Effect of Bile Salts and Fatty Acids on the Colonic Absorption of Oxalate

Vol. 70, No.6

70: 1096-1100, 1976 Copyright © 1976 by The Williams & Wilkins Co.

GASTROENTEROLOGY

Printed in U.S.A.

EFFECT OF BILE SALTS AND FATTY ACIDS ON THE COLONIC ABSORPTION OF OXALATE JOHN

W.

DOBBINS, M.D., AND HENRY J. BINDER, M.D.

Department of Internal Medicine, Yale University, New Haven, Connecticut

These studies were designed to evaluate the effect of bile salts and fatty acids on colonic oxalate absorption. Five millimolar deoxycholate significantly increased oxalate absorption from 34.2 ± 9.4 nmoles per min per g dry weight to 330.4 ± 47.3 (P < 0.001) and changed water absorption to water secretion. Deoxycholate also increased the absorption of urea, decreased the electrical potential difference, and increased colonic clearance of oxalate, observations which are consistent with an increase in colonic mucosal permeability. In contrast, taurocholate did not increase oxalate absorption. Ricinoleic acid also significantly increased the absorption of oxalate. Oleic acid had similar effects on oxalate absorption but was less effective than ricinoleic acid. Octanoic acid, a medium chain fatty acid, did not alter oxalate absorption. These results suggest that bile salts and fatty acids increase colonic absorption of oxalate by a nonspecific alteration of mucosal permeability. These observations may further explain many of the clinical phenomena associated with enteric hyperoxaluria. An increase in the incidence of nephrolithiasis occurs in patients with ileal disease. 2 , 3 During the past few years, several studies have demonstrated that these calculi are often calcium oxalate and that hyperoxaluria is frequently present in these patients. 4 - 6 Recent studies indicate that the hyperoxaluria is secondary to an increased absorption of dietary oxalate. 7 - 9 The mechanism of this increased absorption is not known, although it has been suggested that steatorrhea may be an important determinant in that fatty acids prevent the formation of insoluble calcium oxalate. 8 , 10 The demonstration of hyperoxaluria in patients with steatorrhea of various etiologies other than ileal disease is consistent with this hypothesis." 11, 12 The occurrence of hyperoxaluria in patients with ileal disease without steatorrhea requires participation of additional factor(s) other than increased solubility of oxalate in the genesis of the hyperoxaluria. 8 Further, some studies indicate that the colon is the major site of the increased oxalate absorption, and Chadwick and Dowling have observed increased urinary excretion of Received September 29, 1975. Accepted December 2, 1975. This work was presented in part at a meeting of the American Gastroenterological Association in San Antonio Texas on May 20, 1975 and appeared in abstract form. I Address reprint requests to: Dr. Henry J. Binder, Yale University School of Medicine, Department of Internal Medicine, 333 Cedar Street, New Haven, Connecticut 06510. This investigation was supported in part by Research Grant AM 14669 and Training Grant AM 05703 from the National Institute of Arthritis, Metabolism and Digestive Diseases and by grants from John A. Hartford Foundation Inc., and the Connecticut Digestive Disease Society. The authors thank Ms. Sandra Staples and Dianne Whiting for expert technical assistance.

HC-oxalate during perfusion of the colon of the rhesus monkey with oxalate and bile salts. 13, 14 These present studies were, therefore, designed to evaluate the effect of bile salts and fatty acids on oxalate absorption in the colon to determine whether factors other than those that affect the aqueous solubility of oxalate might be responsible for the increased oxalate absorption seen with patients with ileal disease with or without steatorrhea, These results demonstrate increased absorption of oxalate from the rat colon during perfusion with 5 mM deoxycholic acid, 8 mM ricinoleic acid, and 20 mM oleic acid, and suggest that the mechanism of this increased absorption of oxalate may be related to nonspecific alteration of colonic mucosal permeability,

