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The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice

Nature Metabolism volume 6, pages 947–962 (2024)Cite this article

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Abstract

Polycystic ovary syndrome (PCOS), an endocrine disorder afflicting 6–20% of women of reproductive age globally, has been linked to alterations in the gut microbiome. We previously showed that in PCOS, elevation of Bacteroides vulgatus in the gut microbiome was associated with altered bile acid metabolism. Here we show that B. vulgatus also induces a PCOS-like phenotype in female mice via an alternate mechanism independent of bile acids. We find that B. vulgatus contributes to PCOS-like symptoms through its metabolite agmatine, which is derived from arginine by arginine decarboxylase. Mechanistically, agmatine activates the farnesoid X receptor (FXR) pathway to subsequently inhibit glucagon-like peptide-1 (GLP-1) secretion by L cells, which leads to insulin resistance and ovarian dysfunction. Critically, the GLP-1 receptor agonist liraglutide and the arginine decarboxylase inhibitor difluoromethylarginine ameliorate ovarian dysfunction in a PCOS-like mouse model. These findings reveal that agmatine–FXR–GLP-1 signalling contributes to ovarian dysfunction, presenting a potential therapeutic target for PCOS management.

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Fig. 1: B. vulgatus induces PCOS-like phenotype through a non-bile acid-dependent pathway.
Fig. 2: B. vulgatus inhibits GLP-1 secretion, and the GLP-1R agonist liraglutide improves B. vulgatus-induced PCOS-like phenotype.
Fig. 3: B. vulgatus extract inhibits GLP-1 secretion in intestinal epithelial L cells by activating FXR.
Fig. 4: FXR signalling pathway mediates B. vulgatus-induced PCOS-like phenotype by regulating GLP-1 secretion.
Fig. 5: The B. vulgatus derivative agmatine activates FXR in intestinal epithelial L cells and inhibits GLP-1 secretion, inducing a PCOS-like phenotype in mice.
Fig. 6: Inhibiting the production of agmatine prevents B. vulgatus-induced PCOS-like phenotype.
Fig. 7: The speA and bsh of B. vulgatus can participate in the development of PCOS-like phenotypes in mice independently.

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Data availability

All the data relating to the metagenomic sequencing and RNA sequencing of this study have been uploaded to the Sequence Read Archive database and are available for download via accession numbers PRJNA1080049 and PRJNA1080099. Source data are provided with this paper.

Code availability

No custom code was used for this study.

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Acknowledgements

This work was supported by the National Natural Science Foundation of the Peoples’ Republic of China (grant nos. 31925021, 82130022, 92357305 and 82341226 to C.J.), the National Key Research and Development Program of China (grant nos. 2022YFA0806400 to C.J. and 2022YFC2702500 to R.L.), the National Natural Science Foundation of the Peoples’ Republic of China (grant nos. 82022028 and 82171627 to Y.P., 82288102 to J.Q., 82001506 to X.Q., 92149306 and 81921001 to C.J., 82301841 to S.Y.). C.J. acknowledges the support from the Tencent Foundation through the Xplorer Prize. We thank L. Dai (Shenzhen Institute of Synthetic Biology, Institute of Advanced Technology) for providing the Bacteroides tool plasmid pB041; D. L. Gumucio (University of Michigan) for providing the villin Cre mice; G. L. Guo (Rutgers University) for providing the PGL4-Shp-TK firefly luciferase construct and human FXR expression plasmid; P. A. Dawson (Emory University) for providing the human ASBT expression plasmid and D. Drucker for providing the GLUTag cell line.

