Gut: first published as 10.1136/gut.26.5.518 on 1 May 1985. Downloaded from Gut, 1985, 26, 518-524

Hyperenteroglucagonaemia and small intestinal mucosal growth after colonic perfusion of glucose in rats

B M MIAZZA, M Y T AL-MUKHTAR, M SALMERON, M A GHATEI, M FELCE-DACHEZ, A FILALI, R VILLET, N A WRIGHT, S R BLOOM, AND J-CRAMBAUD

From the Research Unit on Pathophysiology of (INSERM U54) H6pital Saint-Lazare, Paris, France, Departments of Medicine and Histopathology, Royal Postgraduate Medical School, London, United Kingdom, Departments of Pathology and ofSurgery, H6pital Lariboisiere, Paris, France

SUMMARY Beside intraluminal factors, humoral agents play an important role in intestinal adaptation. Enteroglucagon, the mucosal concentration of which is maximal in the terminal and colon, is the strongest candidate for the role of small intestinal mucosal growth factor. The present experiment was designed to study the role of colonic enteroglucagon in stimulatiing mucosal growth in rats with a normal small intestine. After eight days of glucose large bowel perfusion, enteroglucagon plasma concentrations were 120 7±SEM 9 2 pmol/l, versus 60-1±6 8 in mannitol perfused control rats (p<0001). Gastrin, cholecystokinin, neurotensin, pancreatic , and plasma concentrations were unchanged. Crypt cell proliferation, measured by the vincristine metaphase arrest technique, increased significantly in the small intestine of glucose perfused animals (p<0005-0001) in comparison with the controls. This resulted in a greater mucosal mass in both proximal and distal small bowel: mucosal wet weight, DNA, protein and oxD-glucosidase per unit length intestine were all significantly higher (p<005-0001) than in mannitol perfused rats. Our data, therefore, support the hypothesis that enteroglucagon http://gut.bmj.com/ is an enterotrophic factor and stress the possible role of the colon in the regulation of small bowel trophicity.

