Clinical Science and Molecular Medicine (1973) 45,593-606.
RELATIONSHIPS BETWEEN I O N A N D WATER
MOVEMENT I N T H E H U M A N JEJUNUM, ILEUM A N D
COLON D U R I N G P E R F U S I O N WITH BILE A C I D S
D. L. WINGATE,' E. KRAG,2 H. S. MEKHJIAN3
S . F. P H I L L I P S
AND
Gastroenterology Unit, Mayo Clinic and Mayo Foundation, Rochester, Minn., U.S.A.
(Received 4 June 1973)
SUMMARY
1. Perfusion of the human jejunum with low concentrations of glycine-conjugated
bile acids in physiological solutions induced net fluid flow that varied between absorption and secretion, with only slight variation of the luminal osmotic and ionic
milieu.
2. Transmucosal net flux rates for water and the principal ions were calculated.
Regression analysis of the flux data was consistent with the concept of a 'net transported fluid' which was iso-osmotic with respect to the lumen, with a superimposed
fixed net anion exchange unaffected by the rate or direction of bulk flow.
3. Recalculation of earlier data from comparable studies of the human colon
showed similar relationships consistent with varying iso-osmotic bulk flow and fixed
ion exchange, the latter differing from that found in the proximal bowel.
4. Studies were performed also in the human ileum. Variable iso-osmotic bulk flow
was again encountered, but ion exchange was of a lower magnitude than in the
jejunum or colon. Qualitatively, ion exchange in the ileum was intermediate between
the jejunum and colon.
5. These analyses suggest that transmucosal bulk flow and ion exchange may be
quantitatively and spatially independent processes. They provide support for the
hypothesis that bulk flow may be intercellular (and hence extracellular), while ion
exchange may take place across the luminal face of the mucosal cell.
6. Secretory agents, such as the dihydroxy bile acids, provide a useful means of
analysing solutesolvent flow relationships in greatly differing bulk flow conditions
with relatively stable physicochemical parameters.
Present address: London Hospital Medical College, London, England.
* Present address: Department of Medicine, Gentofte Hospital, Copenhagen, Denmark.
Present address: Department of Medicine, Ohio State University, Columbus, Ohio, U.S.A.
Correspondence.: Dr D. L. Wingate, Department of Physiology, London Hospital Medical College, Turner
Street, London El 2AD, England, or Dr S. F. Phillips, Section of Publications, Mayo Clinic, Rochester,
Minnesota 55901,iU.S.A.
593
D. L. Wingate et al.
594
Key words : electrolyte absorption, water absorption, human, ileum, jejunum, colon,
bile acids, anion exchange.
In the study of the forces governing bulk flow across the intestinal mucosa, the importance of
osmotic pressure has been the subject of speculation since Reid (1892) demonstrated asymmetric bulk flow across intestine in vitro between identical solutions. These observations
were greatly extended and quantified by the work of Visscher and his colleagues (Visscher,
Fetcher, Carr, Gregor, Bushey & Barker, 1944; Visscher, Roepke & Lifson, 1945), who showed
that net water absorption was not due to osmotic gradients between plasma and intestinal
lumen. Subsequent work has confirmed that the bulk flow across the mucosa between isoosmotic fluids is iso-osmotic, and models have been proposed (Curran, 1960; Diamond &
Bossert, 1967; Diamond, 1971) which would accomplish such bulk flow by local intramucosal
osmotic forces.
The ratio of net solvent to net solute flux is essentially the osmotic concentration of the ‘net
transported fluid’. Since Visscher and his colleagues found that bidirectional water and ion
fluxes greatly exceeded net fluxes, the concept of ‘net transported fluid’ is an abstraction, except
in vitro where such a fluid may be collected as serosal ‘sweat’. But, even in vivo, the concept
is useful in helping to define the possible forces responsible for solvent and solute flows. The
interpretation of solute-solvent relationships in terms of single ions, rather than total osmotic
solutes, has been complicated by the demonstration of ion exchange at different intestinal loci,
such as chloride-bicarbonate exchange in small and large intestine, and sodium-potassium
exchange in the colon (D’Agostino, Leadbetter & Schwartz, 1953; Parsons, 1956; Phillips &
Summerskill, 1967; Swallow & Code, 1967).
