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.     

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).     

Sterol composition of normal human bile. Effects of feeding shellfish (marine) sterols

To examine the sterol composition of normal human bile and the effects of dietary components from certain shellfish upon bile composition, we fed 7 subjects diets rich in shellfish for 2 wk following a typical American diet. The total cholesterol, bile acid, and phospholipid, and the individual sterols and bile acids of the bile samples during each dietary period were measured. In the bile of 7 subjects consuming the typical American diet, nine different neutral sterols, in addition to cholesterol, were identified. Similar patterns of these sterols have been found in human gallstones and in plasma after shellfish feeding. The five shellfish sterols (22-dehydrocholesterol, 24-methylene cholesterol, brassicasterol, isofucosterol, and a C-26 sterol) increased from 0.3% to a total of 5.2% (p less than 0.001) of total sterols. A comparison of the ratios of various shellfish sterols to cholesterol in plasma and in bile suggested selectively greater excretion of shellfish sterols relative to cholesterol. Our data demonstrated that human bile contains a mixture of sterols and that its sterol composition can be readily altered by dietary changes. The lithogenicity of the bile based on the ratio of cholesterol, bile acids, and phospholipids, and the bile acid composition was not affected by the presence of shellfish sterols. However, since some of these sterols occur in human gallstones, their lithogenic capacity cannot be ruled out.     

Cholesterol absorption and sterol balance in normal subjects receiving dietary fiber or ursodeoxycholic acid

Twelve normal subjects were placed on a constant diet and evaluated during three treatment periods, each lasting four weeks. Patients received regular diet alone during period A, regular diet plus 60 g/day wheat bran during period B, and regular diet plus 15 mg/kg/day ursodeoxycholic acid during period C. Cholesterol absorption, plasma lipid concentration, daily fecal excretion of neutral and acidic sterols, and sterol balance were determined following each treatment. No changes in serum lipid levels are observed in the three study periods. Bran administration increases fecal neutral sterol excretion and decreases cholesterol absorption (from 50.1 to 42.0%) with respect to period C. Ursodeoxycholic acid administration has no effect on fecal neutral sterol excretion, whereas bile acid excretion is markedly increased. Sterol balance (evaluated as neutral and acidic fecal sterols excreted per day minus dietary cholesterol plus ursodeoxycholic acid given per day) is lower during ursodeoxycholic acid feeding (360±145 mg/day) than during bran feeding (593±174 mg/day). In conclusion, ursodeoxycholic acid decreases sterol balance values; bran-rich diet increases sterol balance and reduces cholesterol absorption.     

Cholesterol absorption regulates cholesterol metabolism and plasma lipoprotein levels in patients with gut exclusions

The occurrence of cholesterol malabsorption and its role in the regulation of cholesterol metabolism were studied in 30 patients with an earlier gut resection and 9 patients with a jejunoileal bypass for treatment of obesity. Fractional cholesterol absorption varied from 0.1% to 70%, and was lowest in jejunoileal bypass (8.3%) associated with severe fat and moderate bile acid malabsorptions and in 15 patients with a long small-intestinal resection (20.4%) associated with severe bile acid and moderate fat malabsorption. Seven resected patients with normal fecal fat and bile acids and 8 resected patients with malabsorption of only bile acid had normal cholesterol absorption. Low fractional cholesterol absorption was associated with a short length of the remaining proximal small intestine, high dietary intake of plant sterol, and high fecal fat and neutral sterol excretions, but not with bile acid malabsorption. In the whole study population, plasma levels of total, low-density lipoprotein, and high-density lipoprotein cholesterol were positively correlated with fractional cholesterol absorption and the amount of total, dietary, and biliary absorbed cholesterol and were negatively correlated with fecal cholesterol elimination as neutral sterols (less so as bile acids) and cholesterol synthesis. The results emphasize that, in patients with ileal exclusion, plasma levels of low-density lipoprotein and high-density lipoprotein cholesterol are regulated more effectively by cholesterol than by bile acid malabsorption. Moreover, although the fecal loss of bile acids is the main determinant in cholesterol elimination and stimulation of cholesterol synthesis in patients with intestinal exclusions, intestinal cholesterol absorption also contributes noticeably to the regulation of cholesterol synthesis.     

