Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome

Study information

Reviewed Marked as Reviewed by KateRasheed on 2025-6-13

study design

cross-sectional observational, not case-control

Citation

PMID PubMed identifier for scientific articles.

37179374

DOI Digital object identifier for electronic documents.

10.1186/s13148-023-01487-9

URI Uniform resource identifier for web resources.

https://pubmed.ncbi.nlm.nih.gov/37179374/

Authors

Liu K, He X, Huang J, Yu S, Cui M, Gao M, Liu L, Qian Y, Xie Y, Hui M, Hong Y, Nie X

Journal

Clinical epigenetics

Year

2023

Keywords:

Butyric acid, Gut microbiome, Inflammation, PCOS, m6A modification

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells' mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients' serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman's rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.

Experiment 1

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Reviewed Marked as Reviewed by KateRasheed on 2025-6-13

Curated date: 2025/05/11

Curator: Shulamite

Revision editor(s): Shulamite, Victoria

Subjects

Location of subjects: China

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Polycystic ovary syndrome Cystic disease of ovaries,hyperandrogenemia,Multicystic ovaries,multicystic ovaries,Ovarian Degeneration, Sclerocystic,Ovarian Syndrome, Polycystic,Ovarian Syndromes, Polycystic,Ovaries, Sclerocystic,Ovary Syndrome, Polycystic,Ovary, Sclerocystic,PCO - Polycystic ovaries,Pco1,PCOD - Polycystic ovarian disease,PCOS,Pcos,PCOS - Polycystic ovarian syndrome,PCOS1,Polycystic ovarian disease,polycystic ovarian disease,Polycystic ovarian syndrome,Polycystic ovaries,polycystic ovaries,Polycystic ovaries (disorder),polycystic ovary,polycystic ovary syndrome,polycystic ovary syndrome 1,Sclerocystic Ovarian Degeneration,Sclerocystic Ovaries,Sclerocystic Ovary,Sclerocystic Ovary Syndrome,Stein Leventhal Syndrome,Stein-Leventhal synd.,Stein-Leventhal Syndrome,Stein-Leventhal syndrome,Syndrome, Polycystic Ovary,Syndrome, Stein-Leventhal,Polycystic ovary syndrome

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Control + Hyperandrogenism group (HA)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Obese group (FAT)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: The mere obese patients with polycystic ovary syndrome

Group 0 sample size Number of subjects in the control (unexposed) group: 12

Group 1 sample size Number of subjects in the case (exposed) group: 6

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: LEfSe

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: No

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool: 2

Signature 1

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Source: Figure 2B

Description: Linear discriminant analysis (LDA) discriminant histogram of gut microbiota in three groups. Identification of the bacterial taxa with statistically significant difference between groups using LEfSe software and LDA. Taxa enriched in Control, FAT-PCOS, and HA-PCOS group are colored by red, green, and blue respectively (LDA > 2.0 and P < 0.05), the relative abundance of thesebiomarkers are shown in the histogram (mean and standard deviation values are plotted) under the corresponding cladogram.

Abundance in Group 1: increased abundance in Obese group (FAT)

NCBI	Quality Control	Links
Achromobacter
Fusobacterium
Rhizobacter
Streptococcus

Revision editor(s): Shulamite

Experiment 2

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Reviewed Marked as Reviewed by KateRasheed on 2025-6-13

Curated date: 2025/05/11

Curator: Shulamite

Revision editor(s): Shulamite, Victoria

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Control + Mere obese group (FAT)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Hyperandrogenism group (HA)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: The mere Hyperandrogenism group with polycystic ovary syndrome

Lab analysis

Statistical Analysis

Signature 1

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Source: 2B

Description: Linear discriminant analysis (LDA) discriminant histogram of gut microbiota in three groups. Identification of the bacterial taxa with statistically significant difference between groups using LEfSe software and LDA. Taxa enriched in Control, FAT-PCOS, and HA-PCOS group are colored by red, green, and blue respectively (LDA > 2.0 and P < 0.05), the relative abundance of thesebiomarkers are shown in the histogram (mean and standard deviation values are plotted) under the corresponding cladogram.

Abundance in Group 1: increased abundance in Hyperandrogenism group (HA)

NCBI	Quality Control	Links
Clostridium
Romboutsia

Revision editor(s): Shulamite

Experiment 3

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Reviewed Marked as Reviewed by KateRasheed on 2025-6-13

Curated date: 2025/05/12

Curator: Shulamite

Revision editor(s): Shulamite, Victoria

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Mere obese group (FAT )+ Mere hyperandrogenism group (HA)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Control

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Male infertility patients or patients receiving IVF treatment for tubal factors in the control group.

Lab analysis

Statistical Analysis

Signature 1

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Reviewed Marked as Reviewed by KateRasheed on 2025-6-13

Curated date: 2025/05/12

Curator: Shulamite

Revision editor(s): Shulamite

Source: 2B

Description: Linear discriminant analysis (LDA) discriminant histogram of gut microbiota in three groups. Identification of the bacterial taxa with statistically significant difference between groups using LEfSe software and LDA. Taxa enriched in Control, FAT-PCOS, and HA-PCOS group are colored by red, green, and blue respectively (LDA > 2.0 and P < 0.05), the relative abundance of thesebiomarkers are shown in the histogram (mean and standard deviation values are plotted) under the corresponding cladogram.

Abundance in Group 1: increased abundance in Control

NCBI	Quality Control	Links
Enterobacter
Klebsiella
Eubacterium
Citrobacter
Megamonas

Revision editor(s): Shulamite