Fecal bile acids in patients with adenomatous polyps of the colon. Case-control study

Populations with a high colonic cancer incidence excrete larger amounts of bile acids in their feces. Patients with adenomatous polyps of the colon are at a greater risk of developing colonic cancer. Therefore, we studied the fecal bile acid excretion pattern in 12 patients with adenomatous polyps in comparison to 12 control subjects matched for age and sex. Analysis of bile acids was performed using liquid-gel chromatography for the separation of free, conjugated and sulfated bile acids and gas liquid chromatography for quantitation. This case-control study did not confirm the previous finding of an increased fecal bile acid excretion in patients with adenomatous polyps. Total bile acid excretion, the pattern of the primary and major secondary bile acids and their mode of conjugation were essentially the same for both groups. This negative result may be explained by similar dietary habits of both groups.     

Diet,fecal bile acids,and neutral sterols in carcinoma of the colon

Increased concentrations of fecal bile acids and neutral sterols or their degradation products have been linked to certain diets and are implicated in colonic carcinogenesis. We measured fecal bile acid and neutral sterol concentrations by thin-layer and gas-liquid chromatography in 15 patients with colonic adenocarcinoma, 23 controls, and 16 patients with nongastrointestinal cancer. We compared these results with dietary intake. Detailed dietary histories showed no differences among the groups in the ingestion of calories, protein, fiber, fat, or carbohydrate. A wide variation in fecal concentration of individual bile acids and neutral sterols was found within each group, but no significant differences in the total bile acid or total neutral sterol per gram dry weight feces were found. Decreased coprostanol, coprostanone, and lithocholic acid excretion was found in the colon cancer group compared with controls. The fecal excretion of all bile acids and neutral sterols was lower significantly in the nongastrointestinal cancer patients with liver metastases as compared with those without. We conclude that total bile acid and total neutral sterol excretion is similar in the three groups, all ingesting similar diets. We cannot confirm reported increased excretion of total bile acids nor excessive bacterial conversion to degradation products in colonic cancer patients. Hepatic metastases correlate with decreased fecal excretion of both bile acids and neutral sterols, which may be due to diminished hepatobiliary excretion.     

Effects of jejunoileal bypass on the enterohepatic circulation of bile acids, bacterial flora in the upper small intestine, and absorption of vitamin B12

Eleven morbidly obese patients were studied before and at various time intervals after jejunoileal bypass (JIB). Bile acid deconjugation was assessed with the bile acid breath test and bile acid absorption by analyzing the fecal excretion of both radioactively labeled and unlabeled bile acids. In addition, aerobic and anaerobic cultures of upper small intestinal aspirates, the Schilling vitamin B12 absorption test, and fecal fat analysis were performed. All patients developed marked diarrhea and steatorrhea after JIB. The bile acid breath test was positive in all 11 patients after JIB. In 7 of the 11 patients, this test was already slightly positive before JIB. In every instance, however, the bile acid breath test became significantly more abnormal after the bypass operation. The fecal excretion of labeled bile acids increased significantly. However, the increase in the quantitative excretion of the bile acids did not reach statistical significance. The concentrations of bile acids in fecal water were considerably below the levels required to induce diarrhea. This was mainly the result of a low fecal pH and consequent low aqueous solubility. Jejunoileal bypass effected a major shift in fecal bile acids from the secondary bile acids, lithocholic acid and deoxycholic acid, to the respective primary compounds, chenodeoxycholic acid and cholic acid. There were no significant changes in the small bowel bacteriologic findings after JIB. In 5 out of the 9 patients in whom bacteriologic studies were performed, the cultures were positive before the operation. The Schilling vitamin B12 absorption test showed in all patients a significant drop in the 24-hour urinary 57Co excretion rate after JIB.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of bile salts and fatty acids on the colonic absorption of oxalate.

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 less than 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. These results suggest that bile salts and fatty acids increase colonic 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 of oxalate by a nonspecific alteration of mucosal permeability. These observations may further explain many of the clinical phenomena associated with enteric hyperoxaluria.     

Faecal free fatty acids in tropical sprue and their possible role in the production of diarrhoea by inhibition of ATPases.

