The pandemic caused by the SARS-CoV-2 virus is the reason for many deaths globally. It is hypothesized that the upper respiratory tract (URT) microbiome shares similarities with lung microbiota and can modulate host immune responses to the virus. During the pandemic, several SARS-CoV-2 variants have emerged with different clinical outcomes and immune dysfunction, yet their association with changes in the URT microbiome has not been identified, which may provide an assessment of lung health in the presence of those variants with differential disease outcomes. In this study, we sequenced V3-V4 region of the 16S rRNA gene from the URT microbiome of healthy controls (HC), Delta- and Omicron-infected patients from Eastern India, which showed higher inter-individual diversity (β) and lower intra-individual diversity (α) in COVID-19 patients compared to healthy controls. Healthy control microbiome showed enrichment of commensals like Streptococcus symci, Prevotella melaninogenica, Neisseria perflava, Veillonella tobetsuensis, Veillonella nakazawae, Haemophilus parainfluenzae, Fusobacterium pseudoperiodonticum, and Bifidobacterium longum compared to COVID-19 samples. Ct value of patients significantly positively correlated with Streptococcus symci and Streptococcus toyakuensis indicating a possible inverse relation with viral load. We also observed few bacterial taxa like Staphylococcus caprae, Pseudomonas aeruginosa, Vibrio tritonious, and Rothia mucilaginosa are discriminating Omicron from Delta which is, in turn, enriched mostly with Enterobacter mori, Acinetobacter baumannii, and Klebsiella pneumoniae. Further investigation showed nine control-associated bacteria had higher to lower trends among three groups viz., Control > Omicron > Delta. These bacteria also contributed to the successful prediction of disease groups with high accuracy (90% ± 0.5%) by random forest analysis. IMPORTANCE The role of the upper respiratory tract (URT) microbiome in predicting lung health has been documented in several studies. The dysbiosis in COVID patients has been associated with disease outcomes by modulating the host immune system. However, although it has been known that different SARS-CoV-2 variants manifest distinct transmissibility and mortality rates in human populations, their effect on the composition and diversity of the URT microbiome has not been studied to date. Unlike the older variant (Delta), the newer variant (Omicron) have become more transmissible with lesser mortality and the symptoms have also changed significantly. Hence, in the present study, we have investigated the change in the URT microbiome associated with Delta and Omicron variants and identified variant-specific signatures that will be useful in the assessment of lung health and can be utilized for nasal probiotic therapy in the future.
