Gut bacteriome and mood disorders in women with PCOS

Abstract

Study question: How does the gut bacteriome differ based on mood disorders (MDs) in women with polycystic ovary syndrome (PCOS), and how can the gut bacteriome contribute to the associations between these two conditions?

Summary answer: Women with PCOS who also have MDs exhibited a distinct gut bacteriome with reduced alpha diversity and a significantly lower abundance of Butyricicoccus compared to women with PCOS but without MDs.

What is known already: Women with PCOS have a 4- to 5-fold higher risk of having MDs compared to women without PCOS. The gut bacteriome has been suggested to influence the pathophysiology of both PCOS and MDs.

Study design, size, duration: This population-based cohort study was derived from the Northern Finland Birth Cohort 1966 (NFBC1966), which includes all women born in Northern Finland in 1966. Women with PCOS who donated a stool sample at age 46 years (n = 102) and two BMI-matched controls for each case (n = 205), who also responded properly to the MD criteria scales, were included.

Participants/materials, setting, methods: A total of 102 women with PCOS and 205 age- and BMI-matched women without PCOS were included. Based on the validated MD criteria, the subjects were categorized into MD or no-MD groups, resulting in the following subgroups: PCOS no-MD (n = 84), PCOS MD (n = 18), control no-MD (n = 180), and control MD (n = 25). Clinical characteristics were assessed at age 31 years and age 46 years, and stool samples were collected from the women at age 46 years, followed by the gut bacteriome analysis using 16 s rRNA sequencing. Alpha diversity was assessed using observed features and Shannon's index, with a focus on genera, and beta diversity was characterized using principal components analysis (PCA) with Bray-Curtis Dissimilarity at the genus level. Associations between the gut bacteriome and PCOS-related clinical features were explored by Spearman's correlation coefficient. A P-value for multiple testing was adjusted with the Benjamini-Hochberg false discovery rate (FDR) method.

Main results and the role of chance: We observed changes in the gut bacteriome associated with MDs, irrespective of whether the women also had PCOS. Similarly, PCOS MD cases showed a lower alpha diversity (Observed feature, PCOS no-MD, median 272; PCOS MD, median 208, FDR = 0.01; Shannon, PCOS no-MD, median 5.95; PCOS MD, median 5.57, FDR = 0.01) but also a lower abundance of Butyricicoccus (log-fold changeAnalysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC)=-0.90, FDRANCOM-BC=0.04) compared to PCOS no-MD cases. In contrast, in the controls, the gut bacteriome did not differ based on MDs. Furthermore, in the PCOS group, Sutterella showed positive correlations with PCOS-related clinical parameters linked to obesity (BMI, r2=0.31, FDR = 0.01; waist circumference, r2=0.29, FDR = 0.02), glucose metabolism (fasting glucose, r2=0.46, FDR < 0.001; fasting insulin, r2=0.24, FDR = 0.05), and gut barrier integrity (zonulin, r2=0.25, FDR = 0.03).

Limitations, reasons for caution: Although this was the first study to assess the link between the gut bacteriome and MDs in PCOS and included the largest PCOS dataset for the gut microbiome analysis, the number of subjects stratified by the presence of MDs was limited when contrasted with previous studies that focused on MDs in a non-selected population.

Wider implications of the findings: The main finding is that gut bacteriome is associated with MDs irrespective of the PCOS status, but PCOS may also modulate further the connection between the gut bacteriome and MDs.

Study funding/competing interest(s): This research was funded by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant Agreement (MATER, No. 813707), the Academy of Finland (project grants 315921, 321763, 336449), the Sigrid Jusélius Foundation, Novo Nordisk Foundation (NNF21OC0070372), grant numbers PID2021-12728OB-100 (Endo-Map) and CNS2022-135999 (ROSY) funded by MCIN/AEI/10.13039/501100011033 and ERFD A Way of Making Europe. The study was also supported by EU QLG1-CT-2000-01643 (EUROBLCS) (E51560), NorFA (731, 20056, 30167), USA/NIH 2000 G DF682 (50945), the Estonian Research Council (PRG1076, PRG1414), EMBO Installation (3573), and Horizon 2020 Innovation Grant (ERIN, No. EU952516). The funders did not participate in any process of the study. We have no conflicts of interest to declare.

Trial registration number: N/A.

Keywords: PCOS; anxiety; depression; gut bacteriome; gut microbiome; mood disorders; polycystic ovary syndrome.

Figure 1.

Comparisons of the gut bacteriome in relation to MDs in the whole population. The gut bacteriome profile of the subjects in the whole population, including both women with PCOS and control women, was analyzed. Alpha richness was analyzed using observed features and the Shannon index, and beta diversity was assessed using Bray–Curtis dissimilarity. In (a) observed features and (b) Shannon index. The box plots show the IQR, and the middle line represents the median values. Whiskers in the box plots denote minimum to maximum values. Blue represents no-MD and orange represents MD. A P-value was defined using the Kruskal–Wallis test adjusted with the Benjamini–Hochberg method. In the Bray–Curtis distances of (c) no-MD and MD cases, each dot represents a single individual, and the variation is shown by the percentages at the two axes. Blue represents no-MD and orange represents MD. A P-value was defined by PERMANOVA analysis. (d) The relative abundances of the four major phyla are represented as median values. The phyla with a relative abundance of <1% were grouped as others. (e) The bacterial features classifying the cases based on MDs were analyzed using the Extra-Trees model. The abundance of each feature (log10 frequency) is indicated by the color scale of the heatmap. A P-value was calculated by the Mann–Whitney U-test adjusted with the Benjamini–Hochberg method. FDR, false discovery rate; IQR, interquartile range; MD, mood disorder; PC, principal component; PERMANOVA, permutational analysis of variance.

Figure 2.

Comparisons of the gut bacteriome in relation to MDs in the PCOS and control groups. Alpha richness was analyzed using observed features and the Shannon index, and beta diversity was assessed using Bray–Curtis dissimilarity. In (a) observed features and (b) Shannon index, The box plots show the IQR, and the middle line represents the median values. Whiskers in the box plots denote minimum to maximum values. Blue represents no-MD and orange represents MD. A P-value was defined using the Kruskal–Wallis test adjusted with the Benjamini–Hochberg method. In the Bray–Curtis of (c) PCOS and (d) control groups, each dot represents a single individual, and the variation is shown by the percentages at the two axes. Blue represents no-MD and orange represents MD. A P-value was defined by PERMANOVA analysis. FDR, false discovery rate; IQR, interquartile range; MD, mood disorder; PC, principal component; PERMANOVA, permutational analysis of variance.

Figure 3.

The partial correlation of the top 10 most abundant genera with common clinical characteristics of PCOS and MDs. Correlations between the 10 most abundant genera in (a) the PCOS group (i.e. PCOS no-MD+PCOS MD cases, n = 102), controlled by the presence of MDs, and (b) the MD group (i.e. control MD+PCOS MD, n = 43), controlled by the presence of PCOS. A negative correlation is indicated as blue and a positive correlation is indicated as red in the color key. A P-value was determined by the Kruskal–Wallis test adjusted with the Benjamini–Hochberg method. *FDR < 0.05, **FDR < 0.01, and ***FDR < 0.001. FDR, false discovery rate; MD, mood disorder; SHBG, sex hormone-binding globulin; FAI, free androgen index; HOMA-IR, homeostatic model assessment for insulin resistance; hs-CRP, high-sensitive C-reactive protein; FABP2, fatty acid-binding protein 2.