When drugs meet microbes: a bidirectional dialogue with therapeutic implications

The gut microbiota acts as a metabolic organ, supporting digestion, immunity, and homeostasis ¹. Its interaction with drugs, however, is bidirectional: medications can disrupt microbial balance, while microbes can alter drug activity. This makes the microbiome a significant yet often overlooked factor in adverse drug reaction (ADR) risk ^{2, 3}. Gut microbial enzymes can transform drugs into more toxic forms, increasing tissue exposure and harmful effects. Growing evidence highlights microbial variability as a key driver of individual differences in drug response and ADRs ^{2, 4}. Integrating pharmacomicrobiomics into risk assessment alongside genetics and clinical data could help predict susceptibility to drug-related harm and guide personalized prevention strategies.

Drug-induced microbiota disruption: antibiotics and beyond

Antibiotics are well known to disrupt the gut microbiota by reducing diversity, altering composition, and promoting resistant strains (table 1) ^{5, 6}. Van Zyl et al. found that antibiotics especially quinolones and β-lactams consistently disrupt microbial communities across body sites, with combination regimens causing prolonged dysbiosis and increased pathogenic burden ⁵. Similarly, Maier et al. showed that different antibiotic classes have distinct effects on gut bacteria, with macrolides and tetracyclines causing sustained losses in anaerobes, and drugs like amoxicillin and ceftriaxone shifting populations toward Proteobacteria. Despite individual variability, a common trend emerged: depletion of obligate anaerobes (e.g., Firmicutes) and enrichment of facultative and potentially pathogenic microorganisms ⁶.

Beyond antibiotics, many non-antibiotic drugs including PPIs, metformin, NSAIDs, antipsychotics, and statins also alter the gut microbiota (figure 1, table 2) ^{7, 8}. Drugs influence the gut microbiota through various mechanisms direct antimicrobial action, altered pH, bile acid modulation, intestinal motility changes, and mucus secretion ⁹.

Gut microbiota modifies drugs metabolism

The gut microbiota can biotransform therapeutic drugs, altering their activity, efficacy, and toxicity (figure 2, table 3) ^12-14. Zimmermann et al. mapped microbial metabolism by screening 271 oral drugs against 76 gut bacterial strains, finding that 176 were metabolized by at least one strain. Notably, Bacteroides dorei and B. uniformis metabolized nearly 100 drugs. Over 40 microbial enzymes were identified,
mediating a wide range of reactions including reduction, hydrolysis, decarboxylation, dealkylation, and demethylation ¹².

Javdan et al. developed a personalized platform (MDM-Screen) to assess microbial drug metabolism using ex vivo microbiota from individual donors. Screening 575 drugs, they found that 13% were metabolized by gut microbes, including many previously unrecognized interactions. These transformations such as hydrolysis, reduction, and deacetylation can activate, inactivate, or increase drug toxicity. The study also revealed significant inter-individual variability and identified key microbial genes (e.g., uridine phosphorylase, β-glucuronidase) linked to specific metabolic pathways ¹⁵.

The efficacy of some drugs may depend more on the microbiota composition than on the host genetics.

Clinical consequences: toward personalized medicine

Microbiota-drug interactions have major clinical implications, as individual differences in gut microbiota may explain variability in drug response and side effects. Importantly, it is not just microbiota composition but also its functional stability that influences treatment outcomes.

These insights underscore the need to integrate both human and microbial genomics into pharmacological assessments. In drug development, simulating microbiota–drug interactions in silico has become key. Dodd and Cane proposed a detailed framework combining in vitro systems (e.g., strain libraries, stool-derived communities), genetic tools (gain/loss-offunction assays), and metagenomics to identify microbial genes involved in drug metabolism. Gnotobiotic mouse models further help disentangle microbial from host effects on pharmacokinetics.

As this field advances, microbiota-informed prescribing is emerging as a way to tailor treatments and reduce adverse effects. In the future, pharmacomicrobiomics could guide drug choices and dosages based on microbial biomarkers, enabling truly personalized medicine ¹⁷.

Personalizing treatment could one day require a microbiota fingerprint.

Preserving and restoring the microbiota: a therapeutic frontier

Protecting the gut microbiota during drug therapy is a promising strategy to reduce ADRs and preserve efficacy. While probiotics and prebiotics show some benefit against drug-induced dysbiosis, their effectiveness varies. Targeted probiotics tailored to specific drug effects, and fecal microbiota transplantation (FMT), particularly for recurrent C. difficile infection, offer more reliable options.

Precision tools such as microbial enzyme inhibitors (e.g., β-glucuronidase blockers for irinotecan toxicity), bioengineered probiotics,
microbiota-sparing drug designs, and diet-based interventions are under investigation. Clinical trials are exploring synbiotics customized to drug regimens to improve outcomes with minimal microbiota disruption. Postbiotics like butyrate are also being evaluated for anti-inflammatory and gut barrier-supporting effects.

Integrating microbiota-targeted strategies into pharmacology will require advanced tools multi-omics, machine learning, and systems microbiome modeling to predict and manage microbiota–drug interactions effectively.

Manipulating the gut microbiota may enhance treatment success and reduce complications.