Author information

Author notes

  1. These authors contributed equally: Chuyu Yun, Sen Yan.

Authors and Affiliations

  1. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China

    Chuyu Yun, Sen Yan, Baoying Liao, Xinyu Qi, Min Zhao, Rong Li, Jie Qiao & Yanli Pang

  2. National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China

    Chuyu Yun, Sen Yan, Baoying Liao, Xinyu Qi, Min Zhao, Rong Li, Jie Qiao & Yanli Pang

  3. Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China

    Chuyu Yun, Sen Yan, Baoying Liao, Xinyu Qi, Min Zhao, Rong Li, Jie Qiao & Yanli Pang

  4. Institute of Advanced Clinical Medicine, Peking University, Beijing, China

    Chuyu Yun, Sen Yan, Xinyu Qi, Rong Li, Jie Qiao & Yanli Pang

  5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China

    Yong Ding, Kai Wang, Yingying Zhuo, Qixing Nie, Chuan Ye & Changtao Jiang

  6. Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China

    Xinyu Qi, Rong Li, Jie Qiao & Yanli Pang

  7. Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University, Beijing, China

    Pengyan Xia & Changtao Jiang

  8. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Ming Ma

  9. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China

    Changtao Jiang

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  1. Chuyu Yun
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Contributions

Y.P., C.J., J.Q. and R.L. designed the study. C. Yun and X.Q. enroled the patients and collected the patient samples. C. Yun, S.Y., B.L. and M.Z. performed the animal experiments and analysed the data. Y.D. and K.W. guided the microbial genetic operations. S.Y. and Q.N. performed the LC–MS analysis. Y.Z., C. Ye, P.X. and M.M. analysed the metagenomic and RNA sequencing data. S.Y., C. Yun, C.J., J.Q. and Y.P. wrote the paper with input from all authors.

Corresponding authors

Correspondence to Rong Li, Changtao Jiang, Jie Qiao or Yanli Pang.

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Nature Metabolism thanks John Chiang, Wendong Huang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Yanina-Yasmin Pesch, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Bv-Δbsh colonization leads to a PCOS-like phenotype in mice without affecting the bile acid profile.

a, DNA gel electrophoresis experiment to verify the knockout of Bv-Δ1032, Bv-Δ2699, and Bv-Δ3993 in B. vulgatus. b, Growth curve of wild type B. vulgatus (Bv) and Bv-Δ2699 (Bv-Δbsh) in BHI medium. c-l, SPF mice were gavaged with wild type B. vulgatus (Bv), BVU2699-knockout B. vulgatus (Bv-Δbsh), or PBS (Vehicle) for three weeks. c, Colonization of Bv and Bv-Δbsh in mice. d, The total bile acid profile of serum. e, The content of UDCA in feces. f, The content of UDCA in serum. g, The levels of IL-22 in serum. h, Quantitative analysis of cystic follicles in the ovaries. i, Area under the curve (AUC) of GTT. j, The levels of fasting glucose in serum. k, The levels of insulin in serum. l, HOMA-IR. All data are presented as the mean ± s.e.m. (b-g, i-l) n = 6/group; h, n = 5/group. In c, the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test. The P values were determined by one-way ANOVA with Tukey’s multiple comparison post hoc test in e, i, j, and one-way ANOVA with LSD test in f-h, k, l.

Source data

Extended Data Fig. 2 Cholestyramine cannot reverse B. vulgatus-induced PCOS-like phenotype.

a and b, Cholestyramine reduces the content of bile acids in mouse intestinal epithelium (a) and serum (b). (a) CA, P = 2.32 × 10−7; α-MCA, P = 0.000008; TCA, P = 2.85 × 10−7. (b) TUDCA, P = 0.000016. c-j, Cholestyramine treatment mice were gavaged with wild type B. vulgatus (Bv) or PBS (Vehicle) for three weeks. c, Quantitative analysis of cystic follicles in the ovaries. d, Levels of testosterone in serum. e, Levels of LH in serum. f, Glucose tolerance test (GTT) (15min: ***P = 0.0007; 30min: *P = 0.0249; *P = 0.0183; *compared with the vehicle + Cholestyramine). g, Area under the curve (AUC) of GTT. h, Insulin tolerance test (ITT) (15min: *P = 0.0152; 30min: **P = 0.0087; *compared with the vehicle + Cholestyramine). i, The levels of fasting glucose in serum. j, The level of insulin in serum. All data are presented as the mean ± s.e.m. (a, b, c) n = 5/group. (d-j) n = 6/group. In a, b, d-g, i, j, the P values were determined by two-tailed Student’s t-test. In c, h, the P values were determined by two-tailed Mann–Whitney U-test.

