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(Jut, 1987, 28, 707-713
Mucosal surface pH of the large intestine of the rat and
of normal and inflamed large intestine in man
N I McNEIL, K L E LING, AND J WAGER
From the Department of Medicine, University College, London
The surface pH of rat distal colonic mucosa and human rectal mucosa was measured in
vitro using first a small pH electrode with a flattened tip. In buffer with pH 7 56 the mean rat colonic
surface pH was 6-72. Lowering the buffer pH in steps resulted in a small fall in surface pH, the
values being buffer pH 7*06 surface pH 6*64, buffer pH 6&58 surface pH 6 61 and finally buffer pH
6-09 surface pH 6-39. Similar results were obtained with a buffer where butyrate, 30 mmol/l
replaced chloride and when a C02/bicarbonate buffer was used. During the time taken for the
study transmural potential difference only changed by 1-2 mV. Serosal surface pH changed with
buffer pH, suggesting that the maintained surface pH is a property of the mucosal surface only. The
surface pH of human rectal mucosa was similar to that of rat distal colonic mucosa. As buffer pH
fell from pH 7 51 to 5-96 mucosal surface pH only fell from pH 6*80 to 6.26. The values obtained in
ulcerative proctitis did not differ from normal mucosa. Secondly pH microelectrodes were used to
measure the juxta mucosal pH and the pH-microclimate thickness when luminal pH was
controlled. The microclimate had a pH 6-63 adjacent to the mucosa with a thickness of 840 [tm.
The importance of mucus in maintaining the microclimate was shown by n-acetyl cysteine thinning
and prostaglandin E2 thickening the layer. These results describe a surface microclimate in the
large intestine of appreciable thickness and a constant juxta mucosal pH. Luminal pH changes
produce only a small change in microclimate pH.
SUMMARY
It has been proposed that adjacent to the mucosa of
the gastrointestinal tract there is a thin layer whose
composition changes little despite large changes in
luminal composition. In the stomach the mucus
bicarbonate layer'' provides a pH gradient such that
the juxta mucosal surface is around pH 7. In the small
intestine the thin layer has been called the unstirred
layer and its thickness determined using absorption
studies of lipids' and glucose.4 Studies of drug
absorption in the small bowel' have concluded that
there is a mucosal region of low pH, and this has
been measured as a microclimate using small pH
electrodes at pH 5-5 adjacent to the mucosal
surface.`~The microclimate pH was higher in
intestinal disease, an increase related to reduced
absorption of folic acid."
Addrcss for correspondlence: Dr N McNcil. D)cprnircnti ot Medicinc.
University (Co lcc I ondioni School ot Medicine R;ovmie Iniiuie. University
St rcvt 1 o(1on WC F 6JJ
Received for publitction 24 Octohcr 1986.
Similar studies in the large intestine have used drug
absorption to propose that there is a region of pH 6-5
between lumen and blood through which absorption
occurs. "' This concept of a region close to the mucosa
where pH changes little has not been fully studied in
the colon and may be of consequence for the absorption of weak electrolytes, particularly ammonia" and
short chain fatty acids."
We have studied this potential juxta mucosal
surface layer, first with small flattened tip glass pH
electrodes and second with pH-microelectrodes to
assess the pH and thickness of the layer under various
conditions in vitro.
Methods
GLASS ELECTRODES
A flat tipped glass electrode, 2 mm in diameter and
produced by the method of Lucas et al,' was used to
measure the pH adjacent to the mucosa when luminal
707
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708S
pH was varied. The response of the electrode was
linear over the range pH 5 to 8, 50(5+0 2 mV/pH
unit, and within 1 minute reached 93% of the
maximum response. The electrode, with a calomel
reference electrode was connected to a Radiometer
model PHM25 pH meter, input impedence over
10'Q, and the response recorded on a Servoscribe 2S
recorder. The electrode was calibrated by measuring
its response to buffers of known pH at 37°C before
each study. Pressing the electrode onto a cork surface
in buffer produced the same results as the pH of the
buffer. In order to reduce interference all studies
were done within an earthed wire cage surrounding
the specimens and electrode.