Materials and Methods Colonic absorption of oxalate was studied by an in vivo perfusion technique in nonfasting male Sprague-Dawley rats weighing 250 to 400 g.'s Each animal was anesthetized with intraperitoneal Inactin (120 mg per kg of body weight), and a tracheostomy was performed. The colon was cannulated proximally at the cecal colonic junction and a distal collection catheter was placed in the rectum, The colon was cleansed with Ringer solution until clear and then perfused at constant rate (0,50 to 0,65 ml per min) by a peristaltic perfusion pump, Body temperature was maintained at 37°C with a thermostatically controlled heating lamp, The perfusion solution was maintained at 37°C, In all experiments, each animal served as its own control in that the colon was perfused initially with a 140 mM NaCl control solution and then with the test solution. The test solutions consisted of 5 mM sodium deoxycholate, 5 mM sodium taurocholate, 8 mM sodium ricinoleate, 8 and 20 mM sodium oleate, or 20 mM sodium octanoate added to the NaCl solution, When the 20 mM fatty acids were employed, the NaCl concentration in the test solution was reduced to 120 mM, Sodium oxalate, 1.5 mM, "C-oxalate (California Bionuclear

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BILE SALTS. FATTY ACIDS. AND OXALATE ABSORPTION

Corp., Sun Valley, Calif., 0.01 JIC per ml), used to quantitate oxalate absorption, and 3R-polyethylene glycol (approximately 0.02 JIC per ml, New England Nuclear Corp., Boston. Mass.). used as a nonabsorbable marker, were added to all solutions. Because preliminary experiments indicated that 40 min of perfusion were required to establish a steady state, the first 50 min of perfusion were discarded and four lO-min collections were obtaineq. After completion of the control period, the test solution was then perfused for 90 min in an identical fashion. The animals were then killed; the colons were removed, dried overnight at 110°C, and then weighed. In a separate series of experiments, the effect of 5 mM sodium deoxycholate on the absorption of 5 mM urea was also determined. "C-urea (New England Nuclear Corp., Boston, Mass.) was added to the perfusate in these studies. In an additional experiment, the effect on oxalate absorption of fluid secretion produced by a hyperosmolar solution was also evaluated. In these studies the test solution contained 140 mM NaCI and 100 mM mannitol. Standard formulae were used to determine water, oxalate, and urea absorption. '5 Oxalate and urea absorption are expressed as nanomoles per minute per gram dry weight and water movement as microliters per minute per gram dry weight. Positive numbers represent net absorption and negative ones represent net secretion. Oxalate clearance was determined after ligation of both renal pedicles and injection of 3 JIC of "C-oxalate intravenously. The colon was initially perfused with the control solution and then with a 5 mM sodium deoxycholate solution. Blood was collected from the tail vein at 30-min intervals to determine serum oxalate activity. Oxalate clearance was calculated by the equation (VeOxe)/Ox p , where Ve is the effluent volume in microliters per minute and OX p and OXe are "C-oxalate activity in plasma and effluent, respectively. Oxalate clearance is expressed as microliters per minute per gram of dry weight. Transmural electrical potential difference (PD) was measured in another series of experiments. Polyethylene tubing (PE 205) containing 4% agar in a Ringer Solution was placed in the rectum and the peritoneal cavity and connected to balanced calomel electrodes (Beckmann Instrument Co., Newton, Mass.). The PD between the large intestine and the peritoneal cavity was measured by a high impedance direct current potentiometer every 5 min after the establishment of a steady state. A single value for each solution in a single animal was obtained. All results are represented as a mean ± SEM. The paired t-test was employed to determine statistical significance. 16

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FIG. 1. Effect of 5 mM sodium deoxycholate on oxalate and water movement. The results of eight paired experiments are presented. The details of the experimental methods are presented in the text.