The large bowel mucosa is rich in endocrine cells. l-5 glucagon is significantly increased both in blood and It is tempting to speculate as to whether these cells, in colonic mucosa.13 In this model, small intestinal on September 23, 2021 by guest. Protected copyright. triggered by unabsorbed nutrients, participate in a absorption is impaired, and a direct effect of a feed-back control of upper gastrointestinal compensatory increase in food intake on the functions. Acute intracolonic infusion of some stimulation of mucosal growth of the residual small nutrients does induce inhibition of gastric6 7 and bowel has been suggested.14 pancreatic exocrine8 secretions. Another possible The present experiment was an attempt to study role for the colon as an endocrine organ could be a further the role of colonic enteroglucagon as an trophic action on the small intestine. Indeed, colonic enterotrophin by using an experimental model mucosa has, after the ileum, the highest content of which maintains small intestinal integrity. Glucose glucagon-like immunoreactivity both in man9 and in perfusion of the large bowel was used to trigger rats,l1 and enteroglucagon is currently the strongest enteroglucagon release, as it has been shown to candidate as a small intestinal mucosal growth factor induce hyperenteroglucagonemia in man.6 (enterotrophin).11 12 Moreover, in rats with 50% and 90% ileal resection, which induces a mild but Methods significant structural and functional adaptation of the residual proximal small intestine, entero- STUDY DESIGN Male SPF wistar rats weighing 250-300 g were used. Address for correspondence: Dr Jean-Claude Rambaud. Unite de Recherches After a short laparotomy under pentobarbital sur la Physiopathologie de la Digestion, Inserm U54 - H6pital Saint-Lazare 107bis, rue du faubourg Saint-Denis 75475 Paris CEDEX 10. France. anaesthesia (Nembutal Abbott, 4 mg/100 g body Received for publication 22 June 1984 weight), a vinyl tube (Portex Ltd) (id 1-0, od 2.0 518 Gut: first published as 10.1136/gut.26.5.518 on 1 May 1985. Downloaded from Enteroglucagon and intestinal hyperplasia 519 mm) was inserted into the caecum. Its proximal end compared with that found in 10 cm segments of was pulled subcutaneously to the interscapular area, distal ileum and proximal jejunum. Results showed where it was connected to the perfusion system, that the radioactivity in the small intestine was 1-2 attached to the rat by a dorsal harness. Solutions orders of magnitude less than in the caecum were infused at a flow rate of 1-8 ml/h by a constant (p<0001). Furthermore, there was no significant peristaltic pump (Neotechnique, France). The difference between jejunal and ileal radioactivity. animals could move freely in individual cages and The presence of significant amount of 14C-PEG in had free access to food and water. Cages had a wire the small bowel was very likely caused by netting bottom allowing the passage of stools and coprophagia, which could not be totally avoided, urine to an underlying tray. because all animals had diarrhoeic stools soiling the Non-fasted rats were killed after eight days of wire netting floor of the cages. In agreement with continuous intracaecal perfusion of 10% glucose these findings, the appearance of small intestinal (osmolality 555 mOsm/kg) (n=10). The resultant contents was normal in all control and experimental changes in plasma concentrations of several animals, in contrast with the watery appearance of , in intestinal cell proliferation (Crypt cell the colonic contents. production rats = CCPR) and in small intestinal structure and function (see below) were compared HORMONAL STUDY with those found in 10% mannitol (osmolality 550 Pancreatic glucagon and enteroglucagon were mOsm/kg) (n=8) perfused control animals. measured using two different antibodies to porcine In all rats, 4-6 ml blood were taken by cardiac pancreatic glucagon.15 Total (gut and pancreatic) puncture in heparinised tubes, containing also 0-2 glucagon immunoreactivity was measured first using ml aprotinin (Iniprol, Laboratoires Choay, France). an antibody reacting with the N-terminal region of The plasma was then separated by centrifugation both peptides. Pancreatic glucagon was measured and stored at -70°C until assay. At 0900 on the day separately with a specific antibody to the C-terminal they were killed, 10 glucose and eight mannitol portion of the . Enteroglucagon plasma perfused rats received vincristine sulphate concentrations were then obtained by substracting (Oncovin, Lilly) at a dose of 1 mg/kg by intra- pancreatic from total glucagon immunoreactivity. peritoneal injection. The first rat in each group was and were measured using killed 30 minutes after vincristine administration, two antiserea. 16 One was directed to the C-terminal http://gut.bmj.com/ the remaining animals were killed at 15 minute region, fully and equally cross reacting with both intervals thereafter. The whole intestinal tract, and CCK and gastrin, the other was specific for the the , and kidneys were then removed. C-terminal region of the molecular form of gastrin The intestine was stripped of its mesentery and its G17. Cholecystokinin plasma concentrations were contents washed out with ice cold isotonic saline. Six then obtained by subtracting G17 from total CCK 2 cm samples were taken for CCPR measurement at plus gastrin immunoreactivity. Neurotensin17 and sites 10, 25, 50, 75, and 90% of the small bowel insulin'18 were also measured by specific length (measured between the pylorus and the radioimmunoassays. on September 23, 2021 by guest. Protected copyright. ileocaecal valve) and in the distal colon (3 cm above the rectum); two rats in the glucose group were CRYPT CELL PRODUCTION RATE (CCPR) subsequently discarded because of inaccurate Tissues were fixed in Carnoy's fluid for four hours vincristine injection. Two samples (adjacent to sites and then transferred to 70% ethanol. After 10% and 75%) were also taken for morphometry rehydration, followed by hydrolysis in HCl for six and fixed in Bouin's solution. Approximately 10 cm minutes at 60°C, the samples were stained with segments of jejunum (lying between sites 10 and Feulgen's reagent. The crypts were individually 25%) and of ileum (75 to 90% of gut length) were dissected under the microscope. Vincristine-blocked sectioned and measured under 5 g tension. The metaphases were then counted in 10 crypts per mucosa was then scraped, weighed, and deep frozen sample. The mean metaphase counts were plotted (-70°C). were carefully dissected free against time after administration of the blocking and weighed, as were and kidneys. agent. The crypt cell production rate per hour for In order to establish that the colonic perfusate did each sampling site and in each group was given by not reflux into the small intestine, five animals were the slope of the regression line fitted by the method infused with either 10% glucose or 10% mannitol, of least squares.'9 containing a non-absorbable water soluble marker ('4C-polyethylene glycol (PEG-14C), MW 4000, 10 BIOCHEMICAL DATA ,uCi/l). The radioactivity of the total caecal content Small intestinal mucosa was homogenised in ice cold was measured by scintillation counting and isotonic saline (Ultra-Turrax homogeniser, Janke Gut: first published as 10.1136/gut.26.5.518 on 1 May 1985. Downloaded from 520 Miazza, Al-Mukhtar, Salmeron, et al and Kunkel, FGR). After appropriate dilution, Enteroglucaqon Gastrin (x-D-glucosidase activity was assayed 2001 10- fluorometrically,t20 DNA was measured according to pcO00l NS Prasad et a121 and protein was estimated by the 8- method of Lowry et al.22 150 8 Control ( i|Glucose El 6- MORPHOM ETRY Tissues were stained with haematoxylin and eosin pmol/I 1100 for the measurements of villus height, crypt depth, 4- and total mucosal thickness. The results were the mean reading of 10 well orientated villi and crypts in 50- 2- each section and expressed in microns.

