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REVIEW ARTICLE
Small Bowel Review
Normal Physiology Part 1
A.B.R. THOMSON, MD, PhD,* M. KEELAN, PhD,* A. THIESEN, MD,* M.T. CLANDININ, PhD,*
M. ROPELESKI, MD,† and G.E. WILD, MD, PhD†
In the past year there have been many advances in the area of small bowel physiology and
pathology and therapy. In preparation for this review, over 1500 papers were assessed. The focus
is on presenting clinically useful information for the practising gastroenterologist. Selected
important clinical learning points include the following: (1) glucose absorption mediated by
SGLT1 is controlled by mRNA abundance, as well as by posttranscriptional processes including
protein trafficking; (2) inducers of cytochrome P-450 decrease glucose and fructose absorption
and increase glucose consumption in the intestine; (3) the regulated release of nutrients from the
stomach into the upper intestine ensures that the modest intestinal transport reserve capacity is
not exceeded; (4) hepatocyte growth factor and short-chain fatty acids may enhance intestinal
adaptation and prevent the atrophy seen when total parenteral nutrition is infused; (5) inhibitors
of pancreatic lipase and phospholipase H
2
may be useful clinically to reduce absorption as part of
a treatment program for obesity and hyperlipidemia; (6) several membrane-bound and cytosolic
proteins have been identified in the enterocyte as well as in the hepatocyte and may be the target
for the future therapeutic manipulation of bile acid metabolism and control of hyperlipidemia; (7)
suspect bile acid malabsorption in the patient with otherwise unexplained chronic diarrhea; (8) a
proportion of lipid absorption is protein-mediated, and this opens the way to targeting these
proteins and thereby therapeutically modifying lipid absorption; (9) a high protein diet may be
useful to increase the intestinal absorption of drugs transported by the H
⫹
/dipeptide cotrans-
porter; (10) a metal transporter DCT1 has been identified, and this may open the way to a better
understanding of disorders of, for example, iron and zinc metabolism; (11) the nutrient trans-
porters such as SGLT1 are responsible for a portion of the intestinal absorption of water; (12) the
influence of nitric oxide on intestinal water absorption and secretion depends on its concentra-
tion; (13) a trial of bile acid-sequestering agent may prove useful in the treatment of the patient
who experiences diarrhea while taking an enteral diet; (14) a proteolytic extract from pineapple
stems may prove to be useful to treat diarrhea, although the mechanism of this effect remains to
be established; and (15) the antisecretory effect of the new peptide, sorbin, needs to be tested in
a clinical situation on patients with diarrhea. Other new and promising antidiarrheal agents
include bromelain, an extract from pineapple stems, and igmesine, a final sigma ligand.
KEY WORDS: small bowel; physiology; pathology; therapy; absorption; metabolism.
ABSORPTION
Carbohydrate
The intestinal brush border membrane enzyme lac-
tase-phlorizin hydrolase digests lactose, the main car-
bohydrate in milk. Lactose is an important constitu-
ent of the diet of human children and adults. In
people living in many parts of the world, lactase-
phylorizin hydrolase activity declines in early life.
However, in descendants of northern European an-
cestry, enzyme activity may persist into adult life. The
persistence of lactase-phylorizin hydrolase activity is
dominant to non-persistence. The genetic difference
responsible for the persistence/nonpersistence poly-
morphism, which determines high or low lactase-
phylorizin hydrolase mRNA expression, respectively,
is cis-acting to the lactase gene. Using retrospective
analysis of enzyme activity and prospective study for
lactase–phylorizin hydrolase mRNA analysis, it was
Manuscript received December 4, 2000; revised manuscript re-
ceived June 1, 2001; accepted June 3, 2001.
From the *Cell and Molecular Biology Collaborative Network in
Gastrointestinal Physiology, Nutrition and Metabolism Research
Group, Division of Gastroenterology, Department of Medicine,
University of Alberta, Edmonton, Alberta, Canada, and †Division
of Gastroenterology and Department of Anatomy and Cell Biol-
ogy, McGill University, Montreal, Quebec, Canada.
Address for reprint requests: Dr. Alan B.R. Thomson, 519
Newton Research Building, University of Alberta, Edmonton, Al-
berta, Canada.
Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001), pp. 2567–2587 (© 2001)
2567Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
0163-2116/01/1200-2567/0 © 2001 Plenum Publishing Corporation
determined that the genetically programmed down-
regulation of the lactase gene is detectable in children
from the second year of life (1).
Enzymes that which are highly expressed in the
brush border membrane at birth such as lactase-
phylorizin hydrolase decline, while others, which are
low or undetectable in the first two postnatal weeks,
such as sucrase-isomaltase, show increases beginning
early in the third week and then reach adult levels.
These enzymatic changes coincide with weaning and
enable the switch from a milk to a solid diet. The
changes are not cued by the dietary change, but
instead are initiated by an intrinsic timing program
that is modulated by changing the hormonal mileu in
the postnatal period. Glucocorticoid hormones and
thyroxin act synergistically to elicit a precocious in-
crease of sucrase-isomaltase activity that is paralleled
by increased sucrase-isomaltase mRNA The syner-
gism between these hormones is due to greater accu-
mulation of sucrase-isomaltase per epithelial cell (2).
Feeding a high-starch diet causes an elevation on
sucrase–isomaltase mRNA in rat jejunum within 12 h
of a sucrose load, and perfusion of the intestine with
fructose results in increased sucrase-isomaltase activ-
ity and mRNA levels as well as the mRNA for the
fructose transporter in the brush border membrane,
GLUT5 (3). The premature increases in sucrase–
isomaltase activity and mRNA as well as maltase
activity in response to insulin are dose-dependent and
are associated with increases of the intracellular poly-
amines spermine and spermidine (4).
The mRNAs for brush border membrane lactase–
phylorizin hydrolase and sucrase–isomaltase are lo-
calized in the brush border membrane of the villus
enterocytes, whereas the mRNAs for intestinal alka-
line phosphatase and for

-actin are detected both
apically and basally relative to the nucleus (5). Lac-
tase–phylorizin hydrolase carries two hydrolytic sites,
and there is multistep proteolytic processing of pro-
lactase–phylorizin hydrolase to mature brush border
membrane lactase–phylorizin hydrolase (6). Females
with lactose malabsorption may have signs of the
irritable bowel syndrome, premenstrual syndrome,
and mental depression (7).
The gene expression of lactase–phylorizin hydro-
lase and sucrase–isomaltase has been studied exten-
sively. These enzymes are anchored in the brush
border membrane of the enterocyte, and are crucial
in the digestion of dietary carbohydrates. Lactase–
phylorizin hydrolase hydrolyzes lactose from milk,
which is the primary energy source for newborn chil-
dren. Sucrase–isomaltase is essential in the final hy-
drolysis of starch and becomes more important in
later life when starch has become the predominant
carbohydrate source in the diet. The precursor form
of the sucrase–isomaltase complex is synthesized as a
single polypeptide, which is transferred to the brush
border membrane where it is cleaved into sucrase and
isomaltase subunits for maturation by the action of
pancreatic proteases such as trypsin and elastase. In
the senescence-prone mouse the sucrase–isomaltase
complex may be unstable against pancreatic proteases
(8). Both lactase-phylorizin hydrolase and sucrase–
isomaltase protein levels correlate with their respec-
tive mRNA levels and are thus transcriptionally reg-
ulated. Aging from one to eighteen years does not
result in significant changes in mRNA or protein
levels of either lactase–phylorizin hydrolase or su-
crase-isomaltase (9).
Glucocorticosteroids play a role in the rise in su-
crase–isomaltase activity at the time of weaning. A
decline in lactase–phylorizin hydrolase activity and
the accelerated appearance of sucrase–isomaltase in
suckling rat pups may be associated with orogastri-
cally administered insulin-like growth factor (IGF)-1
(10). The liver is the main source of circulating IGF-1,
and there may be an altered profile of IGF-1 binding
protein in hepatic cirrhosis. In cirrhotic rats, D-
galactose absorption is reduced, and IGF-1 may cor-
rect these changes by modulating the cytoskeletal
organization in the enterocyte (11). Sucrase–
isomaltase activity is increased in diabetic patient.
Insulin also reduces the mRNA level of the sucrase–
isomaltase complex in intestinal explants (12). Kera-
tinocyte growth factor is a fibroblast-derived member
of the fibroblast growth factor family that down reg-
ulates sucrase–isomaltase mRNA and protein expres-
sion in Caco-2 cells (13).
The 3⬘-untranslated region of all sorted mRNAs
studied thus far contain cis-acting sequences that are
responsible for the localization and sorting of specific
mRNAs to distinct cytoplasmic regions, and are a
mechanism of protein localization. The expression of
lactase–phlorizin hydrolase mRNA in humans with
adult-type hypolactasia is patchy, whereas this patch-
iness does not occur in individuals who are lactase-
sufficient. Some homologies between human lactase–
phylorizin hydrolase and sucrase–isomaltase 3⬘-
untranslated regions have been identified. It remains
unclear whether these sequences play a role in the
intracellular localization of these mRNAs.
A method has been developed for assaying intesti-
nal brush border membrane sucrase–isomaltase in an
intact intestinal preparation (14). The topic of human
THOMSON ET AL
2568 Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
glucose transporters has been reviewed (15). The
mRNA for human sodium-dependent glucose trans-
porter in brush border membrane (SGLT1) is local-
ized to the apical region of the enterocyte (16). The
octyl-glucosides are specific inhibitors of SGLT1 (17).
