DUODENAL REGULATION OF GASTRIC SECRETION*

RenC Menguyt Deportinen1 I!/ Sirr,@ry, I ‘nirlersily 01 l ienlircky Medico1 Cenler, Le.rington, Ky.

In the domain of gastric physiology i t has become customary to think of the duodenum as a gastric regulatory agency distinct and separate from the re- mainder of the small bowel. ’I‘hat this is not entirely justilied will be pointed out in this paper. However, one important characteristic of the prosimal small intestine with respect to regulation of gastric function is the presence of pancreatic and biliary juices that directly and indirectly affect gastric ac- tivity. A discussion of the influence of the intestines 011 stomach function can be divided into two phases, stimulatory and inhibitory.

Itztesfinal Slimulution of Gastric Secrefioit

Ivy el al.’ thoroughly investigated this “intestinal phase” of gastric secretion and showed a gastric secretory response in dogs prepared with dencrvated total gastric pouches after meals of meat juice, Licbig’s extract, peptone, or milk. This suggested intestinal stimulation of gastric secretion via a humoral pathway. Sircus? provoked HCI secretion from denervated fundic pouches by balloon distention of jejunal or duodenojejunal loops. This stimulus could be inhibited by local application of procaine to the mucosa. These data suggest a gastric stimulatory mechanism proper to the small bowel and similar in many respects to that of the antrum. Protein substances seem to be very active as gastric secretagogues.’ Undoubtedly, end products of protein digestion arc the effective stimulating agents, since raw meat introduced into the small intestine is without action unless predigested, whereas meat extract is ;in effeclivc secretagogue.’ The action of peptone when introduced into the small intestine is worth discussing. Sircus? observed inhibition of histamine-stimu- lated Heidenhain pouch secretion after instillation of 10 per cent peptone solution into the duodenum. Using a similar preparation, we found that 30 per cent peptone uniformly stiinulated secretion of a previously resting Heiden- hain pouch. However, the stimulation was usually delayed by 10 to 20 min- utes, during which time we observed some decrease in basal secretion in those experiments in which basal secretion was measurable (FIGURE 1). Therefore, peptone solutions when introduced into the intestine appear to have a diphasic effect: an initial short phase of inhibition (more apparent if the preparation is previously stimulated with histamine) and a second more prolonged phase of stimulation which, on the other hand, is more apparent if a resting preparation is used. The initial, transitory phase of inhibition is probably non-specific and related to hyperosmolarity of the peptone solution. It has been suggested4 that end products of protein digestion cause the release of a gastrin-like ma- terial from the mucosa of the small intestine. However, the suggestion5 that I*-histidine resulting from protein digestion liberates histamine after decarboxyl-

* This work was suplmrtetl in part by NIH grant A-3934 and Atnerican Cancer Society, grant E-186.

t John and Mary K. Markle Scholar in Medical Sciences.

45

46 ation by intestinal bacteria is more plausible. Histamine would then be absorbed into the blood stream. That this is indeed possible is shown by experiments in which both L-histidine and histamine were found to have an appreciable gastric stimulatory effect when introduced directly into the small intestine.6 On the basis of these remarks, one would expect a greater 24hour output of hydrochloric acid with a high protein dietary intake. This was found to be true in dogs by Saint-Hilaire et aL6 Recently? there has been consider- able interest in the role played by the liver in regulating the intestinal phase of gastric secretion by removing histamine from portal vein blood.

Annals New York Academy of Sciences

2Omiaa

FIGURE 1. Illustrative example of effects of intraduodenal peptone (100 cc. of 30 per cent solution injected over a 10-min. period) on resting Heidenhain pouch secretion. Two e eriments on the same dog. Note delayed pouch response and initial transitory phase of izibition in Experiment B in which there was a measurable degree of basal secretion.

Intestinal Inhibition of Gastric Secretion Inhibitory influences of intestinal origin have been studied more extensively.

It is well-known that gastric inhibition is initiated by the presence of fat, carbohydrate, and hydrochloric acid in the proximal small intestine.

