A new evaluation system for drug-microbiota interactions

Abstract

The drug response phenotype is determined by a combination of genetic and environmental factors. The high clinical conversion failure rate of gene-targeted drugs might be attributed to the lack of emphasis on environmental factors and the inherent individual variability in drug response (IVDR). Current evidence suggests that environmental variables, rather than the disease itself, are the primary determinants of both gut microbiota composition and drug metabolism. Additionally, individual differences in gut microbiota create a unique metabolic environment that influences the in vivo processes underlying drug absorption, distribution, metabolism, and excretion (ADME). Here, we discuss how gut microbiota, shaped by both genetic and environmental factors, affects the host's ADME microenvironment within a new evaluation system for drug-microbiota interactions. Furthermore, we propose a new top-down research approach to investigate the intricate nature of drug-microbiota interactions in vivo. This approach utilizes germ-free animal models, providing foundation for the development of a new evaluation system for drug-microbiota interactions.

Keywords: drug metabolism; drug–microbiota interactions; genetic and environmental factors; gut microbiota.

Figure 1

The clinical significance of gut microbiota in pharmacological research and the regulation of drug‐targeting genes. (A) Pharmacomicrobiomics provides new opportunities for preclinical investigations of drug efficacy and safety. ① The effect of drugs on disease characterization depends on a combination of genetic and environmental factors. ② Pharmacogenomics employs human genomic information (genetic factors) to decode the reasons behind individual variability in drug response (IVDR). ③ Pharmacomicrobiomics employs gut microbial genomic information (environmental factors) to decode the reasons behind environmental factors in drug response. ④ A better understanding of the role of environmental factors on drug safety and efficacy is expected to provide preclinical research strategies to improve the success of clinical drug development. (B) Involvement of gut microbiota in drug ADME. Up: Gut microbiota is a primary site for the drug ADME. Whether the drug is administered orally or injected, it directly reaches the gut microbiota or via the bloodstream. Down: Gut microbiota produced new drugs or druggable metabolites. It concludes short‐chain fatty acids (SCFAs), vitamins, 5‐hydroxytryptamine (5‐TH), γ‐aminobutyric acid (GABA), trimethylamine oxide (TMAO), and bile acids, as well as secondary metabolites of related metabolic pathways. Gut microbiota is involved in a variety of metabolic reactions, mainly involving reductive metabolism and hydrolysis. Drug‐induced gut microbiota remodeling. Most drugs are metabolized through endogenous enzymes and coupling reactions, resulting in ectopic microbiota colonization and remodeling of the gut microbiota. (C) Interactions between gut microbiota genes and drug‐targeted host genes. ARGs: Drugs can influence the expression of antibiotic resistance genes (ARGs) in the gut microbiota. Gut phenotype: The relationship between personalized gut phenotype and drug efficacy based on genetic sequencing of the gut microbiota has been demonstrated. Immunotherapy: Gut microbiota can modulate the safety and efficacy of targeted immunomodulators. Encoding enzyme: CRISPR gene editing of engineered bacteria targets the elimination of ARGs in gut microbiota.

Figure 2

Environmental factors influencing gut microbiota. (A) Natural conditions: natural environment contributions to the gut microbiota. The climatic extremes including cold and heat exposure or stress and high‐altitude hypoxia environment can alter the specific bacteria in gut and have an impact on the host response to extreme environments. (B) Environmental pollution: Environmental contamination including PM2.5 pollution, microplastic pollution, and antibiotic resistance genes (ARGs) contributes to the gut microbiota and human health. (C) Psychological factor and stress: There is an important relationship between gut microbiota and cognitive and behavioral processes caused by psychological stress, which mainly include hypothalamic‐pituitary‐adrenal axis (HPA‐axis), neuroimmune regulation, immune system, and endocannabinoid (eCB). Moreover, psychiatric factors are one of the most important influences on drug metabolism. (D) Lifestyle: The intervention effect of lifestyle including western diets, modern lifestyles, sedentary behaviors, smoking habits, and alcohol dependence on the gut microbiota is evident.

Figure 3

Drug preclinical research strategies based on precise germ‐free animal models. (A) Precise germ‐free animal models. Single functional microbe colonization, germ‐free treatment of genetically engineered disease animals, and liver‐gut humanization model system provide support for studying the in vivo function of gut microbiota in drug metabolism. (B) Gut microbiota in vivo function. The drug‐containing serum from GF disease model animal can not only screen small molecule pharmacodynamic substances modified by gut microbiota enzyme but also achieve more refined research of “host cell—gut microbiota—drug” by the intervention on host cells in vitro. (C) High‐resolution sequencing for single‐cell recognition. The single‐cell resolution sequencing of the microbiota (Microbe‐seq) can realize the high‐precision cognition on the cell individual level of the in vivo function of drug transformation. (D) Function‐oriented precise bacterial culture. The construction of GF animals with specific functional phenotypes will realize the transformation of small molecule drugs modified by microbial enzymes from in vitro function to in vivo function. (E) Coculture based on the in vivo function of gut microbiota. The microbiota‐loaded organoids are excellent media for host “cells and microbes” coculture.