SGLT1 may act as a molecular pump for water, and
can account for almost half the daily re-uptake of
water from the small intestine (18).
The satiety factor leptin decreases the maximal
transport rate (V
max
) for glucose transport in the rat
small intestine (19). Leptin, a 167-amino acid protein
transcribed from the ob gene, is strongly correlated
with the body fat mass. Leptin acts on the hypothal-
amus to regulate body weight by decreasing food
intake and by increasing physical activity and energy
expenditure. Leptin is produced in fat cells as well as
in skeletal muscle. Leptin has been described in the
stomach, where it may be involved in early cholecys-
tokinin-mediated effects activated by food intake
(20). Leptin activates STAT3, the signal transducer
and activator of transcription 3 in the hypothalamus,
mediating increased satiety and increased energy ex-
penditure. A leptin receptor has been described in the
jejunum of the mouse. Intravenous injection of leptin
rapidly induces nuclear STAT5 DNA binding activity
in the jejunum of ob/ob mice, but has no effect in the
diabetic db/db mouse that lacks the leptin receptor
isoform (21). Leptin also induces the immediate-early
gene c-fos in the jejunum and causes a twofold reduc-
tion in the apolipoprotein (apo) A-IV transcript level
in the jejunum 90 min after a fat load. This suggests
that the jejunum is a direct target for the action of
leptin.
The intake of food is suppressed in a dose-
responsive fashion by nutrients in the intestine. This
suppression varies with the load (amount per minute)
of nutrient entering the intestine, independent of the
nature of the nutrients themselves. In rats, the secre-
tion of apo A-IV is a putative signal of hypothalamic
satiety. Calorie-dependent inhibition of food intake
depends on feedback from sensors in the proximal
and distal bowel contacted after high intakes of nu-
trients (22). When rats are ingesting food, infusion of
fat rather than sucrose suppresses their continued
intake of fat (23).
The apical uptake of
␣
-methyl-D-glucoside, a non-
metabolizable glucose analogue, falls with aging (24).
The
␣
-1,4-glucose linkages of dietary starch are effi-
ciently hydrolyzed by luminal
␣
-amylase and by brush
border membrane
␣
-glucosidase in the upper small
intestine. The released glucose is absorbed by the
brush border membrane-independent glucose trans-
porter, SGLT1, and by a facilitated sodium-indepen-
dent glucose transporter, GLUT2, at the basolateral
membrane. The structure–function relationship of
SGLT1 has been studied in COS-7 cells in culture.
The replacement of an alanine residue by an
␣
-cys-
teine residue at position 166 decreases transporter
turnover rate, possibly because the mutation alters
the movement of sodium with the transporter (25).
Dextran, an
␣
-1,6-linked glucose polymer, is not nor-
mally present in the diet. It is resistant to
␣
-amylase,
but there is some residual activity of mucosal isoma-
ltase towards
␣
-1,6-glucose linkages. Feeding dextran
increases SGLT1-mediated glucose uptake after
short-or long-term exposure to luminal dextran or to
a hydrolytic product (26).
The topic of regulation of intestinal sugar transport
has been reviewed elsewhere (27, 28). Messenger
RNA sorting in polarized cells exists in human en-
terocytes. The mRNA for villin (a microvillus cy-
toskeletal protein) sorts to the basal region of the
enterocyte, the mRNA for SGLT1 is localized to the
apical region, and the mRNA for the liver form of the
fatty-acid-binding protein (L-FABP) is distributed
diffusely thoughout the cytoplasm (29).
There is increased SGLT1 expression in obese II
(non-insulin-dependent) diabetic rats, which may be
partially associated with postprandial hyperglycemia
(30). In cirrhotic rats there is a reduced V
max
of
glucose uptake, which can be corrected by giving
IGF-1 (11). Enteric glucagon-37 (also called oxynto-
modulin), but not pancreatic glucagon-29, potently
stimulate intestinal glucose absorption by SGLT1
(31). Vascular infusion of gastric inhibitory polypep-
tide (GIP) or glucagon like peptide (GLP-2) in-
creases glucose uptake (32).
The activity of SGLT1 is increased within 30 min of
infusion of GLP-2 when studied using isolate brush
border membrane (33). This stimulation by GLP-2 is
the result of an increase in the value of the V
max
of
SGLT1 and is associated with an increased abun-
dance of the SGLT1 protein. This effect of GLP-2 is
blocked by luminal brefeldin A or by wortmannin.
This suggests that the trafficking of SGLT1 from an
intracellular pool to the brush border membrane may
be altered rapidly and involves phosphoinositol 3-ki-
nase in the intracellular signaling pathway.
Clinical Learning Point: Glucose absorption medi-
ated by SGLT1 is controlled by mRNA abundance, as
well as by post-transcriptional processes including
protein trafficking.
When administered in a vascular perfusion system
in rats, cholecystokinin octapeptide reduces the rate
SMALL BOWEL REVIEW: NORMAL PHYSIOLOGY 1
2569Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
of glucose and of 3-O-methyl-D-glucose absorption.
Cholecystokinin octapeptide also diminishes the
SGLT1 protein abundance (34). This suggests that
cholecystokinin octapeptide, in addition to delaying
gastric emptying, may directly regulate the rate of
glucose absorption across the small intestine.
The facilitated diffusion of glucose through the
plasma membrane of mammalian cells is mediated by
members of the GLUT glucose transporter family of
proteins, and six isoforms have been described. The
GLUT protein crosses the plasma membrane 12
times, and the transmembrane stretches show highly
conserved primary amino acid sequences between the
various isoforms. By introducing single amino acid
mutations, it has been shown that certain portions of
the transmembrane stretches are important for bind-
ing. The domains responsible for the fructose speci-
ficity of GLUT5 have been investigated by creating
chimeras of GLUT5 with the selective glucose trans-
porter GLUT2. The GLUT5 domain from the amino
terminus of the third transmembrane domain and
between the fifth and eleventh transmembrane
stretches are necessary for fructose uptake (35).
The turnover of GLUT5 protein is diurnally influ-
enced (36). The rat intestine up-regulates the hexose
transporters prior to the onset of feeding, and this
diurnal pattern of expression is hard-wired because
GLUT5 is up-regulated in the absence of dietary
fructose. The phenomenon of diurnality has been
linked to the daily differentiation process whereby
crypt cells migrate past the crypt–villus junction of
mature enterocytes. The crypts are thought to be the
initial site for the reception of dietary signals.
Inducers of cytochrome P-450 1A1 (CYP1A1) re-
sult in an increased rate of glucose consumption, as
well as the modification at the protein and mRNA
abundance level of the expression of a number of
differentiation-associated proteins involved in the up-
take, transport, and metabolism of glucose. These
include decreased expression of sucrase–isomaltase,
SGLT1, GLUT2, and GLUT5, without modifications
of the morphological differentiation of the cells or the
expression of other differentiation-associated pro-
teins such as villin. In Caco-2 cells inducers of
CYP1A1 also decrease the activity of
␥
-glutamyl-
transpeptidase (
␥
-GTP) activity and mRNA (37, 38).
It is unclear whether the CYP1A1 inducers or the
signal transduction system, which controls CYP1A1,
is involved in the regulation of the expression of
␥
-GTP through a mechanism involving glucose me-
tabolism. The authors suggest that there may be a
physiological interpretation of the signal-transduction
pathway responsible for CYP1A1 induction.
Clinical Learning Point: Inducers of cytochrome
P-450 decrease glucose and fructose absorption and
increase glucose consumption in the intestine.
In humans, fructose is transported across the brush
border membrane by GLUT5-facilitated diffusion as
well as paracellularly via glucose-activated solvent
drag. GLUT5 contains a transmembrane domain that
is responsible for fructose transport (35). GLUT5
mRNA protein levels are increased within 4 hr of
fructose exposure, an effect that occurs in the mature
enterocytes. The protein synthesis inhibitor cyclohex-
imide blunts the diurmal and fructose-driven increase
in GLUT5 mRNA expression in the morning but not
in the evening (36). This suggests there may be two
mechanisms of regulation. When the dietary nutrient
load and intestinal capacity are varied in mice in
studies involving intestinal resection, there is an in-
crease in food intake, digestive efficiency, and glucose
uptake. This allows for better survival of the animal,
but greater degrees of resection are not necessarily
associated with survival, possibly because the intesti-
nal reserve uptake capacity has been exhausted (39).
The V
max
of glucose and amino acid transport ex-
ceeds daily intakes by a factor of about 2. Gastric
emptying is regulated by feedback control by the
small intestine, in which nutrients enter the duode-
num and jejunum and inhibit gastric emptying. The
degree of this inhibition depends on the concentra-
tion of nutrients and the length of intestine exposed
to nutrients, ie, the intestinal load of nutrients. In
addition, the presence of nutrients in the ileum slows
gastric emptying (the “ileal brake”). This feedback
control of gastric emptying provides an additional
reserve capacity for absorption (40).
Clinical Learning Point: The regulated release of
nutrients from the stomach into the upper intestine
ensures that the modest intestinal transport reserve
capacity is not exceeded.
