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 ... read moreimmune 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