formed with trihydroxy bile salts which do not alter fluid and electrolyte absorption in either the colon or the small intestine. 15, 17 In these experiments, 5 mM taurocholate neither increased oxalate absorption nor altered water absorption (table 1). A small decrease in oxalate absorption was observed. In order to exclude the possibility that the increase of oxalate absorption was secondary to water secretion and not to the effect of the bile salt on the colonic mucosa, additional studies were performed with a hyperosmolar solution. Although water secretion occurred during perfusion with the mannitol solution, there was no change in oxalate absorption (table 1). The effect of deoxycholate on colonic transmucosal PD, which may in part reflect mucosal permeability, was also determined. Perfusion with 5 mM deoxycholate resulted in a decrease in PD from 20.9 ± 1.3 to 9.5 ± 2.6 mv (lumen positive) (n = 5, P < 0.02). To assess further the effect of deoxycholate on mucosal permeability, studies were performed to evaluate the effect of bile salts on the absorption of urea, a small water-soluble molecule Results which is absorbed by passive diffusion .. Figure 2 demonEffect of Bile Salts strates that the absorption of urea increased from 254.6 The absorption of oxalate and water during both ± 33.9 nmoles per min per g dry tissue weight during the control and deoxycholate perfusions is presented in control period to 1738.4 ± 345.9 nmoles per min per g dry figure 1. During perfusion with 140 mM NaCI, absorption tissue weight during perfusion with deoxycholate (P < of 1.5 mM sodium oxalate was 34.2 ± 9.4 nmoles per min 0.02), despite simultaneous water secretion. per g dry tissue weight, and water absorption was 102.3 If the increased absorption of oxalate that is demon± 34.1 JII per min per g dry tissue weight. In contrast, strated during perfusion with deoxycholate is secondary oxalate absorption increased almost lO-fold to 330.4 to the increased mucosal permeability, then an increase nmoles per min per g dry tissue weight (P < 0.001) in both plasma to lumen and lumen to plasma moveduring perfusion with the 5 mM deoxycholate solution. ment of oxalate should be present. Figure 3 demonNet water secretion occurred during the deoxycholate strates the effect of deoxycholate on the clearance of oxalate by the colon in a representative study. In five perfusion. To determine the relative specificity of the effect of paired experiments, the clearance of 14C-oxalate was deoxycholate on oxalate absorption, studies were per- measured during both control and deoxycholate perfu-

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TABLE 1. Oxalate and water absorption during bile salt and hyperosmolar perfusions· Solution

No. animals

Sodium deoxycholate, 5 mM Sodium taurocholate, 5 mM Mannitol, 100 mM

8 6

Oxalate absorption Control

Water absorption

Test

Control

nmoles/min/g dry wt

34.2 ± 9.4 40.9 ± 9.2 43.5 ± 13.8

Test Ill/min/g dry wt

330.4 ± 47.3" 3.8 ± 13.7 c 37.7 ± 7.5

102.3 ± 34.1 56.5 ± lOA 79.6 ± 7.2

-104.4 ± 19.5" 51.7 ± 10.5 -13.5 ± 5.5"

• All results expressed as mean ± SEM. Each animal was studied during a control and an experimental period. The composition of the test solution was the substance indicated under solution added to the control 140 mM NaCI solution. Positive numbers represent net absorption and negatives ones represent net secretion . b P < 0.001 compared with control. c P < 0.01 compared with control.

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2. Effect of 5 mM sodium deoxycholate on the absorption of urea and water. Deoxycholate resulted in a significant increase in urea absorption and net water secretion in the eight paired experiments . Details of the experimental methods are presented in the text. FIG.

sions. Oxalate clearance was 9.7 ± 1.0 JlI per min per g dry tissue weight during the saline perfusion and increased to 178.7 ± 62.1 JlI per min per g dry tissue weight during perfusion with deoxycholate (P < 0.05) . Effect of Fatty Acids The effect of fatty acids on oxalate absorption and water movement is summarized in table 2. Three fatty acids-ricinoleic acid, a long chain hydroxy fatty acid, oleic acid, a long chain nonhydroxy fatty acid, and octanoic acid, a medium chain fatty acid-were studied. Ricinoleic acid perfusion produced results similar to those observed during perfusion with deoxycholate: an increase in oxalate absorption and net water secretion. In previous studies, ricinoleic acid had been demonstrated to decrease PD and increase colonic inulin clearance, another index of mucosal permeability. 15 Perfusion with 20 mM oleic acid increased oxalate absorption and significantly decreased water absorption, although 8 mM oleic acid did not significantly affect either oxalate or water absorption. In contrast, 20 mM

octanoic acid, a medium chain fatty acid, did not significantly alter oxalate absorption. Water absorption increased during perfusion with octanoic acid.

