Clinical Science and Molecular Medicine (1978) 54,337-348
EDITORIAL REVIEW
Intestinal transport of salt and water
L. A. TURNBERG
Department of Medicine, Hope Hospital (University of Manchester School ofMedicine), Salford, Lanes., U.K.
Of the developments which have occurred in this
field in the last few years, several stand out. The
importance of a 'shunt' pathway for ion transport,
which passes between rather than through, the
epithelial cells, and its role in determining the
differing transport characteristics of jejunum, ileum
and colon has been recognized. The links between
sodium transport and the transport of several other
solutes and ion-exchange processes have been
examined in some detail. The role of intestinal
secretion in the pathogenesis of many types of
diarrhoea has been elucidated and the exciting
advances in our knowledge of the biochemical basis
for intestinal secretion are providing leads for the
potential pharmacological control of secretory
diarrhoea. This review will focus on these
particular topics.
The paracellular shunt pathway
Transport across epithelia in which the individual
epithelial cells are tightly bound to each other is
largely dependent upon ion-transport processes in
the cell membranes. Such is the case, for example,
in toad bladder and frog skin (Ussing &
Windhager, 1964). In intestinal mucosa, however,
individual epithelial cells are rather loosely attached
to each other and much of the net transfer of salt
and water occurs via pathways which bypass the
cells (Frizzell & Schultz, 1972). This 'shunt' path­
way almost certainly resides anatomically in the
'tight junctions', which join adjacent cells together
near their apical borders, and the lateral inter­
cellular spaces (Fromter & Diamond, 1972).
Although the contribution of this 'shunt' to the
overall net transfer of solute and water varies from
region to region in the intestine, there seems little
Correspondence: Professor L. A. Turnberg, Department of
Medicine, Hope Hospital, Eccles Old Road, Salford M6 8HD,
Lanes., U.K.
25
doubt that it plays a major role in these tissues,
which are characterized by low electrical potential
differences and resistances.
Several lines of evidence point to the lateral inter­
cellular spaces as major routes for fluid transfer.
When water is absorbed these spaces are widely
distended and when water secretion is induced by
placing a hypertonic solution on the luminal side,
the spaces are collapsed (Tomasim & Dobbins,
1970; Loeschke, Bentzel & Csaky, 1970). Studies
demonstrating that the permeability of the mucosa
to small solutes varies with the state of the lateral
spaces also support this conclusion (Loeschke,
Hare & Csaky, 1971). Permeability is greater
when the spaces are dilated than when they are
closed.
Furthermore, since the lateral spaces are open to
the interstitial fluid compartment at one end and
closed by the tight junctions at the other, it might
be predicted that raising the hydrostatic pressure in
the lumen would have little effect on fluid transfer
by this route but that doing so in the interstitial
fluid would inhibit absorption. This prediction is
borne out by experiments in which increases in
hydrostatic pressure in the lumen of up to 22 cm
water did not influence absorption whereas
pressures of only 2-6 cm on the serosal side
inhibited fluid absorption, higher pressures
inducing secretion (Hakim & Lifson, 1969).
These structural changes are likely to be
responsible for the functional changes in fluid
transport which occur in some physiological
circumstances. Thus rapid plasma volume
expansion with saline intravenously depresses
intestinal absorption or induces secretion in a
number of animals (Higgins & Blair, 1971;
Humphreys & Earley, 1971). The opposite
situation of a reduced plasma volume, produced by
experimental haemorrhage or upward head tilting,
significantly enhancesfluidabsorption (Maihnan &
Ingraham, 1971).
337
338
L.A. Turnberg
Thus it is clear that in the villi, as in the kidney
(Bentzel, 1972), interstitial fluid pressure, which
itself is determined by capillary and lymphatic
hydrostatic, and plasma osmotic, pressures, will
influence fluid and electrolyte transport by altering
the physical shape and hence the permeability of
the paracellular shunt pathways.
It is highly likely that a considerable portion of
the absorption of small solutes also bypasses the
epithelial cells. Thus the imposition of an electrical
potential difference across intestinal mucosa
reveals that the flux of ions is made up of two
components. The first probably passes across the
cell membranes but the second, and larger,
component behaves in accordance with the laws of
simple diffusion of ions passing through water-filled
pores, almost certainly in the tight junctions
(Frizzell & Schultz, 1972). These observations fit
with electrophysiological studies of intestinal
mucosa which clearly indicate the presence of a
relatively low-resistance shunt, in parallel with the
high-resistance apical and basal cell membranes
(Rose & Schultz, 1971).
In the rabbit ileum the conductance of the shunt
pathway accounts for about 85% of total tissue
conductance (Frizzell & Schultz, 1972). Thus, of
the total transfer of ions which occurs in answer to
electrical potential and concentration gradients
across the mucosa, only about one tenth will pass
through the cells. The flux of sodium from the
interstitial fluid compartment into the lumen, the
'back flux', occurs almost entirely passively
through the shunt pathway.
