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PubMed2026

A Mobile Glycosylation Locus Modulates Cell Wall Architecture in Lactobacillus crispatus.

Lactobacillus crispatus dominance in the vaginal microbiome is associated with beneficial health outcomes, yet strain-level variation and its implications remain poorly understood. Here, we resolve the genomic context of three glycosyltransferase gene fragments (GT1-3) previously linked with dysbiotic states. Long-read resequencing revealed that GT1-3 are part of a ~18.7 kb Wzx/Wzy-dependent cell wall polysaccharide (CWPS) locus, containing several IS256-family transposases. Serial propagation in vitro produced isolates with 4.1 kb excised via a composite transposon encompassing the GT3, UDP-galactopyranose mutase, flippase, and hypothetical protein, demonstrating structural plasticity. Transmission electron microscopy showed a ~20%-25% thinner peptidoglycan layer in the derived strains, while FT-IR and monosaccharide analysis indicated no gross changes. Molecular dynamics simulations suggest that GT3 contributes to the structural stability of the glycosyltransferase complex, without compromising catalytic function. Together, these findings establish the CWPS locus as a mobile, structurally plastic element that directly influences cell wall architecture in L. crispatus.

Lactobacillus crispatus↗

PubMed2026

Human Milk Oligosaccharides Modulate Nitrogen Utilization in Lactobacillus crispatus in a Glucose-Dependent Manner.

The vaginal microbiome's transition to a dysbiotic state increases susceptibility to pathogens like group B Streptococcus. While human milk oligosaccharides are established prebiotics in the neonatal gut, their impact on the vaginal niche remains largely unexplored. This study investigated the effects of pooled human milk oligosaccharides on the growth and physiology of vaginal (Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners) and gut-derived (Lactobacillus reuteri, Lactobacillus rhamnosus) commensals. Growth analyses revealed that human milk oligosaccharides significantly and selectively stimulated growth across all vaginal strains tested, whereas gut commensals exhibited variable or inhibited growth. Carbohydrate utilization assays and comparative genomics against Bifidobacterium infantis showed that Lactobacillus crispatus and Lactobacillus reuteri lack the canonical metabolic machinery to catabolize human milk oligosaccharides. Instead, nitrogen utilization assays identified a glucose-dependent pathway where human milk oligosaccharides are associated with the depletion of primary amines and amino acids in Lactobacillus crispatus supernatants. These results suggest that human milk oligosaccharides act as noncatabolic modulators of vaginal lactobacilli. Collectively, these in vitro findings may warrant investigation of human milk oligosaccharides as modulators of vaginal commensal physiology in more complex experimental systems.

Humans↗

PubMed2026

Intra-individual genetic diversity of vaginal Lactobacillus crispatus revealed through citizen science-driven isolation and pangenome analysis.

AIMS: A vaginal microbiome dominated by Lactobacillus crispatus is associated with positive reproductive and sexual health outcomes, yet intra-individual genetic diversity within this species remains largely unexplored. This study characterized inter- and intra-individual genomic variation in L. crispatus strains isolated through a citizen science initiative and assessed implications for multi-strain probiotic development. METHODS AND RESULTS: Fifty-three women participated in this citizen science project. Self-sampling resulted in 48 shotgun metagenomes. Twenty-two participants isolated their own L. crispatus strains using selective enrichment and LAMP-based species confirmation, resulting in 53 whole-genome-sequenced isolates. Lactobacillus crispatus dominated 20 of 48 metagenomes (50.1%-99.6% relative abundance). Pangenome analysis revealed 3456 gene families, of which 43.7% were core and 56.3% accessory. A 14-kb plasmid harbouring a Fic-domain toxin-antitoxin protein, but devoid of antimicrobial resistance genes, was present in 44 of 53 strains. Strains from the same individual clustered closely together yet harboured 1-123 gene differences. Intra-individual variation was observed in the pullulanase type I gene required for glycogen degradation: 40 strains were predicted to grow on glycogen, six showed genetic disruptions with unknown consequences, and seven were predicted to lack this ability entirely. Variation within individuals was also found for bacteriocin classes and CRISPR-Cas genes. CONCLUSIONS: Substantial functional diversity exists within L. crispatus, even among strains from the same individual, supporting the rationale for multi-strain vaginal probiotics. This citizen science approach enabled discovery of host-specific adaptations while ensuring participant ownership of their strains.