Discussion In 1970, Hofmann et al. described hyperoxaluria in 2 patients with ileal resection with recurrent calcium oxalate stones. 18 Initial hypotheses to explain the hyperoxaluria associated with ileal disease proposed that the hyperoxaluria was secondary to either a defect in the enterohepatic circulation of bile salts or an alteration in glyoxylate metabolism. 4 , 5, 18 These hypotheses were rejected when Chadwick et al. demonstrated increased absorption of 14C-oxalate in patients with ileal disease and markedly diminished oxalate excretion during administration of an oxalate-free diet. 7 Increased absorpof dietary oxalate has been confirmed in subsequent reports.8, 9 ' - . Andersson et al. and Earnest et al. have recently described a direct correlation between steatorrhea and urinary oxalate excretion. 10, 8Andersson suggested that the "solubility" theory could explain the increase in absorption of dietary oxalate. Briefly stated, this hypothesis proposes that nonabsorbed fatty acids in the intestine bind calcium, preventing the formation of insoluble calcium oxalate and thus increasing the concentration of oxalate in the aqueous phase of intestinal

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June 1976

TABLE 2. Effect of fatty acids on oxalate and water absorption in the rat colona Fatty acid

No. animals

Oxalate absorption

- - - - _..

Water absorption --~--~-.--

Test

Control

nmoleslminl" dry wt

Sodium Sodium Sodium Sodium

ricinoleate, 8 mM oleate, 8 mM oleate, 20 mM octanoate, 2Q mM

6 4 7 11

30.6 26.5 8.3 31.0

± ± ± ±

6.8 15.5 10.8 9.8

124.7 ± 28.8 ± 112.8 ± 15.1 ±

31.1" 12.1 13.3 c

14.1

-------------

Control

Test

ill/mini" dry wt

86.5 54.8 118.6 41.0

± ± ± ±

13.1 19.8 15.8 8.7

-41.1 37.5 43.9 97.0

± ± ± ±

15.9" 11.0 6.5" 11.7"

a All results expressed as mean ± SEM. Each animal was studied during a control and experimental period. The composition of the test solution was the substance indicated under fatty acid added to the control 140 mM NaCl solution, except when 20 mM fatty acid was studied, when a 120 mM NaCl solution was used. Positive numbers represent net absorption and negative ones represent net secretion. " P < 0.01 compared with control. c P < 0.001 compared with control.

fluid. This increase in oxalate concentration then results in an increase in oxalate absorption. Support for this hypothesis is provided by two recent observations. One, sodium oleate prevents the precipitation of calcium oxalate in vitro, and because the mechanism of oxalate absorption is passive nonionic diffusion in both small and large intestine, the rate of oxalate absorption depends in large part on its aqueous concentration in the intestinal lumen 19; and two, administration of oral calcium to patients with ileal resection and hyperoxaluria has resulted in a decrease in oxalate excretion. 11, 20 The recent reports of hyper oxaluria in patients with steatorrhea secondary to pancreatic insufficiency, celiac sprue, and blind loop syndrome provide additional clinical support for this hypothesis.·, 11, 12 In addition, some patients with ileal disease but without steatorrhea have also been reported to have hyperoxaluria, which would indicate that factors other than solubility may be important in the increased absorption of dietary oxalate. 8 Since hyperoxaluria may, therefore, be present in patients with increased fecal excretion of either bile salts or fatty acids, a common effect of bile salts and fatty acids on the colonic mucosa may be responsible for the increase absorption of oxalate seen in these patients. Recent studies suggest that certain bile salts and fatty acids increase colonic mucosal permeability. BrightAsare and Binder demonstrated that ricinoleic acid increases the clearance of inulin by the rat colon,15 and Rummel et al. observed an increased clearance of EDT A and inulin into the rat colon during perfusion with deoxycholate. 21 Therefore, the mechanism for increased absorption of dietary oxalate in ileal dysfunction might be increased colonic permeability secondary to the effect of bile salts and fatty acids. Preliminary observation by Chadwick and Dowling that the absorption of 14C-oxalate increased when the colon of the rhesus monkey was exposed to increased amounts of bile salts provided the basis for the present studies. 14 In these present studies, deoxycholate resulted in an unequivocal increase in colonic absorption of oxalate. In addition, deoxycholate produced three phenomena, each consistent with an increase in mucosal permeability: an increase in the absorption of urea, a decrease in PD, and an increase in the clearance of oxalate by the colon. Direct correlation was observed between the effect of bile