“Safety factors”are defined in engineering terms as
the ratio of a component’s designed strength or ca-
pacity to the maximum load that it is designed to bear.
The safety factors of enzymes and transporters are
defined as the ratio of the maximal reaction rates at
high substrate concentrations (V
max
) to the reaction
rate under actual physiological conditions. Capacities
both of sucrase–isomaltase and of SGLT1 increase
with sucrose load and remain approximately matched
to each other except when animals are on a carbohy-
drate-free diet (41). Neither sucrase–isomaltase nor
THOMSON ET AL
2570 Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
SGLT1 is the rate-limiting step for sucrose digestion;
both steps are equally limiting.
After an 80% resection of the small bowel in rats,
a 14-day infusion of hepatocyte growth factor up-
regulates SGLT1 mRNA and GLUT5 mRNA (42). It
is unknown whether hepatocyte growth factor-
enhanced gene expression of carbohydrate transport-
ers may be useful for patients with short bowel syn-
drome. Short-chain fatty acids are the by-products of
dietary fiber fermentation in the colon. Acetate, pro-
pionate, and butyrate account for about 85% of these
short-chain fatty acids and are produced intralumi-
nally in a nearly constant molar ratio of 60:25:15. One
week of short-chain fatty acid supplementation re-
tards total parenteral nutrition-associated intestinal
atrophy in rats with intact bowels and as early as three
days after an 80% intestinal resection. Short-chain
fatty acids lead to rapid changes in ileal proglucagon
mRNA abundance after 24 h of total parenteral nu-
trition plus short-chain fatty acid infusion, and as well
increase GLUT2 mRNA and protein but not GLUT5
and SGLT1 (43).
Clinical Learning Point: Hepatocyte growth factor
and short chain fatty acids may enhance intestinal
adaptation, and prevent the atrophy seen when total
parenteral nutrition is infused.
Epidermal growth factor (EGF) is a 53-amino acid
peptide derived from numerous sources in the gastro-
intestinal tract including saliva, bile, Paneth cells, and
Brunner’s glands. It is a mitogen that promotes DNA
synthesis and transcription of RNA, leading to pro-
tein synthesis. EGF increases intestinal nutrient and
ion absorption by the recruitment of a pool of pre-
formed brush border membrane. EGF increases glu-
cose absorption by enhancing the insertion of pre-
formed membrane and SGLT1 into the brush border
membrane through a mechanism involving the poly-
merization of actin (44). Milk contains a number of
peptide growth factors such as EGF, growth factors
IGF, and somatostatin. Milk EGF is usually degraded
in the intestinal lumen. The defatted and decasein-
ated supernatant of bovine milk prevents the degra-
dation of EGF in both gastric and duodenal luminal
fluids. Dietary derived protease inhibitors, such as
soya bean trypsin, also prevent EGF degradation in
the duodenal lumen (45).
Interleukin-1

, known to be a hypoglycemic cyto-
kine, is produced by activated macrophages, B lym-
phocytes, and endothelial cells. The administration of
interleukin-1 (IL-1) to normal or diabetic mice in-
duces hypoglycemia without hyperinsulinemia, possi-
bly by inhibiting the mucosal uptake of glucose by
inhibiting the Na
⫹
,⫺K
⫹
⫺ATPase in the basolateral
membrane (46). Atrial natriuretic peptide binds to
specific receptors along cell surfaces, and the signal-
ling of two of these receptors is coupled to guanylate
cyclase. Atrial natriuretic peptide inhibits sodium,
water, and glucose absorption in the intestine by
increasing the value of the affinity constant (K
m
)
without modifying the V
max
(47).
The topic of glucose–galactose malabsorption has
been reviewed (48). Denervation of the canine jeju-
noileum decreases the in vivo and in vitro uptake of
glutamine, alanine, leucine, and glucose (49). Mi-
crovillus inclusion disease is a congenital disorder
characterized by severe fluid and electrolyte losses
from the gastrointestinal tract. There is villous atro-
phy, loss of microvilli, and internalized inclusions of
microvilli within the cytoplasm of the enterocytes. It is
not known if this contributes to the clinical features of
the disease. These patients have reduced brush bor-
der membrane expression of the sodium/hydrogen
exchangers (NHE2, NHE3) and SGLT1 (50).
In the rabbit model of chronic ileal inflammation,
there is inhibition of coupled NaCl absorption due to
a reduction of Cl
⫺
/HCO
3
⫺
but not of Na
⫹
/H
⫹
ex-
change; inhibition of SGLT1 via decreasing the num-
ber of contransporter; a decrease in Na
⫹
–amino acid
cotransporter affinity; and reduced Na
⫹
–bile acid co-
transport as a result of a decrease both in the affinity
and the number of cotransporters. The glucocorticoid
methylprednisolone has no effect on SGLT1 in nor-
mal rabbit ileum, but in the presence of chronic ileal
inflammation methylprednisolone reverses the reduc-
tion in SGLT1 in villus cells seen with inflammation
and also reverses the decrease in Na
⫹
,K
⫹
-ATPase
(51). The thyroid hormone T3 stimulates SGLT1
cotransport activity in Caco-2 cells by involving both
transcriptional and translational levels of regulation
(52). Two interrelated levels of regulation may coex-
ist: a differentiation-related control due to the induc-
tion in the crypt cells of SGLT1, and modulation of
SGLT1 protein and mRNA abundance in already
mature enterocytes.
Fat
The topic of the intestinal absorption of fatty acids
has been reviewed previously (53). The lipid content
of the intestinal brush border membrane changes with
fasting: there are decreased ratios of cholesterol/
phospholipid, sphingomyelin/phosphatidylcholine,
protein/lipid, decreased oleic and linoleic acids, and
increased brush border membrane total phospholipid,
double-bond index, as well as an increased percentage
SMALL BOWEL REVIEW: NORMAL PHYSIOLOGY 1
2571Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
of stearic and arachidonic acids (54). These changes
alter the physicochemical properties of the brush
border membrane and may modify its transport prop-
erties.
The diffusion of cholesterol from the lipid-rich
phases of the intestinal contents across the unstirred
water layer to the brush border membrane is depen-
dent on its emulsification and micellar solubilization
by biliary lipids and by the detergent by-products of
dietary lipid glycolysis. Phosphatidylcholine is an
emulsifier of dietary cholesterol. Biliary cholesterol,
the major portion of cholesterol entering the intes-
tine, cannot be effectively solubilized in bile without
biliary phosphatidylcholine. Although phosphatidyl-
choline solubilizes cholesterol, it suppresses choles-
terol absorption by a phosphatidylcholine-dependent
shift of the lipid–water partitioning of cholesterol
towards the micellar phase. Inhibition with phos-
phatidylcholine-containing micelles results in reduc-
tions in the absorption, esterification, and secretion of
cholesterol, without any influence on the absorption
of oleic acid, its conversion to acylated lipids, or
triacylglycerol secretion (55). Pancreatic phospho-
lipase A
2
(pPLA
2
) enhances cholesterol absorption
from phosphatidylcholine-containing micelles, sug-
gesting that inhibitors of pPLA
2
may be useful to
reduce cholesterol absorption. Orilistat is an inhibitor
of pancreatic and other lipases. It is used in the
treatment of obesity by inhibiting intestinal fat ab-
sorption (56, 57).
Clinical Learning Point: Inhibitors of pancreatic
lipase and phospholipase A
2
may be useful clinically
to reduce absorption as part of a treatment program
for obesity and hyperlipidemia.
Bile acids are synthesized from cholesterol in the
liver and are secreted with bile into the small intes-
tine. In the terminal ileum the luminal bile acids are
actively reabsorbed by enterocytes and are returned
to the liver via the portal circulation. This process is
known as the enterohepatic circulation. About 95%
of bile acids are conserved in each cycle as a result of
the presence of high-affinity transporters located at
the brush border membrance of the enterocyte and at
the sinusoidal membrane of the hepatocyte.
A small fraction of the more lipophylic conjugates
of bile acids is absorbed passively in protonated form
in the acid pH of the duodenum. Conjugated bile
acids are absorbed in the jejunum by anionic ex-
change and by an antiport transport mechanism (58).
The ileal Na
⫹
-dependent bile acid transporter has
been cloned and has homology to the Na
⫹
-dependent
transporter for conjugated bile acids that is present in
the basolateral membrane of the hepatocyte.
The topic of the physiology and molecular basis of
the intestinal absorption of bile acids has been re-
viewed elsewhere (59). Photoaffinity labeling tech-
niques have identified many putative proteins in-
volved in the ileal bile acid transport system. After the
Na
⫹
-coupled 99-kDa protein-mediated uptake, bile
acids are transported by actin (43 kDa) or by cytosolic
proteins (14 and 35 kDa), either to the microsomal
20-kDa protein or directly to the basolateral mem-
brane. Here the bile acid leaves the cell by an anionic
exchange process mediated by a 54-kDa integral ba-
solateral protein, and exit is possibly preceded by the
binding of bile acid to a 59-kDa basolateral associated
protein. The cDNAs encoding rat ileal apical Na
⫹
-
dependent bile acid transporter have been cloned.
The apical Na
⫹
-dependent bile acid transporter con-
tains a glycosylation site, and a novel apical sorting
signal is localized to the cytoplasmic tail of the apical
Na
⫹
-dependent bile acid transporter (60).
