Gut, 1975, 16, 894-902

Bile acids and colonic motility in the rabbit andthe humanPart 1 The rabbit

W. 0. KIRWAN, A. N. SMITH, W. D. MITCHELL, J. DIANE FALCONER, ANDM. A. EASTWOOD

From the Department of Clinical Surgery and Wolfson Gastrointestinal Laboratories, Western GeneralHospital and University ofEdinburgh

SUMMARY Colonic motor activity was initiated by infusions of bile salts into the caecum or rectumof the anaesthetized rabbit. Primary bile acids were examined proximally and distally in the colonand elicited marked motor responses. Since dihydroxy bile acids are known to be potent inhibitorsof electrolyte and water absorption in the colon, the secondary bile acid deoxycholic acid, thedihydroxy compound most related to cholic acid which is the main bile acid in the rabbit, wasexamined distally and was also active, but to a lesser extent than cholic acid conjugates in thisspecies. In man, a relationship was found between the faecal bile acid excretion and colonic motility:the introduction of bile acids directly into the human sigmoid colon and rectum also stimulatedcolonic motility. In man, the dihydroxy compound chenodeoxycholic acid was slightly more activethan conjugates of cholic acid.

Reports on the motor action of bile salts on thegastrointestinal tract have been conflicting. Inhibi-tion of the contractility of strips of intestinal smoothmuscle has been reported (D'Errico, 1910; Boulet,1921; Schwartz and Magerl, 1924). In vivo experi-ments indicate that bile salts may stimulate motility(Horrall, 1938; Haney et al., 1939) and the intro-duction of bile into the colon and rectum results indefaecation (Hallion and Nepper, 1907; Schiipbach,1908). However, the purity must nowadays bequestioned of bile salt preparations which wereformerly precipitated or crystallized from bile withother biliary constituents present as contaminants.Since these were the ones used in the experimentsbefore modern methods ofpreparation, itwas decidedto reinvestigate the effect of some bile acids, in therabbit.

Cholic acid was examined for its action on theproximal colon, since it is the principal primary bileacid present at that site, and also because it is knownto have a modest effect on water and electrolytereabsorption; any motor effect would be more clearlyshown to be independent of this action, and attri-butable to true motor stimulation of the bowel,

Received for publication 18 September 1975.

more so if precipitate defaecation or diarrhoea werealso produced. In the rabbit, the principal faecal orsecondary bile acid is deoxycholic acid, derivedfrom cholic acid and conjugated with glycine. Theeffects of cholic acid were therefore contrasted withdeoxycholate, but the taurocholate conjugate wasused more frequently than the glycocholate becauseof its greater solubility.

Methods

The animals used were Edinburgh University Bushstrain rabbits, 4 to 6 months old, weighing between2.5 and 3 kg. They were fed on rabbit pellets, werefree of disease, and were fasted for a period of 12hours preceding each experiment.The bile acid conjugates used were obtained from

the Maybridge Chemical Company, Tintagel,Cornwall, and their purity was at least 90% asmeasured by gas liquid chromatography.

Three types ofanimal experiments were performed.

ACUTE EXPERIMENTThe abdomen was opened under general anaesthesia(nitrous oxide, oxygen, halothane) and the appendixcannulated. A pressure recording tube was passed

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Bile acids and colonic motility in the rabbit and the human

per rectum and motility recorded 15 cm from thesphincter. Basal motility was recorded for one hour.At the end of this period 50 ml glyco- or tauro-cholicacid, dissolved in distilled water, was infused intothe caecum over five minutes. Motility was measuredby the method described by Smith et al. (1971) andthe results expressed as a motility index. A basalmotility index was calculated from the 15 minutesof maximum motility in the 30 minutes beforeinfusion and a post-infusion motility index wascalculated from the 15 minutes of maximum motilityafter infusion. In five acute experiments indigocarmine dye was added to the infused bile acidsolution. The animals were killed at the end of therecording period.