McNeil, Ling, anbd Wager
the large intestine in vivo." The second buffer was
prepared by replacing 30 mmol/l chloride with
butyrate 30 mmol/l, using hydrochloric acid to
correct pH ('butyrate buffer'). We used butyrate as it
has been considered a better energy source for the
large intestinal mucosa than glucose,'4 and so might
alter the behaviour of the mucosa. The third buffer
used bicarbonate/CO2 to control pH.
Specimens were examined histologically and
showed no damage from these studies.
Hulman studies
The surface pH of human large intestinal mucosa was
measured on rectal biopsy specimens. The specimens
were taken from eight women and three men, aged
22-79 years, for clinical diagnostic purposes and
Studies on rats
For these studies the distal colon of freshly killed studied before routine histological examination. Six
female Wistar rats weighing 150-200 g was used. biopsies were taken from a rectum that appeared
After cleansing the intestine with saline, a 2 cm normal when examined through the sigmoidoscope
length was opened, pinned onto a cork sheet with the and was also normal when examined histologically.
mucosal surface exposed and immersed in 250 ml Five were taken from patients with ulcerative
proctitis. The proctitis was graded using the criteria
oxygenated buffer at 37°C.
After an equilibration period of five minutes in the of Baron et al'` into active disease in four and inactive
buffer the pH electrode was lowered onto the disease in one. These studies were carried out in a
mucosal surface. The response was rapid and steady similar manner to that used for rat distal colon with
values were obtained when the electrode had been on the exception that 125 ml chloride buffer only was
the mucosal surface for about three and a half used because of the small size of the biopsies.
minutes. Buffer pH was simultaneously measured Transmural potential difference was not obtained on
with a standard glass pH electrode and this value these biopsies.
used. The buffer was then drained out of the study
bath and replaced immediately by a buffer of similar MICROELECTROI)E STUDIES
composition but different pH. This process was The thickness and pH gradient of the juxta mucosal
repeated four times with each colon studied. The layer were measured using glass pH microelectrodes.
order in which the buffers of differing pH were used These were prepared by drawing glass tubing,
internal diameter 200 Rtm, to a tip diameter of
did not affect the results obtained.
An adjacent length of large intestine was excised 0 5 ,um. After silanizing, the tip was broken back to
and incubated simultaneously in the same oxygen- 5-10 jm. The pH sensitive solution of 10% tridoated buffer. The transmural potential difference of decylamine with 0.7% sodium tetraphenyl boron in
the length, which had one end tied off, was measured o-nitrophenyl octyl ether was introduced by capillary
with chloride silver wire electrodes at both the into the electrode tip. "' The electrode, was back-filled
beginning and end of the study period. Studies were with pH 5 citrate buffer. The reference electrode
completed within 40 minutes of the death of the rats. contained 4 mol/l KCI with an agar plug in the tip.
On three occasions the gut was mounted in the The electrodes were connected through silver-silver
buffer with the mucosal surface against the cork and chloride wires to millivoltmeter and chart recorder.
The electrode system was robust, needing minimal
the serosal surface pH was measured using the same
buffers under identical conditions. This was to see screening and produced a response of approximately
whether the results were generated by anaerobic 60 mV/pH unit. Electrode pairs were calibrated in
metabolism of the tissue which might lower pH by buffers of known pH at 37C.
Studies were undertaken on rat distal colon. Male
producing lactic and other organic acids.
The first buffer system used was a Krebs-Henseleit Wistar rats, mean weight 350 g, were killed and the
buffer which contained: sodium 162 mmol/l, distal colon exposed. This was divided distally and a
potassium 5 mmol/l, chloride 142 mmol/l, bicarbon- 2 cm length flushed clean with 50 ml of one of three
ate 24 mmol/l, and glucose 11 1 mmol/l. This was flushing solutions over two minutes. The colon was
brought to approximately pH 7-5, 7-0, 6 5, and 6-0 then excised, opened and mounted in oxygenated
using 1 mol/l hydrochloric acid ('chloride buffer'). Krebs-Henseleit buffer, mean pH 7 70 at 37°C. The
These pH values are within the ranges described in colonic specimen was pinned firmly over a cork
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MlacosalslrfaccepH of tlhe large intestine of the rat and ofn(ormal and inflamed large intestine in man
709
7-0
.