STATISTICAL ANALYSIS (8) (10) (8) (10) Results are expressed as mean values ± SEM. The significance of the differences between mean values Cholecystok inin Insulin was tested by paired or unpaired Student's t test, as 10 - NS appropriate. 8- Results L.A 6- BODY, PANCREAS, LIVER, AND WEIGHTS pmol /1 These results are shown in the Table. After eight days of continuous colonic perfusion, all animals 4. appeared healthy. There were small and statistically non-significant variations in body weight in both 2- glucose and mannitol rats. Glucose perfusion provoked no change in the weight of pancreas, liver nL- J 2/ (8) (10) (8) (10) and kidneys, in comparison with mannitol perfused http://gut.bmj.com/ animals. Fig. 1 Plasma conzcentrations ofenteroglucagon, gastrin, CCK and insulin in controls and glucose perfused rats. Number ofanimals in each group is indicated at the base of Non-fasting plasma concentrations of entero- each column. NS denotes no significant difference. glucagon, gastrin, cholecystokinin, and insulin are shown in Figure 1. After glucose perfusion, entero- glucagon plasma concentrations were significantly glucose. Pancreatic glucagon and higher (p<0-001) than in the controls. In contrast, results were less than 5 and 3 pmol/l respectively, on September 23, 2021 by guest. Protected copyright. gastrin, cholecystokinin, pancreatic glucagon, and not significantly different between controls and neurotensin, and insulin plasma concentrations were glucose rats; therefore they are not shown on Figure not significantly influenced by colonic perfusion of 1.

CRYPT CELL PRODUCTION RATE (CCPR) Table Total body, pancreas, liver and kidney weights Data for CCPR per hour in five sites of the small before and after 8 days ofmannitol (n=8) or glucose intestine and in the distal colon are shown in Figure (n=10) large bowel perfusion 2. Crypt cell production rate per hour increased Mannitol Glucose significantly (p<0-005-l-001) in sites one to four after glucose perfusion, whereas the differences did Initial body weight (g) 276 3±5-5 ns 273 7±7-1 not reach statistical significance in the most distal T T site of the small bowel (terminal ileum) nor in the ns ns colon. Final body weight (g) 263 9+5 8 ns 278 7+5-2 Pancreas (g) 1-19+0-04 ns 1 13±004 SMALL INTESTINAL STRUCTURE AND FUNCTION Liver(g) 11-2±0-2 ns 10 4±0-3 After eight days colonic perfusion of glucose, small Kidneys (g) 2 1±0-1 ns 2-1±0-1 intestinal mass increased significantly in both Results are mean+SEM; ns denotes no statistically significant jejunum and ileum (Fig. 3). Mucosal wet weight, differences. DNA and protein content per unit length of Gut: first published as 10.1136/gut.26.5.518 on 1 May 1985. Downloaded from Enteroglucagon and intestinal hyperplasia 521

40 expressed per milligram DNA, cY-D-glucosidase _ o Glucose activity was significantly greater in the ileum (p<0-05) but not in the jejunum (Fig. 4). Results of 30 -_____ - NS _O _-- quantitative are shown in * * / Controls histology Figure 5. 0 * * * * Despite a trend towards longer villi, deeper crypts _ 20 and a thicker mucosa, particularly in the ileum, a. 0) none of these differences reached statistical C- * p<0 005 significance. |** p<0 001| NS0 Discussion 0 1 2 3 4 5 Colon Segments Besides the role of luminal nutrition and pancreatico-biliary secretions," there is good Fig. 2 CCPRIh infive different small intestinal segments evidence that hormonal factors play a role in and the colon for eight animals in each group. Segments 1-5 intestinal adaptation. Direct evidence for a humoral correspond to sites distant of10, 25, 50, 75 and 90% oftotal control was found in cross circulation small bowel length measuredfrom the pylorus. experiments:23 24 small bowel resection stimulated a hyperplastic response not only in resected animals, but also in the unoperated partners of the parabiotic intestine were all greater (p<0O05-0O01) than in pairs. Similar results were observed after controls. The activity of ox-D-glucosidase, expressed jejunectomy,25 jejunal exclusion,'2 ileal infusion of per unit length of small bowel, increased 30% dextrose26 and during lactation27 in intestinal significantly (p<0-054-02) in both proximal and segments completely isolated from the topical action distal intestine (Fig. 4). When the results were of nutrients and pancreatico-biliary secretions.