The net active absorption of sodium is but a
small difference between large bidirectional fluxes
and represents the almost completely rectified
transcellular active sodium transfer.
Studies in the human intestine in vivo also
demonstrate a high permeability to sodium, which
is highest in the jejunum and least in the colon
(Fordtran, Rector, Ewton, Soter & Kinney, 1965).
Calculations have been made of the apparent
diameter of the water-filled 'pores' in human
intestinal mucosa by using the 'reflection
coefficient' of a number of small solutes. A
'reflection coefficient' (σ) is the ratio of the osmotic
pressure which a solute exerts across a membrane
compared with the osmotic pressure exerted by a
completely impermeant solute. Mannitol, to which
jejunal mucosa is impermeable, exerts its full
osmotic pressure and thus has σ 1, whereas Na,
which permeates the mucosa relatively freely and
can exert only about one-half of the osmotic
pressure of mannitol, has σ 0-5 (Fordtran et al.,
1965). Potassium permeates jejunum even more
freely and has σ 0-4 (Turnberg, 1971 a, b). Based
on these types of observation, it has been cal­
culated that the diameter of human jejunal 'pores'
is around 0·7-0·9 nm, whereas human ileal 'pores'
are 0-3-0-4 nm (Fordtran et al., 1965), and
colonic 'pores' are 0-2-0-3 nm (Levitan & Billich,
1965). It has been suggested that these estimates
may be too low (Schultz, Frizzell & Nellans, 1974),
but nevertheless they do provide an idea of the
relative permeabilities of the different regions of the
human gut.
Although apparently large, at least in the
jejunum, these 'pores' are not unselective for all
small ions. Thus, there is good evidence that jejunal
and ileal 'pores' are more permeable to cations than
anions, suggesting that they are lined with negative
charges (Turnberg, Bieberdorf, Morawski &
Fordtran, 1970a). Indirect evidence suggests that
colonic 'pores', however, may be selective for
anions rather than cations (P. C. Hawker, K.
Mashiter & L. A. Turnberg, unpublished obser­
vation).
Clearly, a freely permeable human jejunal
mucosa must be advantageous for rapid osmotic
equilibration. It allows the process known as
'solvent drag' to play an important role in the
absorption of electrolytes in this part of the
intestine (Fordtran, Rector & Carter, 1968). The
bulk flow of water through the large pores is
believed to sweep up small solutes in its stream and
'drag' them across the mucosa. In the human
jejunum the 'pores' are large enough to allow Na
and K to be transferred by this means and experi­
ments in vivo designed to test this have indeed
demonstrated that these ions closely followed water
movement in either direction across the mucosa
when this was manipulated by creating osmotic
gradients (Fordtran et al., 1968; Turnberg, 1971a).
Under normal circumstances, after a meal, the
active absorption of sugars, peptides and amino
acids in the jejunum is followed by osmotically
induced water flow, which in turn 'drags' Na and K
with it. A reduction in jejunal permeability might be
expected to impair jejunal absorptive function and
such is the case in coeliac disease. Here small
solutes permeate the mucosa poorly, suggesting a
reduction in 'pore' size, which may reflect the gross
change in mucosal architecture (Fordtran, Rector,
Locklear & Ewton, 1967). This defect may well
increase the liability of coeliac patients to
diarrhoea.
Two further physical attributes of the intestine
influence salt and water absorption: the 'unstirred
Intestinal transport of salt and water
layer' or microclimate immediately adjacent to the
mucosa and the lymphatic and venous drainage.
The unstirred layer is likely to be made up of
several elements. First, any tissue will have a
relatively unmixed zone of fluid adjacent to it even
when the bulk phase of the fluid bathing it is
vigorously stirred. Secondly, the 'fuzzy coat' or
glycocalyx on the mucosa must increase this zone
of poor mixing and, thirdly, the packing of adjacent
intestinal villi is such that only their tips will be
bathed well with luminal contents. The sides of the
villi must come into contact with the luminal bulk
phase only poorly. Clearly these factors will
markedly influence absorption rates and although
attempts have been made to measure their effects,
this area is one which is relatively poorly under­
stood and often ignored (Dietschy & Westergaard,
1975; Read, Barker, Levin & Holdsworth, 1977).
The rates at which solutes are removed from the
mucosal side of epithelial cells influences the
concentration gradients across the cell and, hence,
the absorption rates. Thus lymphatic and venous
flow rates may be rate limiting for some solutes. In
addition, it has been recognized that the vascular
architecture within the villi makes it well suited to
act as a countercurrent exchanger and thus main­
tain concentration gradients along the length of the
villi. Experimental evidence is now available which
supports this concept (Svanvik, 1973; Bond, Levitt
& Levitt, 1977) and clearly this factor has to be
taken into account, for example, when comparing
studies of transport in vivo with studies in vitro.
