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Pessary Therapy Restores Vaginal Microbiome Homeostasis in Severe Pelvic Organ Prolapse: A Longitudinal Metagenomic and Metabolic Analysis

ABSTRACT: Pelvic organ prolapse (POP), affecting up to 50% of elderly women, disrupts vaginal microbial homeostasis, yet the impact of first-line pessary therapy on microbiome dynamics remains poorly characterized. This prospective cohort study employed metagenomic sequencing and clinical metrics to longitudinally analyze vaginal microbiota in 41 postmenopausal POP-III/IV patients undergoing pessary therapy, compared to surgical intervention and healthy controls. Pre-treatment POP patients exhibited dysbiosis marked by elevated aerobic pathogen (e.g., Gardnerella vaginalis, Streptococcus agalactiae) and bacterial vaginosis (BV)-associated taxa, which may correlating with anatomical oxygen exposure. pessary therapy drove time-dependent microbial stabilization: within 3 months, Lactobacillus crispatus and Lactobacillus jensenii reclaimed dominance (∼90% abundance), suppressing BV-associated genera (Corynebacterium spp., Streptococcus spp.), while surgery failed to improve dysbiosis. Patients developing pessary-associated ulcers showed distinct enrichment of G. vaginalis, S. anginosus, and Atopobium vaginae, enabling a predictive model (AUC: 0.848) for complication risk. Metabolomic profiling revealed pessary-induced activation of pentose phosphate and glycerophospholipid pathways, aligning with microbial recovery. These findings establish pessary therapy as a dual restorative intervention—anatomically and microbially—while identifying actionable biomarkers for complication prevention. Our work advocates integrating microbiome-guided strategies into POP management to optimize therapeutic outcomes.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS12722 | MetaboLights | 2025-07-16

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12722_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS12722_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12722_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12722_LC-MS_positive_hilic_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Background. Food can affect the microbial balance in the human intestine, and the ingestion of probiotics may play a role in the current obesity pandemic. The objective of our study was to determine if increased Lactobacillus spp. in the intestinal microflora of mice can promote growth and if changes in the intestinal microflora are associated with modifications in metabolism. Methodology. Female BALBc mice were divided between one control and two experimental groups and inoculated either once or twice with 4×1010 Lactobacillus per animal in PBS or with PBS alone. Fecal samples were collected and tested using qPCR to detect and quantify Lactobacillus spp., Bacteroidetes and Firmicutes. Gene expression by microarray and RT-PCR was studied in liver and adipose tissue. Finally, metabolic parameters in the plasma were tested. Principal Findings. In three independent experiments, we observed an increase in both weight gain and liver weight in mice inoculated with 4×1010 Lactobacillus. Inoculation with Lactobacillus sp. (ostrich) increased the Lactobacillus spp. and Firmicutes DNA copy number in feces. The transcriptional profile of liver tissue from mice inoculated with Lactobacillus sp. (ostrich) was enriched for Gene Ontology terms related to the immune response and metabolic modifications. The mRNA levels of fatty acyl synthase (Fas), sterol regulatory element binding factor 1 (Srebp1c), tumor necrosis factor alpha (Tnf), cytochrome P450 2E1 (Cyp2e1) and 3-phosphoinositide-dependent protein kinase-1 (Pdpk1) were significantly elevated in liver tissue in experimental group animals. In gonadal adipose tissue, the expression of leptin, peroxisome proliferator-activated receptor gamma (Pparg and Srebp1c was significantly higher in experimental group animals, whereas the expression of adiponectin was significantly lower. Conclusions. Alterations in the intestinal microbiota resulted in increased weight gain. Furthermore, increased Lactobacillus spp. in the intestinal microflora of mice inoculated with Lactobacillus sp. (ostrich) resulted in accelerated weight gain, liver enlargement and metabolic changes in the plasma, liver and adipose tissue.