A 14- to 15-kDa cytosolic binding protein, the
intestinal bile acid-binding protein, belongs to a fam-
ily of hydrophobic ligand-binding proteins, the fatty
acid-binding proteins. In Caco-2 cells incubated with
bile acid, there is a 7.5-fold increase in intestinal bile
acid-binding protein mRNA levels occurring in a
time- and dose-dependent manner, and this mRNA
increase is associated with enhanced abundance of
cytosolic intestinal bile acid-binding protein protein
(61). This implies transcriptional regulation. This
stimulatory effect of bile acids is prevented by the
pretreatment of Caco-2 cells with actinomycin D or
cycloheximide. The binding of bile acids to ileal lipid-
binding protein (ILBP) increases the affinity of ILBP
for bile acids (62). This may be a substrate-load
modification of transport activity and a positive-
feedback regulation for active uptake of bile acids in
the ileum. The ileal bile acid transporter (IBAT) is
up-regulated by administration of glucocorticoste-
roids, and the enhanced V
max
corresponds to an in-
crease in both IBAT mRNA and protein (63). Inhi-
bition of IBAT inhibits the development of
hypercholesterolemia in rabbits in a manner similar
to bile acid sequestrants (64).
Clinical Learning Point: Several membrane-bound
and cytosolic proteins have been identified in the
enterocyte as well as in the hepatocyte and may be the
target for the future therapeutic manipulation of bile
acid metabolism and control of hyperlipidemia.
Common bile duct ligation or feeding a bile acid-
binding compound may be used to reduce ileal brush
THOMSON ET AL
2572 Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
border membrane bile acid uptake. Bile acid pool
expansion or depletion results in an increased or
decreased bile salt transport capacity of the liver,
respectively. A reduction in the presentation of bile
salts to the brush border membrane does not modu-
late the expression of the genes involved in their
transport (65).
During chronic ileal inflammation in rabbits, Na
⫹
-
glucose cotransport is inhibited by a decrease in the
cotransporter numbers and Na
⫹
-amino acid cotrans-
port is inhibited by a decrease in the affinity for amino
acid, whereas Na
⫹
-bile acid cotransport is inhibited
by both a decrease in the affinity as well as a decrease
in the V
max
of the uptake of bile acid, associated with
reduction in transporter protein and mRNA (66).
The topic of ideopathic bile acid malabsorption has
been reviewed by Bai (67). This malabsorption may
occur in about one sixth of patients with otherwise
unexplained chronic diarrhea (68). The patient usu-
ally has a symptomatic response with the use of a bile
acid sequestrant such as cholestyramine. While the
pathogenesis of idiopathic bile acid malabsorption is
unknown, there may be morphological changes in the
patient’s ileal biopsies or abnormalities in their up-
take of bile acids. The mechanism of diarrhea does
not depend on an enrichment of the bile acid pool
with dihydroxy bile acids (69).
Clinical Learning Point: Suspect bile acid malab-
sorption in the patient with otherwise unexplained
chronic diarrhea.
The absorption of ursodeoxycholic acid occurs in
the proximal intestine by nonionic diffusion, and this
is impaired in patients with Crohn’s disease (70).
Fatty acid-binding proteins are a group of homol-
ogous, 14- to 16-kDa soluble proteins in the entero-
cyte cytosol that noncovalently bind long-chain fatty
acids (LCFA) with affinities in the nanomolar range.
Intestinal fatty acid-binding protein is specifictothe
intestine, whereas the liver fatty acid-binding protein
(L-FABP) is present in the intestine as well as in the
liver. Intestinal fatty acid-binding protein (I-FABP)
binds a single molecule of LCFA in an interior cavity
surrounded by two five-stranded antiparallel

-sheets.
Intestinal fatty acid-binding protein is important for
the intracellular trafficking and processing of dietary
fatty acids. The
␣
-helical region of acid bindin protein
I-FABP is involved in membrane interactions, and
plays a critical role in the collision mechanism of fatty
acid transfer from I-FABP to phospholipid mem-
branes (71). Intestinal fatty acid-binding protein is a
monomeric, cytoplasmic protein that binds long-chain
fatty acids such as palmitic acid. Intestinal fatty acid-
binding protein is regulated by collagen in Caco-2
cells (72); and it may target dietary fatty acids to
triglyceride synthesis pathways, while L-FABP liver
fatty acid-binding protein may target fatty acids to
oxidation and phospholipid synthesis. However, fac-
tors in addition to I-FABP play a role in determining
the metabolic fate of LCFA in small intestinal epi-
thelial cells (73). These binding proteins facilitate the
cytoplasmic movement of fatty acids (74).
Most of the interindividual variation in the plasma
lipoprotein response to dietary fiber can be attributed
to the polymorphism in the gene which encodes I-
FABP (75). Feeding sunflower oil increases L-but not
I-FABP mRNA and protein levels in the intestine
(76). Liver fatty acid-binding protein gene expression
is usually silent in the distal ileum but can be induced
by feeding fatty acids, and fatty acids may up-regulate
gene expression in many tissues such as the intestine
but down-regulate gene expression in the liver (77).
Only L-FABP expression increases fatty acid uptake
in fibroblasts (78). Intestinal fatty acid-binding pro-
tein does not affect fatty acid incorporation into cy-
tosolic triglyceride (73). It is not known what impor-
tance these fatty acid-binding protein have in the
control of lipid absorption.
The membrane-bound fatty acid-binding protein is
a 40-kDa protein postulated to mediate fatty acid
uptake through an active sodium-dependent process
in the intestine. The regulation of this protein is
unknown, since it has not yet been cloned. The fatty
acid translocate (FAT) protein is a 88-kDa mem-
brane protein which has been cloned. FAT RNA
abundance is higher in the jejunum than in the ileum,
is present in the upper two thirds of the intestinal villi,
and the FAT protein is limited to the brush border
membrane (76).
Cholesterol is thought to be absorbed by passive
diffusion in the intestine, but a receptor mediating the
absorption of dietary cholesterol has been identified.
Sterol carrier proteins mediate the intracellular trans-
fer and metabolism of cholesterol and are encoded by
a single gene with two initiation sites. Sterol carrier
protein-2 is involved in the uptake and intracellular
fatty acid trafficking in L-cell fibroblasts (79).
Dietary unsaturated fatty acids increase cellular
retinol-binding protein type II (CRBP II) mRNA and
protein levels in rat jejunum, but CRBP II gene
expression in rat jejunum is not regulated by dietary
retinoids (80). CRBP II-retinal and -retinol com-
plexes serve as substrate for the conversion of retinal
into retinol catalyzed by retinal reductase, but also for
the conversion of retinol into retinyl esters. The trans-
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2573Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
acting factors such as peroxisone proliferator-
activated receptors (PPARs) may mediate gene tran-
scription, and dietary fatty acids may lead to
induction of CRBP II transcription through increases
in PPAR-
␣
as well as its ligand levels (80).
Clinical Learning Point: A proportion of lipid ab-
sorption is protein-mediated, and this opens the way
to targeting these proteins and thereby therapeuti-
cally modifying lipid absorption.
Short-chain fatty acids are produced by bacterial
degradation of complex carbohydrates and proteins
entering the colon. Short-chain fatty acids are avidly
absorbed. The absorption of medium-chain fatty ac-
ids (C
7
-C
12
fatty acids) are absorbed at the same rate
as short-chain fatty acids in the human rectum (81).
Short-chain fatty acids stimulate electroneutral so-
dium absorption via the activation of apical Na
⫹
/H
⫹
exchange, which results from the short-chain fatty
acids changing the intracellular pH gradients (82).
NHE2 and NHE3 are expressed in the brush border
membrane. NHE3 is involved in the transepithelial
Na
⫹
absorption, and during ontogeny NHE3 is likely
regulated at the transcriptional as well as the post-
transcriptional levels. NHE2 functional protein levels
are lowest in 2-week-old rats and are highest in
6-week-old animals, although NHE2 mRNA levels in
the jejunum are unchanged. However, nuclear run-on
analyses show a higher NHE2 transcription rate in the
6-week-old as compared with the 2-week-old animals,
suggesting that the increases in NHE2 expression
upon weaning are mediated by increased gene tran-
scription (83).
Cholesterol esterase (bile salt-dependent lipase) is
activated by the primary bile salts (cholic and chonic
acids) and catalyzes the hydrolysis of a wide range of
substrates. These include the hydrolysis of cholesterol
esters into free cholesterol and fatty acids, and bile
salt-dependent lipase participates in the intestinal
free cholesterol absorption as a cholesterol transfer
protein. Bile salt-dependent lipase is present in brush
border membrane and in the endosomal compart-
ment of enterocytes, but curiously bile salt-dependent
lipase mRNA is not expressed by the intestinal mu-
cosa (84).
The intracellular formation of cholesteryl esters is
catalyzed by the action of the enzyme acyl-CoA (co-
enzyme A): cholesterol acyltransferase. Acyl-
CoA:cholesterol acyltransferase attaches a fatty acid
to the free hydroxyl group of cholesterol, thereby
limiting the solubility of the esterified cholesterol in
the lipids of the cell membrane and influencing the
regulation of cholesterol signaling. The majority of
cholesterol absorbed from the intestinal lumen by the
mucosal cell is esterified by acyl-CoA:cholesterol
acyltransferase and is incorporated into chylomicron
particles.