Links between sodium transport and transport of
other solutes
There is a large body of experimental evidence
supporting a direct link between Na absorption and
the absorption of several other actively absorbed
solutes such as glucose and amino acids (see
reviews by Crane, 1965, and Schultz & Curran,
1970). In this scheme it is envisaged that a brushborder carrier translocates Na and glucose together
into the epithelial cell. Glucose stimulates Na entry
and glucose absorption is inhibited by the absence
of luminal Na, supporting such a linked absorption.
The maintenance of a concentration gradient for
Na across the brush-border membrane, by keeping
intracellular Na at a lower concentration than in
the lumen, is held to be an important prerequisite
for this postulated mechanism, which is under­
stood to act as follows. Sodium attaches to the
carrier in the high concentration of the lumen,
339
facilitating uptake of glucose. This complex then
realigns itself, by unknQwn mechanisms, so that the
sites of the carrier occupied by glucose and Na face
the interior of the cell. The low intracellular Na
concentration then promotes release of Na from
the carrier. The Na-free carrier can then no longer
hold glucose, which is also released into the cell.
The unoccupied carrier then springs back to face
the lumen. The low intracellular Na concentration
is maintained by active extrusion at the basolateral
cell membrane, by the activity of the Na,Kdependent adenosine triphosphatase sited there.
It seems unlikely that the 'flip-flop' molecular
gymnastics conceived above for the carrier protein
can be provided with sufficient energy for it to
occur in this way. More reasonable is the idea of
proteins (carriers), which extend from the internal
to external surfaces of the cell membrane and
which provide a route for ion movement, assisted
by some conformational changes.
Kimmich (1973) has proposed that the 'standing
gradient' for Na is not an essential part of this
coupled absorption and suggests instead that an Na,
K-dependent adenosine triphosphatase on the
brush-border membrane may provide the energy
for the entry of solutes such as glucose and amino
acids against their gradients. This view requires the
demonstration of the enzyme in the brush border
and recent evidence suggests that less than 6% is
found there (Mircheff & Wright, 1976).
It has been difficult in vivo to demonstrate a
dependence of glucose transport on the presence of
a higher luminal than intracellular Na con­
centration. This may be because of the difficulties
in maintaining a low luminal Na concentration
when it moves so rapidly into the lumen across the
freely permeable mucosa. Nevertheless, doubt was
cast on the theory when Saltzman, Rector &
Fordtran (1972) could not find a dependence on
high luminal Na concentrations for glucose ab­
sorption in human ileum. Even in vitro the
inhibition of glucose absorption appears to be
dependent not only on the removal of luminal Na
but also on the nature of the substituting ion. For
instance, substitution with K impaired glucose
absorption to a much greater extent than
substitution with ammonium or choline (Annegers,
1964; Boyd & Parsons, 1976).
Despite these observations the majority of
experiments in vitro designed to test the standing
gradient hypothesis have supported it (Schultz et
al., 1974). The 'common carrier' mechanism has
been proposed not only as a link between Na
absorption and glucose, but also for Na plus a
340
L.A. Turnberg
number of other solutes including amino acids, bile
salts and even chloride.
It seems very likely that in vivo both 'solvent
drag' passive forces and the 'common carrier'linked active transport processes are responsible
for the stimulation of Na transport provoked by
glucose and other solutes (Modigliani & Bernier,
1972). From a physiological, as against a bio­
chemical, standpoint it seems to me that the
'solvent drag' is likely to be quantitatively more
important.
Ion-exchange processes
From studies in vivo of ion transport in man a
number of ion-exchange mechanisms have been
postulated (Turnberg et ai, 1970a; Turnberg,
Fordtran, Carter & Rector 1970b). Although
studies in vivo, of necessity, treat the intestinal
mucosa as a 'black box' and cannot define the
nature of transport processes closely, they do
indicate overall behaviour. A Na/H, neutral,
exchange in the human jejunum has been pos­
tulated on the following evidence (Turnberg et al.,
1970b). Bicarbonate is absorbed from the jejunal
lumen against steep electrochemical gradients and,
since carbon dioxide is generated within the lumen
during bicarbonate absorption, it seems most likely
that it is removed by hydrogen secretion. It has
also been shown that luminal bicarbonate stimu­
lates Na absorption and it is therefore tempting to
suggest that hydrogen secretion drives Na ab­
sorption in an ion-exchange process. There is no
change in electrical potential difference, supporting
the idea of a neutral exchange. The pH gradient
between cell and lumen is visualized as being a
driving force for hydrogen secretion and, hence, for
Na absorption. The presence of a Na/H exchange
cannot be taken as proven, however, since a small
change in potential difference generated for ex­
ample by active hydrogen secretion would be easily
missed in the jejunum, where the freely permeable
mucosa would allow Na to pass down even small
electrical gradients and nullify them. The obser­
vation that, when the lumen is made alkaline with
phosphate, rather than with bicarbonate, sodium
absorption is not enhanced (Sladen & Dawson,
1968) does not support the idea of a pH gradientlimited Na/H exchange, but cannot disprove it. In
the ileum several pieces of evidence point to the
existence of ion-exchange processes (Turnberg et
al., 1970a). Here Na and Cl are absorbed and
H C 0 3 secreted against steep electrochemical
gradients but their transport does not apparently
generate any electrical current, suggesting neutral
processes. In the absence of Cl, Na absorption
continues and is associated with luminal
acidification suggesting a Na/H exchange. If
luminal contents are made acid Na absorption is
inhibited, in support of this notion. In addition a
Cl/HCOj anion exchange is suggested by the
observations that (a) the rate of H C 0 3 secretion is
equal to the rate of Cl absorption when Na
absorption is zero, any Na absorption being
associated with H secretion which dissipates as
carbon dioxide some of the H C 0 3 secreted, (b) Cl
absorption can be manipulated by changing the
luminal H C 0 3 concentration (high bicarbonate
concentrations reducing Cl absorption or even
driving Cl secretion), and (c) a high Pco 2 is
generated in the ileal lumen.