Serum cholestanol and plant sterol levels in relation to cholesterol metabolism in middle-aged men

Serum cholestanol was studied in relation to fecal cholestanol excretion and cholesterol metabolism in a random middle-aged population of 61 men. The serum concentrations of cholestanol ranged from 1.6 to 10.8 mumol/L and were positively correlated with those of serum total LDL and HDL cholesterol. In terms of millimole per mole of cholesterol, these correlations disappeared; inverse associations were found with VLDL cholesterol and triglyceride levels, the P/S ratio of dietary fat, and the amount of fecal plant sterols, but not with fecal cholestanol. The serum contents of cholestanol (1) were also closely positively associated with those of serum plant sterols (campesterol and sitosterol) and fractional cholesterol absorption, (2) were inversely related to the fecal excretion of neutral sterols and cholesterol synthesis which were measured either by the sterol balance technique or serum cholesterol precursor sterols (desmosterol and lathosterol), and (3) were unrelated to bile acid synthesis. Fecal cholestanol (mean = 12.5 mg/d) was (1) clearly higher than the dietary cholestanol intake (less than 2 mg/d), (2) unrelated to serum cholestanol, and (3) positively correlated with the intestinal cholesterol (dietary plus endogenous) flux as well as fecal plant sterols, neutral sterols, and bacterial products of cholesterol. The study emphasizes that, in normal men, high serum cholestanol levels reflect high efficiency of intestinal sterol absorption and low cholesterol synthesis. Thus, the changes in the serum contents of cholestanol are parallel with those of plant sterols and opposite to those of cholesterol precursor sterols.     

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.     

Effect of dietary fiber on colonic bacterial enzymes and bile acids in relation to colon cancer.

Because of the potential significance of colonic bacteria and secondary bile acids in the pathogenesis of colon cancer, the present study investigated the effect of different types of dietary fiber on fecal bacterial enzymes, namely, beta-glucuronidase, 7 alpha-dehydroxylase, nitroreductase, and azoreductase, and on bile acids and neutral sterols in premenopausal women. The subjects consumed 13-15 g of wheat, oat, or corn bran daily for 8 weeks in addition to their normal diet. Stools collected during the normal and fiber diet periods were analyzed for the above constituents. Dietary wheat bran decreased the concentrations of fecal deoxycholic acid, lithocholic acid, 12-ketolithocholic acid, and neutral sterols and the activities of all bacterial enzymes. Oat bran had no effect on secondary bile acids and 7 alpha-dehydroxylase but decreased beta-glucuronidase, nitroreductase, and azoreductase levels. Dietary corn bran increased 7 alpha-dehydroxylase, lithocholic acid, and cholesterol levels and decreased deoxycholic acid coprostanol, cholestenone, nitroreductase, and azoreductase levels. These results show that the modifying effect of dietary fiber on secondary bile acids and bacterial enzymes that may play a role in carcinogenesis depends on the type of fiber consumed.     

Clinical value of the cholesterol test in patients with arteriosclerosis

Capacity for the excretion of cholesterol (CS) and bile acids was studied, using an original cholesterol load test, in atherosclerotic patients. They showed reduced fecal excretion of neutral sterols and bile acids following cholesterol load, unlike normal subjects, whose respective values were increased irrespective of age. Fecal excretion of these substances was particularly low in second-type hyperlipoproteinemia. Atherosclerosis-related changes of sterol balance may be an evidence of latent incompetence of mechanisms of hepatic evacuation of substances that may be regarded as atherosclerotic risk factors.     

Increased sterol excretion with polyunsaturated-fat high-cholesterol diets

Previous studies have shown that polyunsaturated ruminant fats in the diets of human subjects cause an increase in cholesterol and bile acid excretion during the first 3 weeks of such diets. The present studies were designed to compare the effects of polyunsaturated (P) and conventional (S) ruminant fats at two levels of dietary cholesterol intake: a higher (HC) and lower (LC). Four study periods, each of about 3 weeks' duration, were conducted in 5 healthy subjects providing these dietary combinations: HCS, HCP, LCS, LCP. Neutral sterols and bile acids were measured in the feces, and sterol balances were calculated.Plasma cholesterol levels were significantly lower with P than with S diets at both HC and LC intakes. Changes attributable to differences in fatty acids and to differences in cholesterol intake appeared to exert independent effects. The major changes occurred in lipoproteins with density 1.019–1.045.Cholesterol absorption expressed as a percentage of the dietary intake was not significantly different with the four diets. Neutral sterol excretion of probable endogenous origin and bile acid excretion were significantly higher during the HCP than during the HCS periods, but the difference between LCP and LCS periods was less marked. Net sterol excretion was therefore significantly greater with HCP and LCP than with HCS and LCS diets, the differences being greater at HC than at LC intakes. Comparisons of diets with similar fatty acid but differing cholesterol intakes showed lower net sterol excretion with HCS than with LCS diets (presumably due to suppression by HC of cholesterol synthesis), but this difference was not seen between HCP and LCP diets. This finding, together with greater sterol excretion with HCP than with HCS diets, showed that enhanced sterol excretion with polyunsaturated fat was potentiated with higher cholesterol intake. This enhanced excretion was generally greater during the first than during the second 3-week period of polyunsaturated fat.     

Dietary fiber and cholesterol metabolism in rats fed a high cholesterol diet.

