From Microbiome to Medicine: A Comprehensive Review of Gut Microbiome–Drug Interactions and Their Implications for Personalised Drug Delivery Systems

Table 1. Major Microbial Enzymes Involved in Drug Metabolism and Their Pharmaceutical Significance ^15,16

4. CLINICALLY IMPORTANT DRUG–MICROBIOME INTERACTIONS

4.1 Digoxin and Eggerthella lenta Interaction

Perhaps the most well-studied example of microbiome-driven drug metabolism is the interaction between digoxin and Eggerthella lenta, which demonstrates the ability of intestinal bacteria to influence treatment response. Digoxin is a cardiac glycoside used in the treatment of atrial fibrillation and heart failure. It has a narrow therapeutic index, and even slight differences in systemic drug exposure may have clinical implications. The considerable inter-individual variability observed during therapy cannot be fully explained by host factors such as renal function, pharmacogenetics, and drug interactions, although these factors are undoubtedly important mediators of response.¹⁹

Mechanistic studies have demonstrated that E. lenta metabolises digoxin to dihydrodigoxin, a metabolite with considerably reduced pharmacological activity. Only strains possessing the cardiac glycoside reductase (cgr) operon efficiently metabolize digoxin, suggesting that drug metabolism is determined by microbial functional genes rather than microbial abundance alone. Subsequent experimental work demonstrated that dietary arginine suppresses expression of the cgr operon, thereby reducing microbial inactivation of digoxin and increasing the amount of bioavailable drug. This interaction represents one of the foundational examples of pharmacomicrobiomics, demonstrating that microbial functional capacity can modulate treatment response and may be considered in personalized therapy and microbiome-based dose adjustment.²⁰

4.2 Metformin and Gut Microbiome Modulation

Metformin is a first-line pharmacological treatment for type 2 diabetes mellitus. It is commonly used to improve insulin sensitivity and inhibit hepatic glucose production. Unlike many oral medications, metformin is not extensively metabolized and is mostly excreted unchanged in the urine. However, because it reaches high concentrations in the gastrointestinal tract, it can directly modify the resident microbiota, which in turn may contribute to the therapeutic response to the drug.²¹

Metagenomic and metabolomic findings demonstrate that metformin can alter the abundance of bacterial taxa associated with metabolic phenotypes and influence pathways involved in short-chain fatty acid production, carbohydrate fermentation, and bile acid metabolism. In addition to the direct effects of the medication, these microbiome-mediated alterations may contribute to intestinal barrier function, glucose homeostasis, and glucagon-like peptide-1 production. Individual differences in microbiome-mediated effects might account, in part, for differences in glycaemic control and gastrointestinal responses during treatment, since baseline microbiota composition varies widely among individuals. Overall, these findings demonstrate the complex, multimodal interactions between the microbiome, medication, and host metabolism that contribute to the observed effects of metformin and provide mechanistic insight into microbiome-based approaches for disease management.^21,22

4.3 Irinotecan-Induced Gastrointestinal Toxicity

Irinotecan is a semisynthetic derivative of camptothecin that is indicated for the treatment of colorectal carcinoma as well as a number of other solid tumours. Its clinical application, however, is frequently limited by significant gastrointestinal toxicity, particularly delayed-onset diarrhoea. Despite inherent host genetic variation and differences in hepatic metabolism, gut microbiome composition has also been implicated in irinotecan-induced intestinal toxicity, providing one of the clearest examples of microbiome-mediated drug toxicity.^16,23

Irinotecan is converted into the active metabolite SN-38 by host carboxylesterases after administration. SN-38 is subsequently inactivated in the liver through glucuronidation to form SN-38G. Following biliary excretion into the intestine, bacterial β-glucuronidase enzymes can hydrolyze SN-38G and regenerate active SN-38, which can contribute to intestinal inflammation, cellular damage, and persistent diarrhoea. Thus, microbial reactivation of a host-detoxified drug metabolite contributes to intestinal toxicity. Selective suppression of bacterial β-glucuronidase activity has been investigated as a targeted approach to reduce irinotecan-induced gastrointestinal toxicity while preserving its antitumor activity, demonstrating the potential of microbiome-targeted strategies for preventing chemotherapy-associated adverse effects.^16,24

