A recent Signal Transduction and Targeted Therapy study explored the role of the gut microbiome and its metabolites in altering the therapeutic outcomes of human diseases.
This study reviewed and summarized the available research on how the gut microbiome influences therapeutic drug absorption, distribution, metabolism, and excretion (ADME).
Study: Drug-microbiota interactions: an emerging priority for precision medicine. Image Credit: Meeko Media/Shutterstock.com
Variable drug reaction among different individuals
Drugs that respond well for one patient might cause serious adverse reactions (ADRs) in others. This occurrence has been termed individual variability in drug response (IVDR).
This variability is attributed to multiple factors that include genetics, age, gender, lifestyle, disease state, surrounding environment, gut microbiota, and drug-drug interactions. All these factors play a crucial role in the optimal efficacy of the newly developed pharmaceutic therapy and in reducing the risk of ADR.
Genetic factors are associated with 95% of inter-individual variability in drug pharmacokinetics (PK) and pharmacodynamics (PD) for drug classes or specific drugs.
The evolution of genetics to genomics has led to the emergence of pharmacogenomics, which assists in recommending specific drug therapies to genetically defined patient subpopulations.
Genetic variations influence drug targets, transport, as well as metabolism. Environmental factors also influence drug efficacy, metabolism, and toxicity.
The difference in PK between drug-metabolizing enzymes and transporters can lead to IVDR and increase the risk of ADR. There is a need for a more in-depth phenotypic and mechanistic study of drug metabolism, which can be applied to clinical models to avoid ADRs.
The association between microbial diversity and IVDR
Gut microbial composition, diversity, and function are important in the immune system, drug response, and disease progression. Importantly, unlike the human genome, the gut microbiome is completely adaptive and mobile. Therefore, these can be manipulated to improve drug efficacy.
Gut microbial diversity provides an exceptional metabolic capacity, which might exceed the host's. These microorganisms can directly modify drug metabolism in multiple ways, including the production of enzymes that catalyze or degrade the drug molecule, changing the metabolic levels of drugs in the host, and competing with drug molecules for a metabolic enzyme.
Microbiota-encoded enzymes could be used as a potential target for PK modification, which could ultimately improve clinical response. It must also be noted that drug administration affects gut microbial composition, growth, and diversity, which could lead to variable microbial function.
Alterations in metabolic enzyme and drug transporter expressions and changes in pathological state influence the synthesis of metabolic compounds, which affects drug PD and PK.
Underlying mechanisms and interactions between human genomes and gut microbiota genomes that influence IVDR
The interactions between the human genome and gut microbial genomes lead to the synthesis of compounds, such as short-chain fatty acids (SCFAs), amino acids (AAs), and bile acids (BAs), that are beneficial to human health.
Genes encoded by gut microbiota significantly enhance the metabolic capacity of humans. Therefore, measuring the metabolites to manage and enhance drug response to disease is imperative.
It is extremely important to understand how the interaction between the heterogenous human genome and gut microbial diversity influences IVDR. This insight will immensely help improve precision medicine's development with minimized ADRs.
Gut microbiota influences IVDR in multiple ways. Pharmacomicrobiomics plays a critical role in assessing the efficacy and safety of a drug, considering various mechanisms of interaction between microbiota and IVDR.
Mechanistically, microbiota can modify the activities of enzymes that metabolize drugs within the body. As a result, the drug's efficacy is reduced and enhances ADRs. For instance, beta-lactamases are an enzyme a gut microbe produces that can degrade beta-lactam antibiotics, making them ineffective.
Gut microbiota can induce drug resistance over time, possibly due to the acquisition of resistance genes from others or mutations in the microbial DNA. Furthermore, gut microbes can alter drug targets in the body, reducing therapeutic efficacy.
For instance, the target site of fluoroquinolone antibiotics was altered by gut microbiota, which inhibited drug molecules to bind and inhibit the enzymatic function.
Several studies have indicated that gut microbes can modify the ADME of drugs by impacting PK, which leads to altered therapeutic efficacy and ADRs. Antibiotics disrupt the natural ecosystem of the host’s microbiota and cause enhancement of pathogenic species, such as Clostridium difficile.
These alterations in gut microbial structure and composition can cause infection and increase ADRs. Furthermore, gut microbiota can influence drug absorption by regulating tight junction protein expression in the intestine.
The gut microbiome plays an important role in the efficacy and safety of drugs. These biomarkers can be potentially used for disease diagnoses and prognostic predictions.
Although the inter-individual variability of the human microbiota and the emergence of new multi-drug resistance microbiota strains can hamper the efficacy of precision medicine, these shortcomings could be overcome to enhance the applicability of precision medicine for future theranostics.
An in-depth understanding of how gut microbes influence IVDR based on microbiota types, specific biomarkers, and metabotypes will significantly contribute to developing effective precision medicine.