0
I
0
2:VI
t-
a 65-
GP*
0
0
a
w
0
0
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
6-0 ,0(
5.5
6*0
7-0
65
7.5
8-0
Buffer pH
Fig. I Surface pH of rat colonic mucosa incubated in 'chloride' buffer with mean points linked.
support. The microelectrodes were lowered through
the buffer and juxta mucosal layer using a micromanipulator, the study being complete within 15-20
minutes of exposing the distal colon. Measurements
were taken from the electrode position where pH
started to change from the buffer pH and both
thickness and final pH taken at the step prior to
entering the mucosa. The rate of fall in pH per
millimetre was used as a measure of the mucus
protective properties.
7'0-
65
c:
0-
0
60-
I
5-5
Fig. 2
6-0
I
65
70
I
75
I
80
Buffer pH
Siurfac e pH of rat colonic mnuc osa incubated in 'butvrate' buffer. The results for individual colonic samples are linked.
Downloaded from http://gut.bmj.com/ on June 16, 2017 - Published by group.bmj.com
McNeil, Ling, and Wager
710
Three flushing solutions were used. One hundred
and fifty millimoles/litre sodium chloride solution was
used as a control. To ascertain the role of mucus in the
maintenance of the j uxta mucosal layer a second flushing solution contained 20 mmol/l n-acetyl cysteine in
saline to thin the mucus layer. The third flushing
solution contained 0-28 mmol/l prostaglandin E2 in
saline which was chosen because it stimulates mucus
production and secretion at this concentration. 17
Student's t-test was used for statistical comparison
and the results expressed as mean ± standard error.
Results
Gl-ASS ELECTRODE STUDIES
Rat colonic mucosa
The surface pH of rat distal large intestine when
measured in the chloride buffer at four initial pH
values is shown in Figure 1, for colonic samples from
11 rats. The mucosal pH was 6-72±0 08 when buffer
pH was 7-56±0 02 (t=9-53, p<0-001). When the
more acid buffer pH of 7(06±0 03 was used mucosal
pH was 6-64+±005 (t=9.10, p<0.001). The third
buffer whose pH was 6-58±0+02, proved to be almost
identical to mucosal surface pH, 6 61+0-05, however, the mucosal surface pH was significantly
higher, 6-39+0-04, than the most acid buffer, pH
6 09±0-04, (t=8.79, p<0001).
Nine rat colonic samples were studied in butyrate
buffer, to see if the presence of butyrate enhanced or
altered the response when compared with the
chloride buffer. Very similar results were obtained
(Fig. 2): the four paired values were buffer pH
7-69±0-04 mucosal pH 6-78±0 04 (t=13.42,
80-
7.51
(n =4).
Transmural potential differences measured on
adjacent lengths of intestine were - 11 3±+()7 mV at
the end of the study with only a slight rise, 1-2 mV,
during the study.
When the serosal surface was studied a different
response was obtained (Fig. 3). The surface pH fell at
the same rate as the buffer pH without being maintained within a narrow pH range as occurred on the
mucosal surface.
Human inucosa
The results of the studies done on normal rectal
biopsies were similar to those found in the studies of
rat distal colonic mucosa (Fig. 4). The pHs of the
buffer and of the mucosal surface were found to be:
buffer pH 7-51±0 03, mucosal pH 6 80±0(08 (n=6)
(t= 10-17, p<0.001); buffer pH 6-98±0 06, mucosal
pH 6-77±0+06 (t=3-71, p<0 (2); buffer pH
6 56±0+06, mucosal pH 6 71 ±006 (N.S.) and finally
buffer pH 5-96+±007, mucosal pH 6-26±0(09
(t=6-38, p<0(001).
When the surface pH of rectal biopsy specimens
taken from patients with ulcerative proctitis was
studied in the chloride buffer, results were similar to
those obtained on the normal rectal biopsies without
differences between varying degrees of inflammatory
activity (Fig. 4).
PH MICROELECTRODE STUDIES
M:
Q.