4.4 Sulfasalazine Activation by Colonic Bacteria

Sulfasalazine is a well-established example of a microbial-dependent prodrug in which bacterial metabolism enables site-specific drug release. Colonic bacterial azoreductases cleave the azo linkage between 5-aminosalicylic acid (5-ASA), the anti-inflammatory component, and sulfapyridine. The azo linkage helps prevent premature drug release during transit through the stomach and upper gastrointestinal tract, allowing 5-ASA to be released in the colon, while sulphapyridine is subsequently absorbed and excreted.²⁵

The activation of sulfasalazine therefore depends on the metabolic capability of the intestinal microbiota. Conditions such as dysbiosis and antibiotic therapy may modify microbial composition and azoreductase activity and, consequently, may influence the metabolism and therapeutic response to the drug. This established mechanism has also provided a basis for developing colon-targeted delivery technologies, including enzyme-responsive coatings and polysaccharide-based formulations, that use microbiologically driven metabolism for local drug release.^16,25

4.5 Levodopa Metabolism by Gut Microbes

Despite being a major pharmacological treatment for Parkinson's disease, the response to levodopa shows considerable inter-individual variability, including differences in dose requirements. Levodopa bioavailability can be influenced by presystemic microbial metabolism, although gastrointestinal transit time, intestinal absorption, and host metabolism must also be considered.^26,27

After oral administration, levodopa is predominantly absorbed in the proximal small intestine and transported to the brain, where it is converted into dopamine. Levodopa is often administered with aromatic L-amino acid decarboxylase inhibitors, such as carbidopa or benserazide, to reduce peripheral metabolism. However, these inhibitors do not suppress bacterial enzymes with similar decarboxylase activity. In particular, some gut bacteria, including Enterococcus faecalis, possess tyrosine decarboxylase, which converts levodopa to dopamine before absorption in the intestine. Dopamine can then undergo further bacterial metabolism, reducing the amount of intact levodopa available to enter the circulation and reach the brain. Differences in the abundance and activity of these bacterial enzymes may therefore contribute to variations in drug exposure and therapeutic outcomes. This example highlights the relevance of microbiome-related factors in precision pharmacology and personalized medicine, with bacterial metabolism representing an additional source of pharmacokinetic variability.^26,27

The clinically important drug–microbiome interactions discussed above, along with their underlying mechanisms and therapeutic consequences, are summarised in Table 2.

Table 2. Clinically Important Drug–Microbiome Interactions and Their Therapeutic Consequences ^20-27

5. LIMITATIONS OF CONVENTIONAL DRUG DELIVERY SYSTEMS

5.1 Lack of Consideration of Inter-Individual Microbiome Variability

Standard considerations for designing conventional oral dosage forms include solubility, stability, permeability, gastrointestinal transit, and host pharmacokinetics. These approaches, however, often neglect the substantial heterogeneity of the gut microbiome, which has increasingly been recognized as an important factor influencing drug response.¹⁵

The composition of the gut microbiota can be highly variable and is continuously influenced by diet, age, disease state, antibiotic history, lifestyle, and environmental factors, in contrast to the relatively stable human genome. Since the metabolic activity, diversity, and functional capacity of microbes, as well as their interactions with drugs, can vary between individuals, these factors may be important in determining drug response. Hence, patients may have different microbial metabolic phenotypes despite receiving the same formulation, potentially resulting in substantial variability in treatment outcomes.²⁸

The gut microbiome can influence drug response through mechanisms such as activating prodrugs, inactivating drugs, or generating metabolites that may contribute to toxicity, as demonstrated in several important drug–microbiome interactions. These effects may result in variations in efficacy or safety that cannot be adequately explained by the formulation alone.²⁷

