Pharmacological Reviews April 2019, 71 (2) 198-224; DOI: https://doi.org/10.1124/pr.118.015768
APC Microbiome Ireland (G.C., K.V.S., B.T.G., T.G.D., J.F.C., N.P.H.), INFANT Research Centre (G.C.), Department of Psychiatry and Neurobehavioural Science (G.C., T.G.D.), School of Pharmacy (B.T.G.), and Departments of Anatomy and Neuroscience (J.F.C.), Pharmacology and Therapeutics (N.P.H.), and Physiology (N.P.H.), University College Cork, Cork, Ireland
APC Microbiome Ireland (G.C., K.V.S., B.T.G., T.G.D., J.F.C., N.P.H.), INFANT Research Centre (G.C.), Department of Psychiatry and Neurobehavioural Science (G.C., T.G.D.), School of Pharmacy (B.T.G.), and Departments of Anatomy and Neuroscience (J.F.C.), Pharmacology and Therapeutics (N.P.H.), and Physiology (N.P.H.), University College Cork, Cork, Ireland
APC Microbiome Ireland (G.C., K.V.S., B.T.G., T.G.D., J.F.C., N.P.H.), INFANT Research Centre (G.C.), Department of Psychiatry and Neurobehavioural Science (G.C., T.G.D.), School of Pharmacy (B.T.G.), and Departments of Anatomy and Neuroscience (J.F.C.), Pharmacology and Therapeutics (N.P.H.), and Physiology (N.P.H.), University College Cork, Cork, Ireland
APC Microbiome Ireland (G.C., K.V.S., B.T.G., T.G.D., J.F.C., N.P.H.), INFANT Research Centre (G.C.), Department of Psychiatry and Neurobehavioural Science (G.C., T.G.D.), School of Pharmacy (B.T.G.), and Departments of Anatomy and Neuroscience (J.F.C.), Pharmacology and Therapeutics (N.P.H.), and Physiology (N.P.H.), University College Cork, Cork, Ireland
APC Microbiome Ireland (G.C., K.V.S., B.T.G., T.G.D., J.F.C., N.P.H.), INFANT Research Centre (G.C.), Department of Psychiatry and Neurobehavioural Science (G.C., T.G.D.), School of Pharmacy (B.T.G.), and Departments of Anatomy and Neuroscience (J.F.C.), Pharmacology and Therapeutics (N.P.H.), and Physiology (N.P.H.), University College Cork, Cork, Ireland
APC Microbiome Ireland (G.C., K.V.S., B.T.G., T.G.D., J.F.C., N.P.H.), INFANT Research Centre (G.C.), Department of Psychiatry and Neurobehavioural Science (G.C., T.G.D.), School of Pharmacy (B.T.G.), and Departments of Anatomy and Neuroscience (J.F.C.), Pharmacology and Therapeutics (N.P.H.), and Physiology (N.P.H.), University College Cork, Cork, Ireland
Abstract
The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.
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I. Introduction
The principles of xenobiotic metabolism, which is defined as the metabolism of ingested exogenous molecules, emphasize the role of the liver as the predominant site of biotransformation after ingestion by the host. Within this convention, the liver is anatomically, morphologically, and physiologically specialized as a metabolic organ and unrivalled in metabolic capacity in comparison with extrahepatic host sites of chemical transformation (Michalopoulos, 2007). This viewpoint overlooks the fact that before orally delivered compounds reach the liver, an increasing number are first exposed to the gut microbiota and their associated collection of metabolic enzymes (which exceeds the repertoire of the liver) (Li et al., 2014). Indirectly, metabolites produced by the gut microbiome can also tune the expression and function of key liver enzymes such as those in the pivotal cytochrome P450 (CYP) superfamily. Thus, the metabolism of many clinically used drugs is likely to be influenced by either direct or indirect effects of the gut microbiome.