Acyl-CoA:cholesterol acyltransferase may have the
primary function of the secretion of cholesteryl esters
into apoB-containing lipoproteins (85). The

apoli-
poproteins (apoB48 and apoB100) are important in
the formation of triglyceride-rich lipoproteins.
ApoB48 is essential for the assembly of chylomicrons
in the intestine, and apoB100 is essential for the
formation of very low density lipoprotein (VLDL) in
the liver. The expression of the human apoB gene in
the intestine is dependent on DNA sequences located
at great distances from the structural gene (86).
The surface component of the chylomicron is com-
prised primarily of apolipoproteins (apoB
48
, A-I,
apoA-IV, and apoC), cholesterol, and phospholipids.
The intestine responds to a requirement for increased
triacylglycerol transport by producing chylomicrons
of increased size rather than by increasing their num-
bers, thereby conserving their surface components.
When the circulation is entered from the thoracic
lymph duct, the surface components of the chylomi-
crons change, with the surface predominantly gaining
apoE and losing apoA-I and apoA-IV.
Apolipoprotein A-IV is a major glycoprotein com-
ponent of intestinally synthesized and secreted tri-
glyceride-rich lipoproteins. Dietary fat stimulates the
expression, synthesis, and secretion of intestinal
apoA-IV. Peptide tyrosine-tyrosine stimulates the
synthesis and lymphatic secretion of apoA-IV, but has
no effect on mucosal apo AIV mRNA levels (87).
Lipid absorption stimulates apoA-IV synthesis and
secretion by the jejunum. Lipid absorption in the
distal small intestine stimulates the synthesis and re-
lease of apoA-IV by the jejunum, probably as a result
of release of peptide tyrosine–tyrosine. Both apoB-
IVA and apoB100 are important in the formation of
triglyceride-rich lipoproteins. ApoB-IVA is essential
for the assembly for chylomicrons in the intestine, and
apoB100 is essential for the formation of VLDL in
the liver. Chylomicron formation may involve the
synthesis of apoB-free triglyceride-rich particles
within the endoplasmic reticulum lumen. Transport
of these lipid particles out of the endoplasmic retic-
ulum to the Golgi apparatus and to the interstitium is
facilitated by the acquisition of apoB (53).
Triacylglycerol is resynthesized at the level of the
endoplasmic reticulum where triacylglycerol “flips”
across the inner membrane of the endoplasmic retic-
ulum. The triacylglycerol is then transported to the
THOMSON ET AL
2574 Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
growing chylomicron by the microsomal transport
protein (MTP). MTP rescues apoB from intracellular
degradation during early lipidation of the protein
(88). It is unknown how the triacylglycerol goes from
the endoplasmic reticulum to the Golgi. Brefeldin A
is a fungal metabolite that causes disruption of the
Golgi. This process may be sensitive to brefeldin A
and is time-, ATP-, temperature- and cytosol-
dependent (89).
The intestine can vary its triacylglycerol output rate
depending on different physiological conditions. The
rate-limiting step in the complex process from fatty
acid and monoacylglycerol entry to triacylglycerol ex-
port may involve a protein for the transport of triac-
ylglycerol from the endoplasmic reticulum to the
Golgi complex (90). This transport particle has been
isolated and characterized: electron microscopy
shows a 200-nm vesicle containing immunoidentifi-
able apoB48 and apoA-IV, but very little apo A-I
(91). The surface of the chylomicron contains both
exchangeable apo A-I, apo A-IV, apo C, and apoE
and nonexchangeable apoB48.
Postprandial lipidemia is determined by the contri-
bution of chylomicrons containing triacylglycerol
from dietary sources as well as that of VLDLs that
carry liver-derived triacylglycerols. Various dietary
fatty acids have specific effects on plasma triacylglyc-
erol concentrations. Trans fatty acids, derived from
partly hydrogenated vegetable oils and associated
with a risk of developing coronary heart disease,
increase triacylglycerol secretion and apoB48 and
apoB100 secretion from Caco-2 cells (88).
Intestinal sensors for specific nutrients signal re-
ductions of food intake, and these sensors are arrayed
along the entire intestine. The timing and degrees of
satiety do not correlate with the timing and extent of
gastric distension, but rather correlate with the timing
and extent of the spread of lipolytic products along
the length of the small intestine (22).
The topic of the malabsorption syndromes has
been reviewed previously (67). Steatorrhea and a
decrease in the coefficient of fat absorption occur in a
reversible manner in approximately half of patients
with Grave’s disease (92). The mechanism of the
steatorrhea does not appear to be associated with
pancreatic exocrine dysfunction. In the presence of
biliary obstruction, vitamin A absorption is impaired,
but the absorption of electrolytes and glucose is un-
changed (93). In patients with nephrotic syndrome,
hypercholesterolemia is common. The mechanism of
this hypercholesterolemia is unknown, but it is not
due to enhanced absorption of cholesterol (94).
Most cystic fibrosis patients malabsorb dietary fat
because of pancreatic insufficiency, which leads to
impaired lypolysis. Pancreatic enzyme replacement
therapy frequently fails to correct intestinal fat mal-
absorption in cystic fibrosis patients, partially because
of incomplete intraluminal solublization of long-chain
fatty acids as well as reduced mucosal uptake (95).
Gymnemic acid, a mixture of triterpene glycosides
extracted from the leaves of Gymnema sylvestre, in-
hibits the intestinal absorption of glucose as well as
oleic acid (96). The therapeutic implication of this
finding remains to be established.
Amino Acids and Protein
Two different protein families of amino acid trans-
porters, designated CAT and BAT (broad-specificity
amino acid transporters), mediate the plasma mem-
brane transport of cationic amino acids. The isolation
and functional expression of BAT has been described
for this y
⫹
L basolateral membrane transport in the
intestine, kidney, and placenta (97).
The topic of the role of glutamine and nucleotide
metabolism within enterocytes has been reviewed
(98). Glutamine is the preferred substrate for the
small intestine, and this amino acid is released by
proteolysis during catabolic states. The intestinal up-
take of glutamine is diminished in septic patients and
is increased during surgical stress. After sepsis both
growth hormone and IGF-I increase glutamine up-
take (99).
Fluoxetine, a selective serotonin reuptake inhibi-
tor, may cause diarrhea. One of the mechanisms by
which this drug may cause is by reduction of the brush
border and basolateral transport of the neutral, es-
sential amino acid, L-leucine (100).
The absorption of dipolar amino acids by the intes-
tine is mediated by multiple pathways, including sev-
eral Na
⫹
-dependent and Na
⫹
-independent mecha-
nisms. For example, in the chicken intestine
L-methionine is transported by four transport systems
(101). The brush border membrane uptake of L-
glutamate is Cl
⫺
-independent and Na
⫹
-dependent,
and L-glutamate and D-aspartate share a common
transport system in the rabbit small intestine (102).
L-Carnitine is a
␥
-amino acid that serves as an essen-
tial cofactor for the transfer of long-chain fatty acids
across the mitochondrial inner membrane in which

-oxidation occurs.
The intestinal absorption of L-carnitine is saturable
(103). Serotonin is contained in the enterochromatin
cells of the intestinal mucosal epithelium as well as in
the enteric nervous system. Mucosal crypt epithelial
SMALL BOWEL REVIEW: NORMAL PHYSIOLOGY 1
2575Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
cells of the rat intestine express mRNA encoding the
serotonin transporter, and the epithelial reuptake of
serotonin is responsible for terminating the mucosal
actions of serotonin (104).
Vasoactive intestinal peptide (VIP) inhibits alanine
absorption through the capsaicin-sensitive primary
afferents and the myenteric plexus, by a process that
may involve cholinergic muscarinic mechanisms
(105). The acute stimulation of the vagal capsaicin-
sensitive primary afferent fibers decreases the jejunal
absorption of alanine, whereas chronic blockade of
these fibers results in an increase in the absorption of
this amino acid.
The uptake of di- and tripeptides by the small
intestine is mediated by the proton-coupled peptide
transporter, PepT1. PepT1 is unaffected by 5-fluorou-
racil, whereas glucose transport is diminished by this
agent (106). The abundance PepT1 and its mRNA
can be increased in response to the exposure of
Caco-2 cells to glycyl-L-glutamine (107). Delta-
aminolevulinic acid is a photosensitizer and a precur-
sor for cellular porphyrin synthesis. Aminolevulinic
acid uptake is by PepT1 in the intestine, and by PepT2
in the kidney (108). A cDNA encoding a human
intestinal peptide transporter has been cloned and
has a high degree of similarity and homology with the
rabbit intestinal peptide transporter. A computer
model has been used to elucidate the transmembrane
protein structure of this dipeptide transporter (109).
The mucosal-to-serosal transport of acyclovir, an
agent used to treat herpes virus infection, is increased
by conjugation with L-valine. This is likely the result
of uptake occurring by the oligopeptide transporter,
followed by intracellular hydrolysis. The distance be-
tween the N-terminal amino group and the C-
terminal hydroxyl group is important for the interac-
tion with the apical oligopeptide transporter in
Caco-2 cells (110). The tyrosine 167 in transmem-
brane domain 5 contributes to the function of this
protein-coupled peptide transporter (111).