The effect of administering blackgram (Phaseolus mungo) fiber (isolated as neutral detergent residue) at the 30% dietary level has been studied with regard to lipid concentration in the tissues and that of biliary and fecal bile acids and sterols. Rats were fed a high fat-cholesterol diet and compared with those fed a cellulose diet. The results indicate that blackgram fiber significantly lowers cholesterol in both serum and aorta [11]. There was an increased concentration of biliary sterols and bile acids and increased fecal excretion of sterols and bile acids, each of these effects being significantly greater than those observed in the rats fed cellulose.     

Faecal lipids in familial adenomatosis coli

Faecal sterols and bile acids from six patients with familial adenomatosis coli (FPC) and 61 healthy men were analysed preoperatively. Faecal concentrations and secretion of neutral sterols, plant sterols, and degradation products of cholesterol were identical in the two groups. No increase was found in the faecal bile acid excretion, and the distribution of individual bile acids was normal in FPC. The results suggest that the development of adenomas in FPC is not associated with abnormal cholesterol and bile acid excretion.     

Steroid pattern of bile and feces in response to a fruit-enriched diet in hypercholesterolemic hamsters

The effect of a fruit (apple)-enriched diet on bile secretion and on fecal steroid excretion was studied in two strains of hamster: normal hamsters with normal cholesterolemia and spontaneous hypercholesterolemic hamsters with high-level hepatic cholesterol esters (FEC hamsters). Quantitative and qualitative alterations in the steroid composition in bile and feces were accompanied by changes in intestinal morphology. The fruit diet displayed a choleretic effect and increased the output of bile acids from liver in FEC hamsters. In addition, bile collected continuously from cannulated apple-fed animals was enriched with conjugates of cholic acid. Moreover, apple consumption lowered the lithogenic index of the bile. In response to the fruit diet, fecal excretion of bile acids and neutral sterols increased, essentially in the form of primary bile acids and sterol esters, respectively.     

Effects of feeding cholesterol and mixed plant sterols on the fecal excretion of acidic steroids in rhesus monkeys

The effects of feeding diets with high or low amounts of cholesterol and with low or high levels of mixed plant sterols (sitosterol: campesterol: stigmasterol, 60:35:5) on the daily fecal excretion of acidic steroids were studied in rhesus monkeys. During periods of low dietary plant sterol, total fecal acidic steroid excretion was 43% lower (P less than 0.01) during low dietary cholesterol than during high dietary cholesterol. During periods of high dietary plant sterols the fecal acidic steroid excretion was 113% higher (P less than 0.01) with low dietary cholesterol than with high dietary cholesterol. Addition of mixed plant sterols to the low-cholesterol diet produced nearly a 2-fold increase (P less than 0.005) whereas, such an addition to the high cholesterol diet produced a significant decrease by about 53% (P less than 0.025) in the total fecal acidic steroid excretion. The results suggest that the effect of cholesterol feeding on fecal acidic steroid excretion depends on the level of plant sterols in the diet. This interaction of the effects of cholesterol and plant sterols on the fecal acidic steroid excretion is probably related to the inhibitory effect of plant sterols on cholesterol absorption.     

Faecal weight, constituents, colonic motility, and lactose tolerance in the irritable bowel syndrome

Lactose intolerance and faecal characteristics were compared in 16 patients with symptomatic irritable bowel syndrome and in age- and sex-matched controls. Faecal stool weight was increased in the irritable bowel syndrome patients, whereas faecal bile acids, fat, volatile fatty acids, and neutral sterols were not significantly different. No lactose intolerance was found in irritable bowel syndrome subjects. Measurements of colonic motility showed only modest activity for both basal and food-stimulated activity. There was a weak correlation between the concentration of total bile acids, deoxycholic acid, lithocholic acid and the motility index.     

Relationship between changes in plasma lipoprotein concentrations and fecal steroid excretion in man during consumption of four experimental diets

Limited information is available on the mechanism by which changes in nutrient intake influence plasma lipids. We compared the effects on plasma lipoprotein levels of 3 dietary modifications involving changes in total fat intake (27-40% of calories), cholesterol intake (100-250 mg/1000 kcal), the dietary polyunsaturated to saturated fatty acid ratio (0.3-1.0) and intake of vegetable-derived fiber and protein. On these 3 diets, plasma low density lipoprotein was reduced by 26-34%. Fecal bile acid excretion was similar on all diets (363-379 mg/day). There was no alteration in fecal bile acid output associated with an increase in polyunsaturated or total fat intake. Sterol balance became significantly more negative during consumption of only 1 of the 3 cholesterol-lowering diets. The observed reduction in plasma cholesterol levels was not associated with an increase in fecal bile acid output suggesting that diet-induced changes in circulating cholesterol are not maintained by an increase in sterol turnover but may reflect alterations in hepatic cholesterol and lipoprotein synthesis.     

