Isolation of folate-producing probiotic candidates and their effects on homocysteine metabolism and gut microbiota composition.

Authors

Mingfang Pan, Changming Ye, Yun Song, Minqing Tian, Runming Wang, Ping Chen

Published in

Frontiers in nutrition. Volume 13. Pages 1845105. Epub Aug 20, 2026.

Abstract

Folate deficiency is a global nutritional problem associated with multiple adverse health outcomes, including impaired one-carbon metabolism and elevated homocysteine levels (hyperhomocysteinemia). Gut microbiota-mediated folate biosynthesis has emerged as a promising strategy for improving the host's folate status. This study aimed to isolate folate-producing probiotic strains, clarify their folate synthesis mechanisms, and evaluate their regulatory effects on folate metabolism and gut microbiota.
High-throughput cultivation and screening were performed to isolate folate-producing candidate probiotics. Whole-genome sequencing analysis, pathway reconstruction, and metabolite profiling in fermented milk were performed to explore folate biosynthesis pathways and microbial cross-feeding interactions. A folate-deficient mouse model was established to evaluate the effects of a candidate probiotic cocktail on serum folate, homocysteine (Hcy) levels, and gut microbiota composition using quantitative PCR (qPCR) and 16S rRNA gene sequencing.
High-throughput screening identified 8 high-folate-producing candidate probiotic strains, including Lactiplantibacillus plantarum and Heyndrickxia coagulans, from over 1,000 isolates. Genomic analysis revealed that most commonly used probiotics lacked para-aminobenzoic acid (pABA) biosynthesis genes but retained downstream modules, suggesting a reliance on cross-feeding with pABA-producing gut commensals such as Bacteroides. Metabolite profiling of fermented milk demonstrated that selected strains significantly increased bioactive 5-methyltetrahydrofolate (5-MeTHF) and tetrahydrofolate levels. In vivo, only a high-dose candidate probiotic cocktail significantly elevated serum folate (p < 0.05) and reduced homocysteine levels (p < 0.05) in deficient mice. Fecal qPCR confirmed dose-dependent transient persistence of the administered bacterial species. Consistent with the qPCR data, 16S rRNA gene sequences demonstrated significant enrichment of these administered species observed in the high-dose group. Furthermore, beta-diversity analysis found that high-dose candidate probiotic supplementation promoted a shift in the gut microbiota composition toward a normal profile, partially mitigating the dysbiosis induced by the folate-deficient diet. This effect was accompanied by a significant enrichment of potential short-chain fatty acid producers (e.g., Lachnospiraceae and Oscillospiraceae) and the depletion of potential opportunistic pathogens.
This study screened high-folate-producing candidate probiotic strains and demonstrated their ability to synthesize the active form of 5-MeTHF. Moreover, folate-producing candidate probiotic cocktail treatment significantly improved folate status and Hcy metabolism and modulated the gut microbiota by enriching potential beneficial bacterial taxa. These findings suggested that folate-producing probiotics may serve as a promising microbiota-based strategy to improve folate availability and homocysteine metabolism.

PMID:
42694526
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.

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