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

•Folic acid supplementation reduced serum levels of CRP in adults, particularly in trials that prescribed folic acid at doses less than 5mg/d for more than 12 weeks.•Folic acid supplementation decreased serum TNF-α concentrations in adults, especially in trials that prescribed folic acid at doses 12 weeks.•Folic acid supplementation decreased serum IL-6 levels in adults, notably in studies administered folic acid at doses < 1mg/d and including more than 50 participants. 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. 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. 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