In some experiments the rabbits were repeatedlyused, thus serving as their own control and mini-mizing within-subject differences. In this group aPortex intravenous cannula, implanted under generalanaesthesia through the rabbit's abdominal wall,was inserted into the appendix which was sutured tothe peritoneum of the abdominal wall. The proximalend was buried under the skin. After a two weekinterval, when the animal had recovered from theoperation, infusion experiments were performedby the mere puncture of the skin with a needle.Motility was recorded under general anaesthesia asin the acute experiments. A basal motility indexwas calculated as described above.

Motility indices were calculated for the four 15minute periods following the start of infusion. Theanimals were allowed to recover after each experi-ment and were used not more than 10 times. Liver

function tests were repeated after each experiment.At the end of the series of experiments the histologyof the liver, appendix, and colon was examined.

INTRODUCTION OF BILE SALTS INTO THESIGMOIDThe animal was anaesthetized as before and thepressure recording tube passed rectally into the largeintestine to 15 cm. Basal motility was recorded andcalculated as in the previous experiment. Fivemillilitres of the test solutions (glyco- or tauro-cholicacid and deoxycholic acid) were infused throughthe pressure recording tube into the sigmoid at 15cm. The post-infusion motility was calculated fromthe 15 minutes of maximum activity during the 30minutes after infusion.

DETERMINATION OF CHARACTERISTICS OFRABBIT BOWEL CONTENT

The gastrointestinal tract was removed from fivefasted rabbits and the quantity, pH, osmolality, andbile acid concentration of its contents measured inorder to establish baseline values for the rabbit.

Results

RABBIT BOWEL CONTENT

The results are set out in Table 1.

INTRODUCTION OF BILE SALTS INTO CAECUM1 Single experiments In five single experimantswhere indigo carmine dye was added to the infusedbile acid the colour was confined to the proximal

Weight (g) pH Osnmolality (m.mol/kg) Bile acid concentration (mM)

Caecal contents lleal contents Caecum Ileum Caecum Ileum Caecum Ileum

93.6 ± 37 2-2 i 0 44 5-88 8-8 466 ± 74 431 1-98 2-63

±0 53 (pooled) (pooled) ±0.61 (pooled)

Table 1 (Part 1) Characteristics of ileal and caecal content offive rabbits (mean ± SD)

Conjugated bile acid Concentration Motilitv index* Change in MI(mM) (no.)

Pre-inJusion Post-infusion(±SE) (±SE)

Sodium taurocholate 2 4 871 ± 276 1531 ± 219 + 650 p < 0-014 4 433 151 1211 394 + 778 p < 0-0128 3 385 165 932 428 + 547 p < 0-02516 3 195 ± 193 373 ± 209 + 178 (NS)

Sodium glycocholate 8 3 23 ± 13 397 ± 147 + 274 P < 0-0116 3 283±215 484±124 +201 p

W. 0. Kirwan, A. N. Smith, W. D. Mitchell, J. Diane Falconer, and M. A. Eastwood

colon at the end of the experiment. This experimentwas performed on 34 animals (23 bile acid and 11control solutions) using solutions of bile acids(sodium taurocholate (2mM to 16mM) and sodiumglycocholate (8mM to 24mM)). It is possible togroup the taurine and glycine salts together as theireffect was similar in equivalent concentration. Theresults are set out in Table 2. All the concentrationsof bile acid conjugates infused stimulated colonicmotility, whereas water and sodium chloride in thesame volume had no such effect. Only in the 8mMconcentration of sodium taurocholate did themotility response fail to reach statistical significance.When the 23 rabbits, of this experiment, were con-sidered as a group. there was a statistically significantdifference between the pre-infusion motility index(501 ± 100) and the post-infusion motility index(1005 ± 139) (p < 0-005). The osmolality of thebile salt in solution was 40 mmol. Since the osmo-lality of the caecal contents (containing bile) was466 ± 74, equivalent concentrations of bile saltsbut of osmolality of less than 40 and of 466 (in-creased with NaCI), were compared and gave similarresponses. The maximum motility response occurredbetween 30 and 45 minutes after infusion. Therelationship between the basal motility and thepercentage change in motility after bile acid infusionis plotted on Fig. 1.

