A daily dose of 5 mg folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults

Clovis Paniz, Juliano Felix Bertinato, Maylla Rodrigues Lucena, Eduardo De Carli, Patrícia Mendonça da Silva Amorim, Guilherme Wataru Gomes, Cecília Zanin Palchetti, Maria Stella Figueiredo, Christine M. Pfeiffer, Zia Fazili, Ralph Green, Elvira Maria Guerra-Shinohara

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown. Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon g (IFNG), tumor necrosis factor a (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers. Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells. Results: Serum folate concentrations increased by ~5-fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased ( > 1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both). Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells.

Original languageEnglish (US)
Pages (from-to)1677-1685
Number of pages9
JournalJournal of Nutrition
Volume147
Issue number9
DOIs
StatePublished - Sep 1 2017

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Folic Acid
Natural Killer Cells
Serum
Messenger RNA
Tetrahydrofolate Dehydrogenase
Interleukin-8
Tumor Necrosis Factor-alpha
Mononuclear Leukocytes
Methylenetetrahydrofolate Reductase (NADPH2)
Tandem Mass Spectrometry
Interferons
Tablets
Real-Time Polymerase Chain Reaction
Flow Cytometry
Body Mass Index
Biomarkers
High Pressure Liquid Chromatography
Clinical Trials
Cytokines

Keywords

  • 5-methyl-THF
  • Folic acid supplementation
  • MRNA expression
  • NK cell cytotoxicity
  • Serum folate
  • Unmetabolized folic acid

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics

Cite this

A daily dose of 5 mg folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults. / Paniz, Clovis; Bertinato, Juliano Felix; Lucena, Maylla Rodrigues; Carli, Eduardo De; Amorim, Patrícia Mendonça da Silva; Gomes, Guilherme Wataru; Palchetti, Cecília Zanin; Figueiredo, Maria Stella; Pfeiffer, Christine M.; Fazili, Zia; Green, Ralph; Guerra-Shinohara, Elvira Maria.

In: Journal of Nutrition, Vol. 147, No. 9, 01.09.2017, p. 1677-1685.

Research output: Contribution to journalArticle

Paniz, C, Bertinato, JF, Lucena, MR, Carli, ED, Amorim, PMDS, Gomes, GW, Palchetti, CZ, Figueiredo, MS, Pfeiffer, CM, Fazili, Z, Green, R & Guerra-Shinohara, EM 2017, 'A daily dose of 5 mg folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults', Journal of Nutrition, vol. 147, no. 9, pp. 1677-1685. https://doi.org/10.3945/jn.117.247445
Paniz, Clovis ; Bertinato, Juliano Felix ; Lucena, Maylla Rodrigues ; Carli, Eduardo De ; Amorim, Patrícia Mendonça da Silva ; Gomes, Guilherme Wataru ; Palchetti, Cecília Zanin ; Figueiredo, Maria Stella ; Pfeiffer, Christine M. ; Fazili, Zia ; Green, Ralph ; Guerra-Shinohara, Elvira Maria. / A daily dose of 5 mg folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults. In: Journal of Nutrition. 2017 ; Vol. 147, No. 9. pp. 1677-1685.
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abstract = "Background: The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown. Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon g (IFNG), tumor necrosis factor a (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers. Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95{\%} CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95{\%} CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells. Results: Serum folate concentrations increased by ~5-fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased ( > 1.12 nmol/L) in 29 (96.6{\%}) participants at day 45 and in 26 (86.7{\%}) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both). Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells.",
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TY - JOUR

T1 - A daily dose of 5 mg folic acid for 90 days is associated with increased serum unmetabolized folic acid and reduced natural killer cell cytotoxicity in healthy Brazilian adults

AU - Paniz, Clovis

AU - Bertinato, Juliano Felix

AU - Lucena, Maylla Rodrigues

AU - Carli, Eduardo De

AU - Amorim, Patrícia Mendonça da Silva

AU - Gomes, Guilherme Wataru

AU - Palchetti, Cecília Zanin

AU - Figueiredo, Maria Stella

AU - Pfeiffer, Christine M.

AU - Fazili, Zia

AU - Green, Ralph

AU - Guerra-Shinohara, Elvira Maria

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Background: The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown. Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon g (IFNG), tumor necrosis factor a (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers. Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells. Results: Serum folate concentrations increased by ~5-fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased ( > 1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both). Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells.

AB - Background: The effects of high-dose folic acid (FA) supplementation in healthy individuals on blood folate concentrations and immune response are unknown. Objective: The aim of the study was to evaluate the effects of daily consumption of a tablet containing 5 mg FA on serum folate; number and cytotoxicity of natural killer (NK) cells; mRNA expression of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), interferon g (IFNG), tumor necrosis factor a (TNFA), and interleukin 8 (IL8) genes; and concentrations of serum inflammatory markers. Methods: This prospective clinical trial was conducted in 30 healthy Brazilian adults (15 women), aged 27.7 y (95% CI: 26.4, 29.1 y), with a body mass index (in kg/m2) of 23.1 (95% CI: 22.0, 24.3). Blood was collected at baseline and after 45 and 90 d of the intervention. Serum folate concentrations were measured by microbiological assay and HPLC-tandem mass spectrometry [folate forms, including unmetabolized folic acid (UMFA)]. We used real-time polymerase chain reaction to assess mononuclear leukocyte mRNA expression and flow cytometry to measure the number and cytotoxicity of NK cells. Results: Serum folate concentrations increased by ~5-fold after the intervention (P < 0.001), and UMFA concentrations increased by 11.9- and 5.9-fold at 45 and 90 d, respectively, when compared with baseline (P < 0.001). UMFA concentrations increased ( > 1.12 nmol/L) in 29 (96.6%) participants at day 45 and in 26 (86.7%) participants at day 90. We observed significant reductions in the number (P < 0.001) and cytotoxicity (P = 0.003) of NK cells after 45 and 90 d. Compared with baseline, DHFR mRNA expression was higher at 90 d (P = 0.006) and IL8 and TNFA mRNA expressions were higher at 45 and 90 d (P = 0.001 for both). Conclusion: This noncontrolled intervention showed that healthy adults responded to a high-dose FA supplement with increased UMFA concentrations, changes in cytokine mRNA expression, and reduced number and cytotoxicity of NK cells.

KW - 5-methyl-THF

KW - Folic acid supplementation

KW - MRNA expression

KW - NK cell cytotoxicity

KW - Serum folate

KW - Unmetabolized folic acid

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