Gastric Inhibition by Fat in the Intestine Ewald and Boass first described inhibition of gastric motor activity by fat in

the proximal small intestine. Later reports of a similar inhibitory action on gastric secretory activity originated from Pavlov's lab~ra tory .~ Subsequent investigations'O suggested that this inhibition occurs only when fat is in the duodenum. Pavlov and his co-workers attributed this inhibitory action to a nervous reflex between the duodenum and the stomach. However, the classi- cal experiments in which Farrell and Ivyll showed secretory and motor inhibi- tion by fat of a totally denervated, autotransplanted pouch suggested the participation of a humoral mechanism. The recognition of a humoral mecha- nism mediating gastric inhibition by fat led to testing of canine small bowel

Menguy: Duodenal Regulation of Gastric Secretion 47 extracts that were found to inhibit Heidenhain pouch secretion. It was postulated that these extracts contained a hormonal substance, which was called “enterogastrone.”L2 According to the now classical conception of gastric inhibition by fat, the mucosa of the proximal small bowel, when in contact with a sufficient concentration of fat, would release this inhibitory substance.13 However, the validity of this theory is by no means well-estab- lished. Exogenous enterogastrone does not inhibit the motility of a dener- vated gastric pouch, whereas fat in the proximal small intestine does have an inhibitory effect under these conditions.14 Enterogastrone has little if any

I I 1 I) 75 ml of oil into duodawn

4 .7

6 -

- W W E

u z = - =.4 - ww a .3

.2

. I

0’

- - -

2) SOml ofoil+SOml of He0 into duodenum

20 mln

FIGURE 2. Two experiments on one dog. In both instances constant histamine stimu- lation was used (50 per cent of maximum), Note complete absence of inhibition when olive oil alone was introduced into the duodenum in Experiment 1 and pronounced inhibition of secretion when a smaller amount of oil was administered along with water in Experiment 2.

effect on gastric secretion of human beingP and does not alter gastric secretion in the rat, although fat is a very effective secretory inhibitor in this animal.I6 Recently Gregory” suggested that fat in the duodenum acted by inhibiting the release of gastrin from antral mucosa. This conclusion was based on his observation that fat has only a weak inhibitory action on histamine- stimulated secretion but suppresses gastric response to a m-al. I t is indeed true that in some dogs fat may have little or no inhibitory action on histamine- stimulated secretion. However, in such instances we have found that apprecis- ble inhibition of gastric secretory activity usually occurs when the fatty substance is introduced into the duodenum with sufficient HzO to facilitate emulsification (FIGURE 2).

Recently we have investigated some other aspects of this phenomenon.

48 Annals New York Academy of Sciences Working with rats, we found that fat failed to inhibit gastric secretion or motility in the absence of bile salts, lipase, or both from the small intestine.*E These data, fully confirmed by recent experiments in dogs (FIGURE 3), imply that emulsification of fat within the lumen of the intestine is a prerequisite to acute inhibition of gastric function by fat. Because of previous experiments in which we observed gastric secretory inhibition in dogs after parenteral

ColTRQ APTER PANCEAW-BILIARY SHUNT TO ILEUM

OIL OIL I OIL a L I ~ loiLa BILE SALTS IOIL.LimsEaniLE s

FIGURE 3. Graphic summary of 15 experiments on a dog prepared with a Heidenhain pouch and a duodenal fistula. Left to right: In the first column are 3 control ex eriments with oil alone injected into duodenum over a 20-min. period. Note the usual ingibition. Pan- creatic and biliary ducts were then transplanted to the terminal ileum. Then 3 experiments with each of the following were performed: oil alone, oil + lipase, oil + bile salts. Note absence of any appreciable inhibition. In the last column are 3 experiments in which bile salts and lipase were added to the same amount of oil. Note inhibition. Doses were: oil, 50 ml. + 50 ml. of normal saline; lipase, 50 mg.; ox bile salts, 1 gm. Identical data were obtained from 3 other dogs. Constant histamine stimulation (50 per cent of maximum) was used in all experiments.

administration of bile salts,19 we have suggested that gastric inhibition by fat could possibly be mediated by bile salts reabsorbed during fat digestion and absorption. Of course, such a conclusion is by no means proven.

From early investigations on this phenomenon, it has been concluded that gastric inhibition by fat occurs only when the fatty material is in contact with the mucosa of the proximal small intestine, the duodenum in particular.'O However, we found that in dogs gastric motility is effectively suppressed by oil injected into the terminal ileum when bile salts are added to the oil (FIGURE

4). Although this study has not yet been extended to the parameter of secre-

Menguy : Duodenal Regulation of Gastric Secretion 49

50 Annals New York Academy of Sciences tion, it seems true that one aspect of gastric inhibition by fat is controlled by the entire small intestine. Herein lies the basis for our introductory remarks in which we questioned the validity of considering the duodenum as an inde- pendent unit with regard to the regulation of gastric function.

