Genome-scale metabolic modeling reveals specific vaginal <i>Lactobacillus</i> strains and their metabolites as key inhibitors of <i>Candida albicans</i>

As the predominant constituents of the vaginal microbiome in healthy women, <i>Lactobacillus</i> species are considered essential in maintaining a homeostatic vaginal microbiome. Specific <i>Lactobacillus</i> species can produce beneficial metabolites to support their persistence within the host environment and inhibit <i>Candida albicans</i> colonization. Due to the extensive diversity of <i>Lactobacillus</i> species and their metabolites, comprehensively investigating all possible interactions remains challenging. This study employed an integrative approach combining genome-scale metabolic modeling, metagenomic sequencing, and <i>in vitro</i> validation to explore <i>Lactobacillus</i> and <i>C. albicans</i> interactions. Pairwise simulations of 159 <i>Lactobacillus</i> strains with <i>C. albicans</i> revealed that most strains exhibit inhibitory effects, altering fungal amino acid and carbohydrate metabolism. Key inhibitory metabolites identified included formate, L-lactate, and L-malate. Metagenomic analysis of vaginal swabs from 20 vulvovaginal candidiasis (VVC) patients and 20 healthy women showed a correlation between <i>Lactobacillus</i> species abundance and reduced <i>C. albicans</i> colonization. <i>In vitro</i> experiments confirmed the inhibitory effects of these metabolites and the selected <i>Lactobacillus</i> strains on <i>C. albicans</i> growth, thereby validating our computational predictions. These findings provide insights into the metabolic interactions within the vaginal microbiome and pave the way for targeted microbial or metabolite-based therapeutic strategies to manage VVC.IMPORTANCEVulvovaginal candidiasis is a prevalent fungal infection with significant implications for women's health, caused primarily by <i>Candida albicans</i>. Although the protective role of a <i>Lactobacillus</i>-dominated vaginal microbiome is well established, the metabolic mechanisms underlying the interactions between <i>Lactobacillus</i> species and <i>C. albicans</i> remain inadequately understood. Specifically, the <i>Lactobacillus</i> species that effectively inhibit <i>C. albicans</i> and the metabolic pathways involved warrant further investigation. This study offers novel insights into the metabolic mechanisms underlying <i>Lactobacillus</i> antagonism against <i>C. albicans</i>. By identifying critical metabolic pathways and inhibitory metabolites, this study enhances our understanding of vaginal microbiome dynamics and host-microbe interactions. The findings suggest that key <i>Lactobacillus</i> strains and their metabolites could significantly reduce harmful levels of <i>C. albicans</i>, paving the way for future therapeutic strategies that leverage these microbial characteristics to promote vaginal health.