Oral Microbiome and Inferred Functions Predict Kaposi's Sarcoma Progression

Kaposi's sarcoma (KS) is a common cancer among people living with HIV and is caused by infection with Kaposi's sarcoma-associated herpesvirus (KSHV). While previous studies have linked the oral microbiome to KSHV infection and KS development, its role in KS progression remains poorly defined. We performed 16S rRNA gene sequencing targeting the V1-V2 and V3-V4 hypervariable regions to characterize the microbiome in 20 patients with AIDS-associated KS, including 10 with nonprogressive disease and 10 with progressive disease. Samples were obtained from three anatomical sites: oral cavity, peripheral blood, and tumor biopsies. The highest number of microbes were identified in the oral cavity at species, genus, and family levels. Beta diversity analysis revealed significant compositional differences in the oral microbiome between progressive and nonprogressive KS (p value = 0.044). Differential abundance analysis identified 16 species in the oral cavity associated with disease progression, compared to only three species in tumors and one in blood (p value < 0.05). Notably, Prevotella pallens and Megasphaera micronuciformis, both known producers of short-chain fatty acids, were significantly enriched in the oral microbiome of patients with progressive KS (log-fold changes = 2.8 and 2.4, respectively). Functional pathway inference revealed 39 differentially abundant microbial pathways in the oral cavity, including pathways related to denitrification, ubiquinone biosynthesis, and arginine metabolism (all p values < 0.05). Our findings provide the first evidence that specific oral microbiome alterations are associated with KS progression. The enrichment of short-chain fatty acid-producing bacteria and changes in microbial metabolic pathways may promote inflammation and KSHV lytic replication, offering potential mechanistic insights into KS pathogenesis and highlighting novel microbiome-based prognostic markers.