These observations were interpreted in terms of a
double ion-exchange process, Na/H and C1/HC0 3
(Fig. 1). This mechanism allows the ileum to
display a wide range of transport activity. If both
exchanges acted at the same rate NaCl absorption
would occur and the secreted H and H C 0 3 would
exactly nullify each other and be dissipated as
carbon dioxide. Since, usually more Cl is absorbed
than Na, more H C 0 3 is secreted than H, hence the
accumulation of H C 0 3 in the lumen.
This model has been used to explain the defects
in electrolyte absorption which occur in the rare
condition of congenital chloridorrhoea (Bieberdorf,
Gordon & Fordtran, 1972; Turnberg, 1971b).
This disease is characterized by severe watery
diarrhoea from birth, associated with a metabolic
alkalosis. The stool electrolyte concentrations are
grossly distorted by an inordinately high Cl
concentration, which usually reaches more than the
sum of the Na and K concentrations. An absent, or
even reversed, C1/HC0 3 exchange process in the
ileum and colon (Holmberg, Perheentupa & Launiala, 1975) could theoretically produce these abnor­
malities, by allowing the loss of Cl, which, acting as
a non-absorbed 'osmotic purgative', provokes
diarrhoea. The alkalosis will result, according to
this hypothesis, from the excretion of H, in
exchange for Na, and the retention of HC0 3 .
Although small intestinal behaviour in vivo can
be interpreted overall in terms of these ion
exchanges, it is clear that proof of the existence of
such processes requires their demonstration on one
or more of the specific membranes separating the
lumen from interstitial fluid.
The existence of several cell types in the
intestinal mucosa, each having apical and basal cell
membranes, with variably leaky 'tight' junctions
Intestinal transport of salt and water
Lumen
Mucosa
FIG. 1. Double ion-exchange mechanism in human ileum.
between cells, emphasizes the difficulties in in­
terpreting overall behaviour in terms of specific
transport processes in one or other of these
barriers. Although studies in vitro have the
potential for clarifying the underlying processes, it
has not yet been possible to confirm or deny the
existence of ion-exchange mechanisms with con­
fidence.
In the colon, too, there is good evidence, both in
vivo and in vitro, of a C1/HC03 exchange
(Devroede & Phillips, 1969; Parsons, 1956; Frizzell, Koch & Schultz, 1976; Binder & Rawlins,
1973), but here, unlike jejunum and ileum, there is
no evidence for a Na/H exchange. Na is absorbed
entirely by an active electrogenic process, at least
in man and rabbit (P. C. Hawker, K. Mashiter &
L. A. Turnberg, unpublished work; Frizzell et al.,
1976). In the rat a coupled Na C1 absorption has
also been demonstrated (Binder & Rawlins, 1973).
The ion-exchange behaviour is thus distributed
asymmetrically down the intestinal tract: a Na/H
exchange in jejunum and ileum and a C1/HC03
exchange in ileum and colon.
Intestinal secretion
Neurological mechanisms
Gastrointestinal physiologists recognized early
that the small intestine was capable of secreting as
well as absorbing (Florey, Wright & Jennings,
1941). The intestinal secretions, the 'succus entericus', were soon recognized not to have the role
initially postulated for them of a 'digestive' sec­
retion but rather were simple saline secretions
(Wright, Jennings, Florey & Lium, 1940). Atten­
341
tion focused on the possibility of neurological
control. The demonstration that sympathectomized
loops of mammalian intestine in vivo spon­
taneously secreted and that atropine blocked this
secretion, suggested that the parasympathetic
innervation was responsible (Florey et al., 1941).
Similarly, the inhibition by neurotransmitter
blockade of the secretion provoked by distension of
intestinal loops, supported a role for the autonomic
innervation (Caren, Meyer & Grossman, 1974).
