Absorption of dietary folate

In the human, the entire small intestine is capable of
absorbing monoglutamyl folate. Absorption is somewhat
greater in the proximal than in the distal jejunum
which, in turn, is much greater than in the ileum.
Folate transport across the brush-border membrane
of the enterocyte proceeds by two parallel processes
(Selhub & Rosenberg, 1981). At physiological concentrations
(<5 μM) of luminal folate, transport occurs
primarily by a saturable process, whereas at higher
concentrations, transport occurs by a non-saturable
process with characteristics of simple diffusion. Zimmerman
et al. (1986) produced data which suggest
that the latter process occurs in part through a conductance
pathway that involves anionic folate and a
cation (perhaps Na+) whose membrane permeation
properties affect the rate of folate transport. The saturable
component is discussed in the following with no
further mention of unsaturable transport.
Transport of folate is mediated by the reduced folate
carrier and is markedly infl uenced by changes in pH
(Schron, 1991). Folate exists primarily as an anion at
the pH of the lumenal contents. In vitro studies using
everted rat jejunal rings showed that absorption was
maximal at pH 6.3 and fell off sharply between pH
6.3 and 7.6 (Russell et al., 1979). In studies using
brush-border membrane vesicles (Said et al., 1987),
folate uptake increased as the pH of the incubation
buffer was decreased from 7.4 to 5.5. This increase in
folate uptake appeared to be partly mediated through
folate–/OH– exchange and/or folate–/H+ co-transport
mechanisms driven by the proton gradient across the
membrane and partly through a direct effect of acidic
pH on the carrier. Inhibition of folate transport by
the anion transport inhibitor DIDS suggested the
involvement of the folate–/OH– exchange mechanism.
Data reported by Mason et al. (1990) suggest that
the effect of pH on the carrier is attributable to an
increased affi nity of the carrier for its folate substrate.
The physiological relevance of the pH dependency
may be related to the existence of the acidic microclimate
at the luminal surface of the jejunum. This socalled
‘unstirred layer’ has a pH that is approximately
2 units lower than the bulk luminal pH and therefore
provides the necessary extracellular acidic conditions
for folate uptake.
Said et al. (1987) also found that folate transport
across the brush-border membrane was saturable,
competitively inhibited by structural analogues of
folic acid, unaffected by transmembrane electrical potential,
and Na+-independent. The human intestinal
reduced folate carrier has been cloned and characterized
at the molecular level (Nguyen et al., 1997).
Said et al. (1997) studied the intracellular regulation
of intestinal folate uptake using monolayers of
cultured mature IEC-6 epithelial cells. These cells are
derived from the proximal small intestine of a normal
rat and possess all of the cellular structures of native
enterocytes. Uptake of folic acid by IEC-6 cells was
similar to that of the native small intestine. Intracellular
cyclic AMP was found to affect the uptake of
folic acid independently of protein kinase A. Protein
tyrosine kinase also affected uptake, but protein kinase
C and Ca2+/calmodulin mediated pathways had
no signifi cant effect.
During intestinal transport some of the folate is
converted within the enterocyte to 5-methyl-THF in
a pH-dependent manner (Strum, 1979). This conversion
is extensive at pH 6.0 and negligible at pH 7.5
presumably because dihydrofolate reductase, the
rate-limiting enzyme in the reduction and methylation
process, has an acidic pH optimum. The percent
conversion is reduced by increasing the concentration
of folate in the mucosal medium, thus indicating saturation
of the process. Since at higher concentrations
most transported folate remains unmodifi ed, intestinal
conversion of absorbed folic acid is not obligatory
for transport into the circulation.
The mechanism of folate exit from the enterocyte
into the lamina propria of the villus is also carriermediated
and sensitive to the effect of anion exchange inhibition. In addition, the exit mechanism is electroneutral
and Na+-independent and has a higher
affi nity for the substrate than has the system at the
brush-border membrane (Said & Redha, 1987).
Absorption of milk folate by the suckling infant
Milk from humans and several species of other mammals
contains a folate-binding protein (FBP) which
may be important for folate absorption by the suckling
infant. In neonates, the uptake of folate bound
to milk FBP occurs preferentially in the ileum as opposed
to the jejunum. The incomplete development
of pancreatic and intestinal absorptive functions
could allow the FBP to reach the ileum without being
digested. This situation was demonstrated by Salter
& Mowlem (1983) who showed that a proportion
of goat’s milk FBP administered orally to neonatal
goats survived along the length of the small intestine.
Protease inhibitors inherent to colostrum may assist
the passage of bound folate along the small intestine
(Laskowski & Laskowski, 1951). In vitro, the addition
of goat’s milk FBP to the medium enhanced the transport
of 5-methyl-THF in brush-border membrane
vesicles isolated from the small intestine of neonatal
goats (Salter & Blakeborough, 1988). Mason & Selhub
(1988) observed that the characteristics of FBP-bound
folate absorption in the suckling rat resemble in some
respects the characteristics of endocytotic absorption
of macromolecules – a well-documented feature of
the suckling mammal’s intestinal physiology.
Adaptive regulation of folate absorption
Said et al. (2000) induced folate defi ciency in rats
by feeding a folate-defi cient diet that contained an
antibiotic to decrease the bacterial synthesis of folate
in the intestine. Using everted intestinal sacs and
brush-border membrane vesicles, they showed that
folate deprivation causes a specifi c up-regulation in
the transport of physiological concentrations of folic
acid across the brush-border membrane of both the
small and large intestines. The effect in the small intestine
took place not only in the jejunum, but also in
the ileum, a region that does not usually absorb folate.
The up-regulation was mediated through an increase
in the number and/or activity of functional reduced
folate carriers (increased Vmax) with no signifi cant effect
on the affi nity of the transport system (unchanged
Km). The up-regulation was associated with a marked
increase in the levels of carrier mRNA and protein,
suggesting a possible involvement of transcriptional
regulatory mechanisms. In addition to the up-regulation
of transepithelial folate transport, folate defi -
ciency was associated with a 10-fold increase in the
activity of brush-border membrane conjugase. The
intestine is therefore able to maximize its ability to
extract the limited amount of folate ingested during
periods of deprivation.