Gut microbiome shift in long COVID: impact of disease and montelukast treatment.

Background: Long COVID-19 is a post-infectious syndrome with persistent symptoms that can involve multiple organ systems. Evidence suggests that SARS-CoV-2 infection may disrupt gut microbiome composition, potentially contributing to long-term effects. As treatment remains symptom-based, interest has grown in repurposing drugs like montelukast. However, non-antibiotic medications may also alter gut microbial communities, raising questions about their impact. Here, we compare gut microbiota between long COVID patients and healthy controls and examine how montelukast treatment affects microbial composition. Methods: We analysed stool samples from long COVID patients and healthy controls using 16S rRNA gene sequencing (Illumina MiSeq). We evaluate alpha (Shannon) and beta (Bray-Curtis) diversity, followed by relative abundance and linear discriminant effect size analysis, to identify differentially abundant taxa. This proof-of-concept study included a cross-sectional comparison and a longitudinal analysis of montelukast-treated patients vs. placebo. Results: Cross-sectional analysis revealed a significant structural reorganisation of the gut microbial community in long COVID patients, although overall species richness was largely maintained. Linear discriminant effect size analysis revealed that this architectural shift was driven by an enrichment of Firmicutes (Agathobacter and Faecalibacterium genera) in the long COVID group, while healthy controls were characterised by higher abundances of the phyla Verrucomicrobiota and Actinobacteriota, as well as genera Alistipes and Akkermansia. Longitudinal analysis demonstrated that the broader community structure remained stable in both groups; however, montelukast treatment led to a specific enrichment of the genus Dialister, suggesting targeted and potentially transient effects without disrupting the overall microbial landscape. Conclusions: Long COVID is characterised by a significant restructure of the gut ecosystem. This qualitative dysbiosis reflects a shift in homeostatic balance, where the core microbial community remains present, but its proportions are altered. Short-term montelukast treatment shows a minimal impact on the microbial landscape, suggesting treatment does not further destabilise the gut environment. These findings highlight the specific and targeted nature of gastrointestinal involvement in long COVID.