Consequently, effective drug delivery and precision medicine may require consideration of microbiome-associated variability. By adopting a systems-based pharmacological approach, characterizing microbial functional profiles, and incorporating microbiome-derived indicators into formulation development, patient stratification, formulation selection, dose optimization, and prediction of treatment outcomes may be improved. This approach supports the development of more personalized and predictable drug delivery routes.^29,30

5.2 Poor Prediction of Microbiome-Mediated Drug Metabolism

Host-based pharmacokinetic models, focusing on parameters such as gastrointestinal physiology, hepatic metabolism, renal clearance, and pharmacogenomic variability, have predominantly been used in the development of conventional medicines. However, the contribution of the gut microbiome, which acts as an additional enzymatic system capable of activating or inactivating many therapeutic agents before and after systemic absorption, is not fully captured by these parameters.¹³

Microbial enzymes can differ considerably in abundance, location, and catalytic activity between individuals. Reduction, hydrolysis, deconjugation, decarboxylation, and dehydroxylation are among the processes catalyzed by intestinal microbes that can potentially alter the pharmacological activity, toxicity, or bioavailability of drugs. Thus, the efficacy of the same formulation may vary between individuals depending on the metabolic potential of their microbiome.²⁶

Emerging advances in metagenomics, metabolomics, and functional microbiome analyses suggest that the use of microbial gene profiles, enzymatic activities, and metabolite profiles in combination with pharmacokinetic assessment could improve the prediction of drug disposition and therapeutic outcomes. Therefore, the incorporation of microbiome-based predictive markers during drug development may contribute to more accurate formulation design, targeted dosing strategies, and improved therapeutic predictability, representing an important component of microbiome-centered precision drug delivery.^29,30

5.3 Stability and Bioavailability Challenges

Conventional delivery systems generally aim to improve the stability and bioavailability of drugs by overcoming physicochemical barriers within the gastrointestinal tract, including poor solubility, chemical degradation, variations in pH, and low intestinal permeability However, many of these approaches do not fully consider the influence of the gut microbiota, which can play an important role in determining the fate of drugs after oral administration.¹⁶

Orally administered drugs are exposed to intestinal bacteria for varying periods before complete absorption. During this exposure, bacterial enzymes can catalyze biotransformations that may alter drug stability, produce inactive metabolites, or modify pharmacological activity, potentially contributing to differences in the response to formulations that show favorable in vitro performance.²⁶

Inter-individual variability in microbial composition and enzyme expression may further influence the extent of these effects and make systemic exposure more difficult to predict. Therefore, incorporating microbiome-related metabolic characteristics into formulation development and bioavailability assessment may help guide the development of more robust microbiome-informed pharmaceutical formulations.^29,30

5.4 Inadequacy in Targeted and Colon-Specific Drug Delivery

Targeted and colon-specific drug delivery systems aim to release drugs at localized sites within the gastrointestinal tract and reduce systemic adverse effects, thereby improving the treatment of gastrointestinal diseases. Various conventional colon-specific drug delivery systems, including time-dependent systems, pH-sensitive coatings, and biodegradable polymeric carriers, are generally designed according to broad characteristics of the gastrointestinal environment rather than the highly individualized characteristics of the gut microbiota.³¹

This is particularly relevant to microbiome-dependent treatments such as sulfasalazine, which relies on bacterial azoreductase activity for prodrug activation. Identical formulations administered in different microbial environments, influenced by factors such as diet, previous antibiotic use, inflammatory bowel disease, or dysbiosis, may therefore experience differences in enzymatic activity and treatment outcomes.^25,26

Additionally, existing targeted delivery systems generally cannot adapt to changes in the metabolic activity and microbial composition of an individual during the course of therapy because they depend on predetermined release mechanisms. Incorporating microbiome-responsive materials, enzyme-cleavable carriers, and individual microbial biomarkers into dosage-form design may provide more precise site- and time-specific drug delivery. Such approaches could support the transition from classical population-based dosage forms toward microbiome-guided precision delivery systems and potentially improve the reproducibility of therapeutic outcomes.^29,30,31