Role of Biliary and Pamcrealic Juices Because of the anatomical relationships of the duodenum to both the liver

and pancreas, the role played by these secretions in regulating gastric function may be considered germane to this discussion. I t is well-known that duodenal ulcers can be readily produced in dogs by diverting bile*O or pancreatic juicezl

FIGURE 5. Pouch response to intraduodenal histamine and liver function before and after biliary exclusion. Each bar represents average (5 experiments on the same animal) Chour output of free HCl in response to intraduodenal administration of 100 mg of histamine di- hydrochloride. In this dog measurements of gastric secretion and B.S.P. retention were made before and 2 weeks after diversion of bile to the terminal ileum.

from the small intestine. Such experimental lesions have been attributed to loss of the buffering capacity of pancreatic or biliary juices, but the production of gastric hypersecretion by removal of pancreatic juice from the small intes- tinen suggests a more complex mechanism. Also, we recently observed gastric hypersecretion after diversion of bile from the proximal small intestine.23 Why the absence of pancreatic or biliary secretion from the small bowel should increase gastric secretion is not entirely clear. Loss of fat inhibition for reasons discussed above may be one factor. However, we recently observed after biliary diversion in dogs an appreciable alteration of hepatic function and a concomitant increase in Heidenhain pouch response to a standard dose of histamine introduced into the proximal small intestine (FIGURE 5). Therefore, i t is possible that the gastric hypersecretion due to bile loss may be caused by an increased intestinal phase of gastric secretion due to a diminished ability

Menguy: Duodenal Regulation of Gastric Secretion 5 1

of the liver to destroy histamine absorbed from the intestines. Whether the gastric hypersecretion due to loss of pancreatic juice from the intestine can be explained similarly is a matter still under study at the present time.

Effect of Carbohydrate Substances in the Intestinal Gastric Secretory Activity

Carbohydrates, when introduced into the duodenum exert an inhibitory influence on gastric secretion and motility. This action is less pronounced than the one observed with fat and seems related to the amount of solute introduced into the duodenum and to its c~ncent ra t ion .~~ Also, the effects may vary considerably from one animal to another and with the type of stimu- lus used to induce secretion. In general, inhibition is only slight when the stomach is secreting under the influence of histamine.24 Because inhibition occurs before any substantial alteration in blood glucose levels, it seem= un- likely that this inhibition is due to the reabsorbed solutes. The fact that dextran and hypertonic NaCl have a similar action3 suggests the existence of a common osmoreceptor mechanism sensitive to various solutes above a critical level of osmolarity. Whether or not a specific humoral gastric inhibitory agent may be released is not proven.

h o d e n a1 A cid Inhibition Since the original work of Sokolov,26 there have been numerous publications

on the now classical phenomenon of gastric secretory and motor inhibition induced by introduction of acid into the duodenum. This phenomenon is most interesting because of the implied existence of an autoregulatory mecha- nism of HCl secretion similar to that of the gastric antrum. Pincus el a1.26 found that for acid inhibition of meat-stimulated secretion to be effective, duodenal pH had to be lowered to at least 2.5. In 1954, Woodward el aLn re- ported failure to inhibit meat-stimulated secretion by infusing 0.1 N HC1 into the duodenum through a fistula. Failure of this experiment has been ex- plained by the fact that the latter workers used a Heidenhain pouch prepara- tion, whereas Code and Watkinson% found later in a careful study that acidifi- cation of the duodenum following a meat meal inhibited gastric secretion only of Pavlov pouch dogs. They failed to obtain any inhibition at all in animals with Heidenhain pouches. The latter observations have been partially con- firmed by Sircus: who found constant inhibition of histamine-stimulated secretion in Pavlov pouch preparations during duodenal acidification but inconstant inhibition with Heidenhain pouch preparations. On the other hand, Jones and hark in^^^ carried out experiments with innervated and de- nervated gastric pouches in which they measured the effect of duodenal per- fusion with 0.1 N HC1 on pouch response to a test meal of 10 per cent ethanol. They found a greater inhibition of secretion in the dogs with Heidenhain pouches.

The mechanism by which duodenal acidification would cause gastric secretory inhibition is not known. A neural pathway is suggested by the data of Code and WatkinsonF8 The inhibitory action of secretin on meat-stimulated pouch secretionao would imply that one of the factors involved is the release of secre- tin by duodenal mucosa under conditions of low duodenal pH. However,

52 Annals New York Academy of Sciences histamine-stimulated secretion is not inhibited by secretin,3O whereas duodenal acidification has been found effective under similar conditions.