Source data

Extended Data Fig. 3 GLP-1R agonist liraglutide improves B. vulgatus-induced PCOS-like phenotype.

a, The levels of GIP in patients with PCOS and healthy control serum. b, The levels of GDF15 in patients with PCOS and healthy control serum. c, The correlation between the total GLP-1 level in the serum and LH/FSH ratio. d, The correlation between the total GLP-1 level in the serum and HOMA-IR. e, Quantitative analysis of cystic follicles in the ovaries. f, Area under the curve (AUC) of GTT. g, The levels of fasting glucose in serum. h, The level of insulin in serum. All data are presented as the mean ± s.e.m. (a-d) n = 20 in the control group and n = 20 in the PCOS group. (e) n = 5/group. (f-h) n = 6/group. In a, the P values were determined by two-tailed Mann–Whitney U-test. In b, the P values were determined by two-tailed Student’s t-test. In c, d, correlation analysis was determined by one tailed Pearson r-test. In e, the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test. In f-h, the P values were determined by one-way ANOVA with Tukey’s multiple comparison post hoc test.

Source data

Extended Data Fig. 4 B. vulgatus inhibits GLP-1 secretion and induces PCOS-like phenotype depended on intestinal epithelial FXR.

a, The expression levels of Fgf15 and Shp in intestinal epithelium. b, The levels of C4 in serum. c, FXR expression in siFXR STC-1 cells. d, The levels of total GLP-1 in the cellular supernatant. e, The relative expression of Gcg. f, The levels of total GLP-1 in the cellular supernatant. g, Luciferase activity. h, The expression levels of Tgr5 in GLUTag cells. i, The levels of total GLP-1 in the cellular supernatant. j, Relative fold change of total GLP-1 levels to vehicle. k, The expression levels of Fxr and downstream genes in the intestinal epithelium of Fxrfl/fl and FxrΔIE mice. l-q, FxrΔIE or Fxrfl/fl mice were gavaged with Bv or PBS for three weeks. l, Quantitative analysis of corpora lutea. m, Quantitative analysis of cystic follicles. n, AUC of GTT. o, The levels of fasting glucose in serum. p, The level of insulin in serum. q, HOMA-IR. All data are presented as the mean ± s.e.m. (a, k-q) n = 5/group. (b) n = 20 in both control and PCOS group. (c, h) n = 3/group. (d-g, i, j) n = 4/group. In a, the P values were determined by two-tailed Mann–Whitney U-test. In b, d, e, k, the P values were determined by two-tailed Student’s t-test. The P values were determined by one-way ANOVA with Tukey’s multiple comparison post hoc test in c, f, h, m, o-q; one-way ANOVA with Dunnett’s T3 test in g and one-way ANOVA with LSD test in n. In i, j, l, the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test.

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Extended Data Fig. 5 GLP-1 receptor inhibitor reversed the improvement of B. vulgatus-induced PCOS-like phenotype in intestinal Fxr knockout mice.

a, Quantitative analysis of corpora lutea in the ovaries. b, Quantitative analysis of cystic follicles in the ovaries. c, Area under the curve (AUC) of GTT. d, The levels of fasting glucose in serum. e, The level of insulin in serum. f, HOMA-IR. All data are presented as the mean ± s.e.m. (a-f) n = 5/group. In a, b, d, the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test. In c, e, f, the P values were determined by one-way ANOVA with LSD test.

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Extended Data Fig. 6 Agmatine induces PCOS-like phenotype via a FXR signaling pathway.

a, The content of cytidine 5′-diphosphocholine in the feces of B. vulgatus model mice. b-h, FxrΔIE or Fxrfl/fl mice were gavaged with agmatine or PBS (Vehicle) for three weeks. b, Quantitative analysis of cystic follicles in the ovaries. c, Levels of testosterone in serum. d, Levels of LH in serum. e, Area under the curve (AUC) of GTT. f, The levels of fasting glucose in serum. g, The level of insulin in serum. h, HOMA-IR. All data are presented as the mean ± s.e.m. (a) n = 6/group. (b-h) n = 5/group. In a, the P values were determined by two-tailed Student’s t-test. In b, the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test. The P values were determined by one-way ANOVA with Tukey’s multiple comparison post hoc test in c-f, and one-way ANOVA with LSD test in g, h.

