Oral and gut microbiota relate to symptom subphenotypes in long COVID, independent of viral persistence

Long COVID presents a significant public health challenge, complicating diagnosis and treatment. In a prospective study of 349 individuals with long COVID (March 2021-December 2023), latent class analysis identified three symptom subphenotypes: high constitutional symptom burden (21%), predominant smell/taste disturbances (17%), and minimal persisting symptoms (62%). While viral persistence in saliva and stool was limited, 16S rRNA gene sequencing revealed microbiota associations with symptomatology. Alpha diversity was lower in individuals with high symptom burden, and specific taxa correlated with nausea and smell/taste disturbances. Distinct oral and gut microbiota patterns emerged across symptom clusters, with microbiota profiles also linked to patient-reported outcomes, including employment and overall health impact. These findings suggest that bacterial dysbiosis may contribute to long COVID symptom variability and highlight the microbiome's potential role in its pathophysiology. Understanding microbial influences on symptom persistence may inform microbiome-targeted therapeutic strategies and improve long COVID management.