6. EMERGING STRATEGIES FOR MICROBIOME-GUIDED PERSONALIZED DRUG DELIVERY

6.1 Microbiome-Informed Drug Delivery Design

In recent years, the expanding body of evidence indicating the influence of the gut microbiome on drug absorption, metabolism, and efficacy has encouraged a transition from conventional population-based formulation strategies toward microbiome-directed approaches to drug delivery. Conventional oral dosage designs generally rely on drug physicochemical properties and host physiological factors while giving limited consideration to the substantial inter-individual differences in microbial composition and functionality. As a result, microbiome-driven differences in drug metabolism can contribute to differences in treatment response among patients receiving the same formulation.^15,31

The aim of microbiome-informed formulation design is to utilize microbial enzymes either as biological triggers for site-specific drug release or to protect drugs from microbial degradation. The identification of microbial biomarkers of drug response through metagenomics, metabolomics, and systems pharmacology approaches has supported the development of formulations that consider individual microbial metabolic profiles. Enzyme-responsive materials can therefore enable target-specific drug release in the colon, whereas protective carriers such as polymeric matrices, lipid-based formulations, and hydrogels can protect drugs from premature degradation. Hence, the microbiota is increasingly being considered not only as a variable influencing treatment but also as an additional target for precision pharmaceutical design.^30,32

This microbiome-mediated approach to site-specific drug release is illustrated in Figure 1.^31,32

Figure 1  Overall mechanism of microbiome-responsive colon-targeted drug delivery.^31,32

6.2 Colon-Targeted Drug Delivery Systems

Colon-specific delivery systems achieve targeted and controlled drug release by exploiting the fact that the microbial environment of the large intestine differs considerably from that of the small intestine. Most existing systems depend on biodegradable polymers, pH-responsive coatings, or transit-time-based mechanisms, but they may overlook inter- and intra-patient variations in microbial enzyme activity that can affect the release and bioavailability of the drug.^28,31

This limitation can potentially be addressed by using microbiome-specific biological triggers, such as bacterial azoreductases, β-glucuronidases, glycosidases, and esterases, in microbiome-guided colon-specific delivery systems. These delivery systems can be designed to release their active agent after exposure to microbial enzymes in the colon, thereby minimizing release in the upper gastrointestinal tract. The microbiota-mediated activation of sulfasalazine represents an established example of this concept. Further integration of microbiome profiling with targeted materials may allow drug delivery to become more precise and colon-specific.^25,31,32

6.3 Nanocarrier-Based Drug Delivery Approaches

Another promising approach to addressing microbiome-related challenges in oral pharmacotherapy is the application of nanocarrier-based drug delivery systems. Microbial enzymes within the gastrointestinal tract can contribute to the degradation or transformation of unstable compounds before systemic absorption. Encapsulating drug molecules in nanocarriers such as polymeric nanoparticles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, or micelles can help protect the drug from premature degradation while also improving solubility, stability, and release characteristics.^31,32

Recent advances have enabled the development of microbiome-responsive nanocarriers that can be activated by bacterial enzymes, microbial products, or intestinal conditions associated with disease. These smart nanocarriers can resist degradation within the upper gastrointestinal tract and release their contents after microbial activation in the colon. Such approaches have the potential to enhance therapeutic efficiency, minimize off-target effects, and provide site-specific drug delivery. Microbiome-responsive nanotechnology therefore remains a promising approach for future precision drug delivery, although challenges related to production, long-term stability, and regulatory approval remain.^30,32,33

6.4 Microbiome-Responsive Smart Drug Delivery Systems

Microbiome-responsive smart drug delivery systems represent an important advance in precision pharmaceutics because they enable drug release in response to biological cues generated by the gut microbiota rather than relying solely on predetermined release kinetics. Gut microbial enzymes, metabolites, inflammatory biomarkers, or disease-associated changes in the intestinal environment can be used as triggers for targeted and controlled drug release, potentially improving therapeutic precision and reducing systemic toxicity.^31,32

