Abstract
Lactobacillus crispatus is a dominant member of the healthy vaginal microbiota, yet the mechanisms by which it modulates host immunity remain poorly defined, in part due to the lack of tractable in vivo models. Here, we integrate bacterial genetics, in vitro epithelial systems, human-derived data and proteomic approach (Olink) to uncover a critical role for L. crispatus exopolysaccharides (EPS) in shaping the bacteria-vagina interactions. Comparative genomics identified a conserved EPS biosynthetic locus, with the priming glycosyltransferase gene epsE emerging as a regulatory node, in line with its distinct expression in human vaginal samples. Functional disruption of epsE abrogated L. crispatus EPS production and revealed its role for immune modulation. In human vaginal epithelial monolayers, EPS presence enhanced immune-regulatory (LAP TGF-beta-1) and anti-inflammatory (CST5) responses, whereas its absence triggered elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8) and matrix metalloproteinase (MMP-10). In a 3D vaginal organotypic model, EPS increased chemokines (CXCL5, CXCL6) linked to immune surveillance and the presence of the markers was validated in vaginal samples of healthy volunteers. These findings position EPS as a key immunomodulatory structure of L. crispatus , advancing our mechanistic understanding of host-commensal interactions and informing microbiome-based strategies to promote vaginal health.
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Abstract
Lactobacillus crispatus is a dominant member of the healthy vaginal microbiota, yet the mechanisms by which it modulates host immunity remain poorly defined, in part due to the lack of tractable in vivo models. Here, we integrate bacterial genetics, in vitro epithelial systems, human-derived data and proteomic approach (Olink) to uncover a critical role for L. crispatus exopolysaccharides (EPS) in shaping the bacteria-vagina interactions. Comparative genomics identified a conserved EPS biosynthetic locus, with the priming glycosyltransferase gene epsE emerging as a regulatory node, in line with its distinct expression in human vaginal samples. Functional disruption of epsE abrogated L. crispatus EPS production and revealed its role for immune modulation. In human vaginal epithelial monolayers, EPS presence enhanced immune-regulatory (LAP TGF-beta-1) and anti-inflammatory (CST5) responses, whereas its absence triggered elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8) and matrix metalloproteinase (MMP-10). In a 3D vaginal organotypic model, EPS increased chemokines (CXCL5, CXCL6) linked to immune surveillance and the presence of the markers was validated in vaginal samples of healthy volunteers. These findings position EPS as a key immunomodulatory structure of L. crispatus, advancing our mechanistic understanding of host-commensal interactions and informing microbiome-based strategies to promote vaginal health.
Competing Interest Statement
Author SL serves as Guest Editor of this journal and had no involvement in the peer-review process or the decision to publish this manuscript. Author SL declares no financial competing interests. SL declares to be a voluntary academic board member of the International Scientific Association on Probiotics and Prebiotics (ISAPP, www.isappscience.org), and scientific advisor for Freya Biosciences. She declares research funding from YUN, Bioorg, Puratos, Lesaffre/Gnosis, DSM i-Health & dsm-firmenich (not directly involved in the content of this work). DSM i-Health & dsm-firmenich provided funding for the collection of human samples used as a reference in this work. IS has received funding from ISAPP and the International Probiotics Association (IPA) to attend conferences. PAB is an independent consultant for several companies in the food and pharmaceutical industry bound by confidentiality agreements. BV has scientific collaborations with SACCO System and DEPOFARMA and she is a scientific consultant for EOS2021. JD and SL are co-inventors on a patent application on L. crispatus AMBV-0815 related to its unique antimicrobial peptide production. This patent application is not directly linked to the content of this manuscript, with EPS being a more conserved immunomodulatory property.
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