,077*0-
-3
in
Ln
0
65
60
p<0(00l), buffer pH 7 15±0 05 mucosal pH
6-74±0+06 (t=7 19, p<0.001), buffer pH 6 61±0(04
mucosal p1H 6 61±0+04 and finally buffer pH
6 08+0(05 mucosal pH 6-32±0+06 (t=3-62, p<0.01).
When a CO2/bicarbonate buffer system was used the
results obtained were similar to those obtained with
the previous buffers: buffer pH 7 45±0 07, mucosal
pH 6*87±0*05; buffer pH 6-99±0+04, mucosal pH
6-79+0-04; buffer pH 6-65, mucosal pH 6-77±0(02
and buffer pH 6 16±0 05, mucosal pH 6-28±0-02
65
70
Buffer pH
Fig. 3 SerosalsurfacepH of rat colon.
75
8.0
A typical recording obtained during a study is shown
(Fig. 5). The values below the trace show the depth of
the juxtamucosal region in this example (Rm). At (a)
the electrodes were being lowered in large, 500 [tm,
steps through the buffer till the juxta mucosal region
was reached, (b). As soon as this response was
detected the electrodes were withdrawn to their
previous position and time allowed for equilibration,
(c). From (c) the electrodes were cautiously lowered
in progressively smaller steps until a plateau of pH
was reached at which time the electrodes were being
advanced very slowly, (d). The mucosa was breached
at (e), thereafter the electrodes were withdrawn in
large steps, (f) and (g), until the buffer pH was again
obtained. The thickness was 750 ,im in the recording
depicted here. Thickness measurements in the with-
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Muicosal surface pH ofJthe large initestine of the rat and oJ normizal a1td inflametd large initestine in nman7
71
70
0l.
w1 6 5a
4-
0
6-0-
I
I
I
I
I
60
6-5
7*0
7.5
8-0
Buffer pH
Fig. 4
A--
Surface pH of human large intestinal mucosa. 0--------- normal mucosa; A .........
A active proctitis.
drawal phase proved unreliable, probably due to the
mucus that could be seen adhering to the electrode
tips.
Duplicate studies were done on the so-ime tissue
sample using either the same electrodes or, more
usually, a second pair mounted alongsidev vhich were
9
Ic
a
b
mV
\*
A inactive
proctitis;
used because mucus tended to adhere to the first
electrode pair. Close agreement between the duplicate results was found for both thickness and the
ultimate pH measured.
With the control flushing solution the thickness of
the juxta mucosal layer was 840 Itm (Table). The
juxta mucosal pH was 6-63 and pH fell at 1-16
units/mm. A two minute wash with 20 mmol/l nacetyl cysteine significantly thinned the microclimate
to 430 ltm and raised the juxta mucosal pH to 6-79.
The rate of fall of pH was twice as great at 2 33 units/
mm. On the other hand, prostaglandin E2 resulted in
a microclimate thickness 1340 sm but lowered juxta
mucosal pH insignificantly. The rate of fall of pH/mm
was unchanged from control values.
Discussion
d
e
These results show that the immediate surface of the
distal colon in rat and man has a region where pH is
maintained over a narrow range. The theory of a
400
650
large intestinal microclimate put forward by
750 Approximate
depth (um) Schanker"' has been confirmed by a physical method.
The microelectrode studies have confirmed these
findings with a similar juxta mucosal pH but have
added a dimension, thickness, to the microclimate.
o
Time
They have placed the region of pH 6-5 just above the
Fig. 5 A typical tra e oaopH microelect rode stu dyvof rat
epithelial cell, an identical position to studies in the
colon. For explatnatioin see te- t.
small intestine."
I
250
.
Downloaded from http://gut.bmj.com/ on June 16, 2017 - Published by group.bmj.com
712
McNeil, Ling, and Wager
considers that the integrity of the mucus is maintained when pH is kept constant,"4 and the constant
pH of mucus when released by goblet cells will help
Fat/i,,
Thickness
Flushitig
Fitia(l
maintain the microclimate. The ability of mucus to
pHI/mmn
pH
Wn
solutioli
retard diffusion has been shown for both the hydro1 16±0-11
840±6(0
663+ 012
Saline control n=8
gen ion' and for butyrate,` one of the three major
2-33±0.29.