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Extended Data Fig. 7 The ability of Bv-ΔspeA to induce PCOS-like phenotype is significantly reduced compared to B. vulgatus.

a, The percentage Bacteroides vulgatus strains with or without speA. b, The relative abundance of speA gene in the metagenomic dataset from PMID: 31332392. n = 25 in Control (BMI < 25) group; n = 25 in PCOS (BMI < 25) group; n = 18 in Control (BMI ≥ 25) group; n = 25 in PCOS (BMI ≥ 25) group. For box plots, the midline represents the median; box represents the interquartile range (IQR) between the first and third quartiles, and whiskers represent the minimum to maximum values. Bacteroides vulgatus: Control (BMI < 25) vs PCOS (BMI < 25) P = 2.56 × 10−7, Control (BMI ≥ 25) vs PCOS (BMI ≥ 25) P = 0.000015; Bifidobacterium longum: Control (BMI ≥ 25) vs PCOS (BMI ≥ 25) P = 0.000025. c, DNA gel electrophoresis experiment to verify the knockout of Bv-ΔspeA in B. vulgatus. d, Growth curve of wild type B. vulgatus (Bv) and Bv-ΔspeA in BHI medium. e-m, SPF mice were gavaged with Bv or Bv-ΔspeA for three weeks. e, Colonization of Bv and Bv-ΔspeA in mice. f, Quantitative analysis of corpora lutea in the ovaries. g, Quantitative analysis of cystic follicles in the ovaries. h, Levels of testosterone in serum. i, Levels of LH in serum. j, Area under the curve (AUC) of GTT. k, The levels of fasting glucose in serum. l, The level of insulin in serum. m, HOMA-IR. All data are presented as the mean ± s.e.m. (d) n = 3/group. (e, h-m) n = 6/group. (f, g) n = 5/group. In b, the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test. In d, i-m, the P values were determined by two-tailed Student’s t-test. In e-h, the P values were determined by two-tailed Mann–Whitney U-test.

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Extended Data Fig. 8 The arginine decarboxylase (ADC) inhibitor DFMA improves the B. vulgatus-induced PCOS-like phenotype.

a, Inhibition rate of agmatine production by adding DFMA to BHI medium. b, Growth curve of Bv and Bv + DFMA in BHI medium. c-l, SPF mice were gavaged with wild type B. vulgatus (Bv), and treated with PBS or arginine decarboxylase inhibitor DFMA for three weeks. c, Quantitative analysis of corpora lutea in the ovaries. d, Quantitative analysis of cystic follicles in the ovaries. e, Levels of testosterone in serum. f, Levels of LH in serum. g, Glucose tolerance test (GTT) (15min: *P = 0.0401; 30min:*P = 0.0203; * compared with the Bv group). h, Area under the curve (AUC) of GTT. i, Insulin tolerance test (ITT) (15min: ***P = 0.000003; 30min: ***P = 0.0006; 60min: *P = 0.0342; 90min: *P =0.0181; * compared with the Bv group). j, The levels of fasting glucose in serum. k, The level of insulin in serum. l, HOMA-IR. All data are presented as the mean ± s.e.m. (a, b) n = 3/group. (c and d) n = 5/group. (e-l) n = 6/group. In b, e-l, the P values were determined by two-tailed Student’s t-test. In c, d, the P values were determined by two-tailed Mann–Whitney U-test.

