Pharmacomicrobiomics in Psoriasis: Microbiome–Drug Interactions Across Systemic Treatments

Psoriasis is a chronic immune-mediated skin disease with highly variable responses to systemic therapies. Emerging evidence highlights the microbiome as a potential modulator of drug efficacy and toxicity. Gut bacteria can enzymatically metabolize drugs, such as methotrexate, altering bioavailability and therapeutic outcomes, while microbial metabolites-including short-chain fatty acids, branched-chain amino acids, and tryptophan derivatives-shape host immunity and barrier integrity, influencing drug action. Baseline microbial signatures have been linked to treatment response, potentially predicting anti-TNF or IL-17 inhibitor efficacy. Systemic therapies themselves reshape microbial communities: IL-17 blockade induces broad shifts in gut and skin microbiota, whereas cyclosporine and anti-TNF agents exert subtler effects. Small molecules such as apremilast and fumarates may reduce fungal overgrowth and influence microbial composition, whereas data on JAK/TYK2 inhibitors remain limited. Notably, current evidence exhibits a literature bias toward the gut microbiota, while the roles of the oral and skin axes remain understudied. Adjunctive microbiome-directed interventions, including probiotics and fecal microbiota transplantation, have demonstrated potential to enhance treatment outcomes by promoting anti-inflammatory taxa and restoring barrier function. Despite these promising findings, current evidence is heterogeneous, often limited by small sample sizes, short follow-up, and variable methodology. Integrating pharmacomicrobiomics data with clinical, genetic, and multi-omics profiling could enable precision medicine approaches in psoriasis, allowing therapy selection tailored to individual microbial and metabolic signatures. Future research should focus on longitudinal, multicenter studies to identify actionable microbial biomarkers, clarify mechanistic interactions between drugs, microbes, and host immunity, and evaluate microbiome-targeted adjuncts in randomized trials. Understanding the bidirectional crosstalk between systemic therapies and the microbiome may transform psoriasis management, improving efficacy, reducing adverse events, and enabling durable, personalized responses.