Valacyclovir is a prodrug of the antiviral agent
acyclovir and is a substrate for these peptide trans-
porters (112). The membrane transport of valacyclo-
vir is also by the PepT1 H
⫹
dipeptide cotransporter
(113). The presence of a dipeptide in the culture
medium of Caco-2 cells stimulates the uptake of
dipeptide by PepT1 (114). The authors suggest that if
the bioavailability of orally administered peptidomi-
metic drugs is limited, then patients may be tried on
a high-protein diet to enhance their absorption of the
medication.
Clinical Learning Point: A high protein diet may
be useful to increase the intestinal absorption of
drugs transported by the H
⫹
dipeptide cotransporter.
The lamina propria contains various immunocytes
such as mast cells and lymphocytes. Their numbers
increase during inflammation by reacting nonspecifi-
cally to certain bacterial products, or by reacting
specifically to foreign protein antigens. During stress
in a susceptible strain of rats, there is increased trans-
port of the macromolecule horseradish peroxidase
(115). The authors speculate that immune reactions
to foreign proteins may initiate or exacerbate inflam-
mation.
Peptide-derived drugs, such as
␣
-amino-

-lactam
antibiotics, angiotensin-converting enzyme inhibitors,
or renin inhibitors are taken up in the small intestine
by a saturable H
⫹
-dependent active transport system.
This is a 127-kDa microheterogeneous glycoprotein
which is closely associated with the sucrase–
isomaltase complex in the enterocyte brush border
membrane (116).
The small intestine is an important component of
whole-body protein metabolism, accounting for up to
10% of total protein synthesized. A luminal flooding
dose method has been developed to study the effect of
the luminal osmolarity of jejunal mucosal protein
synthesis (117). In humans, duodenal protein synthe-
sis is unaffected by feeding (118).
Enterocytes may play a role in antigen transport as
well as in antigen presentation to the underlying
lymphocytes. This process may lead to oral tolerance,
which is the down-regulation of the systemic immune
response to orally administered antigens via the gen-
eration of active cellular suppression or clonal anergy.
In antigen-presenting cells, exogenous proteins are
taken up by endocytosis; and then are processed by
cathepsins into peptides that bind to MHC class II
molecules. The MHC II/peptide complex is translo-
cated to the external membrane for direct presenta-
tion to lymphocytes. Interferon-
␥
secreted by lympho-
cytes in the intestinal mucosa up-regulates MHC class
II molecule expression and epithelial permeability.
Intestinal cells process proteins such as horseradish
peroxidase into peptides that are potentially capable
of stimulating the immune system, and thereby in-
crease the antigenic load in the intestinal mucosa
(119).
Antibodies against food antigens are usually pro-
duced in healthy people. This hormonal response can
be detected both in serum and secretions. Specific
IgG levels are highest in serum, and the local IgA-
producing population is functionally different in the
various tissues of healthy people (120).
THOMSON ET AL
2576 Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
Minerals and Vitamins
Iron and Other Metals. The topic of hemochroma-
tosis and iron absorption has been reviewed by Bacon
et al. (121). Iron balance in humans and animals is
maintained by modifications of the intestinal absorp-
tive process. A positional cloning strategy has been
used to identify a candidate murine iron transporter
gene (122, 123). In the rat this metal-ion transporter,
DCT1, has a broad range of substrates including
Fe
2⫹
,Zn
2⫹
,Mn
2⫹
,Co
2⫹
,Cd
2⫹
,Cu
2⫹
,Ni
2⫹
, and
Pb
2⫹
(123). This DCT1 mediates active transport that
is proton-coupled, is ubiquitously expressed in the
proximal small intestine, and is up-regulated by di-
etary iron deficiency. Perhaps this explains why nickel
absorption is increased in iron-deficient rats, and the
transport and accumulation of nickel in Caco-2 cells is
depressed in iron-loaded monolayers (124).
The sex-linked anemia (SLA) mouse has an anemia
that results from an inherited defect of intestinal iron
absorption. Mapping of the SLA locus was an impor-
tant first step into identifying the gene itself (125).
Iron deficiency in rats influences lipid metabolism,
resulting in reduced serum lipoproteins; increased
hepatic phosphatidylcholine and phosphatidylethano-
lamine concentrations; lower activities of glucose-6-
phosphate dehydrogenase, malic enzyme, and fatty
acid synthase; and higher triacylglycerol concentra-
tions in serum lipoproteins (126). The basis for this
phenomenon is unknown.
Clinical Learning Point: A metal transporter,
DCT
1
, has been identified, and this may open the way
to a better understanding of disorders of, for example,
iron and zinc metabolism.
The Caco-2 cell monolayer may be used to assess
food iron availability (127). A variety of ligands are
known to inhibit iron absorption including phytates,
tannates, phosphates, oxylates, and carbonates. Reg-
ular tea inhibits the intestinal absorption of nonheme
iron and reduces the frequency of phlebotomies re-
quired in the management of patients with hemochro-
matosis (128). Unbound iron can generate free radi-
cals, and the intestine of iron-deficient rats is more
susceptible to peroxidative damage during iron sup-
plementation (129).
Most of the approximately 110 mg of copper in the
adult body is functional, acting as cofactors of en-
zymes catalyzing oxidation–reduction reactions.
Newly absorbed copper is transported to bodytissues
by plasma proteins, including albumin and ceruloplas-
min (130). The cytosolic protein metallothionein par-
ticipates in the regulation of zinc metabolism. Studies
with transgenic and knockout mice suggest that me-
tallothionein may reduce the efficiency of zinc absorp-
tion (131). Copper and zinc absorption are dependent
on transmucosal fluid movement (132).
Calcium. Intestinal calcium (Ca
2⫹
) absorption in-
volves two processes, a transcellular metabolically
driven transport process, and a passive paracellular
process (133). The major part of the transcellular
component of Ca
2⫹
transport takes place in the du-
odenum, whereas the paracellular pathway takes
place throughout the small intestine. Calcium absorp-
tion is stimulated by a low-Ca
2⫹
diet (134). The
Ca
2⫹
-sensing receptor (CaR) is expressed in the in-
testine (135). The upper small intestine is the major
site for active Ca
2⫹
absorption, and this absorption is
stimulated by calcitriol, which is mediated in part by
vitamin D receptor-mediated genomic actions. This
process results in an increased production of calbi-
ndin-D
9k
, a cytosolic Ca
2⫹
-binding protein that has
been proposed to facilitate the movement of Ca
2⫹
across the cytosol from the brush border membrane
to the basolateral side of the enterocyte. Calbindin D
also modulates the activity of an intestinal ATP-
dependent calcium pump on the basolateral mem-
brane of the enterocyte. Ca
2⫹
absorption during early
postnatal life of pigs involves a calcitriol-independent
mechanism that may include intact microtubule ac-
tions (136).
Dietary carbohydrates such as inulin, resistant
starch, and guar gum hydrosylate increase Ca
2⫹
ab-
sorption. Fructooligosaccharides are low-molecular-
weight indigestible carbohydrates that increase Ca
2⫹
absorption and balance (137). Circulating 1,25-
dihydroxyvitamin D
3
[1,25(OH)
2
D], the hormonal
form of vitamin D
3
, is the prime hormonal regulator
of intestinal Ca
2⫹
absorption. Estradiol stimulates
intestinal Ca
2⫹
, absorption by a direct effect on the
intestine, rather than by an effect on circulating 1,25-
dihydroxyvitamin D or by reduced intestinal respon-
siveness to 1,25-dihydroxyvitamin D (138). The cellu-
lar action of 1,25(OH)
2
D is mediated by an
intracellular vitamin D receptor protein that binds to
promoter regions in specific genes and regulates the
transcription of these vitamin D-responsive genes.
Senescence in humans and animals is associated
with a functional decline in a variety of physiological
systems, including the efficiency of intestinal Ca
2⫹
absorption. In old animals there are reduced circulat-
ing levels of 1,25(OH)
2
D, as well as a relative intes-
tinal resistance to the action of this hormonal form of
vitamin D
3
(139). It has been suggested that osteopo-
rosis is as common in men as in women and that there
SMALL BOWEL REVIEW: NORMAL PHYSIOLOGY 1
2577Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
is an age-related decline in intestinal Ca
2⫹
absorption
and serum 1,25(OH)
2
-D
3
in healthy males (140).
Prolactin enhances the Ca
2⫹
flux in the duodenum
by a sodium-dependent mechanism, whereas in the
proximal jejunum the mechanism of the prolactin-
stimulation of plasma-to-lumen Ca
2⫹
flux is unknown
(141). Dietary phytate inhibits the absorption of a
number of minerals such as Ca
2⫹
and iron by forming
insoluble phytate-mineral complexes. Certain inositol
phosphate break-down compounds chelate and in-
crease the solubility of minerals, and may be used as
absorption enhancers (142).
Vitamin B
12
.Vitamin B
12
(cobalamin) binds to a
plasma transporter, transcobalamin II, and is taken to
tissues by receptor-mediated endocytosis via a
transcobalamin II receptor. Brefeldin A reduces the
cholesterol but not the phospholipid levels of the
basolateral membrane of Caco-2 cells, and brefel-
dinA treatment also results in complete loss of
transcobalamin II receptor activity and protein level
in the basolateral membrane (143).