2. Repeated experiments The response to controlsolutions and cholic acid solutions (two each of

1mM, 3mM, and 6mM sodium glycocholate) in thechronic experiments is illustrated in Fig. 2. Bile acidsolutions caused an increase in motility maximal at30 to 45 minutes, whereas control solutions had aslight inhibitory effect, again maximal at 30 to 45minutes. There was a statistically significant differ-ence (p < 0.01) between the effect of bile acid andcontrol solutions in the 30 to 45 minute period.As in the single experiment it was established,

using dye, that the infused fluid remained confinedto the proximal colon and at the end of the teststhe histology of the liver, appendix, and caecumwas found to be normal. The serum lactic dehydro-genase was unchanged following the repeatedanaesthesia (179 I.U./l before; 134 I.U./l after); theSGOT also remained unchanged (6 I.U./l before;6 I.U./l after).

3. Introduction of bile acids into sigmoid colon Thecolonic motility response after infusion of variousconcentrations of sodium glycocholate (1mM to30mM) and sodium deoxycholate (3mM to 24mM)into the sigmoid colon relates to the concentrationof bile acid injected (Fig. 3). The effect for eachcompound is different, sodium glycocholate beingmore active in eliciting motility effects. Defaecationresulted from concentrations greater than 15mM.The change in motility occurred within 10 to 15minutes of the infusion and was therefore muchmore prompt than with bile salts given into thecaecum. Control experiments with water caused no

Fig. 1 (Part 1) Exponen-tial relationship betweenthe basal motility and thepercentage motility changeafter 50 ml bile acid (cholicacid) infusion into caecumover five minutes in acuteexperiments.

1000 2000% Change in Motility

K1500-

g 1000-

> 800-

0X 600-

Anm 400-

200-

KX

XXaX

XX X

XX A m

3000Index

4000

--wl~~~A

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Bile acids and colonic motility in the rabbit and the human

WU)+3 500.X 400- Bile Acid Solutions

-

300- 62>, 200- InfusionX±2

100- _____3 40

.c -100 -60 ±55 t45 Control Solutions4,+42 -200--c.C t t t t to BASAL 0-15 15-30 30-45 69

Minutes

Fig. 2 (Part 1) Increments of motility after bile acid infusion (maximal at 30-45 minutes) and the inhibition of motilityby control solutions (again maximal at 30-45 minutes).

XV

c2000-

0XC._

C 1000-C.

0

0

Fig. 3 (Part 1) Cor-relation between thechange in motility andthe concentration ofprimary (as sodium gly-cocholate) and secon-dary (as sodium deoxy-cholate) 5 ml bile acidsinfused into the sigmoidat 15 cm.

10 15 20 25Bile acid Concentration (mM)

change in motility (beforeinfusion M.I. 710).

infusion M.I. 625; after

Discussion

The bile acid which is the end product of cholesterolcatabolism in the rabbit is cholic acid, conjugatedwith glycine (Haslewood, 1968); there is virtuallyno chenodeoxycholic acid in these animals. Ourstudies were therefore confined to cholic acid andthe secondary bile acid deoxycholic acid which, in

the rabbit, is the principal bile acid present in thefaeces. It is known from other animal and humanexperiments that dihydroxy bile acids-namely,chenodeoxycholic acid and deoxycholic acid-arepotent inhibitors of sodium and water reabsorptionfrom the colon (Mekhjian and Phillips, 1970;Mekhjian et al., 1968, 1971); hence their associationwith watery diarrhoea. But the diarrhoeal effect ofbile acids could independently be exerted on themotor function of the gut. It seemed necessarytherefore to examine the parent cholic acid since it is