Project description:Objective To characterise the vaginal microbiota, mucosal metabolome and host immune response in early pregnancy and investigate its relationship with adverse pregnancy outcomes, including ectopic pregnancy, within the context of pregnancies of unknown location (PUL). DesignProspective cohort study Setting Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK. Population Ninety-one pregnancies of which 22 patients had a favourable outcome of a viable intrauterine pregnancy (VIUP). The remainder had an adverse outcome including 15 with a non-viable intrauterine pregnancy (NVIUP, i.e. miscarriage), 26 a failed PUL (FPUL), 20 an ectopic pregnancy (EP) and 8 a persistent PUL (PPUL). Methods Two matching pairs of vaginal swab samples were collected from women as early as four weeks gestation in pregnancies that resulted in an ectopic pregnancy, miscarriage or viable intrauterine pregnancy pregnancies matched for age, gestation and body mass index. Sequencing of the V1-V2 region of the 16S rRNA gene amplicon was used to characterize and compare vaginal bacterial compositions. The second of the pair of vaginal swabs was used sequentially first for DESI-MS direct-on swab untargeted metabolite profiling followed by extraction of the protein content for quantitative analysis of chemokine and cytokine levels using a 15-plex Luminex immune-profiling assay. Results Adverse final pregnancy outcomes were associated with reduced Lactobacillus spp. abundance (100% vs. 75.4%, p-value=9.83 x 10-3) and higher Shannon α-diversity (p-value=1.10 x 10-3) when compared to viable pregnancies. This association was independent of vaginal bleeding and observed prior to the diagnosis of the final pregnancy outcome (i.e. before the pregnancy was visible on ultrasound). Ectopic pregnancy had an even stronger association with Lactobacillus spp. depletion when compared to viable pregnancies (30% vs 0%, p-value =5.52 x 10-3). Although a strong immune mediator signature, which included MMP-1, IL-6, CCL-2/MCP-1, TNF-α, amongst others was observed in adverse pregnancy outcomes, vaginal bleeding was identified as a major confounder and adjustment of models for bleeding removed the association with outcome. Vaginal bleeding was also found to impact metabolic profiles, increasing the abundances of multiple lipid species. The prediction of outcome based on metabolic profiles was not possible but metabolic profiles were predictive with high accuracy of vaginal microbial composition at the genera level (L. dominant vs. L. deplete), and metabolic correlates of host immune activation were identified, mainly composed of lipids. Conclusions Early pregnancy vaginal microbiome communities dominated by L. crispatus or L. gasseri were observed in women with a PUL who go onto have a viable intrauterine pregnancy. Conversely, a vaginal microbiota deplete in Lactobacillus spp or dominated by L. iners is associated with a diagnosis of ectopic pregnancy in a PUL population. These findings suggest that vaginal microbiota composition is a risk factor for ectopic pregnancy. Vaginal bleeding is an inevitable cofounding factor that must be taken into consideration when performing multi-omic analysis of vaginal mucosal samples in similar clinical populations. Immune and metabolic profiles were particularly impacted by bleeding and bleeding could greatly impact the diagnostic usefulness of immune marker profiling. Further studies are required to clarify the role of microbes and infection in implantation and ectopic pregnancy, as well as determine the mechanistic pathways by which sub-optimal vaginal microbial composition increases risk. Through the integration of metataxonomics, metabolomic and immune profiling data obtained from corresponding samples, our findings demonstrate the robust predictive capacity of specific metabolome signatures. These signatures enable the simultaneous prediction of both the composition of the vaginal microbiome and the inflammatory status of the host, even in the presence of bleeding. The data derived from direct on-swab metabolic profiling using DESI-MS holds promise for swiftly stratifying the risk of early pregnancy loss by rapidly assessing the dynamics between the vaginal microbiota and host. Further validation, however, is essential for future studies to confirm this potential. Linked cross omic data sets:Meta-taxonomics data associated with this study are available in the European Nucleotide Archive (ENA): accession number PRJEB72306.

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Pessary Therapy Restores Vaginal Microbiome Homeostasis in Severe Pelvic Organ Prolapse: A Longitudinal Metagenomic and Metabolic Analysis

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