Faecal excretion of fatty acids is increased in patients with tropical sprue because of unabsorbed dietary fatty acids. The excretion of fatty acids correlates well with faecal wet weight. In vitro unsaturated fatty acids inhibited Na K-ATPase and Mg-ATPase isolated from basolateral membranes of enterocytes and colonocytes. These findings are a possible explanation for the observed abnormalities in water and electrolyte absorption by the colon in patients with tropical sprue and steatorrhoea.     

Dietary lipids and variations of fecal output and metabolic components in rats

The amount of feces (g/day) and the concentration of fecal secondary bile acids have been measured in ninety-six male Wistar rats C.P.B.: W.U. which received diets varying in their content both in linoleic acid and in total fat (5-10-20 p. 100). The fecal outflow, water excretion and fecal concentration of deoxycholic and lithocholic acids increased exponentially with time of feeding. As early as two weeks after beginning the diets, the increases were significantly greater for the diet with saturated fatty acids than for the diet with polyunsaturated fatty acids. The amount of ingested fat had only a slow influence on fecal metabolic factors. Indeed, the effect of the diet with the highest fat content became significantly different from that of the diet with the lowest fat content only after seven weeks of feeding. The existence of a linear relationship between secondary bile acid concentrations and both fecal water outflow and fresh fecal outflow would seem to indicate that the increase in bile salt fecal excretion was strictly physiological. The proposed experimental protocol can be applied to study the relationship between fat intake, bile acid fecal excretion and tumor yield in experimental colonic tumorigenesis initiated by 1,2-dimethyl-hydrazine.     

Adaptation of cholesterol and bile acid metabolism and vitamin B12 absorption in the long-term follow-up after partial ileal bypass

Cholesterol and bile acid metabolism and vitamin B12 were studied in 19 patients with heterozygous familial hypercholesterolemia in an 8-yr follow-up (3-12 yr after ileal bypass operation), and in 11 unoperated controls. Absorption of cholesterol and vitamin B12 were decreased by the operation, but improved slowly, and at 8 yr cholesterol absorption was normal. Cholesterol excretion as fecal neutral steroids was not increased by the operation, and at 8 yr the flux of endogenous cholesterol to the gut was similar in the operated and control patients. Cholesterol absorption was positively correlated with mouth to anus transit time in the unoperated patients. Fecal bile acid excretion was increased immediately after the operation and continued to increase even after the second postoperative year. In the operated patients fecal excretion of fat, water, and dry matter were positively correlated with fecal bile acid excretion. Our study suggests that adaptive changes occur slowly after ileal bypass, resulting in gradual normalization of cholesterol absorption, despite continuing bile acid malabsorption, and that the intestinal transit time is related to steroid absorption even under physiologic conditions.     

Fecal bile acid excretion pattern in colonic cancer patients

Epidemiological investigations have shown an association between the incidence of colonic cancer, dietary habits, and bile acid metabolism. We analyzed the fecal bile acid excretion pattern in 23 patients with colonic carcinoma and in 21 controls. We determined the total bile acid concentration, the concentration of individual bile acids as a measure for bacterial degradation, and the degree of sulfation. Separation of nonsulfated and sulfated bile acids was achieved by the lipophilic anion-exchanger DEAP-Sephadex-LH 20, quantification of individual bile acids by gas-liquid chromatography. Corresponding with a significantly lower stool mass per day, colonic cancer patients had a lower daily bile acid excretion. But we found no statistically significant difference between the groups in the fecal concentration of total or individual bile acids or their mode of conjugation. There was a wide variation of total bile acid concentration within each group. Most bile acids were expectedly in the free state, only a low percentage in the glycine- or taurine-conjugated form. The sulfated fraction was small and not different in the two groups. Although our data do not refute the hypothesis of bile acids being implicated in the pathogenesis of colorectal cancer, they do not support it.The study was supported by the Deutsche Forschungsgemeinschaft (SFB 102/D2).     

Intestinal perfusion studies in tropical sprue. 2. Movement of water and electrolytes.

Jejunal absorption of sodium and water has been investigated in 10 normal Indians and 11 patients with chronic tropical sprue. Normal saline and solutions containing amino acids and dipeptides were studied. In both groups little absorption of sodium and water from normal saline was seen. Mean water and sodium absorption from the free amino acid or dipeptide solutions showed no significant difference between the groups and was similar to absorption from normal saline. These results differ from data obtained in normal English subjects where at these concentrations significant stimulation of sodium and water absorption was seen. In a proportion of subjects in both groups net secretion was observed. However, no correlation was seen between mucosal histology or luminal bacteriology and sodium or water movement. These findings in patients with chronic tropical sprue are similar to findings in normal Indians and suggest that jejunal handling of sodium and water is abnormal when compared with normal English subjects, but that the mucosa is not in a secretory phase as seen in certain other diarrhoeal states or in the acute early phase of sprue.     

