A Systematic Review of Folate and the Human Enteric Microbiome: Biological Mechanisms and Clinical Implications.

Folate (vitamin B9) is central to one-carbon metabolism, supporting nucleotide biosynthesis, methylation homeostasis, and epigenetic regulation. The gut microbiome both produces and consumes folate, creating a bidirectional axis influencing host health and disease. We systematically reviewed 159 original studies from MEDLINE, Google Scholar, Embase, and Scopus (inception through January 2026) examining enteric microbiota-folate interactions, with intervention evidence graded using the Oxford Centre for Evidence-Based Medicine 2011 framework. Only a minority of gut bacteria possess complete folate biosynthetic pathways; most depend on cross-feeding from prototrophic taxa including Bifidobacterium, Lactobacillus, and Streptococcus. Altered microbial folate metabolism was associated with metabolic, gastrointestinal, oncologic, neuropsychiatric, cardiovascular, immunologic, and reproductive disorders through convergent mechanisms of disrupted methylation, genomic instability, and immune dysregulation. Probiotic interventions achieved the strongest evidence, supported by multiple human controlled and observational trials and animal models. The evidence for prebiotic, dietary, and folate supplementation interventions was moderate due to the predominant animal models and in vitro data. Overall, the predominant associational and observational evidence base is insufficient to establish causal relationships, underscoring the need for adequately powered human randomized controlled trials with folate-specific endpoints, multi-omics integration, and precision approaches matching folate form and dose to individual microbiome and host genetic profiles.