It has not been clear whether ion exchange and bulk flow across the intestine are related
phenomena. Part of this uncertainty has been due to the inability to define relationships
between net ion and net water transport over a wide range of bulk flows without gross chemical
or osmotic alteration of the luminal milieu. Dihydroxy bile acids alter net water movement
in vivo and in vitro when used in concentrations of less than 10 mM. They induce reversed
bulk flow in vivo, with only trivial disturbance of the osmotic gradient across the intestinal wall
(in contrast to the use of mannitol or impermeant ions) and without morphological change.
This phenomenon has been demonstrated in the intact perfused human colon (Mekhjian,
Phillips & Hofmann, 1971), jejunum (Wingate, Phillips & Hofmann, 1973), and ileum (Krag
& Phillips, 1973). Regression analysis of net ion and net water transport over a wide range of
bulk flow rates (net absorption and net secretion), induced by dihydroxy bile acids, suggests
that ion exchange and bulk flow can be separately identified in this way. We report these
observations because dihydroxy bile acid perfusions offer a useful experimental system
susceptible to kinetic analysis, and because our data clarify relationships between intestinal
bulk flow and ion exchange.
METHODS
Jejunal perfusions
Perfusions were performed on eleven healthy volunteers, four test solutions being perfused
through a 25 cm segment of jejunum in each person. One perfusion was with a control electrolyte solution (Table l), and three perfusions used solutions containing pure glycine-conjugated
Ion exchange and bulk flow in human bowel
595
TABLE
1. Composition of solutions
~
Na+ (mmol/l)
K+ (mmol/l)
a-(mmol/l)
HCOj (mmol/l)
Glucose (mmol/l)
Bile acid (mmol/l)
~~
Jejunum
Colon
Ileum
139
5
100
40
11.2
0-10
130
20
95
48
135
5
93
47
11.2
0-10
-
0-10
TABLE
2. Number of studies with each bile acid
Concn. in jejunum
(mmol/l)
Bile acid conjugates
Deoxycholic acid
2-5
5.0
10.0
Concn. in colon
(mmOl/l)
n=4
n=4
n=4
Chenodeoxycholicacid
2.5
n=4
5.0
n=4
10.0
n=4
Cholic acid
2.5
n=3
5.0
n=3
10.0
n=3
Mixed conjugates
Concn in
ileum
(mmol/l)
1 .o
3.0
6.0
n=l
n=2
n=l
1.0
2-5
5.0
n=4
n=4
n=4
3.0
n=l
1.0
25
5.0
n=4
n=4
n=8
10.0
10.0
n=3
n=6
10.0
n=4
n=3
n=4
n=l
1.0
2.5
5.0
n=4
n=4
n=4
n=3
n=3
n=3
n= 1
1-0
2.5
n=4
n=4
5.0
n=4
n=3
10.0
n=4
Unconjugated bile acids
Deoxycholic acid
1 .o
3.0
6.0
Chenodeoxycholicacid
1.o
3.0
5.0
10.0
Cholic acid
10.0
Total
n=M1
n=35
962
Includes eleven control studies (no bile acid).
Includes twenty-four control studies (no bile acid) and twelve studies with
mixtures of conjugates and unconjugated bile acids.
596
D. L. Wingate et al.
bile acids (Table 2). The perfusion system employed a double-lumen tube with a proximal
occlusive balloon (Phillips & Summerskill, 1966). Absorption of water and organic solute in
these studies is described in detail elsewhere (Wingate et al., 1973).
Solutions were iso-osmotic with plasma Qable 1) and also contained glucose to secure
optimal water absorption from the control solution. The results of control and bile acid perfusions have been included here. In a total of forty-four studies, water was absorbed in thirtyone and secreted in thirteen; the range (ml/min per 25 cm ofjejunum) was - 3.81 (secretion) to
+ 3.25.
Sodium and potassium were measured by flame photometry, and chloride was measured
electrotitrimetrically. Volume change was assessed by a non-absorbable volume marker,
polyethylene glycol (PEG). PEG labelled with 14C was used and assayed by liquid-scintillation
counting (Wingate, Sandberg & Phillips, 1972).
