Deciphering the complex interplay between microbiota, HPV, inflammation and cancer through cervicovaginal metabolic profiling

Abstract

Background Dysbiotic vaginal microbiota have been implicated as contributors to persistent HPV-mediated cervical carcinogenesis and genital inflammation with mechanisms unknown. Given that cancer is a metabolic disease, metabolic profiling of the cervicovaginal microenvironment has the potential to reveal the functional interplay between the host and microbes in HPV persistence and progression to cancer. Methods Our study design included HPV-negative/positive controls, women with low-grade and high-grade cervical dysplasia, or cervical cancer ( n = 78). Metabolic fingerprints were profiled using liquid chromatography-mass spectrometry. Vaginal microbiota and genital inflammation were analysed using 16S rRNA gene sequencing and immunoassays, respectively. We used an integrative bioinformatic pipeline to reveal host and microbe contributions to the metabolome and to comprehensively assess the link between HPV, microbiota, inflammation and cervical disease. Findings Metabolic analysis yielded 475 metabolites with known identities. Unique metabolic fingerprints discriminated patient groups from healthy controls. Three-hydroxybutyrate, eicosenoate, and oleate/vaccenate discriminated (with excellent capacity) between cancer patients versus the healthy participants. Sphingolipids, plasmalogens, and linoleate positively correlated with genital inflammation. Non- Lactobacillus dominant communities, particularly in high-grade dysplasia, perturbed amino acid and nucleotide metabolisms. Adenosine and cytosine correlated positively with Lactobacillus abundance and negatively with genital inflammation. Glycochenodeoxycholate and carnitine metabolisms connected non- Lactobacillus dominance to genital inflammation. Interpretation Cervicovaginal metabolic profiles were driven by cancer followed by genital inflammation, HPV infection, and vaginal microbiota. This study provides evidence for metabolite-driven complex host-microbe interactions as hallmarks of cervical cancer with future translational potential. Fund Flinn Foundation (#1974), Banner Foundation Obstetrics/Gynecology, and NIH NCI (P30-CA023074).

The vaginal metabolome and microbiota of cervical HPV‐positive and HPV‐negative women: a cross‐sectional analysis

“…Consistent with the recent study of the urinary metabolome of women varying in HPV status published by Godoy‐Vitorino et al , we also observed higher levels of the central nervous system neuromodulator 4‐hydroxybutyric acid (aka gamma‐ hydroxybutyric acid or GHB), a precursor of GABA, in HPV + women. Consistent with the recent study by Ilhan et al , we also observed higher levels of several lyso‐ and monoacylglycerol‐lipids in HPV + women, including choline phosphate, and glycerophosphorylcholine. Within CST IV, HPV + women had lower levels of glutathione‐related metabolites including oxidised glutathione and reduced glutathione.…”

“…More recently, Ilhan et al . observed an association in the vaginal metabolome between lipids and cervical cancer. However, the impact of HPV infection remains relatively unexplored.…”

“…Emerging data suggest an association between cervical HPV infections and the vaginal microenvironment . The vaginal microbiota can be categorised into one of five major community state types (CSTs), four of which are dominated by Lactobacillus spp.…”

“…Molecular studies have found HPV‐positive participants are more likely to present with L. iners ‐dominated (CST III) or low‐ Lactobacillus molecular‐BV states than are HPV‐negative women . Brotman et al .…”

“…The vaginal microenvironment also comprises both microbially and host‐produced metabolites that may influence clinical endpoints. Although the vaginal metabolome is largely influenced by resident microbiota, prior research has identified metabolites associated with important clinical conditions including BV, pre‐eclampsia, and preterm labour . More recently, Ilhan et al .…”