salts and fatty acids on oxalate absorption and their ability to alter water absorption. Those compounds which increased oxalate absorption were also associated with water secretion or decreased water absorption. These results suggest, and it is proposed, that the increased absorption of dietary oxalate seen in ileal disease is secondary to the effect of bile salts and fatty acids on colonic permeability. This increase in colonic permeability could be secondary to either a functional or a morphological abnormality or both. In addition, hyperosmolar induced fluid secretion in the colon of the monkey is not accompanied by an increase in mucosal permeability, and in these present studies perfusion with a hyperosmolar mannitol solution did not alter oxalate absorption. 22 Previous studies of the effect of bile salts and fatty acids on the absorption of nonelectrolytes have indicated that these compounds decrease, not increase the absorption of glucose. 23 , 24 Frizzell and Schultz found that taurodeoxycholate decreased influx of both alanine and 3-0 methyl glucose but increased that of mannitol in the rabbit ileum. 25 Since oxalate is absorbed in both the small and large intestine by a non-energy dependent nonsaturable diffusion process,19 it appears likely that bile salts depress the absorption of substances that are absorbed by active transport but increase those absorbed by passive diffusion. The major site of oxalate absorption is not known, but several observations suggest that the colon may be the predominant organ responsible for oxalate absorption both normally and in patients with enteric hyperoxaluria. Earnest et al. studied oxalate excretion in 11 patients with ileal resection and ileostomy. Four of these patients had extensive ileal resection, but none had hyperoxaluria. To date, only one patient with ileal disease and an ileostomy has been reported with hyperoxaluria.· In addition, 60 to 70% of dietary oxalate is absorbed by the colon of the rhesus monkey, 13 and a recent study has also indicated that linoleic acid increases oxalate absorption in the colon. 26 Recent studies of therapeutic measures designed to decrease hyperoxaluria can be interpreted in terms of the present results and, therefore, provide additional indirect support for the "permeability" hypothesis. Cholestyramine will decrease urinary oxalate excretion in