Effects of dietary calcium and phosphate on the intestinal interactions between calcium, phosphate, fatty acids, and bile acids.

Luminal free fatty acids and bile acids may damage the colonic epithelium and stimulate proliferation, which may increase the risk of colon cancer. It has been suggested that only soluble calcium ions (Ca2+) precipitate fatty acids and bile acids, thus reducing their lytic activity. Consequently, precipitation of luminal Ca2+ by dietary phosphate should inhibit these effects. To evaluate the proposed antagonistic effects of dietary calcium and phosphate, we studied the intestinal interactions between calcium, phosphate, fatty acids, and bile acids in rats fed purified diets that differed only in the concentrations of calcium and phosphate. Increased dietary calcium drastically decreased the solubility of fatty acids in the ileum, colon, and faeces, as well as the solubility of bile acids in the colon and faeces. Although dietary calcium strongly increased the total faecal fatty acid concentration and hardly affected the total faecal bile acid concentration, the fatty acid and bile acid concentrations in faecal water were drastically decreased by dietary calcium. Consequently, the lytic activity of faecal water was decreased. Dietary phosphate did not interfere with these intestinal effects of calcium. These results indicate that dietary phosphate does not inhibit the protective effects of dietary calcium on luminal solubility and the lytic activity of fatty and bile acids.     

Effects of calcisorb on fecal bile acids and fatty acids in human volunteers

The intake of calcium (Ca) is negatively associated with colorectal cancer (crc) risk. The aim of this study was to investigate in a double-blind, placebo-controlled trial, the effects of the Ca-binder Calcisorb, which is given to kidney stone patients with hypercalciuria type I, on risk factors for crc risk, bile acids (BA), and long-chain fatty acids (LCFA) in fecal water. Results show that the concentration of BA and LCFA in fecal water did not change, although the urinary excretion of Ca and magnesium (Mg) and the concentration of Ca and magnesium in fecal water decreased. The daily excretion of BA and LCFA acids decreased significantly (p < 0.05) during the Calcisorb period. In conclusion, binding dietary Ca and Mg with Calcisorb from a diet with a relatively low amount of fat does not enhance the solubility of BA and LCFA in fecal water.     

Effect of Resistant Starch on Potential Biomarkers for Colonic Cancer Risk in Patients with Colonic Adenomas

Resistant starch decreases the concentration of secondary bile acids in the feces and the proliferation rate of colonic mucosal cells in healthy volunteers. This may reduce the risk of colon cancer. We investigated 23 patients with recently removed colonic adenoma(s) in a controlled parallel trial. They consumed 45 g of maltodextrin per day as placebo for four weeks and were randomly assigned to either 45 g of native amylomaize starch, containing 28 g of resistant starch type II or 45 g of maltodextrin for another four weeks. No effect on colorectal cell proliferation, fecal wet and dry weights, pH, and short-chain fatty acid excretion was seen. The bile acid concentration in fecal water decreased by 15% (P = 0.048) and the percentage secondary bile acids decreased by 14% (P = 0.002) on resistant starch relative to placebo. Whether this has a substantial role in colon cancer prevention in these patients remains to be established.     

Effects of high-lipase pancreatin on fecal fat, neutral sterol, bile acid, and short-chain fatty acid excretion in patients with pancreatic insufficiency resulting from chronic pancreatitis

Summary Conclusions Steatorrhea was almost completely stopped and malabsorption of neutral sterols and shortchain fatty acids was reduced by treatment of high-lipase pancreatin in Japanese patients with pancreatic insufficiency whose dietary fat consumption is low. Methods Fifteen patients with chronic pancreatitis complicated by steatorrhea who consumed an average of 48 g of dietary fats a day were selected as subjects and given 3 g of high-lipase pancreatin (lipase, 379,800 USP U/g), at each meal (total daily dose is 9 g) for a mean duration of 28.5 d. Fecal output and fecal fat neutral sterol, bile acid, and short-chain fatty acid excretion were determined before and after the course of pancreatin therapy. Results Pancreatin administration resulted in significant reductions (P<0.01) in fecal output (from 243.2 to 149.1 g), excretion of fecal fat, (from 12.3 to 3.9 g), animal sterols (from 816.3 to 604.6 mg), and shortchain fatty acids (from 52.6 to 18.5 mM). In contrast, no marked changes were recorded in fecal excretion of β-sitosterol (a plant sterol), bile acids, or the hydroxy fatty acid fraction. Fecal fat and short-chain fatty-acid excretion showed strong correlations with fecal output.     

