Microbial Metabolite Ethylamine as FXR Agonist Promotes Polycystic Ovary Syndrome in Female Mice

I. Research Background and Objectives

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting 6%-20% of women of reproductive age worldwide. Symptoms of PCOS include hyperandrogenemia, ovarian dysfunction, and polycystic ovarian morphology, often accompanied by an increased risk of cardiovascular disease, type 2 diabetes, hypertension, and dyslipidemia. This disease imposes a tremendous economic and emotional burden on patients and their families. However, the etiology and pathological mechanisms of PCOS are currently unclear, and there is a lack of treatment methods based on the underlying causes.

In recent years, the gut microbiome has emerged as an important factor linking the external environment and human health. The gut microbiome can directly affect systemic metabolic homeostasis through bacterial translocation or the production of various bioactive metabolites such as short-chain fatty acids, bile acids, and polyamines. Studies have shown that alterations in the gut microbiome composition, including changes in the diversity and abundance of specific bacterial taxa, are closely associated with the occurrence of PCOS. In multiple clinical cohort studies, the abundance of Bacteroidetes bacteria was found to be significantly higher in the gut of PCOS patients compared to healthy controls.

In our previous research, we discovered that the increased abundance of Bacteroides vulgatus was associated with a PCOS-like phenotype in mice, and we believed this was related to the increased expression of bile salt hydrolase (BSH). However, our new research showed that even after deleting the BSH gene (bv-δbsh) in B. vulgatus, this strain was still able to induce a PCOS-like phenotype in mice, suggesting the possibility of another independent mechanism that is not related to bile acids.

II. Source of the Paper

The author group of this paper includes researchers from renowned institutions such as Peking University Third Hospital, Peking University Health Science Center, and the Chinese Academy of Medical Sciences, with primary authors including Chuyu Yun, Sen Yan, and Baoying Liao. The paper was published in the May 2024 issue of the journal Nature Metabolism.

III. Research Workflow

1. Research Steps and Methods

This research includes multiple experimental steps, each thoroughly exploring the mechanisms of PCOS and its relationship with the gut microbiome:

a. Gene Editing and Strain Cultivation

The authors utilized CRISPR-Cas9 gene editing technology to design and delete the bsh gene in the B. vulgatus strain. Through mass spectrometry detection, the mutant strain bv-δbsh almost completely lost its ability to deconjugate bile acids.

b. Establishment of Mouse Models

The research team introduced bv-δbsh and wild-type B. vulgatus into mice, and both strains successfully colonized the gut. However, the mutant strain did not affect the total bile acid levels in the feces and blood of the mice. Notably, the mice colonized with the bv-δbsh mutant strain still exhibited a PCOS-like phenotype, including estrous cycle disruption, polycystic ovarian follicle formation, hormonal abnormalities, and impaired glucose tolerance, suggesting that B. vulgatus induces PCOS through a pathway independent of bile acids.

c. Mechanism Exploration

By simultaneously administering bile acid-binding resins to the mice to eliminate the effects of bile acids, the researchers found that even with reduced bile acid levels, the mice still exhibited a PCOS-like phenotype. Subsequent examination of hypoglycemic hormone levels revealed that only GLP-1 was significantly decreased in PCOS patients and PCOS model mice. The authors verified the mechanism by which B. vulgatus, through its metabolite ethylamine, activates FXR to inhibit GLP-1 secretion, thereby inducing a PCOS-like phenotype. Ethylamine is produced through the arginine decarboxylase pathway.

2. Data and Methods

The study found that GLP-1 levels were significantly elevated in bv-δbsh and bv-δspea mice, while the bv-δspea mutant strain mice exhibited significant amelioration of PCOS-related phenotypes. The experiments also explored the ability of the ADC inhibitor DFMA to effectively inhibit the formation of ethylamine. Specific experimental data are as follows: - Tudca levels were significantly decreased in wild-type mice, but remained unchanged in the mutant strain groups. - Serum IL-22 levels were significantly decreased in wild-type mice, but unchanged in the mutant strain groups, although estrous cycle and follicular morphology exhibited significant PCOS-like phenotypes.

3. Main Findings and Conclusions

The experimental results showed that B. vulgatus, through its metabolite ethylamine, activates FXR, thereby inhibiting GLP-1 secretion and leading to ovarian dysfunction and insulin resistance associated with PCOS. The use of the GLP-1R agonist liraglutide or the ADC inhibitor DFMA effectively improved the PCOS-like phenotype.

The research results not only uncovered the mechanism by which B. vulgatus induces PCOS through the unique ethylamine-FXR-GLP-1 signaling pathway but also provided potential therapeutic targets for the management of PCOS. This “bacteria-as-drug” approach may become a new strategy for future treatment of PCOS.

4. Research Highlights

• Important Discovery: First demonstration of the mechanism by which B. vulgatus induces a PCOS-like phenotype through its metabolite ethylamine, which activates FXR to inhibit GLP-1 secretion.
• Research Significance: This study elucidates the non-bile acid-dependent mechanism of PCOS and provides a novel therapeutic strategy.
• Innovation: The research methodology is innovative, using gene knockout and drug intervention to validate the crucial role of the ethylamine-FXR-GLP-1 signaling pathway in PCOS.

IV. Research Significance

This research deepens the understanding of the etiology of PCOS and reveals the important role of the gut microbiome in this type of metabolic disorder. By precisely elucidating the interaction mechanisms between the gut microecology and host metabolism, the research results provide new insights for the etiology-based treatment of PCOS. Particularly, the role of ethylamine as an FXR agonist not only suggests potential therapeutic targets for PCOS but also provides new perspectives and possibilities for the treatment of other metabolic diseases.

This study demonstrates the prospect of treating PCOS by “drug intervention on bacteria,” bringing hope for the future development of personalized treatment strategies. This microecology-based research model and methodology may lead to more innovative research and clinical applications in the field.