How does gut microbiota affect the vaginitis axis? The mediating role of plasma metabolites

Abstract

Vaginitis is the most common problem afflicting women of childbearing age. However, the underlying etiological factors remain poorly understood, leading to recurrent vaginitis and constraining clinical management. Here, we explored whether the gut microbiota influences the risk of vaginitis by performing a two-sample Mendelian randomization analysis using the largest genome-wide association studies to date. Four gut taxa in genus levels were identified related to vaginitis: Candidatus Soleaferrea (inverse-variance weighted [IVW] odds ratio [OR] = 2.20, P = 0.026), Dialister (IVW OR = 2.62, P = 0.029), Lachnospiraceae UCG-008 (IVW OR = 0.41, P = 0.0067), and Ruminiclostridium 5 (IVW OR = 0.080, P = 1.42 × 10^-5). We further explored the mediation effect of the plasma metabolites by two-step Mendelian randomization (MR) and multivariable MR. The findings indicated that 3-phosphoglycerate and lysophosphatidylcholine antagonistically act against the two identified risk factors (Candidatus Soleaferrea and Dialister, respectively) of vaginitis, thus appearing to confer protective effects against vaginitis. On the contrary, the elevation of arachidonate/pyruvate ratio and reduction in palmitate/myristate ratio mediated the protective effects of Lachnospiraceae UCG-008 against vaginitis. These findings support a potential causal role for gut microbiota in the development of vaginitis, thereby providing potential strategies for its prevention and intervention.IMPORTANCEVaginitis is the most common problem afflicting women of childbearing age. However, the underlying etiological factors remain poorly understood, leading to recurrent vaginitis and constraining clinical management. Besides, the human gut and vagina are important organs that are both colonized by thousands of microorganisms impacting human physiology and health. Whether there is an interplay between the microecosystems is intriguing and unclear. This study evaluated the potential causal relationship between the gut microbiota and vaginitis and suggested that specific types of gut microbiota may be the potential risk or protective factors of vaginitis mediated or suppressed by certain plasma metabolites. These findings provide treatment insights for vaginitis.

Keywords: Causal relationship; Gut microbiota; Mediation effects; Mendelian randomization; Plasma metabolites; Vaginitis.

Fig 1

Study overview and analysis pipeline. (A) Overview of the study design. (B) Pipeline of the two-sample MR analysis and the mediation analysis. Figures are created with BioRender.com.

Fig 2

Associations between four taxa and vaginitis by Mendelian randomization (MR) analysis. (A) A schematic diagram showing the bidirectional MR analysis between the gut microbiota (GM) and vaginitis. (B) Scatterplot showing the associations between four GM taxa (Candidatus Soleaferrea, Dialister, Lachnospiraceae UCG-008, and Ruminiclostridium 5) and vaginitis. (C) Forest plot of the leave-one-out analysis. Each single-nucleotide polymorphism (SNP) was removed for each calculation of the effects of GM on vaginitis using the rest of the SNPs. The red line indicates the β value and the 95% confidence interval calculated by all SNPs.

Fig 3

Two-step Mendelian randomization (MR) analysis of the mediation effects of plasma metabolites on the associations between gut microbiota (GM) and vaginitis. (A) A schematic diagram showing the data and results of the mediation analysis. (B) Significant results of the MR analysis between the screened GM taxa and four potential mediator plasma metabolites. (C) Significant results of the MR analysis between four potential mediator plasma metabolites and vaginitis.

Fig 4

Summary diagram of the results of MR analysis between the GM and vaginitis, and the effects of plasma metabolites. The β values represent the effect estimates using the IVW method. Arrows and characters in red and blue colors indicate positive correlations and negative correlations, respectively. The mediated proportions of arachidonate/pyruvate ratio and palmitate/myristate ratio are calculated based on the method of two-step MR. If the directions of the two-step MR of metabolites agree with the direction of the initial MR from GM to vaginitis, the effects of metabolites are mediation. Otherwise, the effects are suppression.