Interaction Between Drugs and the Gut Microbiome Gut: First Published As 10.1136/Gutjnl-2019-320204 on 14 May 2020

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Interaction Between Drugs and the Gut Microbiome Gut: First Published As 10.1136/Gutjnl-2019-320204 on 14 May 2020 Recent advances in basic science Interaction between drugs and the gut microbiome Gut: first published as 10.1136/gutjnl-2019-320204 on 14 May 2020. Downloaded from Rinse K Weersma ,1 Alexandra Zhernakova,2 Jingyuan Fu2,3 1Department of ABStract Gastroenterology and The human gut microbiome is a complex ecosystem Key messages Hepatology, University of Groningen, University Medical that can mediate the interaction of the human host There is a complex bidirectional interaction Centre Groningen, Groningen, with their environment. The interaction between gut ► The Netherlands microbes and commonly used non-antibiotic drugs is between commonly used non- antibiotic drugs 2Department of Genetics, complex and bidirectional: gut microbiome composition and the gut microbiome. University of Groningen and can be influenced by drugs, but, vice versa, the gut ► Commonly used drugs such as proton pump University Medical Center inhibitors, metformin, selective serotonin Groningen, Groningen, The microbiome can also influence an individual’s response Netherlands to a drug by enzymatically transforming the drug’s reuptake inhibitors and laxatives influence gut 3Department of Pediatrics, structure and altering its bioavailability, bioactivity or microbiome composition and function. University Medical Center toxicity (pharmacomicrobiomics). The gut microbiome ► Proton pump inhibitor- induced changes in Groningen, Groningen, The the gut microbiome can lead to decreased Netherlands can also indirectly impact an individual’s response to immunotherapy in cancer treatment. In this review we colonisation resistance and the development of enteric infections, including Clostridium Difficile Correspondence to discuss the bidirectional interactions between microbes Dr Rinse K Weersma, and drugs, describe the changes in gut microbiota infections. Gastroenterology and induced by commonly used non-antibiotic drugs, and ► Gut microbiome composition is associated with Hepatology, University of their potential clinical consequences and summarise how antitumour response and the clinical efficacy of Groningen, University Medical treatment with immune checkpoint inhibition. Centre Groningen, Groningen the microbiome impacts drug effectiveness and its role Gut microbes can contribute to drug efficacy 9700 RB, The Netherlands; in immunotherapy. Understanding how the microbiome ► r. k. weersma@ umcg. nl metabolises drugs and reduces treatment efficacy will and safety by enzymatically transforming drug unlock the possibility of modulating the gut microbiome structure and altering drug bioavailability, Received 30 March 2020 to improve treatment. bioactivity or toxicity. Revised 21 April 2020 ► Insights into how the gut microbiome interacts Accepted 28 April 2020 Published Online First with commonly used drugs enable interventions 14 May 2020 to modulate the gut microbiome and optimise treatment efficacy. INTRODUCTION In the past decade we have witnessed exciting http://gut.bmj.com/ discoveries linking the composition and function of the human gut microbiome to numerous common Finally, the gut microbiome can indirectly impact an diseases and phenotypes. Association studies have individual’s response to immunotherapy in cancer documented changes in the abundance of various treatment via its influence on the host’s general 13 gut bacteria in individuals with gastrointestinal immune status. These exciting new insights into phenotypes, including inflammatory bowel disease, the bidirectional interaction between non- antibiotic irritable bowel syndrome and colorectal cancer, and drugs and the gut microbiome are the focus of the on September 28, 2021 by guest. Protected copyright. with diseases of other systems and organs, including current review. cardiovascular and metabolic conditions, auto- immune conditions and psychiatric disorders.1–9 BackGROUND In addition to association analyses, intervention The development of gut microbiome research studies and animal studies have proven not only the Just a few decades ago our ability to analyse the association but also the causality of the gut micro- role of the gut microbiome in relation to human biome in relation to several diseases.10 Moreover, health was mainly defined by large technical chal- the influence of intrinsic and extrinsic factors on lenges. Historically, microbiome studies were gut microbiome composition is increasingly being performed using culturing methods in which one, understood. or a few, bacterial species were isolated and studied One very important recent finding is that many in relation to a disease. This research produced commonly used non- antibiotic drugs—such as numerous