As far as our own experience is concerned we have been unable to inhibit gastric secretion of rats with ligated pylorus by duodenal infusion of 0.1 A’ HC1 (5 to 10 ml. over a 4-hour period). Working with Heidenhain pouch dogs, we have been at a loss to interpret our data because of frequent occur- rence of vomiting, retching, or evidence of nausea whenever sufficient amounts of acid were injected into the duodenum to bring the duodenal flH to levels previously found necessary to cause gastric inhibition. These amounts (200 to 300 ml. of 0.1 N HC1 per hour) seem unphysiological and the subsequent nausea is hardly surprising. Recently, Shapirasl found that the low levels of duodenal pH necessary to cause gastric secretory inhibition occur only in- frequently in the duodenum under physiological conditions.

In addition to the problem of acute inhibition of gastric secretion, one must consider the role played by the acid inhibition phenomenon in regulating gastric secretory activity under more physiological conditions, that is, 24-hour output of HC1. Several workers have now shown that the so-called Mann-William- son preparation in which the duodenum is diverted to the terminal ileum, develops gastric hypersecretion. Baugh et aLs2 attributed this hypersecretion to loss of the duodenal acid inhibition phenomenon because of exclusion of the duodenum from the acid stream. However, we have observed essentially the same degree of hypersecretion after diversion of biliary and pancreatic juices to the terminal ileum without displacing the du0denum.3~ The latter data suggest that increased gastric secretory activity measured in dogs with a Mann-Williamson preparation cannot be attributed solely to impairment of the duodenal acid inhibition phenomenon. Recently, we discovered that diversion of pancreatic and biliary juices to the ileum in dogs caused a definite alteration in liver functi0n.8~ Therefore, it is possible that the gastric hyper- secretion of Mann-Williamson animals could be due to a diminished ability of the liver to destroy histamine absorbed from the intestine.

Although it seems unjustified to conclude that this duodenal acid inhibition phenomenon is not operative under physiological conditions, it seems fairly clear that further studies are necessary.

Summary The role played by the proximal small intestine in the regulation of gastric

secretory activity is discussed. The importance of pancreatic and biliary juices with respect to fat inhibition of gastric secretory activity is stressed. Alteration of liver function seems to be of singular importance in explaining certain experimental gastric hypersecretory states occurring after diversion of bile and pancreatic juice from the proximal small intestine.

References IVY, A. C., R. K. S. Lm 83 J. E. MCCARTRY. Contributions to the study of

gastric secretion. The intestinal phase of gastric secretion. Quart. J. Exptl. Physiol. 15: 55.

SIRCUS, W. 1953. The intestinal phase of gastric secretion. Quart. J. Exptl. Physiol.

SIRCUS, W. Studies on mechanisms in the duodenum inhibiting gastric secre-

1925.

sa: 91. 1958.

tion. Quart. J. Exptl. Physiol. 45: 114.

Mmguy : Duodenal Regulation of Gastric Secretion 53 4. BABKIN, B. P. 1950. Secretory Mechanism of the Digestive Glands. 2nd ed. Paul

B. Hoeber, Inc. 5. IRVINE, W. T., H. L. DUTHIE & N. G. WATON. Urinary output of free hista-

mine after a meat meal. 6. SAINT-HILAIRE, S., M. K. LAVERS, J, KENNEDY & C. F. CODE. 1960. Gastric acid

secretory value of different foods. Gastroenterology. 30: 1. 7. SILEN, W. & B. EISEMAN. 1961. Evidence for histamine as the agent responsible for

gastric hypersecretion after portocaval shunt. 8. EWALD, C. A,, & J. BOAS. 1886. Beitrage zur Physiologie und Pathologie der Ver-

dauung. Virchow’s Arch. Path. Anat. 104: 271. 9. KHIGINE, P. 1894-1895. Activit6 sdcretoire de I’estomac du chien. Arch. Sd. Biol.

3: 461. Analysis of the factors involved

in gastric motor inhibition by fats. Am. J. Physiol. 108: 643. 1926. Studies on the motility of the transplanted gastric

pouch. On the mechanism of the in-

hibition of gastric secretion by fat. A gastric inhibitory agent obtained from the in- testinal mucosa.

New York, N. Y. 1959.

Lancet. 1: 1061.

Surgery. 60: 213.