In this review, we first outline the current knowledge of the gut microbiome in health and disease before focusing on the metabolic activities associated with this community of microbes residing in the gastrointestinal tract and their aggregate genomes. The collective direct and indirect metabolic influence of these microbes in the gastrointestinal tract is evaluated with regard to the chemical modification of pharmaceutical compounds, dietary components, and environmental agents, and the implications for host health. This is considered within the context of our expanding knowledge of the role played by the gut microbiota in health and disease, host–microbial interactions, and the reciprocal relationship between xenobiotics and the gut bacteria involved in their metabolism. We also discuss the potential therapeutic implications arising from these observations before providing recommendations to guide a currently neglected but growing area of research toward therapeutic dividends and the improvement of human health.
II. The Gut Microbiome
The gastrointestinal tract is inhabited by a vast array of microbes—bacteria, fungi, yeasts, archaea, and viruses—termed the gut microbiota (Grenham et al., 2011). The bacterial division of this consortium is best studied and reaches the highest density in the large intestine, with recent estimates of 1013 bacterial cells in the human colon (Sender et al., 2016a,b). This abundance reflects the optimal bacterial growth conditions in the large intestine, with a mean pH of 6.4 to 7, and the high density of bacteria residing there in turn confers this region with a lower redox potential (Sousa et al., 2008). The large intestine is thus an important host site for microbial metabolism, a convenient truth that fortunately aligns with our reliance on the analysis of stool samples to gain insights into our microbial inhabitants (Fraher et al., 2012; Claesson et al., 2017). However, these samples are not representative of the microbiome of more proximal regions of the large intestine, and the nonuniform localization and spatial organization of the gut microbiota along the gastrointestinal tract require further evaluation in terms of the functional implications for microbial xenobiotic metabolism (Tropini et al., 2017). This overreliance on fecal samples, due in part to ease of collection and availability, means we still have an incomplete understanding of the impact of microbial activity in different regions of the gastrointestinal tract and the implications of region-specific microbial metabolism for health and disease. For example, metabolism of dietary methylamines also occurs in the small intestine with differential profiles of caecal and fecal metabolism (Hoyles et al., 2018b). Moreover, microbes in the small intestine may be an important site for lipid metabolism (Martinez-Guryn et al., 2018) and are enriched in functions specific for the metabolism of simple carbohydrates (Zoetendal et al., 2012; Stremmel et al., 2017). Neither is the gut microbiota homogenous moving from the lumen to the mucosa, instead existing as a type of gradient with colonic mucosa-associated and luminal microbial communities potentially giving rise to niche metabolic capabilities even at seemingly geographically identical gastrointestinal sites (Galley et al., 2014; Donaldson et al., 2016). One recent example of this pertains to the mucin utilizer, Peptostreptococcus russellii, which produces indoleacrylic acid from tryptophan, important for the promotion of enhanced intestinal epithelial barrier function and the suppression of host inflammation (Wlodarska et al., 2017). Microbial enzymes residing in the gut lumen can in turn, for example, deconjugate conjugated cathecholamines with ensuing physiologic implications for colonic function such as water transport (Asano et al., 2012).
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Focusing on actual numbers and relative abundances of bacterial cells frequently obscures the importance of their collective genome in the gut ecosystem—the gut microbiome. With an aggregate gene catalog exceeding the human genome by more than a factor of 100 (Qin et al., 2010), the gut microbiome exhibits a diverse functional repertoire, and the encoded metabolic activities of these microbial genes equate to a large metabolic capacity far in excess of its counterpart host genome (Lynch and Pedersen, 2016). According to both 16S rRNA gene sequencing and metagenomic shotgun sequencing of stool samples, the composition of the adult gut microbiota is dominated by the phyla Firmicutes, Actinobacteria, and Bacteroidetes with lower relative abundances of Verrucomicrobia and Proteobacteria (Zhernakova et al., 2016). Although the interindividual variation in microbiota composition is considerable such that an accurate definition of the precise composition of a healthy human microbiota remains elusive, recent evidence supports a shared global core microbiota consisting of 14 different genera with medication use making an important contribution to microbiota compositional variation (Falony et al., 2016). It should be noted that there remains to be a consensus on actual membership of the core taxa present in the gut microbiome, and different sequencing and analysis approaches will give different results. The study by Falony et al. (2016) also looked at different populations than earlier studies by Turnbaugh et al. (2009) and Qin et al. (2010).
