Abstract
Background
Vaginal Lactobacillus has been implicated in modulating the risk of cervical intraepithelial neoplasia (CIN) progression. However, there remains a gap in population-based studies elucidating the underlying mechanisms that link Lactobacillus with CIN progression and carcinogenesis.
Methods
To address this knowledge gap, we conducted an in-depth analysis of vaginal microbiota (VM), metabolome, and host transcriptome profiles in a cohort of 75 Chinese women, stratified into two groups based on their CIN status: low-grade CIN1 (n = 38) and high-grade CIN2+ (n = 37).
Results
Our findings revealed that samples dominated by Lactobacillus were more prevalent in the CIN1 cohort. Furthermore, the vaginal metabolome displayed a significant interplay with the microbiota, with Lactobacillus emerging as a key influencer. Among the 100 metabolites that distinguished the CIN1 and CIN2 + cohorts, 26 were inversely correlated with Lactobacillus levels, including L-Carnitine and UDP-D-glucose. Conversely, five metabolites, such as Succinic anhydride, exhibited a positive correlation with Lactobacillus abundance. Differential gene expression analysis revealed 176 genes upregulated in the CIN1 cohort compared to the CIN2 + cohort, primarily related to immune responses and negative regulation of cell migration. Notably, COL4A2 and CCBE1, both negatively correlated with L-Carnitine, were among the upregulated genes. Conversely, 82 genes were downregulated in the CIN1 cohort, including TP63 and FOXD1, which positively correlated with UDP-D-glucose. Further mediation analysis suggested that L-Carnitine plays a crucial role in mediating the positive association between Lactobacillus and COL4A2 expression, both of which are enriched in the CIN1 cohort. Similarly, UDP-D-glucose emerged as a mediator in the negative association between Lactobacillus and FOXD1, a gene depleted in the CIN1 cohort.
Conclusions
These findings provide insights into the complex interplay between vaginal Lactobacillus, the metabolome, and host gene expression patterns associated with CIN progression. The identified Lactobacillus:L-Carnitine:COL4A2 and Lactobacillus:UDP-D-glucose:FOXD1 regulatory axes underscore the potential significance of these pathways in modulating CIN risk. These population-based discoveries hold promise for future research aimed at developing targeted interventions to prevent or delay CIN progression.