Review ArticleGut microbiome interactions with drug metabolism, efficacy, and toxicity
Introduction
To state the obvious, the aim of very many studies in drug metabolism and toxicity is ultimately to understand the factors that cause compounds to be ineffective therapeutically or cause toxicity in patients and by using this knowledge to design better compounds, provide safe and effective treatments to patients. Although the presence of the gut microbiota has been acknowledged for many years, it was nevertheless generally ignored by those working in drug metabolism and toxicology as being largely an irrelevance (albeit an interesting one). However, there has been a revolution in our understanding of the complexity and system-wide effects of this forgotten organ brought about, in no small measure, by advances in molecular biology. This has revealed the diversity of the gut ecosystem, leading to a major re-evaluation of the role of the gut microbiota in human health and disease. Thus, in adult humans the gut microbiota comprises up to ca 1 kg of bacteria, most of which are obligate anaerobes from the genera Bacteroides, Clostridium, Lactobacillus, Escherichia, and Bifidobacteria together with an assortment of yeasts and other microorganisms, to say nothing of the many viruses. The result is a complex and dynamic ecology comprising at least 2000 species, with the composition varying depending on the region of the gut examined. These microbes then provide benefits to the host via enhanced energy recovery from undigested food, defense against pathogens, and interactions with both immune and nervous systems. These insights have led to a reaffirmation of the view that these microorganisms are not mere passengers but crew, providing multiple benefits for the host and as a by-product of their symbiotic relationship with the host, directly and indirectly affecting the pharmacologic or toxicologic effects of numerous drugs. The rediscovery of the impact that the microbes that go to form this important “external” organ can have has led to a reawakened interest in their study. Furthermore, there is now an increasing appreciation that the microbiome represents a “druggable target” as there is clear potential for altering the composition, and therefore metabolic capability of the microbiome using a range of approaches, including pharmaceuticals. Such manipulations might be intentional, aimed at beneficially modifying the activities of the gut microbiota to improve the health and well-being of the host such as those claimed for prebiotic and probiotic interventions. Alternatively, changes wrought to the microbiome might also cause unintentional “collateral damage” resulting from, for example, exposure to antibiotics, and these modifications may bring adverse consequences. As such changes can be long lasting, the effect of alterations in the composition and functionality of the gut microbiota, given its symbiotic role, should now perhaps be more actively considered as part of the risk assessment process for new drugs. However, it has been clear for a long time that the sheer complexity of the host–gut microbiome interaction means that modeling the various interactions between host and gut microbiota in such a way as to adequately predict the outcome of an intervention will require both novel approaches and the generation of much new knowledge.1, 2, 3
However, for the drug metabolism and toxicology communities, despite many early studies showing its importance in some instances of xenobiotic biotransformation (eg, see refs4, 5), the gut microbiota has not been a focus. Nevertheless, increased awareness is important not only because the microbiota performs a range of important metabolic reactions but because the gut microbiome also represents a source of physiological variability between both individuals and populations. Such variability can affect the disposition and toxicity of drugs and their metabolites. These effects can either be direct or through secondary interactions mediated through, for example, the metabolic exchange and the cometabolism and processing of many diverse endogenous and dietary substrates.6 These “metabolome–metabolome” interactions7 are still poorly understood, but it is clear that some bacterially derived metabolites have the potential to modulate the hosts' drug-metabolizing systems as discussed subsequently.4 There is, however, reason to believe, from the increasing number of research articles and reviews8, 9, 10, 11, 12, 13, 14, 15, 16 on the topic, that the gut microbiota is moving out of the shadows and toward center stage in drug safety studies and personalized health care.
Section snippets
Direct Drug Metabolism by the Gut Microbiota
The gut microbiota has the capability of performing a wide range of metabolic reactions on drugs, drug metabolites, and other xenobiotics. As summarized subsequently, by far the most important biotransformations involve reductive metabolism and hydrolytic reactions (particularly of conjugates). In addition, decarboxylations, dehydroxylations, dealkylations, dehalogenations, and deaminations have also been described.
Demethylations, Deaminations, Dehydroxylations, Deacylations, Decarboxylations, and Oxidations
Important as reductive metabolism is, the gut microbiota is also capable of a range of additional biotransformations including those involving demethylation, deamination, dehydroxylation, deacylation, decarboxylation, or oxidation. The microbial demethylation of drugs such as methamphetamine and 4-hydroxymethamphetamine has been shown in vitro.55 O- and N-demethylation of drugs incubated with rat-derived microbiota has been investigated with the observation of the gut microbial metabolism of
Gut Microbial–Mediated Hydrolysis of Drugs, Prodrugs, and Xenobiotic Conjugates
In addition to reductions, the gut microflora are adept at hydrolytic reactions, which can occur on the drugs themselves, prodrugs, or conjugated metabolites. An early example of drug biotransformation via hydrolysis was the observation that methotrexate was metabolized by the intestinal flora of normal mice.72 Subsequent studies involved the incubation of radiolabeled [3H]-methotrexate with CDF1 mouse cecal contents.73 At least 3 metabolites were formed, the principal one being identified by
Microbial Processing of Xenobiotic Glutathione Conjugates
Many xenobiotics, drugs, agrochemicals, natural products, and industrial chemicals are subject to metabolism, generally through cytochrome (CYP) P450-related biotransformations, resulting in the formation of reactive and potentially toxic metabolites to varying degrees. The glutathione conjugates formed during the detoxication process in the liver are subsequently excreted in the bile where the gut microflora acts on them through bacterial C-S lyases. Studies (on agrochemicals)95 have
Bacterial Acetylation
Reports of conjugation reactions performed by the gut microbiota are comparatively rare but not completely unknown. Both N- and O-acetylation by bacterial n-acetyltransferases (NATs) have been shown, with the former highlighted as potentially important for the bioactivation of genotoxic aromatic amines.97, 98 In addition, the conversion of 5-aminosalicylic acid to n-acetyl-5-aminosalicylic acid by bacterial N-acetylation activity was demonstrated for a number of species.99, 100 4-Aminosalicylic
Microbiome-Conditional Effects and Consequences
The direct effects that the gut microbiota can exert on the metabolism and toxicity of drugs, their metabolites, and related xenobiotics summarized previously in all likelihood represent only the tip of the iceberg as the contribution made by this forgotten organ is not routinely assessed. However, the influence of the gut microbiota extends beyond these direct effects and a number of indirect mechanisms, whereby the microbiome affect the metabolism, disposition, and (potentially) the toxicity
Drug Effects on the Gut Microbiota
Given the interplay between host and gut microbiota, permanent changes in the composition of the latter resulting from drug treatment may have important long-term consequences for the host. So, considering the effects of the microbiota on drug metabolism, there is also the need to consider the potential for the administration of drugs to radically alter its composition either directly on the microorganisms themselves or as a result of toxic or pharmacologic effects on the gut. Clearly, the most
Summary
The range of effects that the gut microbiota can have on drugs and vice versa has obvious implications for drug toxicity testing, where differences in outcomes may reflect not only the strain of animal but also the microbiome-specific effects. Clearly, when moving from animals to patients such effects also have the potential to produce unexpected, and potentially unwelcome, variability in response to the administration of drugs to both individual patients and populations. The resurgence in
Acknowledgments
Conflicts of Interest: All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare.
All authors confirm that they have read the journal's authorship agreement and have reviewed and approved the manuscript.
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