Studies in vitro in rabbit ileum have demonstrated
that adrenaline and noradrenaline enhance Na and
Cl absorption, an effect which is blocked by areceptor blockade (Field & McColl, 1973; Hubel,
1976). Acetylcholine, on the other hand, provoked
secretion of Cl in human ileal and jejunal mucosa
in vitro (Isaacs, Corbett, Riley, Hawker &
Turnberg, 1976). Cyclic nucleotide concentrations
in intestinal mucosa are unaffected by cholinergic
agents.
These studies in vitro support the idea that
adrenergic nerves promote ion absorption whereas
cholinergic nerves are concerned with intestinal
secretion. This attractive possibility has not, how­
ever, been confirmed in vivo. J. S. Fordtran
(personal communication) could not demonstrate
jejunal secretion in response to sham feeding in
man at a time when vagal stimulation, at least of
acid secretion, certainly occurred. Nor could we
demonstrate consistent changes in jejunal or ileal
ion transport in normal subjects given cholinergic
and anticholinergic drugs in amounts which were
sufficient to alter intestinal motility (Morris, Pimblett, Hall & Turnberg, 1977). Thus the role of the
autonomic nervous system in control of ion
transport under normal physiological conditions
appears at present to be unimportant. It remains
possible, however, that cholinergic mechanisms
may be involved in abnormal situations where
diarrhoea occurs.
Cyclic adenosine monophosphate and intestinal
secretion
Increasing evidence has implicated cyclic
adenosine monophosphate (cyclic AMP) in in­
testinal secretion in a number of diseases (Field,
1974). Adenyl cyclase, the enzyme catalysing the
formation of cyclic AMP from ATP, is sited on the
basolateral membrane of intestinal villous epithelial
and crypts cells (Murer, Amman, Biber & Hopfer,
1976). Cyclic AMP and agents which increase its
intracellular concentration induce secretion experi­
mentally in vitro. Cholera toxin is believed to act
342
L.A. Turnberg
by stimulating adenyl cyclase predominantly on the
villi (de Jonge, 1975: Weiser & Quill, 1975), and
this view is supported by the observation that
cyclic AMP concentrations and activity of the
cyclase are increased in jejunal biopsies of patients
with cholera, compared with their values in biopsies
taken from the same patients during convalescence
(Chen, Rohde & Sharp, 1972).
The type of secretion induced experimentally by
cholera toxin is identical with that induced by
cyclic AMP and by theophylline, which inhibits
the phosphodiesterase responsible for its break­
down (Powell, Farris & Carbonetto, 1974). The
toxin of cholera (molecular weight 84 000) attaches
to a receptor, probably a ganglioside (GM,), on the
surface epithelium of villous cells (Cuatrecasas,
1973; Holmgren, Lonnroth, Mansson & Svennerholm, 1975). This triggers, after a delay of some
30 min or more, increased activity of adenyl
cyclase which lies on the basolateral membrane of
the cell (Kimberg, 1974). The mechanism by which
the message is transmitted from the receptor on the
apical surface of the cell to the basolateral surface
of the cell is not clear. Once activated by cholera,
adenyl cyclase activity continues at an enhanced
rate for several hours and possibly until that
particular villous epithelial cell is shed into the
lumen and replaced by a non-activated cell (Guerrant, Chen & Sharp, 1972). The major effect of
cholera toxin is on jejunal and ileal mucosa, its
effect on colon being insignificant, despite the fact
that colonic adenyl cyclase does provoke secretion
there when activated by other stimuli (Conley,
Coyne, Chung, Bonorris & Schoenfield, 1976).
Not all experimental observations are im­
mediately explicable in terms of the theory which
links cholera toxin to cyclic AMP. For example,
application of cholera toxin to the serosal aspect
of intestinal mucosa provokes a marked rise in
adenyl cyclase activity and cyclic AMP con­
centrations, but it is not followed by stimulation of
intestinal secretion (Field, Fromm, Al-Awqati &
Greenaugh, 1972). This separation of the effects of
cholera toxin on cyclic AMP and on ion secretion
leads to the suspicion that the two may not be
related. However, other evidence points to the
existence of several distinct pools of cyclic AMP
within epithelial cells (Flores, Witkum, Beckman
& Sharp, 1975) and it has been proposed that the
pool responsible for effects on ion transport is but a
small part of the whole (Field, Sheerin, Henderson
& Smith, 1975). It may only be stimulated from the
mucosal side of the cell and stimulation of cyclic
AMP production from the serosal side does not
involve the particular pool responsible for ion
secretion (Field et al., 1975). This rather tortuous
explanation does not entirely remove the small
doubt about the theory.
There is some controversy about the basis for
the intestinal secretion provoked by cyclic AMP
and it seems likely that several effects are involved.
