The effect of excess folate intake on immune function and peripheral neuropathy associated with transcobalamin II polymorphism.
Sawaengsri, Hathairat.
2016
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Abstract: Adequate folate intake is necessary for health throughout life. However, previous research showed that excess folic acid, the synthetic form of folate used in supplements and fortified foods, may have harmful effects including worsening clinical symptoms of vitamin B-12 deficiency and decreasing natural killer cell (NK) cytotoxicity in women older than 60 years. NK cells are innate immun... read moree cells important for defense against cancerous and virally infected cells and impairment in their activity increases disease risk. The central hypothesis of this project is that excess folic acid impairs NK cytotoxicity, increases severity of influenza infection in aged female mice, and exacerbates clinical symptoms of vitamin B-12 deficiency in the presence of the 776C>G polymorphism in the vitamin B-12 transporter transcobalamin II (TCN2). In the first aim, we used a mouse model of excess folic acid intake to determine the effects on natural killer cell cytotoxicity. We fed older (14-16 mo) female C57bL/6 mice a control (1xRDA) or high folic acid diets (20xRDA) for 3 months. We found that aged female mice fed a high folic acid diet had reduced NK cell cytotoxicity in spleen (P<0.04), lower mature cytotoxic /naïve NK cell ratio (P=0.03), decreased production of lipopolysaccharide stimulated interleukin (IL)-10 secretion (P<0.05) compared to mice on control diet. The difference in NK cell cytotoxicity between dietary groups was abolished when the splenocytes were supplemented with exogenous IL-10 prior to assessment of the NK cytotoxicity, suggesting that the reduced NK cell cytotoxicity of the high folic acid group was at least partially due to reduced IL-10 production. The second aim of the proposed project was to determine the effect of excess dietary folic acid on the severity of disease in an influenza infection model of mice. Female 16 month old C57bL/6 mice were fed a control (1xRDA) or high folic acid diet (20xRDA) for 3 months before they were infected with H1N1 influenza virus for 2 or 5 days of infection. We found that aged female mice fed a high folic acid had increased viral titer 2 days after infection and reduced inflammatory cytokine gene expression of IL-6, IL-1β, and interferon-gamma (IFN-γ) 5 days after infection in lung cells. These cytokines are important for viral clearance in the lung. There were no differences in weight loss, lipopolysaccharide stimulated cytokine secretion or cytokine protein in lung supernatant. In addition to effects on immune system, high intakes of folic acid may worsen clinical symptoms of vitamin B-12 deficiency. The TCN2 polymorphism of the vitamin B-12 transport protein transcobalamin II (TCN2) gene is associated with reduced bioavailability of vitamin B-12 to tissue. In the third aim, we determined if excess folate intake increased odds of peripheral neuropathy in the presence of the TCN2 776C>G polymorphism in a cross-sectional study of homebound elders in the Nutrition, Aging, and Memory in Elders Study (NAME). We found that odds for peripheral neuropathy were 3 fold higher for GG genotypes when compared to CC genotypes (OR: 3.33; 95% CI: 1.15, 9.64). When folate intake was above twice the recommended dietary allowance (800 μg/day), GG genotypes had 6.9 fold higher odds for peripheral neuropathy compared to CC genotype (OR: 6.9; 95% CI: 1.31, 36.36) but not when folate intake was ≤800 µg (OR: 1.5; 95% CI: 0.18, 12.33). The first two aims demonstrated that excess folate intake led to reduced NK cell cytotoxicity and increased influenza infection. The third aim showed that TCN2 776C>G polymorphism was associated with increased odds for peripheral neuropathy in elderly despite normal vitamin B12 status, especially if their folate intake was in excess of twice the recommended dietary allowance. Overall, these results demonstrate that excess folate may be harmful to the aging population and that further studies are needed to elucidate the mechanisms.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Biochemical and Molecular Nutrition.
Advisor: Jacob Selhub.
Committee: Ligi Paul-Pottenplackel, Dayong Wu, and Simin Meydani.
Keywords: Nutrition, Biochemistry, and Immunology.read less - ID:
- v405sn869
- Component ID:
- tufts:20543
- To Cite:
- DCA Citation Guide EndNote
