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

Glasmacinal reduced phylogenetic richness but not evenness in the gut microbiota of healthy adults.

• Reduction in phylogenetic richness was statistically significant (p < 0.0001)
• Evenness was not significantly affected, suggesting a partial rather than broad disruption of community structure
• Analysis was performed using 16S rRNA gene sequencing of faecal samples
• Daily doses were administered for 2 weeks in healthy participants

Glasmacinal altered beta-diversity of the gut microbiota, with the effect diminishing over the treatment period.

• PERMANOVA R2 = 0.104, p.adj = 0.0018 after 1 week of treatment
• PERMANOVA R2 = 0.059, p.adj = 0.028 after 2 weeks of treatment
• The community shift was approximately 10% after 1 week and approximately 6% after 2 weeks
• The reduction in effect size over time suggests partial adaptation or stabilization of the microbiota

Glasmacinal reduced the abundance of Clostridiaceae, Enterobacteriaceae, and Sutterellaceae.

• These three bacterial families were specifically identified as reduced in abundance during glasmacinal treatment
• Reductions were detected via 16S rRNA gene sequencing
• Core anaerobic phyla of the gut (Firmicutes and Bacteroidetes) were preserved despite these family-level changes
• The selective impact on specific families rather than broad phyla distinguishes this from typical antibiotic-induced dysbiosis

Quantitative culture showed that only Enterobacterales were impacted among cultured organisms.

• Phenotypic culture methods were used alongside 16S rRNA gene sequencing
• Other cultured bacterial groups were not significantly affected by glasmacinal
• This finding is consistent with the sequencing data showing Enterobacteriaceae reduction
• The limited scope of culturally detectable impact supports the characterization of modest microbiome disruption

No increase or selection of azithromycin resistance in Enterobacterales and Bacteroides was detected following glasmacinal treatment.

• Resistance to azithromycin was specifically assessed in Enterobacterales and Bacteroides
• No selection of antimicrobial resistance was observed over the 2-week treatment period
• Glasmacinal has negligible in vitro antimicrobial activity, which may explain the absence of resistance selection
• This is a key safety distinction from antibiotic macrolides such as azithromycin

No increase in Candida spp. or Clostridioides difficile was detected during glasmacinal treatment.

• Overgrowth of Candida species and C. difficile are recognized hallmarks of antibiotic-induced dysbiosis
• Neither organism showed increased abundance or detection during the trial
• The absence of these changes supports the conclusion that glasmacinal does not produce antibiotic-like dysbiosis
• Faecal samples were assessed using both phenotypic and molecular methods

Glasmacinal is an oral macrolide with immunomodulatory properties but negligible in vitro antimicrobial activity, being developed for reducing exacerbations in respiratory conditions.

• Glasmacinal is also referred to as EP395
• It shares immunomodulatory properties with antibiotic macrolides such as azithromycin
• It is intended as a treatment to reduce exacerbations in respiratory conditions
• The trial was registered at ClinicalTrials.gov as NCT06118684 and conducted as an open-label healthy participant trial
• The primary objective of the trial was assessing potential drug-drug interactions, with microbiota assessment as a secondary objective