Female↗

PubMed2025

Genome-wide analysis of Enterococcus faecalis genes that facilitate interspecies competition with Lactobacillus crispatus.

Enterococci are opportunistic pathogens notorious for causing a variety of infections. While both Enterococcus faecalis and Lactobacillus crispatus are commensal residents of the vaginal tract, the molecular mechanisms that enable E. faecalis to take advantage of a vaginal biome with lower counts of lactobacilli to colonize the vaginal tract and induce aerobic vaginitis remain unknown. Here, we show that L. crispatus eradicates E. faecalis in a contact-independent manner. Using transposon sequencing to identify E. faecalis OG1RF transposon (Tn) mutants that are either under-represented or over-represented when co-cultured with L. crispatus, we found that Tn mutants with disruption in the dltABCD operon, that encodes the proteins responsible for the D-alanylation of teichoic acids, and OG1RF_11697 encoding for an uncharacterized hypothetical protein are more susceptible to killing by L. crispatus. Inversely, Tn mutants with disruption in ldh1, which encodes for L-lactate dehydrogenase, are more resistant to L. crispatus killing. Using the Galleria mellonella infection model, we show that co-injection of L. crispatus with E. faecalis OG1RF enhances larvae survival while this L. crispatus-mediated protection was lost in larvae co-infected with either L. crispatus and E. faecalisΔldh1 or Δldh1Δldh2 strains. Last, using RNA sequencing to identify E. faecalis genes that are differently expressed in the presence of L. crispatus, we found major changes in the expression of genes associated with glycerophospholipid metabolism, central metabolism, and general stress responses. The findings in this study provide insights into how E. faecalis mitigate assaults by L. crispatus.IMPORTANCEEnterococcus faecalis is an opportunistic pathogen notorious for causing a multitude of infections. As vaginal commensals, E. faecalis must interact with Lactobacillus crispatus, but how E. faecalis overcomes or mitigate assaults by L. crispatus killing remains unknown. We show that L. crispatus eradicates E. faecalis temporally in a contact-independent manner. Using high-throughput molecular approaches, we identified genetic determinants that enable E. faecalis to compete with L. crispatus. This study represents an important first step for the identification of adaptive genetic traits required for enterococci to tolerate assaults by lactobacilli.

Enterococcus faecalis↗

PubMed2026

Expanding vaginal microbiome pangenomes via a custom MIDAS database reveals Lactobacillus crispatus accessory genes associated with cervical dysplasia.

The vaginal microbiome plays a central role in reproductive health. Vaginal microbiome dysbiosis is associated with many adverse reproductive health outcomes, but most studies have focused on associations at the species level. The potential contribution of intraspecies microbial variation, especially gene content differences across bacterial strains, remains underexplored in reproductive health contexts. The Metagenomic Intra-Species Diversity Analysis (MIDAS) framework enables such analyses, but depends on comprehensive reference databases. We constructed a MIDAS-compatible pangenome database from over 18,000 genomes in the Vaginal Microbiome Genome Collection (VMGC). Compared to the Genome Taxonomy Database (GTDB)-derived reference, the VMGC-derived database expanded the pangenomes of prevalent vaginal species, better capturing vaginal-specific intraspecies diversity. Applying this database to vaginal samples from a cervical dysplasia cohort, we identified 13 Lactobacillus crispatus accessory genes significantly associated with cervical dysplasia, including a HicAB toxin-antitoxin system, three transcriptional regulators, and three phage-derived genes. These findings highlight the utility of body site-specific reference resources and shotgun metagenomic sequencing for uncovering intraspecies microbial variation relevant to reproductive health.IMPORTANCEThe vaginal microbiome plays a critical role in reproductive health, and different bacteria from the same species can carry different genes that influence how the strains interact with the host and other microbes. These strain-level differences are often overlooked when microbiomes are analyzed only at the species level. Existing genomic reference databases are heavily biased toward gut and environmental bacteria, leaving the genetic diversity of vaginal microbes understudied. We built a specialized reference database from over 18,000 vaginal bacterial genomes that better reflects this diversity. We then applied this resource to quantify gene-level variation in vaginal samples from a cervical dysplasia cohort. Focusing on Lactobacillus crispatus, a prevalent and often beneficial vaginal species, we identified 13 genes that were more common in women with cervical dysplasia than in controls. This work demonstrates that body site-specific genomic resources are essential for uncovering strain-level bacterial differences relevant to reproductive health.

