Oral microbial and metabolic alterations in acute exacerbations of COPD across fungal status

Oral dysbiosis has been associated with inflammatory processes in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, whether Aspergillus-associated or Candida-positive status is associated with distinct oral multi-omics profiles, and whether these profiles change following treatment, remains unclear.

In this prospective cohort study (August 2024 to July 2025), 18 AECOPD patients were enrolled and stratified into non-fungal exacerbators (n=6), Aspergillus-associated AECOPD (n=6), and Candida-positive AECOPD (n=6). Oral samples were collected before treatment and, where available, after treatment. The primary analyses compared pretreatment microbial and metabolic profiles across fungal-status groups, whereas longitudinal pre/post-treatment analyses were secondary and exploratory and were performed only in groups with sufficient paired samples.

Baseline characteristics were comparable across groups. At pretreatment, Aspergillus-associated AECOPD showed significantly reduced α diversity and distinct microbial community separation from non-fungal exacerbators (Bray-Curtis R = 0.378, P = 0.009), whereas Candida-positive AECOPD showed no significant global shift. At the genus level, exploratory LEfSe analysis identified distinct subgroup-associated candidate taxonomic signatures. PICRUSt2-based predicted functional profiles were broadly similar across groups. Metabolomic profiling showed the most pronounced baseline differences in the Aspergillus-associated group, with 11 upregulated and 90 downregulated metabolites versus the non-fungal group. Differential metabolites in this baseline comparison were predominantly mapped to sphingolipid metabolism, purine metabolism, one-carbon metabolism, and cAMP/cGMP signaling pathways. In secondary exploratory longitudinal analyses, metabolic shifts were observed in the non-fungal group (4 upregulated and 78 downregulated metabolites) and the Candida-positive group (14 upregulated and 8 downregulated metabolites). No formal longitudinal analysis was performed in the Aspergillus-associated group because only two post-treatment samples were available. O2PLS identified shared cross-omics variation distinguishing pretreatment Aspergillus-associated from non-fungal AECOPD, with several microbial and metabolite features contributing to the shared latent component.

Compared with non-fungal and Candida-positive AECOPD, Aspergillus-associated AECOPD showed the most pronounced pretreatment oral microbial dysbiosis and metabolic alterations. These findings support the presence of a distinct oral microbial-metabolic phenotype associated with Aspergillus status and provide candidate signatures for future validation in larger longitudinal cohorts.

https://www.chictr.org.cn/hvshowproject.html?id=250288&v=1.0, identifier ChiCTR2400083090.