Cervicovaginal Mycobiome Restructuring by HPV and Bacterial Community State Types in a Kazakhstani Shotgun Metagenomic Cohort: Lactobacillus iners as a Candida-Permissive Niche Associated with α-9 HPV in Cytologically Normal Women.

Cervicovaginal dysbiosis is an established co-factor of high-risk human papillomavirus (HPV) persistence and cervical neoplastic development, yet most studies address the bacterial compartment in isolation, leaving fungal communities and bacterial-fungal cross-kingdom interactions underexplored, particularly in Central Asian populations. We performed shotgun metagenomic sequencing (mNGS) of cervicovaginal samples from 311 Kazakhstani women undergoing routine cervical screening. HPV status was determined using combined PCR and mNGS methods, and cervical screening was completed using liquid-based cytology (NILM, ASC-US, LSIL, ASC-H). Bacterial, viral, and fungal taxa were profiled from a single shotgun dataset with Kraken2 pipeline. Bacterial community state types (CSTs) were determined based on dominant bacterial species, functional gene content was annotated against KEGG using eggNOG, and covariate-adjusted associations were estimated using MaAsLin3. Mycobiome β-diversity differed significantly by HPV status (p = 0.003). In particular, Candida positivity was significantly associated with HPV presence and with high-risk α-9 HPV in cytologically normal (NILM) samples (OR = 3.6, [1.6-9.6], p ≤ 0.001). Covariate-adjusted analysis was consistent with this positive association (q < 0.05). Concurrently, among CSTs, Lactobacillus iners-dominated CST III and dysbiotic Gardnerella vaginalis-dominated CST IV showed a 3-fold higher Candida albicans prevalence (p < 0.01). Further analysis demonstrated that, functionally, both of these CSTs had depleted capacity for lactate metabolism (ko00620, p < 0.0001) and, in particular, for the genetic capacity for pyruvate-dependent H2O2 generation (half that of the L. crispatus-dominated CST I). These findings support L. iners as a metabolically permissive rather than protective Lactobacillus and suggest cross-kingdom functional signatures as candidate biomarkers for HPV acquisition and persistence in Central Asia, a region previously absent from the cervicovaginal microbiome literature.