Water and Electrolytes
Sodium enters the enterocyte with cotransported
substrates such as glucose or amino acids or by way of
an exchanger in the brush border membrane. Human
duodenal enterocytes contain at least three acid/base
transporters: the Na
⫹
/H
⫹
exchanger extrudes acid,
the Na
⫹
HCO
3
⫺
cotransporter acts as a base loader,
and Cl
⫺
/HCO
3
⫺
exchanger operates as a base ex-
truder (144). Brush border membrane Na
⫹
/H
⫹
ex-
change (NHE) activity is inhibited by the activation of
the protein kinase C pathway. There are several iso-
forms of the exchanger NHE:NHE1 is on the baso-
lateral membrane of villous and crypt cells, and
NHE2 and NHE3 are on the brush border membrane
of villous cells. NHE1 is the “housekeeper isoform,”
regulating intracellular pH and volume, while NHE3
mediates sodium absorption. The role of NHE2 is
uncertain. Na
⫹
/H
⫹
exchange contributes to the elec-
troneutral absorption of NaCl and to the regulation
of luminal pH.
The activity of NHE3 decreases from the proximal
to the distal small intestine (145). Homozygous mu-
tant mice lacking NHE3 function develop mild diar-
rhea and acidosis (146). NHE3 exchanges extracellu-
lar Na
⫹
for intracellular H
⫹
, with a stoichiometry of
1:1. Physiological regulation and function of epitheli-
al-specific NHEs are dependent on tissue-specific fac-
tors and/or conditional requirements (147). Short-
term regulation of NHE1 is by protein kinases (148),
which alter the affinity for intracellular H
⫹
. NHE1 on
the basolateral membrane does not change in rat
intestine between week 2 and adulthood (149). Short-
term regulation and prolonged transcriptional regu-
lation on NHE2 and NHE3 include changes in the
values of their maximal transport velocity (V
max
).
Glucocorticosteroids stimulate intestinal water and
NaCl absorption, increase Na
⫹
/H
⫹
exchange, en-
hance NHE3 mRNA abundance, and also increase
the NHE3 turnover number (150). X-ray microanal-
ysis has shown that the Na
⫹
concentration of the
villous cells is higher than in the crypts, whereas the
concentration of potassium and chloride is less (151).
The intestinal absorption of water appears to occur
by way of cotransporters such as the intestinal Na
⫹
/
glucose cotransporter (SGLT1), which act as a mo-
lecular water “pump.”For each one molecule of
sugar absorbed by SGLT1, two molecules of sodium
and 225 molecules of water are transported. This
coupling between sugar and water transport is con-
stant, independent of sodium, sugar, voltage, temper-
ature, and osmolarity (18, 152).
Clinical Learning Point: The nutrient transporters
such as SLGT1 are responsible for a portion of the
intestinal absorption of water.
The absorption of ingested water and most solutes
occurs in the proximal small intestine, where the
creation of suitable osmotic gradients promotes the
uptake of water. Thus, the rate of gastric emptying
and therefore the absorption of nutrients is an impor-
tant factor in determining the rate of water absorp-
tion. Dilute hypotonic glucose–sodium solutions are
effective oral rehydration solutions, and the inclusion
of a small amount of glucose or amino acid assists in
the overall rehydration process (153). Low osmolarity
of a nutrient solution decreases intraluminal water
flow rates in the upper intestine of healthy volunteers,
without affecting the absorption rates of total nitro-
gen and carbohydrate. This may lower the water loss
in patients with extensive small bowel intestinal re-
section (154). Total fluid absorption of a 6% carbo-
hydrate–electrolyte beverage from the upper gastro-
intestinal tract of humans during exercise is no
different from the absorption that occurs with water
(155).
Nitric oxide is a modulator of intestinal water and
electrolyte transport (156). Nitric oxide is a lipid-
soluble gas, with a very short half-life under aerobic
conditions. Nitric oxide and L-citrulline are formed
from the oxidation of L-arginine. When its concentra-
tion is low, nitric oxide has a proabsorptive effect on
water and electrolyte transport. This process involves
the enteric nervous system, the suppression of pros-
THOMSON ET AL
2578 Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
taglandin formation, and the opening of basolateral
membrane K
⫹
channels. When nitric oxide levels are
high, net secretion may occur.
Clinical Learning Point: The influence of nitric
oxide on intestinal water absorption and secretion
depends on its concentration.
Both cholera toxin and Escherichia coli heat-labile
enterotoxin increase the intracellular adenosine 3⬘,
5⬘-cyclic monophosphate concentration, but only
cholera toxin-induced secretion is accompanied by
5-hydroxytryptamine (serotonin) release (157). Sub-
stance P is a member of the tachykinin family of
neuropeptides, and is found in enteric neurons and
some endocrine cells in mammalian small intestine.
Several endogenous secretagogues such as substance
P, serotonin, and IL-1

may release nitric oxide,
thereby contributing to the secretory condition (156).
The cystic fibrosis transmembrane conductance
regulator (CFTR) is an adenosine 3⬘,5⬘-cyclic mono-
phosphate (cAMP) regulated Cl
⫺
channel that is
activated by phosphorylation with protein kinase A.
The CFTR gene is tightly regulated, both develop-
mentally and in a tissue-specific manner. In human
and rat gastrointestinal tracts, a decreasing gradient
of CFTR mRNA and protein is observed along the
proximal-distal axis and along the crypt-villus axis.
The transcriptional regulation of the CFTR gene
involves the combination of multiple regulatory ele-
ments, and a 6.6-kb region in rat CFTR derives spe-
cific expression of a reporter gene in cultured mouse
intestinal cells with a crypt phenotype (158). The
regulation of CFTR-mediated Cl
⫺
permeability is
achieved by phosphorylation of multiple serines in the
regulatory domain of CFTR, followed by binding and
hydrolysis of ATP at the nucleotide-binding folds.
Protein kinase A is an holoenzyme consisting of a
regulatory subunit dimer and two catalytic subunits.
Protein kinase A exists as types I and II, which are
defined by the type of regulatory subunit present in
the holoenzyme, RI and RII, respectively. The type-
II-selective analogs activate larger increases in
CFTR-mediated current than do the type-I-selective
analogs. This indicates that the differential activation
of protein kinase A in cellular compartments is im-
portant in CFTR regulation (159). Guanylin is a
15-amino-acid peptide that activates CFTR and ele-
vates the intracellular cGMP levels by activating
guanylate cyclase C. The intravenous injection of
guanylin induces mucous secretion from goblet cells
in rat duodenal crypts (160).
Oxyntomodulin and glicentin are hormones
present in the L cells of the ileum and colon. In these
L cells, proglucagon processing gives rise to oxynto-
modulin and glicentin. When active secretion in the
ileum is induced by an electrogenic challenge, oxyn-
tomodulin reduces hydromineral transport, the am-
plitude of which depends upon the integrity of the
tetrodotoxin-sensitive neurons (161).
The etiology of enteral feeding-induced diarrhea is
unknown, but it may be caused in part by antibiotic
therapy, bacterial overgrowth in the intestine, bacte-
rial contamination of the enteral formulas, hyperos-
molarity of the formula, interaction with other medi-
ators, or the production of choleretic diarrhea (162).
Clinical Learning Point: A trial of bile acid-
sequestering agent may prove useful in the treatment
of the patient who experiences diarrhea while taking
an enteral diet.
Enterotoxigenic Escherichia coli (ETEC) that pos-
sess the K88
⫹
, pilus are commonly associated with
diarrheal diseases in young piglets. Bromelain, a pro-
teolytic extract obtained from pineapple stems, pro-
tects piglets against diarrhea by temporarily inhibiting
the K88
⫹
. ETEC receptor activity (163). Most cur-
rently used anti-diarrheal drugs such as opiate deriv-
atives, alter intestinal motility and secretion. The role
of bromelain in the treatment of humans with diar-
rhea remains to be established.
Clinical Learning Point: A proteolytic extract from
pineapple stems may prove to be useful to treat
diarrhea, although the mechanism of this effect re-
mains to be established.
The topic of the peptidergic regulation of intestinal
ion transport has been reviewed (164). The endocrine
and neural peptide tyrosine–tyrosine and neural pep-
tide Y also have intestinal antisecretory activity, and
this neurally-mediated effect is through the
recep-
tors. These are different from opiate, phencyclidine,
or glutamate receptors and are present in high density
in the wall of the intestine. In healthy volunteers,
igmesine, a
ligand, inhibits intestinal secretion and
diarrhea induced by PGE
2
(165).
In patients with high fecal output (above 2.5 kg/
day) from the short bowel syndrome, the proton
pump inhibitor omeprazole (40 mg twice daily) in-
creases water absorption (166). Serotonin (5-
hydroxytryptamine
3
) may contribute to the diarrhea
of patients with carcinoid syndrome and in cholera
toxin-induced secretion in man. The serotonin recep-
tor antagonist, ondansetron, reverses the impaired
jejunal fluid absorption observed in rats treated with
the antineoplastic drug cisplatin (167), but it does not
have a significant effect on the median diarrhea score,
SMALL BOWEL REVIEW: NORMAL PHYSIOLOGY 1
2579Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
stool weight, loparamide use, and overall colonic
transit in patients with carcinoid diarrhea (168).
The sensory nerves, when stimulated by electrical
field or capsaicin, cause Cl
⫺
secretion but do not
affect net absorption (or secretion) in the human
jejunal mucosa (169).