Role of bile acids and neutral sterols in familial cancer syndromes of the colon

Cholesterol is quantitatively the most significant sterol in mammalian tissues. The major metabolic pathway of this sterol leads to the formation of bile acids. The structural similarities between carcinogenic aromatic hydrocarbons and bile acids aroused the suspicion that bile acids might play a role in carcinogenesis. In familial polyposis, a condition with a strong genetic predisposition to colonic cancer, a failure to degrade fecal cholesterol and bile acids to secondary products has been postulated as a marker of the phenotypic expression of this condition. In contrast, epidemiologic studies in populations at high risk for colonic cancer, and consuming diets rich in animal fat, protein, and refined carbohydrates, show a positive correlation with high fecal concentrations of bile acids and their metabolites. The suggestion that secondary bile acids might act in concert with colonic carcinogens in promoting neoplastic transformation is supported by observations from experimental studies. Among the secondary bile acids, lithocholic acid is unique in that it has been shown to be comutagenic, promote cell transformation, and induce DNA strand breakage,in vitro. It has also been shown to bind covalently to tissue proteins in human liver and in livers of carcinogen-treated rats.     

Influence of age,intestinal transit time,and dietary composition on fecal bile acid profiles in healthy subjects

Bacterial transformation of bile acids is possibly involved in colorectal carcinogenesis. In several epidemiological studies, the secondary bile acid concentration in feces is related to the incidence of colonic cancer. However, data on fecal bile acids in case-control studies are conflicting. We investigated the influence of age, intestinal transit time, and dietary composition on fecal bile acid profiles in healthy subjects of three different age groups (mean ages 22, 48, and 67 years). Fecal bile acids were analyzed by gas-liquid chromatography. The concentration of the major secondary fecal bile acids increased with advancing age and was significantly higher in elderly subjects, compared to young adults. The concentration in middle-aged persons was intermediate. Analysis of dietary constituents showed that the fat intake in the three groups was comparable. The dietary fiber intake in elderly subjects was significantly lower than in the other two groups. The former group did excrete less dry fecal material compared to both other groups. Dietary fiber intake was negatively correlated with the total bile acid concentration. Probably, a decrease in dietary fiber intake results in higher fecal bile acid concentrations with advancing age. From the findings of this study, it is obvious that matching for age is important when case-control studies concerning the role of fecal bile acids in colorectal carcinogenesis are conducted.This work was supported by grants from the Netherlands Cancer Foundation (NUKC 78-4 and 83-10) and in part presented at the Annual Meeting of the American Gastroenterological Association, New York, May 1985 (Gastroenterology 88:1514, 1985).     

Effects of soy protein and saponins on serum, tissue and feces steroids in rat

Four groups of rats were fed, for 45 days, one of the following semipurified diets containing sucrose 55% (w/w) and (a) casein 25%, (b) casein 24%, saponins (from Saponaria officinalis) 1%, (c) isolated soy protein 25%, (d) soy protein 24%, saponins 1%. The soy protein diet, compared to the casein one, produced an increase in the fecal excretion of neutral sterols on the 29th and 42nd days, without any modification in the liver, aorta and serum cholesterol concentrations. The effect of soy protein cannot be attributed to its saponin content but other substances associated to soy protein may interfere. With the casein diet, added saponins increased the fecal excretion of neutral sterols and bile acids and decreased liver and aorta cholesterol levels. Serum cholesterol was found unchanged. The effects of saponins were suppressed or greatly reduced with the soy protein diet. These results could be explained by binding of the sterols in insoluble forms.     

Effect of dietary fat and residues on fecal loss of sterols and on their microbial degradation in cystic fibrosis

Although various etiologic factors have been implicated, the mechanism responsible for bile acid malabsorption in CF remains unknown. Eight CF children studied twice on a normal diet supplemented with pancreatic enzymes and once during a one-month period of Vivonex administered by continuous nasogastric infusion were compared to age-matched controls. On the fat and residue-free elemental diet, there was a modest decrease in steatorrhea and no change in the daily excretion of nitrogen and neutral sterols. However, normalization of bile acid output (485.6±65.0 to 160.6±29.2 mg/24 hr) to control levels (150.2±60.7) was noted. Diminished microbial degradation of both neutral and acidic sterols and a smaller amount of bile acids adsorbed to decreased residues were also found. The data do not support the possibility of a bile acid ileal transport defect and suggest that the most important single factor responsible for the intraluminal sequestration of bile acids in CF is dietary residues. Because of significant ongoing losses of nitrogen and lipids, pancreatic enzymes should be given to CF patients on elemental diets.This work was supported by grant MT 4433 of the Medical Research Council of Canada and by the Canadian Cystic Fibrosis Foundation.