It apparently induces changes in both intestinal
permeability and in ion-transport mechanisms
(Powell et al, 1974). Love (1969) has shown by
indirect studies in vivo that cholera induces an
increase in intestinal permeability to sodium,
although studies in vitro suggest that a decrease in
permeability is produced (Powell, 1974).
In most high-resistance epithelia, such as frog
skin, cyclic AMP increases permeability of the
tissue and the reduction in permeability in the
intestine in vitro is thus paradoxical. One possible
explanation for the paradox may be found in the
structural changes observed in the intestine in
response to cyclic AMP. The epithelial cells swell
and obliterate the lateral intercellular spaces and
this presumably increases the resistance to trans­
port via the paracellular shunt pathway. Under
conditions where the lateral spaces are kept open,
by, for example, stimulating water absorption with
luminal glucose, cyclic AMP then causes an
increase in conductance as in frog skin (Corbett,
Isaacs, Hawker & Turnberg, 1977). The increased
conductance probably occurs in the tight junctions.
With regard to ion-transport mechanisms, cyclic
AMP apparently inhibits a neutral sodium chloride
influx process across the apical brush-border
membrane of the epithelium (Nellans, Frizzell &
Schultz, 1973) and also probably stimulates either
a coupled Na C1 secretion (Powell et al., 1974) or
chloride secretion (Fromm & Field, 1975). It is
uncertain whether these processes are brought
about by the effects of cyclic AMP on a single cell
or on different types of cell. It is of interest that in
the ileum, both a chloride secretion and a coupled
Na C1 absorption inhibition probably occur,
whereas in the colon cyclic AMP induces only a
chloride secretory response (Frizzell et al., 1976),
and in the gallbladder only inhibition of the neutral
sodium chloride entry process occurs (Frizzell,
Dugas & Schultz, 1975).
A number of other toxins have been shown to
stimulate intestinal secretion. These include toxins
from Escherichia coli (Guerrant, Ganguly, Casper,
Moore, Pierce & Carpenter, 1973), Staphyloccus
aureus
(Sullivan & Asano, 1971), Shigella
dysenteriae (Rout, Formal, Giannella & Dammin,
1975), Clostridium perfringens (McDonel, 1974)
343
Intestinal transport of salt and water
Antitoxin-
Toxoid-
•■Cholera toxin
-»■GM, receptor on
brush border
• intracellular
,
signal
Prostaglandin
+
synthesis
: protein synthesis
?EDCl Cyclohexamide I Tenuazonic acidChlorpromazine2\5'-Dideoxyadenosine^
(Adrenaline) -
; Adenyl cyclase on +* '
• basolateral membrane
Indomethacin
Aspirin
?TAP
Enhanced,
absorption
Prednisolone
FIG. 2. Outline of possible biochemical steps leading to cholera toxin-mediated intestinal secretion. Mechanisms
by which agents that interfere with this secretion are presumed to act (see text). EDC, l-ethyl-3-(3-dimethylaminopropyl)carbodi-imide; TAP, 2,4,6-triaminopyrimidine.
and Klebsiella pneumoniae (Klipstein, Horowitz,
Engert & Schenk, 1975). Of these only E. coli and
Cl. perfringens have so far been shown to stimulate
adenyl cyclase activity (Evans, Chen, Curlin &
Evans, 1972).
Despite the effects on ion transport, cyclic AMP
does not apparently interfere with absorption of
nutrients such as glucose and amino acids. Nor
does it interfere with the enhanced Na and water
transport that accompanies glucose absorption and
this has led to a considerable therapeutic advance.
The use of glucose/saline solutions in the oral
treatment of patients with cholera and other forms
of severe diarrhoea has been of considerable
benefit, particularly in parts of the world where
intravenous solutions are not readily available or
are very expensive (Hirschhorn, Kinzie, Sachar,
Northrup, Taylor, Ahmad & Phillips, 1968;
Lancet, 1977).
Increasing information about the biochemical
events involved in cholera toxin-induced secretion
has led to an investigation of a large number of
compounds which may interfere with one or more
of these steps in the hope that an effective
treatment might be found (Fig. 2). Cholera toxoid
attaches to the GMt receptor but does not
stimulate adenyl cyclase. It certainly prevents
cholera toxin-induced intestinal secretion but is
only effective if it is applied before contact with the
toxin (Pierce, 1973).