Colonicperfusion
Thirty-five bile acid perfusions (Table 2) were performed on twenty healthy volunteers, by
the technique of Devroede & Phillips (1969a). Details of these studies have been published
(Mekhjian et al., 1971). In thirty-five bile acid perfusions, water was absorbed in eighteen and
secreted in seventeen. The range of water movement (ml/min) in the colon was - 3.90 (secretion) to +2-79.
The perfusing solution (Table I) was designed to simulate fasting human ileal content
(Devroede & Phillips, 1969a); PEG was the non-absorbable marker, and it was assayed
turbidimetrically (Wingate et al., 1973).
Ileal perfusion
Ninety-six perfusions were performed on eight healthy volunteers, each subject receiving
four test solutions on each day of study. Solutions were control electrolyte with glucose, or the
same solution containing free or glycine-conjugated bile acids (Tables 1 and 2). The perfusion
system and analytical methods were identical to those of the jejunal studies. Fluoroscopic examination at the beginning and end of each study confirmed that the 25 cm segment under study
always terminated within 10 cm of the caecum. Details of bile acid absorption and the influence
of bile acids on water absorption have been described elsewhere (Krag & Phillips, 1973). The
range of water movement in ninety-six studies was (ml/min per 25 cm of ileum) - 1.50 (secretion) to +1*60.
Bicarbonate movement
Bicarbonate concentrations were measured directly in the ileal and colonic studies but not in
the jejunal studies. Moritz, Iber & Moore (1971) showed a close correlation between net
bicarbonate movement as calculated from direct measurement of bicarbonate concentrations
and that calculated from the ‘ion gap’, that is, by utilizing the difference between total cation
(sodium plus potassium) and chloride concentrations.
When net bicarbonate movements, calculated in these two ways, were compared in the ileal
and colonic perfusions, the regression coefficients (0.94 and 0-96 respectively) and the intercepts ( 5 and - 31 ,umol/min) did not differ significantly from the line of equivalence: the
correlation coefficients were 0-84 and 0.87 respectively. The magnitude of differences in individual perfusions is small in relation to observed ion movements. These discrepancies may be
Ion exchange and bulk flow in human bowel
597
due to incomplete bicarbonate recovery in the assay or to the presence of small amounts of
another anion in recovered fluids. We chose to use 'calculated' net bicarbonate movements in
the analysis of our colonic and ileal data so as to present the results of all perfusions uniformly.
Calculations
A similar mathematical treatment of all perfusion systems is justified. If volume V is perfused
into the study segment (in unit time) and initial and final concentrations of non-absorbable
marker are [PEG,] and [PEG,] respectively, the volume change is :
V(1 - [PEGiI/PEGoI)
(1)
If the initial and final concentrations of a perfused solute are ci and co, net solute change is:
V
(Ci
- co [PEGiI/PEGoI>
(2)
The linear regression of net solute change against net volume change may be calculated
in the form y =bx +a. The regression coefficient b represents a concentration which, for convenience, we have expressed as mmol/l. A direct comparison is then available of the ratio of
solute to solvent in the net transported fluid. This can be compared with concentrations of
solute in the perfusate and in the plasma.
Absorption rates for solutes and water for each perfusion at both sites are the means of at
least four steady-state observations at the conclusion of an equilibration period of 1 h. The
number of data points for each regression is the number of separate perfusion studies in the
series.
RESULTS
Relationship between net ion and water movement in the jejunum
Detailed tables of the results from the jejunum, ileum and colon have been deposited with
the Librarian at the Royal Society of Medicine, London, W.l, England, who will issue copies
on request (Clinical Science and Molecular Medicine Tables 73/15-17).
The calculated regression lines for each ion against water are shown in Fig. 1, with the
appropriate regression statistics. Although small intercepts are present on the y axis for both
the sodium and potassium lines, these lines do not differ significantlyfrom lines passing through
the origin. However, both the chloride and the bicarbonate lines differ significantly(P<0401)
from the lines of the same slope passing through the origin.