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W. 0. Kirwan, A. N. Smith, W. D. Mitchell, J. Diane Falconer, and M. A. Eastwood

present in the proximal gut, with modest effects onsodium and water reabsorption; deoxycholic acidwas also examined since it is the predominantcompound in the distal colon and, as a dihydroxycompound, might be expected to have contrastingactions with cholic acid on salt and water reabsorp-tion. In preliminary experiments, taurocholatebehaved as glycocholate so that, despite the in-appropriateness to the species, the biologicallyequivalent taurine salts were used because of greaterwater solubility leading to greater ease of experi-mental handling.Our results show that there was a statistically

significant increase in sigmoid colonic motility afterthe infusion of conjugates of primary bile acids intothe caecum (p < 0.006). This motility response wasnot likely to be due to the infused bile acids advancingdirectly along the lumen to stimulate the sigmoiddirectly as dye infusion showed that the bolusremained in the right side of the colon throughoutthe experiment. Similarly volume alone or osmo-lality were not responsible: the osmolality of the bilesalt solution was < 40 mmol in contrast withdistilled water (0) and saline (275); neither of thelatter had stimulating effects.The experiment involving the indwelling cannula

was developed to allow repeated experiments and toeliminate inter-animal variation. It is interestingthat the maximal response was obtained after thesame interval (30 to 45 minutes) as in the singleexperiment. The control solutions (both saline andwater) exerted an inhibitory effect which was mostmarked at the same time interval as that observedafter maximum stimulation by bile acid solutions.The interval before the response is recorded suggestsa response beginning in the caecum and propagateddistally. The delay in the motility response couldalso be due to the secondary release by bile acids ofintermediary factors which themselves stimulate thecolon.

In the acute experiments, there appears to be anexponential relationship between the basal motilityand the percentage change in motility in response

to bile acid solutions. Animals with a high basalmotility had a poor motility response to the injectionof bile acids, while animals with a low basal motilityhad a high motility response. The possibility existsthat the high basal motility found in some animalsmight be accounted for by the presence in thecaecum, before the experiment, of a high concen-tration of bile acids.The response of the sigmoid colon to direct

contact with bile acids occurred at 10 minutes. Inthese experiments, there was a high degree ofcorrelation between the response of the sigmoidcolon and the concentration of the bile acidsinstilled, the effect being greater with primary bileacids than secondary ones. Since the secondary onesmainly reside in the distal colon, there would belittle spontaneous tendency for motility to bestimulated by bile in the contents of the lumen atthis level. But should primary bile acids for anyreason predominate, then bile might begin tostimulate the gut via its constituent bile acids. Inthe rabbit, the dihydroxy compound most appro-priate to cholic acid, deoxycholate, was less activethan conjugates of this, the main bile acid of therabbit; whereas in man the dihydroxy compound,chenodeoxycholic acid, has been principally assoc-iated with cholerrhoeic enteropathy (Mitchell et al.,1973).Although there is a dose-response relationship

between bile acid concentration and change in themotility index with infusion of bile acids into thesigmoid colon, this relationship was not found aftercaecal instillation; this suggests a direct effect onthe sigmoid colon when locally instilled, but perhapsonly an indirect sigmoid motor response when thecaecum is perfused. When abnormally high con-centrations of bile acids were instilled (15mM to30mM), the colon responded with abnormally highmotor activity and defaecation resulted.

This study suggests that intraluminal bile acidconjugates can affect colonic motility. For thisreason, endogenous and exogenous bile acids wereexamined for motor activity in humans (Part 2).

Part 2 The human

Bile flowing down the intestinal tract from theduodenum onwards has been shown to stimulateintestinal motility (Horrall, 1938). The availabilityof modern synthetic preparations of bile acidsrenders it possible to compare possible motoractions of primary and secondary bile acids. It isknown that chenodeoxycholic acid is principallyresponsible for the watery diarrhoea of ileal resection

(Mitchell et al., 1973). It is not known whether thiseffect relates to changes in water and salt excretionfrom the colon or to an alteration of its segmentalmotor activity.As in the rabbit experiments (Part 1), the effect of

bile acid on motility was studied by a somewhatindirect method.A group of diarrhoeal patients with enhanced

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Bile acids and colonic nmotility in the rabbit and the human

faecal bile acid excretion were examined, all ofwhom had solely primary bile acids in the stool-that is, chenodeoxycholic and cholic acid (Mitchelland Eastwood, 1972).A control group of diarrhoeal patients with

normal faecal bile acid excretion was also studied;the bile acids in this situation were entirely secon-dary-that is, deoxycholic and lithocholic acid.