important findings, but our ability to proton pump inhibitors (PPIs) and metformin— analyse other components of the gut ecosystem change microbiome composition and function.11 12 was limited. The development of the technique to These changes can influence health outcomes (in sequence the bacterial 16S ribosomal RNA gene the case of PPIs) or reduce drug efficacy (in the case allowed overall taxonomic assessment of the gut © Author(s) (or their of metformin). At the same time, more data has microbiome, and this has dramatically increased employer(s)) 2020. Re- use become available showing that the gut microbiome our knowledge of the broad variations in micro- permitted under CC BY. can directly influence an individual’s response to bial composition. More recently, whole genome Published by BMJ. a specific drug by enzymatically transforming the shotgun sequencing, or metagenomic sequencing To cite: Weersma RK, drug’s structure and altering its bioavailability, (MGS), has become a powerful methodology for Zhernakova A, Fu J. Gut bioactivity or toxicity—a phenomenon now studying the microbiome. MGS allows identifica- 2020;69:1510–1519. referred to as pharmacomicrobiomics (figure 1). tion of not only bacteria, but also viruses, protozoa 1510 Weersma RK, et al. Gut 2020;69:1510–1519. doi:10.1136/gutjnl-2019-320204 Recent advances in basic science Gut: first published as 10.1136/gutjnl-2019-320204 on 14 May 2020. Downloaded from http://gut.bmj.com/ Figure 1 Schematic overview of different interactions between the gut microbiome and commonly used non- antibiotic drugs. SCFA, short- chain fatty acids. and fungi, and it enables focussed analysis of bacterial genes and Human cohort- based analysis has further shown that the predicted biological pathways. However, as with all sequencing- dynamic nature of the gut ecosystem reflects a complex inter- based methods, MGS results are very dependent on the method action of the host with lifestyle, dietary, ecological and other on September 28, 2021 by guest. Protected copyright. used to isolate DNA from stool samples, and this is the major factors. Hundreds of intrinsic and environmental factors influ- source of the technical variability in the results of microbiome ence the gut microbiome in healthy individuals, including diet, studies.14 Other omics approaches, such as metatranscriptomics, medication, smoking, lifestyle, host genetics and diseases.15 17 metametabolomics and metaproteomics, are also increasingly Among all environmental factors, commonly used drugs play a being used to get a comprehensive picture of the gut ecosystem. particularly important role in the gut ecosystem. Finally, culturomics analysis, which allows deep characterisation of individual associated species and strains, is again becoming an important method to understand the role of specific taxa in Association of gut microbiome composition with commonly relation to diseases. used drugs in human cohorts Several human cohort studies have reported associations between Intrinsic and extrinsic factors influencing the gut microbiome use of specific drugs and altered microbial composition and func- With the aid of next-generating sequencing, gut microbiome tional profiles (summarised in table 1). One of the first studies analysis has been applied to several human cohorts. One to see this was conducted in the Dutch LifeLines-DEEP cohort, important finding is the large interindividual variability of the and this study reported microbial associations to 19 out of 42 17 gut ecosystem: only a minority of gut microbes are shared across commonly used drugs. In addition to antibiotics, many human- the majority of individuals. For example, in a European data targeted non- antibiotic drugs were associated with changes in set of 3000 samples, only 17 bacteria were identified as a core microbial composition. The top microbiome- associated drugs microbiome present in >95% of all samples.15 The majority of included PPIs, lipid- lowering statins, laxatives, metformin, beta- bacteria are rare. Of the 639 species identified in a population blockers and ACE inhibitors, and selective serotonin reuptake study of 1135 Dutch individuals, 469 (73%) were present in inhibitor antidepressants, and similar associations were also fewer than 10 individuals.16 This high interindividual variability observed in a Belgium Flemish cohort15 and in the TwinsUK potentially leads to variations in the metabolic functions carried cohort18 (table 1). It is also worth noting that these drug- microbe out by the gut microbiome. associations were mostly assessed for individual drugs. However, Weersma RK, et al. Gut 2020;69:1510–1519. doi:10.1136/gutjnl-2019-320204 1511 1512 Recent advancesinbasicscience Table 1 Effect of common drugs on the microbiome in population studies NL% UK% Effect on Effect on beta- div/prop. Name (analogue UK) n=1124 n=2737 alpha div of core genera
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