Glycan mapping reveals what keeps the vaginal microbiome healthy

By Dr. Liji Thomas, MDReviewed by Lauren HardakerJun 9 2025

By revealing how “good” and “bad” vaginal bacteria compete for sugar-binding sites, scientists offer hope for target therapies against infections and pregnancy complications.

Study: Identification and characterisation of vaginal bacteria-glycan interactions implicated in reproductive tract health and pregnancy outcomes. Image credit: Arif biswas/Shutterstock.com

A recent study published in Nature Communications explored glycan-bacteria binding profiles to track their role in reproductive health.

Introduction

Vaginal cells contain polymers of sugar (glycans), either alone or as glycoproteins. Bacteria-glycan binding is central to colonization and infection of the vagina.

Commensal bacteria play a crucial role in maintaining vaginal health, which in turn affects the entire reproductive tract. Lactobacillus species dominate the vaginal microbiome. When these are replaced by other species (especially Gram-negative species), reproductive diseases and preterm birth become more likely.

In pregnancy, L. crispatus dominance is associated with protection against preterm birth. Through the production of lactic acid, its presence decreases vaginal pH to <4.5, adding to the protection of its antimicrobial molecules. Thus, it prevents colonization and inflammation by opportunistic pathogens, such as Gardnerella vaginalis, Streptococcus agalactiae, Sneathia, and Prevotella species.

Conversely, dominance by other Lactobacillus species, such as L. iners, is a high-risk marker.

Glycans and the vaginal epithelium

Glycans play an essential role in cell biology. They form a significant part of the glycocalyx, the sugar-enriched cell covering, and mucus in the cervicovaginal fluid. Glycans form epitopes or immune recognition sites and are the first part of the cell to encounter other cells, including microbes.

The cell membrane is coated with various glycans, including glycosaminoglycans, extracellular matrix glycoproteins, sialylated and neutral glycans, as well as membrane-bound and secreted glycoproteins such as mucins. In the cervicovaginal fluid, glycans are especially rich in fucose and sialic acid.

Glycans serve as microbial adhesion sites and can also function as a nutrient source.

During these interactions, some microbes produce enzymes that modify the structure of host glycans, helping them escape detection or destruction by the immune system. Microbes may also mimic host glycans to trick the immune system into recognizing them as ‘self,’ reducing immune responses and promoting immune tolerance.

Despite their ability to colonize vaginal cells and shape the microbiota in the lower reproductive tract; surprisingly, little is known about the specific mechanisms of these interactions.

About the study

The current study utilized microarrays to investigate glycan interactions with several important commensal and opportunistic pathogens. These tools are glass or silicon slides that function as miniaturized, automated laboratories. They can screen thousands of DNA sequences or genes simultaneously.

The scientists used 187 glycans from the glycocalyx and mucin as probes for this study, as they provide most of the structure of the cervicovaginal fluid. The study covered 22 bacterial strains, of which 17 came from patients. Experimental conditions were based on the well-studied binding of Escherichia coli (E. coli).

Importantly, these laboratory-based experiments provide detailed mechanistic insight, but their direct relevance to real-world clinical outcomes will require further study.

Study findings

The binding study demonstrated that Lactobacillus had distinct glycan binding footprints compared to opportunistic pathogens such as E. coli, Fusobacterium nucleatum, and Streptococcus agalactiae. Fimbriated E. coli strains specifically bound to N-glycans rich in mannose, while the others preferred glycans with galactose and hyaluronic acid termini, respectively.

Some glycans are recognized solely by the opportunistic pathogens E. coli, F. nucleatum, and S. agalactiae. Nearly every species binds firmly to neutral and sialic acid-rich glycans at pH four and pH seven, representing mildly acidic to neutral pH.

Conversely, F. nucleatum was pH specific. It recognized non-sulfated chondroitin and glycans terminating only in fucose, galactose, or sialic acid at neutral pH. The presence of free galactose but not glucose prevented binding.

Sulfated glycosaminoglycans like chondroitin sulfate, a key attachment molecule, are abundant on vaginal cell surfaces and in the extracellular matrix. Binding to these is typically pH and strain-dependent. Under acidic conditions, most strains bound to these glycans but not to non-sulfated probes.

While E. coli binds chondroitin sulfate weakly, species like L. crispatus, L. iners, Gardnerella vaginalis, S. agalactiae, and F. nucleatum bind strongly, accounting in part for their adhesion to the vaginal epithelium.

Both F. nucleatum and S. agalactiae may colonize the less acidic female reproductive tract. This may trigger infection, increasing the odds of preterm birth and newborn infection.

Dominance by L. crispatus during pregnancy may help prevent colonization by S. agalactiae, as it can compete with the latter for binding to chondroitin sulfate. However, these findings are based on in vitro competition, and further research is needed to confirm this effect in vivo. This could help reduce the risk of early-onset Group B Streptococcus (GBS) infection, a leading cause of death among newborns.

Hyaluronic acid is a non-sulfated glycosaminoglycan enriched in the pregnant cervix but not in the vaginal cells. It is bound only by S. agalactiae and a few G. vaginalis strains, but no other species. This suggests that vaginal microbes do not respond equally to changing pH or recognize diverse glycans within the reproductive tract.

The cervicovaginal fluid contains high blood group epitopes, such as A, B, H (O), and Lewis epitopes. All vaginal bacteria bound to most types of glycans terminating in these epitopes, but weakly compared to glycosaminoglycan binding, with low avidity for fucose-rich glycans. Opportunistic microbe binding showed pH- and bacterial strain-dependent characteristics. For instance, L. iners binding was lost at neutral pH.

The adhesion proteins of pathogens, such as enterotoxigenic E. coli or Helicobacter pylori, specifically recognize specific blood group antigens. Blood group thus modifies susceptibility to some infections. E. coli and GBS infections are more common in individuals with blood group B, which is factored into the risk score. Additionally, an individual's ability to secrete specific blood group antigens into body fluid can further influence infection risk.  

The initial E. coli test assay revealed weak oligomannose binding by one strain. Electron microscopy revealed that this was due to its shorter and fewer fimbriae. Thus, glycan microassays can distinguish the differences in bacterial morphology that underlie varying binding characteristics.

It is also important to note that strain-level differences in glycan binding, such as those seen among E. coli strains, could have implications for bacterial colonization and infection risk.

Conclusions

This work represents one of the first comprehensive applications of glycan arrays to investigate how bacteria bind to vaginal epithelial cells through diverse glycans, including glycosaminoglycans and various neutral or sialylated glycans. They found dissimilar bacteria-glycan interaction profiles. Similar methods could help explore bacterial binding events at skin or gut sites.

Prebiotics can regulate the pH, encourage competitive glycan binding by commensals, and inhibit pathogens. Synthetic glycans, known as glycomimetics, are another potential option that could selectively promote or suppress bacterial binding to the vaginal epithelium.

While these findings advance our mechanistic understanding of bacteria-glycan interactions, the authors note that further studies are needed to directly connect these laboratory observations with clinical outcomes in reproductive health and disease.

Further studies could uncover correlations between microbiome profiles, blood group antigen binding, and infections. Such research may also clarify how host genetics, such as secretor status and microbial competition, shape infection risk.

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