1 - Ethyl - 3 - (3 - dimethylaminopropyl)carbodi imide (EDC) has been shown to prevent cholera
toxin-induced rises in cyclic AMP concentrations
in thymus-derived lymphocytes (Holmgren &
Lonnroth, 1975). It apparently does this by inter­
fering with the 'signal' mechanism which transmits
the stimulus across the cell from the receptor to the
adenyl cyclase. It does not interfere either with
toxin-receptor interaction or with adenyl cyclase
activity. Its effects on intestinal mucosa have not
been reported, however. Cyclohexamide and
tenuazonic acid inhibit cholera-induced secretion,
probably by interfering with new protein (?
enzyme) synthesis necessary for secretion to occur
344
L. A. Turnberg
(Kimberg, Field, Gershon, Schooley & Henderson,
1973; Moritz & Womelsdorf, 1973). Cyclohexamide does not influence the increase in adenyl
cyclase activity provoked by cholera toxin and
presumably acts at some protein synthetic step
beyond cyclic AMP leading to secretion. An
adenosine
analogue
(2',5'dideoxyadenosine)
inhibits cholera-induced rises in adenyl cyclase
activity in human embryonic intestinal epithelial
cells (Zenser, 1976), but its effects on intestinal
secretion
have
not
yet
been
reported.
Chlorpromazine given 1 h before cholera toxin
challenge prevented intestinal secretion in the
mouse, probably by inhibiting adenyl cyclase
activity (Lonnroth, Holmgren & Lange, 1977). It
remains to be seen whether it is effective when
given after secretion has been initiated.
Adenaline, too, inhibited cholera-induced rises in
cyclic AMP concentrations in rabbit ileum but
surprisingly did not significantly influence the
intestinal secretory response (Field et ah, 1975). To
explain this paradox resort has to be made to the
notion that ion-transport-related cyclic AMP is
only a small part of total mucosal cyclic AMP. The
agent 2,4,6-triaminopyrimidine (TAP) has been
held to block cation transport through the tight
junctions and it has been shown to inhibit theophylline-induced intestinal secretion in rabbit ileum
(Naftalin & Simmons, 1976). Although there is
some doubt about the specificity of the activity of
2,4,6-triaminopyrimidine and also about the role of
changes in intestinal (presumably tight-junctional)
permeability in cholera secretion, studies of 2,4,6triaminopyrimidine and possible further deriva­
tives may be well worth pursuing.
Ethacrynic acid has been shown to reverse
intestinal secretion provoked by cholera toxin and
it probably exerts its effect at a step beyond the
elaboration of cyclic AMP (Al-Awqati, Field &
Greenhaugh, 1974).
Prednisolone, too, reverses net intestinal sec­
retion after exposure to cholera toxin and it
probably acts by stimulating a simultaneous
increase in the absorptive flux. The increase in Na,
K-dependent adenosine triphosphatase activity in
mucosa after prednisolone treatment is probably
responsible for the enhanced absorption (Charney
& Donowitz, 1976).
Indomethacin and aspirin have both been shown
to inhibit cholera toxin- and Sa//MO«e//a-induced
intestinal secretion without interfering with adenyl
cyclase activity or production of cyclic AMP
(Farris, Tapper, Powell & Morris, 1976; Gots,
Formal & Giannella, 1974; Giannella, Rout &
Formal, 1977). Since these agents are potent
inhibitors of prostaglandin synthesis, it has been
tempting to suggest that their mode of action in
inhibiting intestinal secretion is via this mechanism
and that, as a corollary, prostaglandin synthesis is
involved in the mechanism for the secretion.
However, although prostaglandins can induce
secretion by activating adenyl cyclase there is no
direct evidence of their participation in cholerainduced secretion (Wald, Gotterer, Rajendra,
Turjman & Hendrix, 1977). The action of prosta­
glandins on concentrations of cyclic AMP is
additive to that of cholera toxin, suggesting that
they are not directly involved in the action of
cholera. In addition, aspirin and indomethacin have
been shown to stimulate Na and Cl absorption in
normal tissues and it may be this activity which is
responsible for their effect on cholera. Neither
agent has yet been shown to be therapeutically
useful to my knowledge.
Although much of this work has yet to be
applied in the clinical field, it is clear that there are
likely to be many advances made in this fascinating
area.
Endogenous activators of intestinal adenyl cyclase
There are a number of endogenous stimulators
of adenyl cyclase which may conceivably have a
role in the physiological control of ion transport or
in the production of diarrhoea. The relatively
recently isolated hormone vasoactive intestinal
peptide (VIP) and a number of the prostaglandins
(F2cr and E2) have been shown to have this activity
(Schwartz, Kimberg, Sheerin, Field & Said, 1974;
Kimberg, Field, Johnson, Henderson & Gershon,
1971). Both stimulate adenyl cyclase in intestinal
mucosa in vitro and both induce intestinal secretion
in vivo and in vitro (Matuchansky & Bernier,
1973). Of all the gastrointestinal hormones found
in the small intestinal mucosa, VIP is quantitatively
the most plentiful (Pearse, Polak & Bloom, 1977).
It is produced by specific intestinal mucosal cells,
demonstrated by immunofluorescence. It has also
been shown recently in submucosal nerves, raising
the possibility that it may act as a 'peptidergic'
neurotransmitter (Bishop, Polak, Buchan, Bloom &
Pearse, 1977).
Prostaglandins, too, are synthesized locally in
the small intestine where there is a high con­
centration of prostaglandin synthetase (Waller,
1973).