Enzyme-responsive polymers and biodegradable linkers are important components of these systems and can facilitate specific degradation by bacterial enzymes such as azoreductases, β-glucuronidases, glycosidases, and esterases. Recent innovations include metabolite-sensitive systems, biofilm-sensitive carriers, engineered living therapies that sense the intestinal environment and produce therapeutic molecules at the site of disease, and enzyme-responsive formulations. Thus, concepts demonstrated by microbiome-dependent prodrugs such as sulfasalazine are being extended toward more sophisticated and adaptive drug delivery platforms.^25,32,33

The integration of these biological triggers into smart drug delivery systems is illustrated in Figure 2.^32,33

Figure 2 Major mechanisms and biological triggers of microbiome-responsive drug delivery systems^32,33

The key microbiome-responsive drug delivery strategies, along with their biological triggers, release mechanisms, major advantages, and representative applications, are summarised in Table 3.

Table 3. Microbiome-Responsive Drug Delivery Strategies ^31,32,33

6.5 Precision Dosing and Therapeutic Drug Monitoring

The substantial inter-individual variation in gut microbiota composition has highlighted the limitations of fixed-dose treatment regimens and reinforced the importance of personalised dosing in modern pharmacology. Population pharmacokinetic and pharmacodynamic principles are traditionally used to develop dosage regimens intended to achieve similar therapeutic drug concentrations, assuming that patients will have relatively similar systemic drug exposure when given the same dose. However, host genetics, age, organ function, and body weight may not fully explain the additional variability caused by microbial metabolism. Therefore, incorporating a microbiome component into dose adjustment may provide an opportunity to improve treatment effectiveness while reducing treatment-related adverse effects.^15,30,35

Precision dosing incorporates patient-specific characteristics, such as pharmacogenetic information, into drug-based decisions. Extending this concept, pharmacomicrobiomics considers the gut microbiome as an additional participant in the drug–host interaction, alongside pharmacogenomics, patient clinical data, therapeutic drug monitoring (TDM), and clinical response. Even when the same dose regimen is administered, differences in microbial enzyme activity can alter drug absorption, activation, inactivation, and enterohepatic recycling, resulting in differences in plasma drug concentrations. Pharmacogenetic information, pharmacokinetic models, TDM, and microbiome profiling may therefore be integrated to identify potential differences in medication exposure and effectiveness and to support dose individualisation.^30,35

Further advances in computational modelling, artificial intelligence, and systems pharmacology are expected to enhance microbiome-guided precision dosing, although standardised microbiome sampling, identification and validation of reliable microbial biomarkers, and regulatory considerations remain important challenges before routine clinical application. These developments may enable drug delivery strategies tailored to both the host and microbiome and support computerised decision-making systems for treatment optimisation.^34,35

Emerging microbiome-based therapeutic approaches for personalised drug delivery, together with their underlying principles, major advantages, limitations, and current clinical status, are summarised in Table 4.

Table 4. Emerging Microbiome-Based Therapeutic Approaches for Personalized Drug Delivery ^{29,31,32, 33,35}

7. ARTIFICIAL INTELLIGENCE AND SYSTEMS PHARMACOLOGY IN MICROBIOME-GUIDED PERSONALIZED DRUG DELIVERY

7.1 Artificial Intelligence for Microbiome Analysis

The rapid growth of microbiome research has resulted in an enormous volume of data covering microbial taxonomy, functional genes, metabolic pathways, metabolomic profiles, and other biological characteristics. Artificial intelligence (AI), particularly machine learning and deep learning, provides effective approaches for analysing these complex datasets and extracting therapeutically relevant information. AI can also help predict microbial enzyme activities and metabolite production and identify microbial markers associated with drug metabolism, treatment response, and adverse effects. These computational approaches may support the development of microbiome-guided personalised drug delivery systems and formulation optimization.^15,36,37