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Ann Intern Med 79:383-391, 1973 patients with hyperoxaluria. 4 Although this phenomenon was initially thought related solely to cholestyra- 10. Andersson H, Jagenburg R: Fat-reduced diet in the treatment of hyperoxaluria in patients with ileopathy. Gut 15:360-366, 1974 mine binding of bile salts, and, therefore, to decreased 11. Stauffer JQ, Stewart RJ, Bertrand G: Acquired hyperoxaluria: production of both glyoxlate and oxalate, subsequent relationship to dietary calcium content and severity of steatorrhea reports indicate that cholestyramine binds oxalate in (abstr). Gastroenterology 66:783, 1974 addition to its binding of bile salts. 9, 19 These present 12. McDonald GB, Earnest DL, Admirand WH; Hyperoxaluria correexperiments permit speculation that the beneficial effect lates with steatorrhea in patients with celiac sprue (abstr}. of cholestyramine on hyperoxaluria is possibly related to Gastroenterology 68:949, 1975 its binding of both oxalate and bile acids. A low fat diet 13. Chadwick VS, Modha K, Dowling RH: Hyperoxaluria with ileal or administration of medium chain triglycerides also dysfunction (letter to editor). N Engl J Med 290:108, 1974 decreases oxalate excretion. 10, 20 These findings, when 14. Chadwick VS, Elias E, Bell GD, et al: The role of bile acids in the increased intestinal absorption of oxalate after ileal resection. interpreted in light of the solubility theory, are consistIn Advances in Bile Acid Research. Edited by S Matern, J Hackent with diminished steatorrhea, However, the beneficial enschmidt, P Back, W Gerok. Stuttgart, FK Schattauer Verlag, effects of either a low fat diet or medium chain triglycer1975, p 435-438 ides might also be interpreted in relation to the present 15. Bright-Asare P, Binder HJ: Stimulation of colonic secretion of results: a low fat diet diminishes exposure of the colonic water and electrolytes by hydroxy fatty acids. Gastroenterology mucosa to long chain fatty acids, and medium chain 64:81-88, 1973 fatty acids do not increase colonic absorption of oxalate. 16. Snedecor GW, Cochran WG: Statistical Methods. Sixth Edition. Additional studies are required to determine the relative Ames, Iowa, Iowa State University Press, 1967 contributions of these two phenomena, solubility and 17. Wingate DW, Phillips SF, Hofmann AF: Effect of glycine-conjugated bile acids with and without lecithin on water and glucose permeability, to the production of "enteric hyperoxabsorption in perfused human jejunum. J Clin Invest aluria." REFERENCES 1. Dobbins JW, Binder HJ: Bile salts and fatty acids increase colonic oxalate absorption: a possible mechanism of hyperoxaluria? (abstr). Gastroenterology 68:A-7/864, 1975 2. Deren JJ, Porush JG, Levit MF, et al: Nephrolithiasis as a complication of ulcerative colitis and regional enteritis. Ann Intern Med 56:843-853, 1962 3. Gelzayd EA, Breuer RI, Kirsner JB: Nephrolithiasis in inflammatory bowel disease. Am J Dig Dis 13:1027-1034, 1968 4. Smith LH, Fromm H, Hofmann AF: Acquired hyperoxaluria, nephrolithiasis, and intestinal disease. Description of a syndrome. N Engl J Med 286:1371-1375, 1972 5. Admirand WH, Earnest DL, Williams HE: Hyperoxaluria and bowel disease. Trans Assoc Am Physicians 84:307-312, 1971 6. Dowling RH, Rose GA, Sutor DJ: Hyperoxaluria and renal calculi in ileal disease. Lancet 1:1103-1106, 1971 7. Chadwick VS, Modha K, Dowling RH: Mechanism of hyperoxaluria in patients with ileal dysfunction. N Engl J Med 289:172-176, 1973 8. Earnest DL, Johnson G, Williams HE, et al: Hyperoxaluria in patients with ileal resection: an abnormality in dietary oxalate absorption. Gastroenterology 66:1114-1122, 1974 9. Stauffer JO, Humphreys MH, Weir GJ: Acquired hyperoxaluria with regional enteritis after ileal resection: role of dietary oxalate.

52: 1230-1236, 1973 18. Hofmann AF, Thomas PJ, Smith LH, et al: Pathogenesis of secondary hyperoxaluria in patients with ileal resection and diarrhea (abstr). Gastroenterology 58:960, 1970 19. Binder HJ: Intestinal oxalate absorption. Gastroenterology 67:441-446, 1974 20. Earnest DL, Williams HE, Admirand WH: A physiochemical basis for treatment of enteric hyperoxaluria (abstr). Clin Res 26:439A, 1975 21. Rummel W, Nell G, Wanitschke R: Action mechanisms of antiabsorptive and hydragogue drugs. In Intestinal Absorption and Malabsorption. Edited by TZ Czaky. New York, Raven Press, 1975, p 209-227 22. Kinsey MD, Formal SB, Giannella RA: Role of altered permeability in the pathogenesis of Salmonella diarrhea (abstr). Gastroenterology 68:926, 1975 23. Gracey M, Burke V, Oshin A: Influence of bile salts on intestinal sugar transport in vivo. Scand J Gastroenterol 6:273-276, 1971 24. Ammon HV, Thomas PJ, Phillips SF: Influence of water movement on jejunal absorption in man (abstr). Clin Res 22:634A, 1974 25. Frizzell RA, Schultz SG: Effect of bile salts on transport across brush border of rabbit ileum. Biochem Biophys Acta 211:589-592, 1970 26. Saunders DR, Sillery J, McDonald GB: Regional differences in oxalate absorption by rat intestine: Evidence for excessive absorption by the colon in steatorrhea. Gut 16:543-548, 1975