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(8) (10) (8) (10) (8) (10) Mucosal DNA Protein Jejunum Ileum wet weight Fig. 4 D-glucosidase activity in jejunum and ileum. Fig. 3 Mucosal wet weight, DNA and protein (mglcm) in Panel a: oc-D-glucosidase activity per cm intestine. jejunum and ileum. Panel b: o-D-glucosidase activity per mg DNA. Gut: first published as 10.1136/gut.26.5.518 on 1 May 1985. Downloaded from 522 Miazza, Al-Mukhtar, Salmeron, et al Villus height compared with mannitol controls. The possibility of a reflux of glucose in the distal intestine, which is rich in enteroglucagon cells,' 3 was excluded by inspection of small and large bowel contents and by experiments in which PEG-14C was added to the colonic perfusion solution. As enteroglucagon was measured only eight days after starting the perfusion, it could be argued that it was not released by the colon but by the hyperplastic small bowel. Against this hypothesis is the fact that the small intestinal cholecystokinin was not ,Am increased. Of course, we cannot exclude the possibility that glucose may have released other colonic regulatory peptides or amines such as serotonin, vasoactive intestinal peptide, somato- statin,1 24 , and peptide YY which is especially abundant in the rat large bowel mucosa.3 None of these substances have been considered until now as a putative enterotrophic factor. NS Crypt cell production rate and indices of mucosal (8) (10) mass (mucosal wet weight, DNA and protein per Jejunum Ileum unit length of intestine) were increased by large Crypt depth bowel glucose perfusion, when compared with mannitol treated controls. The increase in CCPR Fig. 5 Quantitative histology in jejunum and ileum was not statistically significant in the most distal showing villus height above, and crypt depth below the small intestine site. This last finding is further horizontal axis. evidence against reflux of glucose into the distal ileum, as an intraluminal glucose load at this site http://gut.bmj.com/ The potential role of some hormones has been should have induced mucosal growth. It is investigated. Gastrin can be trophic to the noteworthy that the effect of large bowel glucose , 28 but not to the rest of the small perfusion seems specific for the small intestine, intestine.28 29The administration of cholecystokinin because colonic CCPR was unaffected and no plus prevented the mucosal hXpoplasia of change was found in the weight of pancreas, liver total parenteral nutrition both in dogs3 and rats.31 and kidneys; however, the was not studied. An indirect action, however, mediated through the The absence of effect on pancreatic weight support secretions of liver and pancreas, is more likely than a the suggestion that enteroglucagon does not mediate on September 23, 2021 by guest. Protected copyright. direct enterotrophic effect.32 Several recent the pancreatic hyperplasia observed after trans- studies'3 3338 have shown that in various situations position of the proximal jejunum between the where intestinal adaptation occurs, circulating stomach and the duodenum.38 enteroglucagon concentrations are raised. A similar pattern of results was found for (x-D- The present experiment was an attempt to study glucosidase activity, when expressed per unit length further the possible role of colonic enteroglucagon intestine. Changes in enzyme specific activity, as a mucosal growth factor, in an animal model however, could only be detected in the ileum. The which maintained small bowel integrity. We results for quantitative histology were somewhat stimulated enteroglucagon release from its disappointing. Despite the tendency towards greater endocrine cells by perfusing the colon with a glucose values after colonic glucose perfusion, none of the solution. Our working hypothesis was that if values were significantly different. This was caused enteroglucagon is enterotrophic, we should be able in part by the large scatter of the results in both to show changes in cellular proliferation and experimental and control groups, but also probably possibly in mucosal mass in the small intestine, at a by the inaccuracy of this technique in detecting small distance, and therefore without contact with the alterations.39 Indeed, it must be stressed that the colonic perfusate. This is indeed what we found. changes in mucosal mass after large bowel perfusion In agreement with the findings of a previous study of glucose were relatively small - approximately in man,6 colonic perfusion of glucose provoked a 30% increases above the control values. In this two-fold increase in enteroglucagon blood levels respect our results are similar to those observed Gut: first published as 10.1136/gut.26.5.518 on 1 May 1985. Downloaded from Enteroglucagon and intestinal hyperplasia 523

