The Effects of Folic Acid Supplementation on Pro-inflammatory Mediators: a Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials.

PURPOSE Despite extensive research, findings regarding the effects of folic acid supplementation on inflammatory mediators have been controversial and inconclusive. This study therefore aimed to summarize the findings of all available clinical trials regarding the effects of folic acid supplementation on inflammatory biomarkers in adults. METHODS A systematic search was conducted of PubMed/MEDLINE, Scopus, Web of Science, EMBASE, and Google Scholar until April 2020. All randomized controlled trials that examined the influence of folic acid supplementation on C-reactive protein, interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were included. Pooled effect sizes were calculated based on the random effects model, and dose-response analysis was modeled by using a fractional polynomial model. FINDINGS In total, 18 randomized controlled trials involving 2286 participants were analyzed. Folic acid supplementation significantly reduced serum levels of C-reactive protein (mean difference [MD], -0.21 mg/L; 95% CI, -0.41 to -0.01; n = 16), TNF-α (MD, -14.88 pg/mL; 95% CI, -23.68 to -6.09; n = 10), and IL-6 (MD, -0.93 pg/mL; 95% CI, -1.72 to -0.14; n = 11). Subgroup analyses suggested a significant reduction at doses ≤5 mg/d and studies longer than 12 weeks in duration. A significant nonlinear association was also found between folic acid dosage (Pnonlinearity <0.001) and duration of administration (Pnonlinearity <0.001) with serum TNF-α levels. IMPLICATIONS This meta-analysis indicates the beneficial effects of folic acid supplementation on pro-inflammatory cytokines. Further studies with a longer duration of administration, higher doses, and larger sample sizes should be performed exclusively on patients with chronic inflammatory disorders to elucidate the favorable role of folate intake on inflammatory biomarkers. International Prospective Register of Systematic Reviews identifier: CRD42021249947.