This local production of both of these agents
suggests that they might have a role in control of
Intestinal transport of salt and water
intestinal function and, possibly, intestinal trans­
port, but a physiological role has not yet been
defined for either of them. However, both agents
have been implicated in the pathogenesis of
diarrhoea. VIP has been found in excess in the
plasma of patients with the Vernier-Morrison
syndrome (watery diarrhoea with hypokalaemia)
and it is believed to be produced by non-jS-cell
adenomata or carcinomata of the islets of Lan­
gerhans (Bloom, Polak & Pearse, 1973). This
condition, characterized by severe watery
diarrhoea, is cured by removal of the pancreatic
tumour, suggesting that the hormone liberated by
the tumour is responsible for the diarrhoea. One
patient was shown to be producing not VIP but
excess amounts of prostaglandins from the
pancreatic tumour and the diarrhoea in that patient
was improved with indomethacin (Jaffe, Kopen, de
Schryver-Kecskemeti, Gingerich& Greider, 1977).
Patients with medullary carcinoma of the thy­
roid frequently have diarrhoea and they also
commonly secrete an excess of prostaglandins from
their tumour (Williams, Karim & Sandier, 1968).
Although other substances are produced by these
thyroid tumours, including calcitonin, prosta­
glandins may well play a part in the pathogenesis of
the diarrhoea.
It has been postulated that local release of
prostaglandins may play a role in the pathogenesis
of infective diarrhoea. Direct evidence in favour of
this mechanism is, however, lacking, even though
indomethacin, a prostaglandin synthetase inhibitor,
inhibits cholera- and Salmonella-induced intestinal
secretions.
Two other classes of compound found in the
lumen of the intestine are also capable of stimulat­
ing adenyl cyclase and intestinal secretion. Deconjugated bile acids can provoke small and large
bowel secretion and these are very likely to be
responsible for the diarrhoea arising in the colon
provoked by removal of the terminal ileum (Mekhjian, Phillips & Hofmann, 1971). In these patients
bile salts escape into the colon in undue amounts
and provoke colonic secretion. Bile salt-chelating
agents (cholestyramine) prevent this activity and
are therapeutically beneficial. Propranolol has also
been shown to inhibit deoxycholate-induced sec­
retion and adenyl cyclase activity in rabbit colon
(Conley et ah, 1976), but to my knowledge it has
not yet been reported to be of benefit
therapeutically in patients with post-ile-ectomy
diarrhoea. Certain long-chain fatty acids (C,8)
have also been shown to stimulate colonic secretion
and they may be responsible for enhancing the
345
diarrhoea of patients with steatorrhoea (Ammon,
Thomas & Phillips, 1974).
Other intestinal secretory mechanisms
Intestinal secretion can be provoked by noncyclic AMP-mediated mechanisms. Thus some of
the gastrointestinal hormones: gastrin (Modigliani,
Mary & Bernier, 1976), cholecystokinin (Barbezat
& Grossman, 1971), secretin, glucagon (Hicks &
Turnberg, 1973, 1974), calcitonin.(Gray, Brannan,
Juan, Morawski & Fordtran, 1976) and serotonin
(Donowitz, Charney & Heffernan, 1977), have
each been shown to be capable of stimulating
secretion in man and experimental animals in vivo,
although the doses used have usually been phar­
macological rather than physiological. Although
adenyl cyclase activity is uninfluenced by these
hormones (Schwartz et al., 1974) it is conceivable
that these agents still act by stimulating cyclic
AMP production but that they have a very specific
action on a small pool relevant to ion secretion.
However, an alternative possibility has been pos­
tulated for glucagon (Mahklouf, 1977; Isaacs &
Turnberg, 1977). Here increased blood flow and
changes in motility which glucagon provokes may
exert an effect on intramucosal hydrostatic
pressure. A pressure rise here has been shown to be
capable of inhibiting absorption and possibly
inducing secretion.
It is unlikely that these hormones exert any
physiological effect on ion transport in the intestine
but it is possible that they could be involved in
intestinal secretion in some forms of diarrhoea. For
example, the raised plasma calcitonin con­
centrations in patients with medullary carcinoma of
the thyroid may be responsible for the diarrhoea in
such patients (Isaacs, Whittaker & Turnberg,
1974; Gray, Bieberdorf & Fordtran, 1973).
Summary
Evidence is accumulating which is helping to
clarify our ideas about the underlying mechanisms
of intestinal salt and water transport. We are
beginning to understand the role played by paracellular as well as cellular routes for transport and
the different characteristics of the apical and basal
cell membranes and their influence on overall
transport. Finally, there are some fascinating
glimpses of future prospects for the biochemical
manipulation of intestinal secretory processes
underlying a number of diarrhoeal diseases.
346
L. A. Turnberg
Key words: intestine, sodium, transport, water.
Abbreviations: cyclic AMP, adenosine 3': 5'phosphate.
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