimentally manipulated. Conversely, some drugs require microbiota to be activated, with the conversion from prodrug to biologically active compound being carried out by bacteria. Similarly, microbial activities can affect concentrations of toxic metabolites, thus influencing drug side effects.
For these reasons, it is possible that differences in the microbiota of different individual humans can contribute to differences in individual responses to drugs by influencing rates of absorption, effective dosages, or toxicity. (An entire additional suite of microbiome effects on drug metabolism arises indirectly, through effects of the microbiome on the metabolism of the host.) Since microbial metabolism of drugs can be effectively studied in vitro and mechanistically explained in great detail, it seems likely that in the near future there will be ways to identify clinically relevant markers in a patient’s microbiome for stratifying treatments. For example, the presence or abundance in a patient of a bacterial strain that interacts with a certain drug could be used to personalize treatment plans and dosage recommendations. Potentially, additional drugs could be developed that directly target these microbial metabolic activities and could be taken with other drugs to improve their efficiency. Combined with knowledge on the effects of human genetic variation (pharmacogenomics), this type of understanding would allow for a more targeted, precise approach to pharmacology, reducing side effects and drug costs while improving patient outcomes.
While the translational potential of microbial drug metabolism is exciting, it also raises more basic questions. How did the pathways involved in microbial metabolism of drugs evolve and what was their original role in microbial fitness? Do microbes benefit from these activities? Does influencing how their host processes drugs ultimately help or harm the microbial community? In a world where pharmaceutical products are increasingly circulating both in humans and in the environment, what will be the long-term effects of these exposures on microbial evolution and diversity? Many effects of microbiomes on health originate from the deep evolutionary history of human-microbe coexistence. In contrast, microbial metabolism of drugs represents a relatively recent dimension of human-microbe interactions. Understanding microbial metabolism of products we artificially synthesize and the subsequent effects on our health and environment is a compelling area of research on the interdependencies of the human and microbial worlds.