In a further group of patients the primary bileacids, chenodeoxycholic acid and cholic acid, wereinstilled into the sigmoid colon.

Methods

Group 1 consisted of seven patients with a daily bileacid excretion in excess of 1000 mg. Six of thesepatients had post-ileal resection and one had post-vagotomy diarrhoea. The second group consistedof five patients with a daily faecal bile acid excretionof less than 1000 mg. Two of these patients hadpost-ileal resection diarrhoea, one had Crohn'sdisease without resection, and two had post-vagotomy diarrhoea. Details of group 1 and group 2patients are shown in Table 1. Group 3 consisted ofpatients who were referred for routine colonicmotility studies as part of their investigation; forundiagnosed abdominal pain, because of theirritable colon syndrome, or diverticular disease.Seven were given taurocholic acid and seven sodium

chenodeoxycholic acid in aqueous solution directlyinto the sigmoid colon. Daily faecal bile acid ex-cretion was not measured in these seven patients.

COLONIC MOTILITY STUDIESColonic motility studies were performed on allpatients in groups 1 and 2 during basal, post foodand post prostigmine periods (Smith et al., 1971).In the group 3 patients, however, the post foodperiod was omitted and in its place 50 ml of a controlsolution or a bile acid conjugate solution was infusedinto the sigmoid at 25 cm over five minutes and themotility thereafter recorded for 30 minutes.The results were expressed as a colonic motility

index.

FAECAL BILE ACID ESTIMATIONStools were collected for a period of at least threedays and daily faecal bile acid excretion was deter-mined using the method of Evrard and Janssen(1968) as modified by Mitchell et al. (1973).

Results

GROUPS 1 AND 2The basal, post food and post prostigmine motilityindices and the daily faecal bile acid and faecal fatresults of patients in groups 1 and 2 are shown in

No. Name Clinical details

1 1. B. Resection of60 cm ofterminal ileum for Crohn's disease2 J. G. Extensive resection removing multiple coils of terminal ileum and 20 cm of right colon3 J. M. Mesenteric infarct. Resection of90 cm of terminal ileum4 M. B. Resection of40 cm of terminal ileum and 12 cm of right colon for Crohn's diseaseS T. I. Resection of60 cm of terminal ileum for inflammatory bowel disease of uncertain pathology6 J. McL. Resection of70 cm ofterminal ileum and 25 cm ofcolon for Crohn's disease7 T. S. Vagotomy and pyloroplasty; post-vagotomy diarrhoea8 A. McA. Resection of 75 cm ofterminal ileum for Crohn's disease9 C. W. Massive ileal strangulation and resection. Jejuno colic anastomosis10 A. M. Vagotomy and pyloroplasty; post vagotomy diarrhoea11 L.H. Vagotomy and pyloroplasty; post vagotomy diarrhoea12 M. P. Crohn's disease. No resection

Table 1 (Part 2) Clinical details ofgroup 1 and 2 patients in present series

Motility indicesPatient Bile acids* Faecalfat

(mg/day) (g/day) Basal Postfood Post prostigmine

I.B. 2876 7 9 1174 2405 4460J. G. 4251 9.9 573 1917 3656J. M. 3340 10.0 305 1349 5157M. B. 2091 28-0 312 316 889J. McL. 1675 26-3 1415 2637 4128T. I. 1158 7.0 - 974 3804T. S. 2310 5S5 724 648 2978Mean ± SE 2528 + 972 13-5 i 3-6 643 ± 140 1463 ± 340 3581 + 525

Table 2 (Part 2) Patients with daily bile acid excretion greater than 1000 mg: colonic motility indices and daily bileacid andfat excretion (group 1)*Solely primary bile acids

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W. 0. Kirwan, A. N. Smith, W. D. Mitchell, J. Diane Falconer, and M. A. Eastwood

Motility indicesPatient Bile acids* Faecal fat

(mg/day) (g/day) Basal Postfood Post prostigmine

A. McA. 572 2.9 - 1103 1831C. W. 664 13-3 397 578 1796A. M. 311 18-0 345 114 478L.H. 723 7.1 - 955 1253M. P. 326 0.7 778 527 1753Mean ± SE 519 + 86 8-4 ± 3-2 304 ± 146 655 ± 178 1442 ± 262

