Immunometabolic Analysis of Mobiluncus mulieris and Eggerthella sp. Reveals Novel Insights Into Their Pathogenic Contributions to the Hallmarks of Bacterial Vaginosis

Abstract

The cervicovaginal microbiome plays an important role in protecting women from dysbiosis and infection caused by pathogenic microorganisms. In healthy reproductive-age women the cervicovaginal microbiome is predominantly colonized by protective Lactobacillus spp. The loss of these protective bacteria leads to colonization of the cervicovaginal microenvironment by pathogenic microorganisms resulting in dysbiosis and bacterial vaginosis (BV). Mobiluncus mulieris and Eggerthella sp. are two of the many anaerobes that can contribute to BV, a condition associated with multiple adverse obstetric and gynecological outcomes. M. mulieris has been linked to high Nugent scores (relating to BV morphotypes) and preterm birth (PTB), whilst some bacterial members of the Eggerthellaceae family are highly prevalent in BV, and identified in ~85-95% of cases. The functional impact of M. mulieris and Eggerthella sp. in BV is still poorly understood. To determine the individual immunometabolic contributions of Eggerthella sp. and M. mulieris within the cervicovaginal microenvironment, we utilized our well-characterized human three-dimensional (3-D) cervical epithelial cell model in combination with multiplex immunoassays and global untargeted metabolomics approaches to identify key immune mediators and metabolites related to M. mulieris and Eggerthella sp. infections. We found that infection with M. mulieris significantly elevated multiple proinflammatory markers (IL-6, IL-8, TNF-α and MCP-1) and altered metabolites related to energy metabolism (nicotinamide and succinate) and oxidative stress (cysteinylglycine, cysteinylglycine disulfide and 2-hydroxygluatrate). Eggerthella sp. infection significantly elevated multiple sphingolipids and glycerolipids related to epithelial barrier function, and biogenic amines (putrescine and cadaverine) associated with elevated vaginal pH, vaginal amine odor and vaginal discharge. Our study elucidated that M. mulieris elevated multiple proinflammatory markers relating to PTB and STI acquisition, as well as altered energy metabolism and oxidative stress, whilst Eggerthella sp. upregulated multiple biogenic amines associated with the clinical diagnostic criteria of BV. Future studies are needed to evaluate how these bacteria interact with other BV-associated bacteria within the cervicovaginal microenvironment.

Interactions between microbiota and cervical epithelial, immune, and mucus barrier

“…Eggerthella sp. and M. mulieris elevate sphingolipids and 2hydroxybutyrate and decrease cysteinylglycine and cysteinylglycine disulphide (McKenzie et al, 2021). Veillonella atypica and Veillonella montpellierensis significantly accumulate histamine.…”

“…Other BVAB such as Eggerthella sp. only causes an increase in IL-1a; Mobiluncus mulieris increases IL-1a, IL-6, IL-8, MCP-1, and TNF-a; while Megasphaera micronuciformis increases IL-1a, IL-1b, IL-1RA, TNF-a, IL-6, and sFasL (McKenzie et al, 2021). Cervical epithelial cells (especially endocervical epithelial cells) exhibit a more robust immune response than vaginal cells after stimulation by BVAB bacteria.…”

“…2-hydroxyglutarate is a metabolite marker of oxidative stress. The depletion of two intermediates in the glutathione synthesis pathway (cysteinylglycine and cysteinylglycine disulfide) indicates increased glutathione biosynthesis and an increase in ROS levels (McKenzie et al, 2021). The distribution of ROS or oxidative stress pathways in human cervical epithelial cells and cervical stromal cells is linked to sterile inflammation (increased IL-6).…”

Vaginom- und „Endometriom“-Diagnostik bei Kinderwunsch

“…Gleiches gilt für den Fall eines wiederholten Implantationsversagens [10]. Ein Grund hierfür könnte die vermehrte Bildung von Tumor-Nekrose-Faktor α, IL-6 und IL-8 im Rahmen eines inflammatorischen Geschehens sowie einer Sialidase durch typische Erreger einer BV sein [17].…”

Effect of a combination of pea protein, grape seed extract and lactic acid in an in vivo model of bacterial vaginosis

“…Alteration of the vaginal microbiota causes change in pH, which allows a variety of anaerobes and facultative bacteria to overgrow and cause chronic infection as well as abnormal vaginal discharge 11 , 12 . Bacteria that colonize vaginal mucosa are mainly Gram-positive cocci or anaerobic species such as Prevotella 13 , Mobiluncus 14 , and the facultative anaerobic bacillus Gardnerella vaginalis (GV) 15 . Particularly, GV has been extensively studied because it has been found from the vaginal samples of almost all women with BV 16 – 18 .…”