7.2 Predictive Modelling of Drug Response

AI-based predictive modelling can integrate functional genes, pharmacokinetic parameters, microbiome composition, and patient-specific factors to predict therapeutic responses before treatment initiation. Prediction algorithms may support the development of individualized formulation designs and dosing strategies by assessing microbiome-regulated drug biotransformation, prodrug activation, and the production of potentially toxic metabolites. Such models represent an important step toward machine-assisted pharmacotherapy, potentially improving the selection of microbiome-responsive pharmaceutical preparations while reducing variability in clinical response. ^15,32,38

7.3 Integration of Multi-Omics Data

The integration of multi-omics data, including metagenomics, transcriptomics, proteomics, metabolomics, and pharmacogenomics, is important for developing a comprehensive understanding of microbiome–drug interactions. These complementary approaches can help identify host–microbiome interactions and microbial functional activities relevant to drug disposition and treatment response. Artificial intelligence can facilitate the parallel analysis of these datasets, making it easier to identify biomarkers, select suitable carriers, and design personalised formulation strategies. Multi-omics integration is therefore an important component of systems pharmacology and next-generation microbiome-guided drug delivery.^15,33,39

7.4 Clinical Decision Support Systems

Microbiome-informed clinical decision support systems (CDSS) can facilitate personalised therapeutic decision-making by integrating pharmacokinetic, pharmacogenomic, and clinical information with microbiome-derived indicators. AI-based systems may assist in recommending drug selection, dosage, and microbiome-adapted drug delivery strategies based on the metabolic functions of an individual's microbiota. Incorporating electronic health records, microbiome sequencing data, and therapeutic drug monitoring may further improve the prediction of treatment outcomes and adverse responses. Recent advances in explainable AI and digital health may support the future implementation of microbiome-guided clinical decision support in precision pharmacotherapy. ^32,37,38,40

8. FUTURE PERSPECTIVES

8.1 Translation to Clinical Practice

To translate pharmacomicrobiomics into clinical practice, microbiome biomarkers will need to be combined with clinical, pharmacokinetic, and pharmacogenomic information. Individual microbial profiles could be used in personalised drug delivery systems to guide dose selection, monitoring, and formulation. Successful application will require accurate profiling, validated biomarkers, global collaboration, and clinical trials.^29,30,33

8.2 Regulatory Considerations

Microbiome-guided drug delivery requires appropriate regulatory pathways for advanced delivery systems, AI-enabled therapeutic decision-making, and microbiome biomarkers. Microbiome-based treatments need to demonstrate safety and reproducibility through standardized microbiome characterisation, biomarker validation, formulation quality, and data governance. Globally harmonised guidelines will support regulatory approval and clinical translation of microbiome therapies.^{33,34,41,42,43,44}

8.3 Standardization Challenges

A major obstacle is the absence of consensus methods for microbiome sampling, sequencing, bioinformatic analysis, and biomarker validation. Differences in microbial profiles and analytical methods may limit reproducibility and comparison across studies. Standard protocols, comprehensive microbiome reference databases, validated functional biomarkers, and consistent formulation approaches are therefore crucial for improving reliability.^{29,30,42,43,44}

8.4 Future of Microbiome-Guided Precision Medicine

Future precision medicine may combine microbiome profiling with pharmacogenomics, multi-omics approaches, AI, and advanced drug delivery systems. AI-guided decision support, smart nanocarriers, and microbiome-responsive formulations could help optimise drug selection, formulation, dosing, and therapeutic monitoring. Continued technological advances, clinical evidence, and appropriate regulatory frameworks will support this approach.^{32,33,35,41,42,44,45}

The key challenges associated with microbiome-guided precision medicine, together with their potential solutions and future implications, are summarized in Table 5.

Table 5. Current Challenges, Regulatory Considerations, And Future Directions In Microbiome-Guided Drug Delivery ^{33,34,35,41-45}