43()+4()0'
N-acctyl cystcinc n=6
6-79±0-11
short chain fatty acids that are absorbed by the
1 16±()014
134()± 130t1
Prostaigliandin E, n=6 6-37±0-05
colon.
There would appear to be a species difference in
Staltistical significaincc: *p< -()X)l v control; 'tp<0()01 v control.
the microclimate with guinea pig distal colon having a
There was a tendency for pH to fall with luminal pH of 6-9 in vitro and in vivo," independent of
pH in study 1 and several possible explanations exist luminal pH. A difference between proximal and
for this. Firstly, the tissue was of small size compared distal colon was also found in the guinea pig-" which
with 250 ml buffer and may have been unable to may exist in rat colon.
The concept of a microclimate with a constant pH
neutralise adequately the increasing H+ ion flux at
the lowest buffer pH. A second explanation is that at its depth has important implications for absorption
the tip was imperfectly flat and in part exposed to the (and secretion) which must occur through it. Though
buffer: thus a composite reading - mostly micro- drug absorption will be modified by the pH barrier,
climate, with some buffer - was obtained. Alterna- these findings may help explain anomalies in the
tively the tip occluded an area of mucosa trapping absorption of weak acids, short chain fatty acids, and
weak bases, ammonia. Short chain fatty acids are
some buffer and altering the final pH.
Using other buffers such as CO2/ bicarbonate to thought to be absorbed principally in the unionised
control pH did not effect the results. Butyrate was form"'7 yet, in man, increasing the chain length-and
used to replace some chloride as butyrate is well hence the lipid solubility of the unionised form does
absorbed'" and considered to be an energy source, not increase absorption.'27 If short chain fatty acids
used in preference to glucose, for the colon.'4 No have to pass through a region of constant pH, 6-5,
difference in effect was found and this suggests that where they will be nearly all ionised however, then
the glucose in the chloride and butyrate buffers or the effects of chain length and lipid solubility would
intrinsic energy sources were adequate under the be slight. Similarly, ammonia is thought to be
absorbed five times more rapidly unionised than
conditions used.
Previous studies of colonic mucosal function con- ionised" 2 yet increasing the proportion of unionised
ducted in vitro have reported continuing viability ammonia 10000-fold by changing perfusate pH from
from one to two and a half hours."'" The present 4-2 to 9-0 resulted in only a three-fold increase in
studies were completed well within these limits and absorption."' If the microclimate pH changes little
potential difference was well maintained. The trans- even under such extremes of luminal pH then the
mural potential difference was within the range observed increased in absorption would be expected.
In summary, these studies have defined a juxta
found by Edmonds for rat distal colon, -8-18 mV.2'
The big difference between mucosal and serosal mucosal microclimate in the large intestine. The pH
surfaces suggest that the phenomenon is a function of of the microclimate is maintained within a narrow
the mucosa.
range and the thickness and effectiveness of the pH
The relationship of the microclimate to mucus is microclimate seems to depend upon the integrity of
emphasised by the alterations produced by n-acetyl the mucus layer. As absorption and secretion will
cysteine and prostaglandin E2. The thickness of the take place through the microclimate its importance
pH microclimate is much greater than the thickness remains to be established.
of mucus measured optically. An unstirred layer is
likely to contribute in part to the pH gradient but our We thank Dr M Sarner for permission to study
finding matches the stomach where the effective patients under his care, Mr E G Roberts, Departthickness of the mucus bicarbonate layer is consider- ment of Chemistry, University College, London, for
ably thicker22 than the visible mucus layer."' In the preparing the electrodes, and Upjohn Ltd for a gift of
small intestine Shiau et al found that the microclimate prostaglandin E,.
could be removed by stirring, and replaced by
incubation with glucose and they considered the References
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Mucosal surf ace pH of the large ititestitn e ofthe rat and of'normal
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Downloaded from http://gut.bmj.com/ on June 16, 2017 - Published by group.bmj.com
Mucosal surface pH of the large
intestine of the rat and of normal and
inflamed large intestine in man.
N I McNeil, K L Ling and J Wager
Gut 1987 28: 707-713
doi: 10.1136/gut.28.6.707
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