Thus, net ion movement shows a linear relationship to net water movement, and, for each
cation species examined, it appears that the net ion concentration in the fluid absorbed or
secreted is identical with the ion concentration of the perfusate. At zero net water movement
(x=O), there is zero net cation movement. But the intercepts of the anion linear regressions
show anion exchange in the absence of bulk flow, the magnitude of this exchange being approximately 87 pmol min- 25 cm test segment (calculated from the mean intercepts for chloride
and bicarbonate on the y axis). From the calculated regressions, when water is secreted at 2
ml/min, the secretion is effectively iso-osmotic saline, since net bicarbonate movement is
effectively zero.
'
Relationship between net ion and water movement in the perfused colon
Linear regressions between ion and water movement are illustrated in Fig. 2. These relation-
D. L. Wingate et al.
598
ships are a striking contrast to those found in the jejunum. The slopes of the lines for sodium
and potassium (Pc0.01) differ from those for the anions. There is also a small, but significant,
intercept on the y axis for both cations (P<O-OOl). A similar but larger intercept is present for
both anions. Both chloride (P<O.OOl) and bicarbonate (P<0*05)
differ by a small magnitude
from their concentrations in the perfusate. The lines for both anions differ significantly from
the lines of the same slope passing through the origin (PcO*OOl).
FIG. 1. Relationships between net movements of ions and water during perfmion of human
jejunum with solutions that evoked marked secretion or absorption of ions and water. Concentrations (c in mmol/l) of ions in perfusates are compared with regressionstatistics( y = b x + u ) for each
relationship as follows:
c1HCO 3-
40
-1
0.92
95
-92
48
80
0.98
0.89
While the composition of net secretion into the jejunum, at 2 ml/min was predominantly
sodium chloride, Fig. 2 shows that similar secretion into the colon at 2 ml/min is predominantly sodium bicarbonate, and fluid absorbed at 2 ml/min is predominantly sodium chloride.
It should be remembered that, although fluid flow rates are in a similar range in jejunal,
ileal and colonic studies, movement in the small intestine is expressed as unit flow min-
'
Ion exchange and bulkJlow in human bowel
599
25 cm of perfused segment- ', whereas colonic flow is expressed as unit flow/min for the entire
large intestine.
Relationship between net ion and net water movement in the perjiised ileum (Fig. 3 )
The slopes of the regression lines for all ions do not differ significantlyfrom the concentration
of the corresponding ions in the perfusing solutions. The lines for sodium and bicarbonate do
- 300Secretion
Fro.2. Relationships between net movements of ions and water during perfusion of human colon
with solutions that evoked marked secretion or absorption of ions and water. Concentrations (c in
mmol/l)of ions in perfusates are compared with regression statistics(y=bx+ u) for eachrelationship
as follows:
not differ significantly from lines of the same slope passing through the origin. The intercept
of the potassium on the y axis, although of small magnitude, is significantlydifferent from zero
(P<O.Ol), because of the extremely small dispersion of potassium net movement. The difference between the observed line for chloride and one of the same slope passing through the
origin is of borderline significance (P=0.05).
Like the jejunum, the ileum secretes mainly sodium chloride but only at rates of water
secretion up to 0.2 ml min-' 25 cm segment-'. At higher rates of secretion, bicarbonate
contributes proportionately greater amounts of secreted anion.
D. L. Wingate et al.
600
Secretion
- 200
I
FIG.3. Relationship between net movements of ions and water during perfusion of human ileum
with solutions that evoked marked secretion or absorption of ions and water. Concentrations (c in
mmol/l) of ions in perfusates are compared with regression statistics (y=bx+u) for each r e
lationship as follows:
Ion
Na+
K+
ClHCO q-
c
b
a
135
5
93
41
131
6
95
41
-24
r
0.98
-5
0.87
- 35
0.96
5
0-84
DISCUSSION
Expression of the relationship between net ion and water movement as the concentration of
ions in the net transported fluid is not a new concept (Code, Bass, McClary, Newnum & Orvis,
1960). Hitherto, variation in water movement has often necessitated the use of greatly altered
intraluminal conditions produced by impermeant solutes (Fordtran, Rector & Carter,
1968), low sodium concentration (Phillips & Code, 1966; Fordtran et al., 1968), or toxic
substances unsuitable for human investigation (Moritz et al., 1971). The difficulty of determining these relationships over a wide range of water movement has limited the value of such
analyses. The use of the dihydroxy bile acids in vivo induces a wide range of water movement,
both absorptive and secretory, while the luminal milieu varies little, particularly with regard to
osmolarity. In our perfusions, osmolarity of the perfusion fluid varied by no more than 10
mosm/l. Moreover, the secretory effect of bile acids is rapidly reversible in vivo and unassociated with mucosal damage (Mekhjian & Phillips, 1970).