Absorption of water and sodium and activity of adenosine triphosphatases in the rectal mucosa in tropical sprue.

In 10 southern Indian patients with tropical sprue, in vivo dialysis showed a defect of absorption of water and sodium from the rectum, when compared with 11 healthy volunteers. Sodium-potassium-ATPase activity, measured in homogenates of rectal biopsies, was significantly diminished in patients with sprue. Magnesium-ATPase and alkaline phosphatase were normal in biopsy homogenates. Decreased activity of colonic sodium-potassium-ATPase may contribute to diarrhoea in some patients with tropical sprue.     

Structure of bile acids associated with secretion in the rat cecum.

An isolated in vivo rat cecal loop technique was utilized to determine what structure of bile acids is required to stimulate net colonic secretion of water and sodium. A dose response curve for water and sodium movement was determined for deoxycholic acid (1-6 mM) and chenodeoxycholic acid (3-6 mM). Both of these bile acids were associated with significant secretion of water and sodium at 4 mM concentration. Therefore, this concentration was used for all test bile acids studied. Test solutions included the tri- and di-substituted bile acids: cholic acid, hyocholic acid, 3 alpha, 7 beta, 12 alpha-trihydroxycholanic acid, 3 alpha, 12 alpha-dihydroxy-7-ketocholanic acid, ursodeoxycholic acid, 3 alpha-hydroxy-7-ketocholanic acid, 7 alpha, 12 alpha-dihydroxycholanic acid, and hyodeoxycholic acid. Only three bile acids, deoxycholic acid, chenodeoxycholic acid, and 7 alpha, 12 alpha-dihydroxycholanic acid were associated with net secretion of water and sodium. Cecal histology after incubation with bile acids revealed mucosal alterations in those sacs in which secretion occurred, but not where absorption was noted. These data indicate that bile acid-associated water and sodium secretion in the rat cecum requires a specific bile acid structure with a definite spatial relationship of the hydroxyl groups. Secretion occurred only with two alpha-hydroxyl groups in either the 3, 7, or 12 positions.     

Prevention of cholesterol gallstones by lignin and lactulose in the hamster

The effect on prevention of cholesterol gallstones by a nonfermentable type of fiber, lignin, and a fermentable fiber analogue, lactulose, was studied in hamsters fed an essential fatty acid deficient diet. Control animals had a high incidence of cholesterol gallstones (21 of 24) and lithogenic bile (lithogenic index 1.08). Animals fed lignin had significantly fewer gallstones (11 of 25), improved cholesterol saturation of gallbladder bile, and increased fecal bile acid excretion. Lactulose-fed animals had significantly fewer gallstones (12 of 24) but no significant change in cholesterol saturation of gallbladder bile or in fecal bile acid excretion. Serum cholesterol concentration was reduced, however, and fecal neutral steroid excretion was increased. Gallstones were completely prevented in animals fed both lignin and lactulose (0 of 22), but gallbladder bile cholesterol saturation was not significantly different from the lignin-fed group. Gallbladder bile mucopolysaccharide concentrations did not differ among groups. Lignin appears to prevent cholesterol gallstones in this model by improving cholesterol saturation of bile. The mechanism of action of lactulose is not yet clear.     

Bile acids and colonic motility in the rabbit and the human.

Colonic motor activity was initiated by infusions of bile salts into the caecum or rectum of the anaesthetized rabbit. Primary bile acids were examined proximally and distally in the colon and elicited marked motor responses. Sinc dihydroxy bile acids are known to be potent inhibitors of electrolyte and water absorption in the colon, the secondary bile acid deoxycholic acid, the dihydroxyl compound most related to cholic acid which is the main bile acid in the rabbit, was examined distally and was also active, but to a lesser extent than cholic acid conjugates in this species. 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 stimulated colonic motility. In man, the dihydroxy compound chenodeoxycholic acid was slightly more active than conjugates of cholic acid.     

