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

What was studied?

This original research article investigated how the gut microbiome–derived metabolite butyric acid influences ovarian granulosa cell inflammation in polycystic ovary syndrome (PCOS), with specific attention to m6A RNA methylation. The study examined the mechanistic link between altered gut microbial composition—particularly reduced SCFA-producing taxa—and downstream changes in ovarian cell epigenetics. The authors focused on the METTL3–FOSL2 axis, showing that reduced butyric acid in PCOS associates with increased METTL3 activity, elevated m6A modification of FOSL2 mRNA, and enhanced inflammatory signaling (IL-6, TNF-α, NLRP3). The study also evaluated whether supplementing butyric acid reverses these epigenetic and inflammatory changes in vitro and in a PCOS mouse model, identifying a microbiome-epigenetic signature linking intestinal dysbiosis, reduced butyrate, and ovarian inflammation.

Who was studied?

The investigation included 18 human participants, comprising 12 PCOS patients and 6 controls. PCOS subjects were stratified into an obese PCOS group (FAT) and a hyperandrogenic non-obese group (HA). Fecal samples were used for microbiome profiling, and serum was evaluated for SCFAs such as butyric acid. Mechanistic experiments used human granulosa KGN cells, stimulated with LPS to mimic inflammatory stress, and treated with butyric acid. Epigenetic assessments included MeRIP-seq and RNA-seq. A mouse model of obese PCOS was also employed to test the physiological relevance of butyric acid supplementation on ovarian morphology, hormone profiles, and expression of inflammatory mediators.

Most important findings

Microbiome sequencing revealed substantial β-diversity shifts in obese PCOS patients, with notable increases in Streptococcaceae and decreases in Rikenellaceae, patterns correlated with lower serum butyric acid. Reduced butyrate was a key microbial signature distinguishing obese PCOS from other groups. At the cellular level, butyric acid improved mitochondrial function, glucose uptake (via increased PPAR-γ and GLUT4), and reduced apoptosis in KGN cells exposed to LPS. Butyrate suppressed METTL3, decreasing m6A levels on FOSL2, resulting in downregulation of IL-6, TNF-α, and NLRP3. MeRIP-seq identified FOSL2 as a significant m6A-modified target with modification sites in the 3′UTR. In PCOS mice, butyrate improved ovarian morphology, reduced cystic follicles, restored endocrine parameters, and decreased inflammatory markers in ovarian tissue. Together, the microbiome signature—specifically reduced butyrate production—links dysbiosis to ovarian inflammation through METTL3-mediated m6A epigenetic regulation.

Key implications

The findings highlight butyric acid as a microbiome-derived epigenetic regulator capable of modifying inflammatory pathways in PCOS via METTL3-dependent m6A methylation. The study identifies a microbiome–m6A–inflammation axis that contributes to granulosa cell dysfunction and ovarian pathology. This suggests that therapeutic strategies aimed at restoring butyrate production—through probiotics, diet, or direct supplementation—may modulate epigenetic signatures and reduce ovarian inflammation in PCOS. These insights enrich microbiome signature databases by linking specific taxa (Streptococcaceae↑, Rikenellaceae↓) and metabolites (butyrate↓) with epigenetic markers (METTL3↑, FOSL2 m6A↑) relevant to disease severity.

Citation

Liu K, He X, Huang J, Yu S, Cui M, Gao M, Liu L, Qian Y, Xie Y, Hui M, Hong Y, Nie X. Short-chain fatty acid–butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome.Clinical Epigenetics. 2023;15:86. doi:10.1186/s13148-023-01487-9