Ion exchange and bulk flow in human bowel
601
The wide range of net water movement found in our studies enables us to define the relationships between net ion and net water movement with considerable precision, as shown by the
closeness of the correlation coefficients (in Figs. 1,2 and 3) to unity, and allows further examination of the relationships.
Interpretation of regression analysis
When solute exchange takes place between two volumes of solution separated by a permeable barrier, the net solute flux (J
is the difference between opposing unidirectional
solute fluxes (Jsin,JsOut),both for single molecular species and for total solute flux.
(3)
This also holds true for solvent flux, and where the exchange takes place between two
aqueous phases, the net water flux (JVnet)is synonymous with net volume flow and bulk
flow.
If net solute flux is determined by net solvent flux so that the ratio of solute to solvent in the
net fluid flow is constant, this may be stated as:
J'net
=J'ln-
JSnetIJVnet
J'out
=K
(4)
or
J S n e t = K (Jvnet)
(5)
In an experimental system, this may be tested by calculating the regression for y =bx, with net
solute change on the y axis, net volume change on the x axis, and the regression coefficient (b)
representing the constant ratio (K). This appears to be true for the regressions of sodium and
potassium ions on net water movement in our jejunal studies, where the regression lines do not
differ significantly from lines passing through the origin.
Where significant intercepts on the y axis are found, net solute flux must be considered in
terms of two components. It is therefore postulated that net solute flux is the sum of net
solute flux determined by volume flow (JG), and a net solute flux of fixed magnitude (Ji).
J; =K ( J V n e t )
(6)
JSnet=JG+J:
(7)
Combining equations (6) and (7), we obtain:
JSnet=K(JVnetl+J:
(8)
It will be seen that this corresponds to the regression equation y = b x + a , and therefore by
solving the equation for the constants a and b, we obtain an estimate of the fixed net solute
flux (Ji) and the proportion of net solute flux (J;) that is governed by volume flow.
Jejunal ion movement
Fordtran et al. (1968) and Turnberg, Fordtran, Carter & Rector (1970b) proposed a sodiumhydrogen exchange in the human jejunum and also noted that sodium absorbed as sodium
bicarbonate is flow independent, and only that portion absorbed as sodium chloride is influenced by water movement.
The present results confirm their experimental observations. However, examination of the
C
602
D . L. Wingate et al.
kinetics of ion movement in relation to water movement in our studies leads to the conclusion
that net cation movement is entirely flow dependent, whereas net anion movement is partially
flow dependent and partially flow independent. The results suggest that the flow-independent
moiety is an anion exchange of fixed magnitude, whereas in the bulk transfer, ions are at the
concentration of both luminal fluid and plasma. Although we have expressed our results in
terms of net absorption of bicarbonate, this absorption might result from hydrogen-ion
secretion by the mucosa (Turnberg et al., 1970b); but again the implication persists that such
a secretion of hydrogen ion is flow independent.
An alternative explanation for our findings is that the bulk solution flowing at all times is one
of sodium chloride, and superimposed on this is an anion exchange. This exchange is zero
during marked bulk secretion but increases linearly as bulk flow is reversed and becomes net
absorption. This would imply that all the chloride absorbed by bulk flow at a net absorption
rate of 1 ml/min is exchanged for bicarbonate. This hypothesis seems unattractive because it
requires that, during secretion, the concentration of chloride in the net transported fluid is
greater than the chloride concentration in either plasma or intestinal lumen ;further, it suggests
that a process of net chloride secretion is activated by secretory agents. However, Binder &
Rawlins (1972) have observed in vitro that bile acids induce chloride secretion in the rat colon.
