Preserving the gut microbiome: hydrogel-forming microneedle delivery of tetracycline reduces gut microbiome disruption compared to oral administration

Abstract Antibiotics cause significant gut microbiome dysbiosis, particularly when administered orally. This contributes to antimicrobial resistance (AMR) and is associated with myriad health conditions. Novel drug delivery strategies that minimize gut exposure while maintaining therapeutic efficacy are urgently needed. This study aimed to evaluate whether a novel transdermal system could reduce gut microbiome disruption compared to oral delivery. Sprague-Dawley rats received a single tetracycline dose via oral gavage, IV injection, or hydrogel-forming microneedle patch. Faecal samples were collected longitudinally and analysed using 16 S rRNA gene sequencing. Oral tetracycline caused the greatest disruption to gut microbiota. Compared to the timepoint immediately prior to treatment (Day 5a), peak dysbiosis was observed at Day 7. The Firmicutes: Bacteroidetes ratio was significantly reduced following oral and IV tetracycline therapy, but not following microneedle administration. The most significant reductions in alpha and beta diversity at Day 7 were observed in the oral group. Differential abundance analysis showed oral treatment resulted in the highest number of depleted and enriched taxa. The microbiome-sparing effect of microneedle delivery was consistent across all analytical measures, offering a promising strategy to preserve host microbiome health. This minimally invasive approach represents a clinically viable alternative to oral and IV antibiotic administration.