Lactobacillus crispatus↗

PubMed2024

Vaginal Lactobacillus fatty acid response mechanisms reveal a metabolite-targeted strategy for bacterial vaginosis treatment.

Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related lactobacilli, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE mediates OA resistance, while OhyA is robustly active in the vaginal microbiota and enhances bacterial fitness by biochemically sequestering OA in a derivative form only ohyA-harboring organisms can exploit. OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro BV model, suggesting a metabolite-based treatment approach.

Vaginosis, Bacterial↗

PubMed2026

Genome-wide association analysis reveals specialization to hosts and niches in multiple species of the Lactobacillaceae.

The Lactobacillaceae inhabit diverse environments, but the extent of their habitat adaptation remains unclear and the colonization factors unknown. First, we applied multiple machine learning models to determine if we can distinguish strains of the same species isolated from two different habitats based on their gene content. Surprisingly, we show that no species is differentially adapted to the oral cavity versus the human gut, or food versus the human gut, while only Lactobacillus crispatus showed specialization to the human urogenital system versus human gut. We then asked which species of Lactobacillaceae are habitat-specialized and how they could be identified. Using multiple lifestyle predictors incorporated in logistic regression models, we found that Limosilactobacillus reuteri, Ligilactobacillus ruminis, L. salivarius, L. crispatus, and L. mucosae displayed the highest degrees of host specialization. Applying our microbial genome-wide association study tool, aurora, to these species identified genes encoding adhesins and bacteriocins as the strongest and most common adaptation factors. This work establishes a generalizable framework for identifying novel species-habitat pairs with strong evidence of specialization and for uncovering the genomic features underlying within-species host and habitat adaptation.

Humans↗

PubMed2026

Species and strain sharing in the vaginal microbiome of mothers and their adult daughters.

The vaginal microbiome is key for women's health. However, its establishment, interindividual variation and dynamics remain poorly understood. Here, we investigate bacterial relatedness at species and strain level in adult mother-daughter pairs from the large-scale citizen-science program Isala. Using metagenomic sequencing with quality control including 16S rRNA profile comparison, along with targeted culturing, we assess intergenerational microbiome sharing. At species level, daughters' vaginal microbiomes are significantly more similar to their mothers' than to those of unrelated mothers, with a strong mother-daughter correlation in Lactobacillus crispatus dominance. Strain-level analyses of metagenomes and isolate genomes reveal intraspecies diversity in L. crispatus, with up to two strains observed within the same host, and support intergenerational vaginal bacteria sharing. SNV counts in shared L. crispatus strains show no correlation with daughters' ages. Together, these findings suggest that maternal transmission, host factors, and (shared) environment collectively shape the vaginal microbiome, providing fundamental ecological insights into vaginal microbiome dynamics and perspectives toward lactobacilli-based applications.

CP: microbiology↗

PubMed2024

From dysbiosis to homeostasis: Oleic acid matters in the vagina.

The role of fatty acids in shaping vaginal microbiota remains unclear. In an issue of Cell, Zhu et al. use genomic and transcriptomic analyses to reveal that oleic acid (OA) selectively inhibits L. iners while promoting L. crispatus, suggesting new strategies for the treatment of bacterial vaginosis (BV).

Female↗