An important consequence of our interpretation is the apparent absence of a solvent drag
effect on the anion exchange. If, as has been argued by Fordtran, Rector, Ewton, Soter &
Kinney (1965), the effective jejunal permeability barrier is a pore membrane, then the absence
of a solvent drag effect on the anion exchange suggests that it does not take place through a
pore membrane which is simultaneously mediating bulk flow. Koefoed-Johnsen & Ussing
(1953) have shown that solvent drag occurs when solute and solvent flow through pores in a
membrane in which solvent and solute are insoluble. We have shown elsewhere (Wingate
et al., 1973) that changes in glucose absorption in our studies may be due to solvent drag.
The regression coefficients for sodium, potassium and chloride do not differ significantly
from the inflow and outflow concentrations of the perfusing solutions, or from the plasma
concentrations of these ions. This suggests that the flow-dependent moiety of the net transported fluid is essentially iso-osmotic.
Colonic ion movement
Our findings are compatible with previous findings that the colon conserves sodium and
chloride during normal absorption (Devroede & Phillips, 1969b). Although sodium-potassium
exchange has been implicated in colonic absorption of sodium (Phillips & Code, 1966), this
process was of relatively small magnitude in the present studies. Cation exchange was greater
when water was secreted, and we cannot exclude the possibility that sodium-potassium
exchange was absent during normal absorption. By contrast, anions were exchanged and chloride was conserved over a large range of net water movement. Solutions employed in the colon
were not similar to plasma, being based on composition of the solutions which are absorbed
from the colon without undergoing a change in composition (Code, Phillips & Swallow,
1966), and the interpretation of our results is thereby limited. Bicarbonate ‘secretion’ by the
colon could be attributed to secretion of hydroxyl ions into the lumen, or removal of hydrochloric acid from the contents, but our observations do not allow bicarbonate secretion to be
specified in these terms. A previous statistical analysis of the colonic data (Mekhjian et al.,
1971) treated absorption and secretion as separate circumstances. However, it is uncertain in
Ion exchange and bulk flow in human bowel
603
the present state of knowledge if such a separation in terms of different transport mechanisms
is justified. Some of the differences previously noted between absorption and secretion may
reflect the ion content of mucus (Giller & Phillips, 1972) which is expelled into the lumen in
significant amounts during net fluid secretion.
The inference drawn from the present analysis of the colonic perfusions is that a similar
fixed anion exchange exists in the colon, as in the jejunum, but in the reverse direction; in
addition, there is evidence of a small fixed cation exchange. The magnitude of these changes
may be assessed from the intercepts on the y axis of the regression lines in Fig. 2, when net
water movement is zero.
Ileal ion movement
The regression coefficient for all ions does not differ significantly from the concentrations
of the perfusing solutions. This suggests that flow-dependent net transport is iso-osmotic. The
composition of perfusates is one at which no changes in electrolyte composition are expected
to occur during bulk absorption and secretion (Phillips & Summerskill, 1967). Since the perfusates at each site are of similar composition, inspection of Figs. 1,2 and 3 reveals the progression of anion movement at zero net water movement from jejunum to colon. For bicarbonate, absorption occurs in the jejunum, secretion in the colon, and zero net movement
in the ileum.
Turnberg, Bieberdorf, Morawski & Fordtran (1970a) characterized ileal electrolyte transport
as a simultaneous double exchange of chloride for bicarbonate and of sodium for hydrogen.
Our results are in general accord with this concept, but some differences are apparent when
Fig. 2 of Turnberg et al. (1970a) and our Fig. 3 are compared. The presence of an additional
absorbable solute (glucose) in our perfusates has the effect of displacing our ion-water regression slightly to the right; this could explain our observation of a small secretion of sodium
at zero net water movement. However, our finding of bicarbonate absorption and chloride
secretion at zero bulk flow is opposite in direction from the results of Turnberg et al. (1970a).
