Folate is absorbed across the colon of adults: evidence from cecal infusion of (13)C-labeled [6S]-5-formyltetrahydrofolic acid

Abstract

Background: Folate deficiency increases the risk of several human diseases. Likewise, high intakes of folate, particularly synthetic folic acid intake, may be associated with adverse health outcomes in humans. A more comprehensive understanding of the "input side" of folate nutrition may help to set dietary recommendations that strike the right balance between health benefits and risks. It is well known that the microflora in the colon produce large quantities of folate that approach or exceed recommended dietary intakes; however, there is no direct evidence of the bioavailability of this pool in humans.

Objective: The objective was to determine whether, and to what extent, the natural folate vitamer 5-formyltetrahydrofolic acid is absorbed across the intact colon of humans.

Design: During screening colonoscopy, 684 nmol (320 microg) [(13)C]glutamyl-5-formyltetrahydrofolic acid was infused directly into the cecum of 6 healthy adults. Three or more weeks later, each subject received an intravenous injection of the same compound (172 nmol). Blood samples were collected before and after each treatment. The ratio of labeled to unlabeled folates was determined in plasma by tandem mass spectrometry.

Results: The apparent rate of folate absorption across the colon of a bolus dose of [(13)C]5-formyltetrahydrofolic acid infused into the cecum was 0.6 +/- 0.2 nmol/h, as determined by the appearance of [(13)C(5)]5-methyltetrahydrofolic acid in plasma. In comparison, the rate of appearance of [(13)C(5)]5-methyltetrahydrofolic acid after an intravenous injection of [(13)C(5)]5-formyltetrahydrofolate was 7 +/- 1.2 nmol/h.

Conclusion: Physiologic doses of natural folate are absorbed across the intact colon in humans.

FIGURE 1

Mean (±SEM) plasma folate concentrations after the administration of [¹³C]5-formyltetrahydrofolic acid by intravenous (IV) injection (A) or cecal infusion (B) to 6 subjects. The data were derived by microbial assay (○) or were calculated as the sum of the peak areas measured by liquid chromatography coupled to tandem mass spectrometry (▴). Note that the y axes differ between panels. The change in total plasma folate after intravenous injection, determined by microbial assay, was statistically significant (P = 0.0005, repeated-measures ANOVA). No statistically significant changes were observed after cecal infusion. Statistical analyses were not performed on the quantitative data obtained by liquid chromatography coupled to tandem mass spectrometry.

FIGURE 2

Mean (±SEM) molar ratios of (M+5) to (M+0) for 5-formyltetrahydrofolic acid (○) and 5-methyltetrahydrofolic acid (▴) after intravenous (IV) injection (A) or cecal infusion (B) of [¹³C]5-formyltetrahydrofolic acid to 6 subjects. Note that the y axes differ between panels. The change in the molar ratio for 5-formyltetrahydrofolic acid (P = 0.0037, repeated-measures ANOVA) but not for 5-methyltetrahydrofolic acid (P = 0.0974) was statistically significant after intravenous injection of [¹³C]5-formyltetrahydrofolic acid. The change in the molar ratio for 5-formyltetrahydrofolic acid was not significant after cecal infusion but was for 5-methyltetrahydrofolic acid (P < 0.0001).

FIGURE 3

Mean (±SEM) plasma folate concentrations of [¹³C₅]5-formyltetrahydrofolic acid (○, M+5), its metabolite [¹³C₅]5-methyltetrahydrofolic acid (▴, M+5), and unlabeled 5-formyltetrahydrofolate (□, M+0) after administration of [¹³C]5-formyltetrahydrofolic acid to 6 subjects by intravenous (IV) injection (A) or cecal infusion (B). Note that the y axes differ between panels. Statistical analyses were not performed on these quantitative data.