Towards a mechanistic understanding of reciprocal drug-microbiome interactions.

Michael Zimmermann,Athanasios Typas,Kiran Raosaheb Patil,Lisa Maier

doi:10.15252/msb.202010116

Abstract

Broad‐spectrum antibiotics target multiple gram‐positive and gram‐negative bacteria, and can collaterally damage the gut microbiota. Yet, our knowledge of the extent of damage, the antibiotic activity spectra, and the resistance mechanisms of gut microbes is sparse. This limits our ability to mitigate microbiome‐facilitated spread of antibiotic resistance. In addition to antibiotics, non‐antibiotic drugs affect the human microbiome, as shown by metagenomics as well as in vitro studies. Microbiome–drug interactions are bidirectional, as microbes can also modulate drugs. Chemical modifications of antibiotics mostly function as antimicrobial resistance mechanisms, while metabolism of non‐antibiotics can also change the drugs’ pharmacodynamic, pharmacokinetic, and toxic properties. Recent studies have started to unravel the extensive capacity of gut microbes to metabolize drugs, the mechanisms, and the relevance of such events for drug treatment. These findings raise the question whether and to which degree these reciprocal drug–microbiome interactions will differ across individuals, and how to take them into account in drug discovery and precision medicine. This review describes recent developments in the field and discusses future study areas that will benefit from systems biology approaches to better understand the mechanistic role of the human gut microbiota in drug actions.

Highlights

Our understanding of how the human gut microbiota contributes to health and disease, and how it changes over time, life stages, different geographic regions, and in response to environmental factors has increased dramatically over the last decade
Evidence from metagenomic-based cohorts and clinical studies—the top-down approach Exploring the factors that explain inter-individual differences in the intestinal microbiome composition across large population cohorts have repeatedly identified medication as a main contributor (Falony et al, 2016; Ticinesi et al, 2017; Jackson et al, 2018; Vich Vila et al, 2020). Such studies have been insightful and have revealed the cumulative and dramatic impact medication has on the gut microbiome composition, they are still underpowered for separating the effects of individual drug classes
A molecular understanding of the drug–microbiome–host triad will open up strategies to fine-tune existing clinical drug treatments, improving drug efficacy and reducing adverse effects

Summary

Introduction

Our understanding of how the human gut microbiota contributes to health and disease, and how it changes over time, life stages, different geographic regions, and in response to environmental factors has increased dramatically over the last decade (TheTherapeutic drugs alter the gut microbiome compositionEvidence from metagenomic-based cohorts and clinical studies—the top-down approach Exploring the factors that explain inter-individual differences in the intestinal microbiome composition across large population cohorts have repeatedly identified medication as a main contributor (Falony et al, 2016; Ticinesi et al, 2017; Jackson et al, 2018; Vich Vila et al, 2020). Mutual Impact drug metabolites influence microbes dysbiosis affects microbial metabolism interact with human/host targets, here referred to as humantargeted drugs.

Results

Conclusion