The latex agglutination test for fecal lactoferrin
may prove to be a highly sensitive, specific, and simple
means for detection of fecal neutrophils, and thereby
may be useful in the evaluation of patients presenting
with chronic diarrhea (170).
The jejunum absorbs bicarbonate by a Cl
⫺
/HCO
3
⫺
exchanger on the basolateral membrane of the en-
terocyte. The presence of Na
⫹
positively affects the
rate of anion antiport, but Na
⫹
itself is not trans-
ported. The jejunal enterocyte lacks a mechanism to
counteract cellular alkalinization (171). The authors
suggest that the main purpose of pH homeostasis
might be to hinder acidification of the cytosol due to
the influx of proteins and the production of acid by
metabolism.
Congenital chloride diarrhea is a recessively inher-
ited disorder characterized by massive loss of Cl
⫺
in
acidic stools, resulting from a defect in Cl
⫺
/HCO
3
⫺
exchange. The congenital chloride diarrhea locus has
been mapped by linkage analysis to chromosome
7q31, adjacent to the CFTR gene, and is 4 chromo-
somal bands away from the Cl
⫺
/HCO
3
⫺
exchanger.
DRA (down-regulated in adenoma) is the gene that is
mutated in congenital chloride diarrhea, and DRA
encodes an intestine-specific sulfate transporter. DRA
also has a Cl
⫺
transporter, which is defective in con-
genital chloride diarrhea (172, 173). DRA is also
down-regulated in patients with ulcerative colitis, pos-
sibly contributing to the pathogenesis of diarrhea in
this condition (174).
In most cell types volume regulatory mechanisms
involve the activation of ionic pathways in order to
restore the original volume of the cells. For example,
in response to a hypoosmotic external solution, the
cell will activate pathways that will result in the net
efflux of K
⫹
and Cl
⫺
. The anionic pathway is primar-
ily activated by cell swelling (175). The Na
⫹
-K
⫹
-
(2)Cl
⫺
cotransporter participates in the homeostatic
control of transmembrane ion gradients and cell vol-
ume. Activation of apical Cl
⫺
channels is generally
viewed as the primary regulatory event of cAMP-
elicited Cl
⫺
secretion. Basolateral Na
⫹
-K
⫹
-Cl
⫺
co-
transport must also increase in order to maintain cell
electrolyte composition. The factors responsible for
“cross-talk”between apical and basolateral transport
events involve a complex interrelationship among in-
tracellular Cl
⫺
activity, cell volume, and the actin
cytoskeleton in the regulation of epithelial Cl
⫺
trans-
port (176).
The stimulation of transepithelial Cl
⫺
secretion
increases the osmotic impetus for fluid secretion.
After colonization of the small intestine by Vibrio
cholerae, binding of the cholera enterotoxin to the
intestinal enterocyte leads to ADP-ribosylation of the
␣
-subunit of a stimulatory G protein, which then
activates adenylate cyclase. The novel plant-derived
inhibitor of cAMP-mediated fluid and Cl
⫺
secretion
has been identified (177). Its role as an antidiarrheal
agent is unknown.
Sorbin is a new peptide localized in enterochroma-
tin endocrine cells located in the enteric nervous
system from the stomach to colon. Sorbin increases
intestinal absorption in basal conditions, and de-
creases stimulated intestinal secretion. Synthetic
sorbin derivatives inhibit the cholera-induced stimu-
lation of the influx of water, Na
⫹
, and K
⫹
(178). The
COOH-terminal heptapeptide of sorbin stimulates
neutral NaCl absorption, and inhibits electrogenic
Cl
⫺
in rat and human intestinal epithelium (179).
Clinical Learning Point: The antisecretory effect of
the new peptide, sorbin, needs to be tested in a
clinical situation on patients with diarrhea. Other new
and promising antidiarrheal agents include brome-
lain, an extract from pineapple stems, and igmesine, a
final sigma ligand.
Angiotensin II stimulates fluid absorption at low
doses, but inhibits absorption at high doses. Angio-
tensin receptors involving cGMP are involved in the
jejunal sodium and water absorption. Angiotensin II
inhibits absorption via the AT
1
receptor by a mecha-
nism that is negatively coupled to cAMP, and in-
creases jejunal PGE
2
production (180). Substance P
and neurokinin A are members of the tachykinin
family, and are important in regulating intestinal
function through the release of prostaglandin and
enteric neurotransmitters (181).
Tolcapone (a catechol-O-methyl transferase inhib-
itor) is used in the treatment of Parkinson’s disease.
The development of diarrhea in patients on this novel
drug may be the result of the intestinal secretion of
fluid and electrolytes (182).
During the consumption of a high-salt diet, young
animals experience a decrease in sodium absorption
with a parallel increase in tissue levels of dopamine,
and in 20-day-old but not in 40-day-old rats Na
⫹
,
-K
⫹
-ATPase is reduced during a high-salt diet (183).
Surreptitious laxative abuse is a syndrome in which
the patient secretly ingests laxatives to fabricate a
THOMSON ET AL
2580 Digestive Diseases and Sciences, Vol. 46, No. 12 (December 2001)
chronic diarrheal syndrome. The key to the diagnosis
is the chemical detection of the laxative substance in
stool. Diagnosing surreptitious use of phosphate lax-
atives has been helped with the establishment of
upper limits of normal for stool soluble fecal phos-
phate concentration and output at 33 mmol/liter and
15 mmol/day, respectively (184).
Drugs
Passage of drugs from the intestinal lumen into the
blood requires transport either through (transcellu-
lar) or between the enterocytes (paracellular). The
Ussing chamber is useful to study the properties of
the human intestinal mucosa in vitro (185). Predicting
the extent of in vivo drug transport in humans has
been achieved from indirect in vitro permeability data
using intestinal epithelial preparations from rat or
rabbits or from human Caco-2 or HT29-18 cell cul-
ture monolayers. In these monolayers, the mucosal
surface area and the cross-sectional area are similar,
but in the intestinal tissue the villi and the microvilli
greatly amplify the surface area. For example, the
amplification of the mucosal-to-serosal surface area is
approximately 4.7 in the jejunum and 2.7 in the ileum.
The mass of drug absorbed from the intestine is also
influenced by its solubility, dissolution rate, luminal
complexation, degradation, transit time, metabolism,
and the physicochemical properties of the drug. Hy-
drophilic drugs are transported by the paracellular
route across the tight junctions, whereas hydrophobic
compounds are dissolved more easily in the lipid
phase of the membrane and consequently generally
have a higher intestinal permeability. Whereas the
permeability coefficients determined for the human
Caco-2 monolayer correlate with human absorption
in vivo, the rat may not be a suitable choice for oral
bioavailability studies of ester prodrugs (186).
The molecular basis for multidrug resistance is the
action of P-glycoprotein (Pgp), as well as other efflux
proteins such as multidrug resistance-associated pro-
tein. Pgp is expressed in the gastrointestinal tract as
well as in other tissues such as the liver, kidney, and
capillary endothelial cells of the brain. Pgp is an
ATP-dependent efflux pump that increases the out-
ward transport of these drugs from tissues. Many
drugs such as the HIV-1 protease inhibitors are sub-
strates of Pgp. Humans have one Pgp and Pgp con-
tributes to the elimination of drugs by mediating their
direct secretion from the blood into the intestinal
lumen. In addition, Pgp may limit oral drug absorp-
tion. Caco-2 cells are a suitable cell line model for
Pgp-mediated studies (187). Pgp causes multidrug
resistance with cancer chemotherapy agents such as
vinblastine, actinomycin D, and daunomycin. Pgp is
also a substrate for several

-blockers and for quini-
dine (188). The calcium-channel blocker, verapamil,
is affected by saturable efflux P-glycoproteins in the
human intestine (189).
Intestinal cytochromes P-450 are involved in the
biotransformation of dietary nutrients as well as
orally ingested toxicants, procarcinogens, and other
xenobiotics. This system plays a major role in the
intestinal microsomal metabolism of retinal to reti-
noic acid (190).
With passage along the length of the small intes-
tine, there is a decrease in the permeability to hydro-
philic drugs and an increase in the permeability for
hydrophobic drugs (191). Drugs with poor membrane
permeability characteristics may be designed as li-
pophilic drug esters in an effort to enhance their oral
delivery. The absorption of the lipophilic polyene
antibiotic amphotericin-B may be enhanced by the
use of bile salt mixed micelles (192). Biosurfactants
such as unsaturated fatty acids, bile salt–fatty acid
mixed micelles, milk fat globule membranes, and fatty
acid sucrose esters have been used to enhance intes-
tinal absorption of drugs with a low oral bioavailabil-
ity. For example, fatty acid sucrose esters enhance the
absorption of ciftibuten transport by rat brush border
membrane vesicles, a property related to the disper-
sion parameter of these pharmaceutical adjuvants
(193).
The clinical bioavailability of 5-fluorouracil follow-
ing its oral administration to humans is low and
erratic, probably due to first-pass metabolism of the
drug in the intestinal mucosa as well as in the liver
(194).
Guidelines for methods to determine efficacy and
safety of drugs acting on the gastrointestinal tract
have been published (195).
ACKNOWLEDGMENTS
The authors wish to express their sincere appreciation for
the excellent word-processing and proof-reading skills of
Ms. Cindy Anaka.
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