10. QUIGLEY, J . P., H. J. ZETTLEMAN & A. C. IVY.

11. FARRELL, J. E., & A. C. IVY. Am. J. Physiol. 76: 227.

12. KOSAKA, T., R. K. LIM, S. M. LING & A. C. LIN.

13. GROSSMAN, M. I . 19.50. Gastrointestinal hormones. Physiol. Rev. 30: 33. 14. KOSAKA, T. & R. K. LIM. On the mechanism of inhibition of gastric motility

by fat. Chinese J. Physiol. 7: 5. 15. KIRSNER, J. B., E. LEVIN & W. L. PALMER. 1949. Effect of dialyzed enterogastrone

upon 12 hour nocturnal gastric secretion in man. Proc. SOC. Exptl. Biol. Med. 70: 685.

16. MORRIS, C. R., M. I. GROSSMAN & A. C. IVY. 1947. Failure of enterogastrone to pre- vent rumenal ulcers in the Shay rat.

17. GREGORY, R. A. 1960. In Symposium on Gastric Secretion. Gastroenterology. 39: 827. 18. MENGUY, I<. Studies on the role of pancreatic and M a r y secretions in the niech-

anism of gastric inhibition by fat. Surgery. 48: 19.5. 19. MENGUY, K. & L. PEISNER. 1960. In Z ~ Z Y J antl in zdro effects of bile salts on gastric

secretory activity. Am. J. Digest. Diseases. 6: 669. 20. BOLLMAN, J. L. & F. C. MANN. Peptic ulcer in experimental obstructive jaundice.

Arch. Surg. 24: 126. 21. DRAGSTEDT, I,. K . 1942. Pathogenesis of gastroduodenal ulcer. Arch. Surg. 44: 438. 22. ELLIOTT, D. W., D. A. TAFT, E. PASSARO & R. M. ZOLLINGER. 1961. Pancreatic in-

fluences on gastric secretions. Surgery. 60: 126. 23. MENGUY, R. 1961. Effect of biliary diversion from the small intestine on gastric

secretory activity: An experimental study in dogs. 24. DAY, J. J. & S. A. KOMAROV. 1939. Glucose and gastric secretion. Am. J. Digest.

1934.

1932.

Chinese J. Physiol. 6: 107.

1933. An inhibitory agent from the intestinal mucosa.

Am. J. Physiol. 148: 382.

1960.

1932.

Gastroenterology. 41: 568.

Diseases. 6: 169. 25. SOKOLOV, A. 1904. Thesis, St. Petersburg. Quoted by Babkin. 26. PINCUS. I. 1.. M. H. F. FRIEDMAN. 1. E. THOMAS & M. E. REHFUSS. 1944. A quanti-

tative st;dy of the inhibitory ekekt of acid in the intestine on gastric secretion.- Am. J. Digest. Diseases. 11: 204.

19.54. The physiology of the gastric antrum. Experimental studies on isolated antrum pouches in dogs. Gastroenterology. 27: 766.

28. CODE, C. I;. & G. WATKINSON. Importance of vagal innervation in the regulatory effect of acid in the duodenum on gastric secretion of acid.

29. JONES, T. W. & H. N. HARKINS. The mechanism of inhibition of gastric acid secretion by the duodenum. Gastroenterology. 37: 81.

30. H. B. GREENLEE, E. H. LONGHI, J. D. GUERRERO, T. S. NELSEN, A. L. EL-BEDKI & L. R. DRAGSTEDT. 19.57. Inhibitory effect of pancreatic secretin on gastric secretion. Am. J . Physiol., 190: 396.

31. SHAPIRA, D., I. SCHNEIDER, S. TINDEL & D. STATE. Appraisal of the natural influence of antral and duodenal acid inhibition mechanisms upon gastric hydrochloric acid secretion in the dog. Gastroenterology. In press.

32. BAUGH, C. M., J. BRAVO & L. R. DRAGSTEDT. 1960. The pathogenesis of the Exalto- Mann-Williamson ulcer. 11. Relation of the antrum to the hypersecretion of gastric juice in Mann-Williamson animals.

33. MENGIJY, K. & H. MINGS. Role of pancreatic antl M a r y juices i n the regulation of gastric secretion. Pathogenesis of the Mann-Williamson ulcer. Surgery. In press.

34. MENGUY, K. 11. Effects of pancreato- Wary shunt to ileum on liver function of dogs. In press.

27. WOODWARD, E. R., E. S. LYON, J. LANDAR & L. R. DRAGSTEDT.

1955. J. Physiol. 130: 233.

19SY.

Surgery. 39: 330.

Pathogenesis of the Mann-Williamson ulcer. Surgery.