Table 3 (Part 2) Patients with daily bile acid excretion less than 1000 mg: colonic motility indices and daily bile acidandfat excretion (group 2)*Solely secondary bile acids

Tables 2 and 3 respectively. There was a significantlyhigher motility index after prostigmine in group 1(3581 ± 525) compared with group 2 (1442 ± 262)(p < 0.005) and to a lesser degree after food (1463 ±140, group 1: 655 ± 178, group 2, p < 0.05).Although in the basal period the motility index washigher in group 1, this difference was not statisticallysignificant.

Correlation between bile acid excretion and motilityindex The regression lines between the daily bileacid excretion and the basal, post food and postprostigmine motility indices are plotted in the

X

X /~~~X/

X

// 0

Figure. The correlation was statistically significantin the post prostigmine period (p < 0.01) and in thepost food period (p < 0.05), but not in the basalperiod. There was no significant correlation betweenthe faecal fat excretion and colonic motility in anyof the three periods.

GROUP 3Instillation ofbile acids into the sigmoid The resultsof infusing solutions of differing concentrations ofthe bile acids, chenodeoxycholic acid and tauro-cholic acid, into the sigmoid of 14 patients are shownin Table 4. These solutions caused a significant

PROSTIGMINE (x)

x

FOOD (A)

A~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

X mA 0

A ~ x BASAL (o)A 00 . - -0

o ft ~~~~~~0A 00

1000 2000 3000 4000DAILY BILE ACID EXCRETION (Mg)

5000

Figure (Part 2) Motility index plotted against daily bile acid excretion.Prostigmine: y = 1305 + 0.81x. n = 0-685. P < 0.01.Food : y = 551 + 0.34x. n = 0-546. P < 005.Basal : y = 332 + 0 lOx. n = 0-301. (NS).

5000-

4000-

3000-X

z

I-.

-J1-0X

2000-

1000-

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Bile acids and colonic motility in the rabbit and the human

MlOsmol.

Soluition (mM) Before injection After injection Change in MI

Sod. tauro. chol. 2.5 1030(n = 2) 1366 (n = 2) + 336Cheno.deoxy. 2.5 820 1266 + 446*Sod. tauro. chol. 5 973 (n = 2) 1274(n = 2) + 301Cheno.deoxy. 5 219(n = 2) 1190(n = 2) + 971Sod. tauro. chol. 10 619 1581 + 962Cheno.deoxy. 10 806 2014 + 1208*Sod. tauro. chol. 15 619 1467 + 846Cheno.deoxy. 15 1003 2275 + 1272Sod. tauro. chol. 20 947 1346 + 399Cheno. deoxy. 20 259(n = 2) 845(n = 2) + 586Distilled water 677 - 677

Table 4 (Part 2) Motility response to injection ofbile acids into sigmoid*Estimated from part of record; defaecation produced after five to 10 minutes.

increase in motility for taurocholic acid (p < 0-0125).There was a comparable response in four subjectsgiven chenodeoxycholic acid; diarrhoea was causedin three more subjects so that the experiment intheir case was incomplete; yet the motor responseestimated for the period studied was excessive(Table 4). The same volume, 50 ml distilled water,caused inhibition of colonic motility and there wasno diarrhoea.

Discussion

Diarrhoea patients with a primary bile acid excretion(group 1 patients) had a significantly greater motilityindex (p < 0-005) than patients with diarrhoea andsecondary bile acid excretion only (group 2 patients).The finding that diarrhoea patients with a highfaecal bile acid excretion had a significantly highercolonic motility index in the post food and postprostigmine periods than patients with a muchlower faecal bile acid excretion suggests that bileacids may be a factor in the production of thisabnormal motility. There was a significant correla-tion (Figure) between motility caused by food andprostigmine and the daily faecal bile acid excretion.The motor action is further supported by the resultsobtained when solutions of taurocholic acid andchenodeoxycholic acid were infused into the sigmoidcolon (Table 4). In view of these findings, it seemspossible that abnormally high quantities of bileacids, mainly primary ones, in the colon causediarrhoea not only by inhibiting the absorption ofwater and electrolytes but also by eliciting colonicmotor activity.