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Extended Data Fig. 9 The arginine decarboxylase (ADC) inhibitor DFMA improves the DHEA-induced hyperandrogenic PCOS-like phenotype.

a, The relative abundance of B. vulgatus in the DHEA model. b, The concentration of agmatine in feces. c, The concentration of agmatine in intestinal epithelium. d, Expression levels of Fgf15 and Shp in intestinal epithelium. e, Levels of total GLP-1 in serum. f, Quantitative analysis of estrous cycles. g, Hematoxylin and eosin staining of representative ovaries. The corpora lutea are indicated by * and the cystic follicle is indicated by #. Scale bar, 200 μm. h, Quantitative analysis of corpora lutea. i, Quantitative analysis of cystic follicles. j, Levels of testosterone in serum. k, Levels of LH in serum. l, Glucose tolerance test (GTT) (15min: ***P = 0.000026, ##P = 0.0034; 30min: ***P = 0.0002, #P = 0.0103; 60min: *P = 0.0297; * compared with the vehicle group, # compared with the DHEA group.). m, Area under the curve (AUC) of GTT. n, Insulin tolerance test (ITT) (15min: **P = 0.0048; 30min: *P = 0.0214; * compared with the vehicle group). o, The levels of fasting glucose in serum. p, The level of insulin in serum. q, HOMA-IR. r, Expression levels of Ucp1, Pgc1a, Cited1, Cox8b, Nr2f6, Prdm16 in the subcutaneous fat. s, Expression levels of Ucp1, Pgc1a, Cited1, Cox8b in the brown adipose tissue. t, Expression levels of Il-8, Il-6, Il-1β, Il-18, Ifng, Ccl20, Ccl2, in the ovaries. All data are presented as the mean ± s.e.m. (a-f, j-t) n = 6/group. (h, i) n = 5/group. In a, the P values were determined by two-tailed Student’s t-test. The P values were determined by one-way ANOVA with Tukey’s multiple comparison post hoc test in c, h-j, l, m, o, q, one-way ANOVA with Dunnett’s T3 test in b and one-way ANOVA with LSD test in k, n. In d-f, p, r-t the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test.

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Extended Data Fig. 10 The speA and bsh of B. vulgatus can participate in the development of PCOS-like phenotypes in mice independently.

a, DNA gel electrophoresis experiment to verify the knockout of Bv-ΔspeAΔbsh in B. vulgatus. b, Growth curve of wild type B. vulgatus (Bv) and Bv-ΔspeAΔbsh in BHI medium. c, The content of agmatine after 24 h cultured with B. vulgatus or Bv-ΔspeAΔbsh in BHI medium. d, The ability of hydrolyzing TUDCA (12 h) after knocking out both the speA and bsh in B. vulgatus. e, Colonization of Bv and Bv-ΔspeA, Bv-Δbsh and Bv-ΔspeAΔbsh in cecum of mice. f, Quantitative analysis of cystic follicles in the ovaries. g, Area under the curve (AUC) of GTT. h, The levels of fasting glucose in serum. i, The level of insulin in serum. j, Expression levels of Ucp1, Pgc1a, Cited1, Cox8b, Nr2f6, Prdm16 in the subcutaneous fat. Ucp1: Vehicle versus Bv, P = 8.06 × 10−7; Bv versus Bv-ΔspeAΔbsh, P = 8.09 × 10−7. k, Expression levels of Ucp1, Pgc1a, Cited1, Cox8b in the brown adipose tissue. Ucp1: Vehicle versus Bv, P = 0.000019. l, Expression levels of Il-8, Il-6, Il-1β, Il-18, Ifng, Ccl20, Ccl2, in the ovaries. All data are presented as the mean ± s.e.m. (b, e, g-l) n = 6/group. (c, d) n = 3/group. (f) n = 5/group. The P values were determined by one-way ANOVA with Dunnett’s T3 test in c, d, one-way ANOVA with Tukey’s multiple comparison post hoc test in g, k and one-way ANOVA with LSD test in f, h-j. In e, l, the P values were determined by Kruskal–Wallis test followed by Dunn’s post hoc test.

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Yun, C., Yan, S., Liao, B. et al. The microbial metabolite agmatine acts as an FXR agonist to promote polycystic ovary syndrome in female mice. Nat Metab 6, 947–962 (2024). https://doi.org/10.1038/s42255-024-01041-8

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