Exploring the link between drugs and microbiota: a growing imperative in precision medicine

In a recent article published in Signal Transduction and Targeted Therapy, researchers extensively reviewed the intricate interactions between gut microbiota and drugs commonly used against several human systemic diseases, e.g., cancer, endocrine disorders, and cardiovascular diseases (CVDs).

Study: Drug-microbiota interactions: an emerging priority for precision medicine. Image Credit: Helena Nechaeva/Shutterstock.com

Background

In particular, they focused on investigating the pharmacomicrobiomics of individual variability in drug response (IVDR), the primary cause of adverse drug reactions (ADRs).

Notably, pharmacomicrobiomics explores the correlation between gut microbiota variations and IVDR and ADRs. Insights into the impact of IVDR are crucial for further research in pharmacomicrobiomics and unlocking its full potential for precision medicine. 

Introduction

Gut microbiota, containing over 100 trillion microbes and five million genes, is increasingly considered a 'metabolic organ' or second genome.

Scientists believe this heterogeneous ecosystem, directly and indirectly, modifies the absorption, distribution, metabolism, and excretion (ADME) of drugs. In addition, they can alter drug pharmacodynamics (PD) and pharmacokinetics (PK).

IVDR prolongs therapy, resulting in a substantial health and economic burden. Recent studies have highlighted that genetic diversity alone can explain a limited proportion of IVDR; thus, gut microbiota and its metabolites are highly likely to modulate therapeutic outcomes in human diseases.

It is also possible that this relationship is bidirectional, and drugs, in turn, also modulate the composition and function of gut microbiota, resulting in altered microbial metabolism and immune response.

Causes of IVDR

Several factors, including genetics, environment, age, gender, lifestyle, diseases, drugs, and gut microbiota influence IVDR.

Given variations in drug metabolism, transport, and targets that affect response to treatment, it is crucial to understand the interactions between genetic and external factors for precision medicine strategies.

Using high-throughput sequencing techniques, the Human Microbiome Project (HMP) has accumulated extensive microbiota data that has advanced the understanding of microbiota-related disorders, contributing to innovative diagnostic methods and treatments and opening new avenues to address IVDR.

The research of drug-microbiota interactions is a systematically developed field, of which pharmacomicrobiomics, pharmacometabonomics, and pharmacometagenomics are sub-disciplines.

Some popular technologies to examine drugs and individual microbiota interactions are 16S and 18S ribosomal ribonucleic acid (rRNA) amplicons and whole-metagenome shotgun sequencing.

Pharmacomicrobiomics in systemic human diseases

The researchers described the mechanisms by which drugs and gut microbiota interact in various systemic human diseases. For cancer, they described microbiota interactions of cyclophosphamide (CTX), irinotecan (CPT-11), oxaliplatin and cisplatin, and immune checkpoint inhibitors (ICIs).

Likewise, for CVDs, they described microbiota interactions of drugs, warfarin, statins, digoxin, and angiotensin-converting enzyme inhibitors (ACE-Is).

Regarding their mechanism of action, it varied for different drugs. For instance, ICIs affected gut immunity, leading to alterations in gut microbiota, and non-steroidal anti-inflammatory drugs (NSAIDs) interfered with microbial metabolism in the gut.

Similarly, laxatives changed the gut's dietary environment, reducing the availability of nutrients for good gut microbes. In general, antibiotics disrupt the natural ecosystem of the microbiota, leading to the overgrowth and colonization of pathogenic species and impacting drug safety.

Thus, a better understanding of these relationships could help find more beneficial and safer drugs for IVDR management.

Conclusions and future perspectives

Some of the challenges in pharmacomicrobiomics research are standardizing  methodologies for sample collection, sequencing, and data analysis.

Understanding of the mechanisms governing drug-microbiota interactions is limited. Moreover, there are ethical considerations when using microbiota data in clinical practice. Addressing these challenges would require collaboration between researchers, clinicians, and industry partners.

The researchers highlighted five strategies to overcome these challenges. First, they emphasized the need to link microbiota reference genome, microbiota-disease relationships, and microbiota-drug association prediction databases to the pharmacomicrobiomic databases.

Second, they raised the need to develop predictive models and computational tools that simulate drug-microbiota interactions.

Third, they proposed using prebiotics and probiotics to modify gut microbiota, enhance drug efficacy, and reduce ADRs. Fourth, the researchers outlined how fecal microbiota transplantation (FMT) could help treat complex digestive diseases and pathogenic microbiota colonization.

Finally, they described the benefits of bacteriophage therapy against bacterial infections.

To conclude, IVDR hinders the effective implementation of microbiota biomarkers, considered promising agents for diagnosis and prediction in precision medicine.

Thus, an innovative approach is needed to integrate several multi-omics datasets in the IVDR Atlas database, integrate human and microbiota genomic data, and translate lab data into clinical practice, facilitating novel therapeutic strategies for human systemic diseases.

More efforts are needed to realize the full potential of pharmacomicrobiomics, the study of drug-microbiota and drug-micro enzyme interactions, in precision medicine, addressing IVDR and improving patient outcomes. 

In the future, it might help develop new therapeutic protocols encompassing pharmacomicrobiomic testing and microbiota typing.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.