ESPGHAN 2025: Focus on microbiota-drug interactions

Mechanisms

Microbiota includes a wide variety of bacteria, viruses, fungi, and other microorganisms which have been found to be crucial for immunologic, hormonal, and metabolic homeostasis of their host. We often referred to it as a “hidden organ”.

When this ecosystem is disrupted (dysbiosis), it can contribute to a wide range of diseases - from gastrointestinal diseases to systemic metabolic and neurological disorders ¹.

At birth, the newborn’s gut is sterile, but it is rapidly colonized by microorganisms from the environment, including Enterobacteria, Enterococci, Lactobacilli, and Bifidobacteria. The gut microbiota undergoes dynamic and gradual changes from infancy to adulthood, shaped by various internal and external factors. These microbial shifts are critical for establishing a stable and resilient microbiome that supports health across the lifespan. In healthy adults, the gut microbiota is estimated to include over 1,000 species of bacteria. Importantly, this microbial community can influence drug pharmacodynamics by either directly metabolizing drugs or modifying the host’s metabolic and immune responses.

Orally administered drugs travel through the gastrointestinal (GI) tract, with their absorption and metabolism influenced at each stage. Drugs that are not completely absorbed in the upper GI tract may reach the colon. In turn, the gut microbiome actively participates in the chemical transformation of these drugs, affecting their pharmacokinetics, bioactivity, and potential toxicity.

Several mechanisms are involved by which drugs affect gut microbiota, including:

1 / direct effects (antibiotics can kill some species of microbiota, including both harmful and beneficial species, leading to imbalances
in gut microbiota);

2 / altered gut motility (particular drugs can slow down gut motility, which can lead to overgrowth of harmful bacteria);

3 / modulation of immune function (several drugs can interact with gut immunity which in turn can affect gut microbiota);

4 / changes in pH in the intestine (the pH balance plays a significant role in the gastrointestinal tract which affects the growth and survival of different types of species of gut microbiota. Some drugs can change the pH value of the gut, which affects the proliferation of different microbes, thereby affecting the overall composition of gut microbiota);

5 / interference with microbial metabolism (several drugs can interfere with microbial metabolism, which may have an effect on gut microbiota);

6 / dietary changes (certain drugs can change the dietary environment in the gut. This may influence gut microbiota by changing the availability of nutrients and other compounds that gut microbiota use to grow and survive) ^2-4.

Gut microbiome-drug interactions are shaped not only by microbial activity but also by host genetics, environmental exposures, and their interplay, posing a complex challenge for personalized therapy. Genome-wide association studies (GWAS) have identified human genetic variants, especially in genes related to immunity, metabolism, and digestion (e.g., C-type lectins and lactase) that influence gut microbiota composition.

The examples of irinotecan and cytochrome p450

Irinotecan, an anti-cancer medication, is reactivated in the gut by microbial enzymes causing severe diarrhea - a major side effect of the chemotherapy. Certain gut bacteria, particularly β-glucuronidase-producing species such as Escherichia coli, Clostridium and Bacteroides, produce enzymes that convert SN-38G back into its active form SN-38 in the intestine. This reactivation is toxic to intestinal
epithelial cells, causing mucosal injury, inflammation, and severe delayed-onset diarrhea ³.

The gut microbiome can profoundly influence the host’s drug-metabolizing enzymes, an emerging factor in personalized medicine. Cytochrome P450 enzymes, particularly CYP3A4, are modulated by gut-derived compounds. Short-chain fatty acids (SCFAs) can modulate enzyme gene expression through epigenetic mechanisms. Meanwhile, secondary bile acids interact with nuclear receptors like FXR, CAR, and PXR, altering drug metabolism ³.

Strategies for reducing the collateral damage of drugs on the microbiome ⁵

To protect the gut microbiome, one key strategy is to avoid drugs known to disrupt microbial balance whenever possible. Minimizing direct interaction between drugs and gut microbes can reduce negative effects. In contrast, restorative approaches aim to repair microbial communities after disruption. These include dietary interventions, probiotics, live biotherapeutic products, and fecal microbiota transplantation. Dietary interventions act as microbiota- targeted therapies. Dietary fibers, for instance, foster the growth of SCFA-producing bacteria, which are essential for immune function, epithelial development, and maintaining an anaerobic gut environment ⁵. Probiotics such as Saccharomyces boulardii CNCM I-745, Lactobacillus reuteri and Bifidobacterium spp. support colonization resistance, immune modulation, and gut barrier integrity. Postbiotics, composed of inactivated microbes or their components, also offer health benefits without requiring live organisms. Meanwhile, live biotherapeutic products represent a new category of medical interventions using live microbes specifically designed to treat or prevent disease, distinct from traditional supplements ³.

Restoring the microbial community involves more than simply recolonizing bacteria. It requires reestablishing a balanced ecosystem that supports immune, metabolic, and barrier functions. Strategies to protect the microbiome during drug therapy fall into two main categories: preventive approaches that minimize drug-induced disruption, and restorative approaches that aim to rebuild microbial diversity and function after damage has occurred ⁵.

Selecting the right strategy requires a precision-based approach, tailored to the drug, disease context, and patient. Success depends on a deep understanding of the ecological and biochemical principles that govern microbiota drug interactions. Ongoing research is essential to guide effective recovery and protection of the gut microbiome during and after drug therapy.