These observations in the human subject are notexactly the same as in the rabbit experiments (Part 1).Whereas, in the rabbit, bile acids were infused intothe caecum, in the human observations we haveresorted to measurement of the faecal bile acid

content as a means of determining the activity of thecompounds present in the colon and passing throughit. The association of diarrhoea with a raised motilityandraised bile acid excretion, in many instances afteran ileal resection, may be a special case and is notnecessarily the same as diarrhoea studied by Connell(1962) where the motility index was low. Our secondgroup with diarrhoea had both a low motility indexand quantitatively and qualitatively a normal bileacid excretion and these cases are perhaps moreakin to those studied by Connell (1962). The bileacids which could be most of all implicated asraising the motility-for example in group 1-werechenodeoxycholic acid and cholic acid. The motoreffects found were marginally higher for the di-hydroxy bile acid, chenodeoxycholic, than forcholic acid, when these compounds were introducedinto the distal bowel, which contrasts with thesituation in the rabbit where the most appropriatedihydroxy compound was less active than a cholicacid conjugate.The motor effect might thus appear to be more

related to the primary or secondary status of thebile acid than to the number of hydroxyl groups.The group 1 patients with primary bile acid excretionhad a higher motility index than the group 2 patientswith secondary bile acids. These two groupsdiffered in other respects. Firstly, the group 1 patientshad a bigher total bile acid excretion than thegroup 2 patients, and, secondly, the group 1 patientshad solely primary bile acids in their stool, whereasthe group 2 patients had solely secondary bile acids.The conclusion that the difference in motility indexis related to total bile acid excretion is supported bythe finding of a significant correlation between thesetwo variables (Fig. 1; Part 2). The secretory effectof bile acids is related to the number of hydroxylgroups rather than to the division into primary andsecondary bile acids, dihydroxy bile acids producing

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902 W. 0. Kirwan, A. N. Smith, W. D. Mitchell, J. Diane Falconer, and M. A. Eastwood

the more marked secretory effect. The precise siteand mechanism of the motility effect of bile acidshowever, remains to be elucidated.

This work was done during the tenure of ScottishHospitals Endowment Research Trust Grant No.418, to Mr. A. N. Smith. We are indebted to MissE. G. P. Drummond for skilled technical assistance.

References

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Connell, A. M. (1962). The motility of the pelvic colon.Part II-Paradoxical motility in diarrhoea and con-stipation. Gut, 3, 342-348.

D'Errico, G. (1910). Wirkung der Galle und der gallensaurenSalze auf den Tonus und die autonatischen Bewegungendes Darmohrs. Zeitschrift far Biologie, 54, 286-298.

Evrard, E., and Janssen, G. (1968). Gas liquid chromato-graphic determination of human faecal bile acids. JournalofLipid Research, 9, 226-236.

Hallion, L., and Nepper, H. (1907). Influence excito-motrice de la bile sur l'intestin. 1: Action sur le rectum.Comptes Rendus des Seances de la Societe de Biologie, 64,182-184.

Haney, H. F., Roley, W. C., and Cole, P. A. (1939). Theeffect of bile on the propulsive motility of Thiry Vella

loops in dogs. American Journal ofPhysiology, 126, 82-88.Haslewood, G. A. D. (1968). Evolution and bile salts. InHandbook of Physiology. Section 6, vol. 5, pp. 2375-2390.American Physiological Society: Washington D.C.

Horrall, 0. H. (1938). Bile: Its Toxicity and Relation toDisease. University of Chicago Press: Chicago.

Mekhjian, H. S., and Phillips, S. F. (1970). Perfusion of thecanine colon with unconjugated bile acids. Gastroenterology,59, 120-129.

Mekhjian, H. S., Phillips, S. F., and Hofmann, A. F. (1968).Conjugated bile salts block water and electrolyte transportby the human colon. (Abstr.). Gastroenterology, 54, 1256.

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