High-dose folic acid therapy ameliorates gut microbiota dysbiosis in reproductive-aged women with hyperhomocysteinemia.

BACKGROUND: Hyperhomocysteinemia (HHCY) in reproductive-aged women is associated with adverse pregnancy outcomes. Although folic acid effectively lowers serum homocysteine (HCY), its relationship with the gut microbiota remains unclear. This study investigated gut microbial alterations associated with HHCY and explored microbiota changes accompanying high-dose folic acid intervention. METHODS: Fecal samples from 38 reproductive-aged women, including 19 patients with HHCY and 19 normal controls, were analyzed using 16S rRNA gene sequencing. Three patients with HHCY receiving high-dose folic acid supplementation at 5 mg/day and multivitamins were additionally monitored longitudinally. Serum HCY concentrations were measured using an enzymatic cycling assay. RESULTS: No significant differences in alpha diversity were observed between the HHCY and control groups. However, HHCY was associated with an increased abundance of Proteobacteria and several genera, including Dialister and Escherichia-Shigella, and a decreased abundance of the [Eubacterium]_eligens_group. Several differentially abundant taxa were significantly correlated with serum HCY concentrations. Predicted functional analysis indicated alterations in pathways related to amino acid, carbohydrate, cofactor, and vitamin metabolism. In the three longitudinally monitored patients, high-dose folic acid supplementation was accompanied by decreased serum HCY levels and genus-level microbiota changes, with substantial interindividual variability. CONCLUSION: HHCY in reproductive-aged women is associated with a specific gut microbial signature rather than a global loss of microbial diversity. The longitudinal observations suggest that high-dose folic acid supplementation may coincide with microbiota alterations; however, the small sample size precludes causal conclusions. Larger, controlled longitudinal studies are required.