Colonic fermentation to short-chain fatty acids is decreased in antibiotic-associated diarrhea

To elucidate the pathogenesis of antibiotic-associated diarrhea, colonic carbohydrate fermentation was investigated in three groups of subjects--a group of controls, a group of patients with antibiotic-associated diarrhea, and a group of patients receiving antibiotic therapy without diarrhea. Compared with controls, the colonic fermentation was markedly impaired in patients with antibiotic-associated diarrhea reflected by both very low concentrations (22.1 vs. 59.5 mmol/L; P less than 0.01) and production rates of short-chain fatty acids. In the group of patients without diarrhea, the effect on the colonic fermentation was dependent on the antibiotic administered. Penicillin and pivampicillin PO did not reduce the concentrations (69.9 and 66.7 mmol/L, respectively) or production rates. Dicloxacillin, erythromycin, and combined IV treatment with ampicillin, netilmicin, and metronidazole reduced both concentrations (27.1, 38.2, and 18.8 mmol/L; P less than 0.01) and production rates of short-chain fatty acids to levels seen in patients with diarrhea. L-Lactate and D-lactate concentrations were normal in all patients (less than 5 mmol/L), but lactate production was reduced in the patients who had reduced production of short-chain fatty acids, including patients with diarrhea. Thus, antibiotic-associated diarrhea was always related to reduced fecal concentrations and production rates of short-chain fatty acids and production rates of lactate. These results suggest that the antibiotic-associated diarrhea might be secondary to impaired colonic fermentation in otherwise disposed subjects, resulting in accumulation of luminal carbohydrate and/or decreased short-chain fatty acid-stimulated sodium and water absorption.     

The Increased Rate of Loss, and Non-Exponential Excretion of Bile Salts in Patients with Tropical Sprue and lleectomy

Summary: Cholic acid-carboxy/¹⁴C was administered to five control subjects, seven patients with tropical sprue and two patients with ileal resection and the daily excretion of the label in the faeces measured for seven to 13 days. Contrary to previous assumptions, the excretion was not always exponential. The practice of calculating decay constants from faecal excretion studies is therefore not valid.
Four out of seven patients with sprue had an increased rate of excretion of the label, which in two subjects was similar to that of the patients with ileal resection. This indicates defective reabsorption of bile salts and may contribute to the pathogenesis of the steatorrhoea of tropical sprue.     

Absence of significant role of bile acids in diarrhea of a heterogeneous group of postcholecystectomy patients

Twenty-five postcholecystectomy (PC) patients who underwent a diagnostic work-up for persistent diarrhea and six control subjects were studied. Fourteen of the 25 patients were also characterized by conditions other than PC which could play a role in the pathogenesis of the diarrhea. However, none of the patients had evidence of ileal disease or resection. The average follow-up of the patients after the study was approximately 4.4 years. Excretion, composition, and aqueous-phase concentrations of fecal bile acids were analyzed using gas-liquid chromatography. Eleven of the 25 PC patients showed an increased fecal bile acid excretion. In three of the 11 patients, the magnitude of the bile acid loss, which ranged from 2.26 to 3.34 mmol/24 hr, indicated the presence of severe bile acid malabsorption. The fecal bile acid composition showed a significant shift from secondary to primary bile acids. In spite of the presence of marked bile acid malabsorption, the aqueous-phase concentrations of the dihydroxy bile acids, chenodeoxycholic and deoxycholic acids, did not, with one exception, reach the secretory level of 1.5 mM. The relatively low aqueous concentrations were the result of low bile acid solubility, due to an acidic fecal pH. Only two of nine patients, one with severe, and the other with equivocal bile acid malabsorption, who were treated with cholestyramine, showed an improvement of the diarrhea. The findings of subsecretory bile acid concentrations in the fecal aqueous phase and of inconsistent therapeutic responses to cholestyramine indicate that, in spite of the presence of bile acid malabsorption, the diarrhea was, with few exceptions, not bile acid-induced. The results of the study also suggest that the diarrhea in many PC patients is multifactorial in origin.This paper was presented, in part, at the American Gastroenterological Association Meeting, New Orleans, Louisiana, May 1984. Dr. Fromm was a recipient of Research Career Development Award AM 00290 from the National Institute of Arthritis, Metabolism and Digestive Diseases.