Integrated Oral Microbiome and Metabolome Profiling Identifies Disease-Associated Multi-Omics Signatures in Alström...

Background: Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) are rare ciliopathies characterized by multisystem involvement, including obesity, insulin resistance, and type 2 diabetes. Systemic metabolic dysfunction may influence the oral microbiome; however, integrative analyses that combine microbial and metabolic profiles in these disorders remain limited. Methods: Saliva and gingival crevicular fluid (GCF) samples were collected from genetically confirmed ALMS and BBS patients, as well as from obesity and healthy control groups. Microbial communities were profiled using V3-V4 16S rRNA gene amplicon sequencing, and untargeted metabolomic profiling was performed by gas chromatography-mass spectrometry. Microbiome-metabolome associations were evaluated using Spearman's rank correlation analysis, followed by multi-omics integration using Multiple Co-Inertia Analysis (MCIA) and the supervised Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) framework (mixOmics). Results: Integrated analysis identified distinct microbiome-metabolome association patterns in ALMS and BBS. Compared with controls, the ALMS+BBS group showed enrichment of Prevotella, Enterococcus, and Eikenella, alongside reduced Lactobacillus abundance. Metabolomic profiling revealed alterations in amino acid, fatty acid, and carbohydrate metabolism. GCF exhibited structured associations between metabolites and Firmicutes, Proteobacteria, and Actinobacteriota, whereas saliva showed broader interaction networks. These associations were absent or markedly weaker in obesity and healthy controls. MCIA demonstrated coordinated variation across the oral microbiome, salivary metabolome, and GCF metabolome, while DIABLO identified a shared multi-omics signature. Conclusions: Coordinated shifts in amino acid, lipid, and central carbon metabolism can be linked to oral microbial reorganization in ALMS and BBS. Integrative multi-omics analyses identified coordinated microbiome-metabolome signatures across the oral microbiome, saliva, and GCF. These findings warrant validation in larger longitudinal and functional studies.