In contrast to this interindividual variation, a typical healthy adult gut microbiota is characterized by both high compositional diversity and stability (Clarke et al., 2014b). Unlike the host genome, the gut microbiome is readily modifiable (e.g., by diet or antibiotic usage), and this can have important implications for expansion or contraction of its metabolic functions. Prebiotics such as short chain fructooligosaccharides can promote the production of equol, an isoflavandiol nonsteroidal estrogen of importance in cardiovascular, bone, and menopausal health, and whose production varies depending on microbiota composition (Setchell et al., 2002). A more extreme example of the modifiable nature of the gut microbiome lies in the transfer of bacterial genes encoding porphyranases, agarases, and associated proteins from marine red algae to bacteria residing in the gastrointestinal tract of Japanese individuals as a consequence of their seaweed consumption (Hehemann et al., 2010). Unfortunately, the flip side of this coin—loss of function—is most likely the more common scenario, and the low-fiber Western diet is held partially responsible for the lower diversity and the possible extinction of important taxa from the gut microbiota of Western populations (Sonnenburg et al., 2016). Reduced microbial gene richness is common in a range of metabolic and hepatic diseases, with inflammation (Cotillard et al., 2013; Le Chatelier et al., 2013; Qin et al., 2014; Hoyles et al., 2018a) and oxygen availability/gradients playing an important role (Albenberg et al., 2014; Schmidt and Kao, 2014; Friedman et al., 2018). The collateral damage inflicted by excessive or inappropriate antibiotic usage on gut microbiota composition is another example currently being debated (Blaser, 2016).
Despite these concerns over under-represented microbes and/or reduced microbial gene richness, the importance of the dictum that structure begets function for the role of gut microbiota composition in xenobiotic metabolism is difficult to gauge given that members of this bacterial ecosystem may exhibit both functional redundancy and pleiotropy (Clarke et al., 2014b; Moya and Ferrer, 2016). As indicated above, colonization of bacteria increases to highest levels in the large intestine such that sites with a higher exposure to xenobiotics in fact may have a lower potential for microbial metabolism, such as the small intestine. However, this needs to be considered in context of the less well studied small-intestinal microbiota, due in part to the difficulty in obtaining relevant samples.
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Consideration of the gut microbiome and xenobiotic metabolism also needs to take account of the variation of the gut microbiome at the extremes of life in comparison with the reported stability during adulthood in healthy individuals. Data indicate a narrowing of diversity and distinctive microbiota configurations associated with ageing in long-stay care individuals compared with that of community dwellers (Claesson et al., 2012; Jeffery et al., 2016). This is a time of life with high parallel medication and dietary supplement consumption, although adverse health events are rarely considered with regard to this narrowing microbiota diversity (O’Dwyer et al., 2016; Walsh et al., 2016; Locquet et al., 2017). Conversely, but equally important, the infant gut is largely thought to be sterile in utero and colonized during birth and postnatally with a trajectory toward an adult-like complexity taking approximately 3 years (Clarke et al., 2014a; Perez-Munoz et al., 2017). There is also a divergence in intestinal microbiome assembly between different birth modes (Bokulich et al., 2016), between breast- and formula-fed infants (Clarke et al., 2014a), and between preterm and full-term infants, with implications for the associated microbial metabolite profile (Hill et al., 2017). Other important factors include the antibiotic usage in early life (Bokulich et al., 2016; Korpela et al., 2018) and malnutrition (Million et al., 2017). Of course, during adulthood there are also a number of factors that shape or distort the gut microbiome in the colonic metabolic niche, reviewed in detail elsewhere, such as diet (Portune et al., 2017; Sandhu et al., 2017; Shanahan et al., 2017), exercise (Campbell and Wisniewski, 2017; Barton et al., 2018), geographical location (Dikongue and Segurel, 2017; Quigley, 2017), host genetics (Kurilshikov et al., 2017), and the experience of stress (Moloney et al., 2014; Martin and Mayer, 2017). The ability of the gut microbiome to remodel and persist in the face of insults such as antibiotic use is probably only matched in the host by the regenerative capacity of the liver (Michalopoulos, 2007) (Fig. 1, A and B).
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