Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier

Abstract

Vaginal microbiome (VMB) dysbiosis is associated with increased acquisition of HIV. Cervicovaginal inflammation and other changes to the mucosal barrier are thought to have important roles but human data are scarce. We compared the human cervicovaginal proteome by mass spectrometry of 50 Rwandan female sex workers who had previously been clustered into four VMB groups using a 16S phylogenetic microarray; in order of increasing bacterial diversity: Lactobacillus crispatus-dominated VMB (group 1), Lactobacillus iners-dominated VMB (group 2), moderate dysbiosis (group 3), and severe dysbiosis (group 4). We compared relative protein abundances among these VMB groups using targeted (abundance of pre-defined mucosal barrier proteins) and untargeted (differentially abundant proteins among all human proteins identified) approaches. With increasing bacterial diversity, we found: mucus alterations (increasing mucin 5B and 5AC), cytoskeleton alterations (increasing actin-organizing proteins; decreasing keratins and cornified envelope proteins), increasing lactate dehydrogenase A/B as markers of cell death, increasing proteolytic activity (increasing proteasome core complex proteins/proteases; decreasing antiproteases), altered antimicrobial peptide balance (increasing psoriasin, calprotectin, and histones; decreasing lysozyme and ubiquitin), increasing proinflammatory cytokines, and decreasing immunoglobulins immunoglobulin G1/2. Although temporal relationships cannot be derived, our findings support the hypothesis that dysbiosis causes cervicovaginal inflammation and other detrimental changes to the mucosal barrier.

Distinct Effects of the Cervicovaginal Microbiota and Herpes Simplex Type 2 Infection on Female Genital Tract Immunology

“…These findings reflect expected levels of vaginal cytokines [44], and are broadly consistent with prior work demonstrating that vaginal dysbiosis is associated with a proteomic profile characterized by elevated proinflammatory cytokines and altered AMPs [45]. Prior studies have also associated Nugentdefined BV with increased proinflammatory cytokines, particularly IL1α and IL1β, as well as decreased levels of IP-10 [11,46].…”

The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next?

“…prevent colonisation of bacterial vaginosis-associated bacterial species through maintenance of a low pH [60–63] and bacteriocin production [64–66]. This is important for maintenance of the cervical epithelial barrier function that inhibits entry of HPV to the basal keratinocytes [67]. When BV-associated strict anaerobes are able to colonise, they produce enzymes and metabolites, which may compromise this barrier, facilitating HPV entry.…”

“…Using samples derived from a cohort of 50 Rwandan sex workers, they examined changes associated with dysbiosis, which causes increased acquisition of HIV infection, using NGS and a proteomics approaches [67]. Irrespective of HIV status, dysbiosis resulted in disruption of key vaginal epithelial cytoskeletal proteins, with increased cell death, which implies epithelial cell damage and desquamation.…”

“…and are found at significantly higher levels in women with BV [96]. Dysbiosis may also result in decreased mucus production [67] and a subsequent decrease viral trapping through antibody capture as well as increased exposure of the cervical epithelium. There also exists evidence that inflammation plays an important role in dysbiosis-induced cervical disease.…”

Does the vaginal microbiota play a role in the development of cervical cancer?

“…The few studies available using NGS continue to show a protective effect in that hormonal contraceptives are associated with Lactobacillus species dominated microbiomes 53-55 . Most of these studies were conducted over short periods of time, so the long-term effect of OCs on the VM and immune cells remains unknown.…”