after ileal resection40 whereas the ileal hyperplasia 5 El-Salhy M, Grimelius L, Wilander E et al. Immuno- induced by proximal small intestinal resection is cytochemical identification of polypeptide YY (PYY) much more marked." As the rise in enteroglucagon cells in the human gastrointestinal tract. Histochemistry plasma concentrations is equivalent in both types of 1983; 77: 15-23. 6 Jian R, Besterman HS, Sarson DL et al. Colonic resection,13 the greater enterotrophic action of inhibition of gastric secretion in man. Dig Dis Sci 1981; jejunectomy could be accounted for by differences 26: 195-201. in luminal factors. We did not measure food intake 7 Seal AM, Debas HT. Colonic inhibition of gastric acid in our study. Hyperphagia was very unlikely, secretion in the dog. Gastroenterology 1980; 79: 823-7. however, because body weight did not significantly 8 Harper AA, Hood AJC, Mushens J, Smy JR. vary in both experimental and control animals. Inhibition of external pancreatic secretion by intra- Moreover a putative hyperphagia secondary to colonic and intraileal infusions in the cat. J Physiol diarrhoea should have happened in both mannitol 1979; 292: 445-54. and glucose rats, and thus cannot explain the 9 Ghatei MA, Bloom R. Enteroglucagon in man. In: difference in small bowel mucosa between Bloom SR, Polak JM, eds. Gut hormones. Edinburgh: growth Churchill Livingstone, 1981: 332-8. the two animal groups. The absence of weight gain 10 Bloom SR. Glucagon: Pancreatic and enteric. In: Chey during the perfusion period was in fact probably W, Brooks FP, eds. Endocrinology of the gut. Thoro- because of decreased ingesta, secondary either to fare, New Jersey: Charles B. Slack, 1974: 88-102. the stress of experimental conditions, or perhaps to 11 Dowling RH. Small bowel adaptation and its regula- a specific inhibition of appetite by the colonic - tion. Adaptation pathophysiology of intestinal re- glucose and mannitol perfusion. sponse to disease. Scand J Gastroenterol 1982; 17: suppl Finally, the present experiment indicates that the 74: 53-74. colon is of influencing not only gastric6 7 and 12 Sagor GR, Chatei MA, Al-Mukhtar MYT, Wright NA, capable Bloom SR. Evidence for a humoral mechanism after pancreatic functions, but also epithelial cell renew- small intestinal resection. Exclusion of gastrin but not al in the small intestine. Whether this is a physiolo- enteroglucagon. Gastroenterology 1983; 84: 902-6. gical function remains to be established, as glucose 13 Gregor M, Bryant MG, Buchan AMJ et al. Effect of is not delivered in significant amounts to the normal intestinal resection on colonic regulatory peptides in colon. Preliminary experiments have also shown the rats: In: Robinson JWL, Dowling RH, Riecken that twice daily starch or oleic acid instillation in the ED, eds. Mechanisms of intestinal adaptation. rat colon for eight days induces an increase in Lancaster: MTP Press, 1982: 549-54. jejunal mucosal weight (unpublished), though the 14 Menge H, Grafe M, Lorenz-Meyer H et al. The http://gut.bmj.com/ amounts administered were than influence of food intake on the development of markedly higher structural and functional adaptation following ileal those probably entering the colon during normal resection in the rat. Gut 1975; 16: 468-72. feeding. 15 Ghatei MA, Uttenthal LO, Bryant MG, Christofides ND, Moody AJ, Bloom SR. Molecular forms of This paper was presented at the Autumn Meeting of glucagon like immunoreactivity in porcine intestine and the British Society of Gastroenterology held in pancreas. Endocrinology 1983; 112: 917-23. Leeds in September 1982. The authors thank Mrs I 16 Adrian TE, Bacarese-Hamilton IJ. Cholecystokinin. on September 23, 2021 by guest. Protected copyright. 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