Impact of the anti-inflammatory macrolide glasmacinal on the gut microbiota of healthy adults: an open-label trial

Abstract Glasmacinal (EP395) is an oral macrolide, with immunomodulatory properties like antibiotic macrolides (such as azithromycin), but with negligible in vitro antimicrobial activity, which is being developed as a potential treatment to reduce exacerbations in respiratory conditions. In an open-label healthy participant trial (ClinicalTrials.gov: NCT06118684), with the primary objective of assessing potential drug-drug interactions of glasmacinal, faecal samples were collected to evaluate the impact on the gut microbiota of daily doses of glasmacinal for 2 weeks, using both phenotypic and 16S rRNA gene sequencing. Glasmacinal produced modest effects: reduced phylogenetic richness (p < 0.0001), but not evenness, and altered beta-diversity (PERMANOVA R 2 = 0.104 p.adj=0.0018 after 1 week, and R 2 = 0.059, p.adj=0.028 after 2 weeks) with reductions in Clostridiaceae , Enterobacteriaceae , and Sutterellaceae abundance. The community shift was approximately 10% after 1-week glasmacinal, and 6% after 2-weeks. With quantitative culture, only Enterobacterales was impacted. No increase or selection of resistance to azithromycin in Enterobacterales and Bacteroides , nor increase in Candida spp . or Clostridioides difficile , were detected. Overall, glasmacinal induced limited restructuring of the gut microbiome (without the defining hallmarks of antibiotic-like dysbiosis), core anaerobic phyla of the gut (Firmicutes and Bacteroidetes) were preserved, and there was no selection of antimicrobial resistance.