Thus, we found less evidence of fixed ion exchange in the ileum and Turnberget al.’s (1970a)
results are in closer accord with our findings in the colon. Whether these differences are related
to technique or reflect an unsuspected influence of bile acids is uncertain. However, we found
a gradation of anion exchange between the jejunum and colon, with the ileum displaying
intermediate features.
Ion exchange and bulk$ow
Simultaneous examination of ion-exchange mechanisms and bulk flow presents a methodological dilemma. The isolated intestine in vitro offers many advantages, but such experimental
systems do not commonly measure bulk flow; conversely, perfusion of the intact intestine
without access to the serosal compartment restricts the inferences that may be drawn. The
nature of the mechanism that is affected by dihydroxy bile acids, thereby modifying bulk flow,
in unknown, but it is permissible to comment on net ion transfer in relation to bulk flow.
The behaviour of our test solution in the jejunum suggests that there is net fluid flow of the
same composition as the luminal fluid (or the extracellular fluid) and that anion exchange (or
hydrogen-ion secretion) is unrelated to bulk flow. There are similar implications from the
colonic perfusions, particularly with the persistence of anion exchange during reversed bulk
flow.
604
D. L. Wingate et al.
The proposition that more than one mucosal site mediates water and electrolyte transfer
derives historically from the ‘fluid-circuit’ hypothesis of Ingraham, Peters & Visscher (1938).
Recently, it has been suggested that absorption and secretion of fluids and electrolytes are
mediated through separate sites (Fordtran et al., 1968). These sites could be represented by
transcellular and intercellular routes (Fromter & Diamond, 1972; Schultz & Frizzell, 1972;
Ussing, 1972), different cell populations, or different functions of villus tip and crypt (Hendrix
& Bayless, 1970).
We cannot identify separate components of bulk flow with our perfusion system, but our
experiments show a fixed rate of ion exchange that is independent of bulk flow. If ion exchange
and bulk flow occur at the same mucosal site, solvent drag might be predicted to influence ion
exchange. That such did not occur implies that these two processes are functionally and possibly
spatially separate.
Tormey, Smulders & Wright (1971) concluded that there was a common pathway for all
fluxes across gall-bladder epithelium. There is increasing evidence that the main transepithelial
bulk flow route is intercellular, and that this route may be across the ‘tight junctions’ (Fromter,
1972; Machen, Erlij & Wooding, 1972), whose nomenclature may be morphologically appropriate but functionally misleading. This suggests an intercellular pathway which is essentially
extracellular; this is consistent with our hypothesis of bulk flow of solution which is virtually
iso-osmotic with extracellular fluid. However, flow along such a route would be likely to
exert considerable solvent drag on strongly hydrophilic ions, such as sodium (KoefoedJohnsen & Ussing, 1953). It seems reasonable to speculate that ion exchange, which is unaffected by solvent drag, cannot be mediated along the intercellular route and to suggest that this
may take place across the brush-border surface of the mucosal cell. Although a useful teleological purpose may be found for ion exchange, in terms of conservation of important ions,
ion exchange may merely reflect the function of the mucosal cell rather than ‘intestinal absorption.’
Recently Lifson, Hakim & Lender (1972) studied transport interactions in the canine
jejunum during secretion induced by cholera toxin. They concluded that cholera-induced
secretion and normal iso-osmotic fluid absorption probably were a single stream of fluid, both
representing net events at that time. However, they could not exclude an effect of choleragen
on two sites, an initial inhibition of active absorption in one area of the mucosa, and a later
stimulation of secretion in another. Our results in man, using a different secretory agent, are in
agreement, and we support their statement that: ‘A fundamental difficulty in formulating
an explanation is that we do not know the underlying mechanisms of the normal or spontaneous variability in net fluid absorption’ (Lifson et af., 1972).
ACKNOWLEDGMENTS
This investigation was supported in part by Research Grant AM 6908 from the National
Institutes of Health, Public Health Service, and by a Public Health Service International
Research Fellowship 1 F 0 5 TW 1934. Dr Wingate was in receipt of a Wellcome Trust Research
Travel Grant.
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Ion exchange and bulk flow in human bowel
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R.L. & ORVIS,A.L. (1960) Absorption of water, sodium
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