Biochemical and Molecular Roles of Nutrients

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1 Biochemical and Molecular Roles of Nutrients Dietary Maltitol Decreases the Incidence of 1,2-Dimethylhydrazine-Induced Cecum and Proximal Colon Tumors in Rats 1,2 Midoriko Tsukamura,* Hidemi Goto,* Tomiyasu Arisawa,* Tetsuo Hayakawa,* Naoya Nakai, Taro Murakami, Noriaki Fujitsuka and Yoshiharu Shimomura,3 *Department of Internal Medicine II, School of Medicine, Nagoya University, Showa-ku, Nagoya, 466, Japan and Department of Bioscience, Nagoya Institute of Technology, Showa-ku, Nagoya, 466, Japan ABSTRACT Maltitol is fermented in the colon due to only partial hydrolysis in the small intestine. In the present study, we examined effects of dietary maltitol on dimethylhydrazine-induced intestinal tumor in rats. In experiment 1, rats were fed a fiber-free diet or diets supplemented with 1 or 5 g/100 g maltitol for 27 wk. Each group of rats was injected with dimethylhydrazine or vehicle alone for the first 14 wk of the experimental period. Maltitol supplementation at 1 g/100 g of the diet significantly reduced tumor incidence in the cecum and the 5% supplement reduced tumor incidence in both the cecum and proximal colon in dimethylhydrazine-treated rats. In experiment 2, we investigated the effect of the 1 g/100 g maltitol diet on the short chain fatty acid concentrations in cecal contents of placebo and dimethylhydrazine-treated rats. Intake of the 1 g/100 g maltitol diet doubled (P õ 0.05) the concentration of butyrate but did not affect acetate or propionate in the cecal contents. These results suggest that dietary maltitol has a protective effect against dimethylhydrazine-induced tumors in rat cecum and proximal colon and that butyrate produced by bacterial fermentation of maltitol in the cecum may be involved in the protection. J. Nutr. 128: , KEY WORDS: maltitol colon cancer fermentation butyrate rats Fermentation by anaerobic bacteria to break down dietary that some insoluble dietary fibers such as wheat bran show a and other substrates in the large intestine is an important protective effect (McIntyre et al. 1993), whereas some soluble component of normal activity of the organ to obtain energy for fibers such as pectin may enhance colon carcinogenesis (Bauer growth and maintenance of cellular functions. Fermentation et al. 1979). Both wheat bran and pectin are fermentable in is mainly dependent upon the amount and type of substrate rat colon (particularly in the cecum). The latter especially is available to the microflora because the substrates will determine highly fermented. Reasons for the difference in these fibers the magnitude and rate of metabolic events in the colon effects on carcinogenesis are not known, but more butyrate is (Cummings and Englyst 1987). Some foods are considered to produced from wheat bran than from pectin by fermentation be indigestible (or poorly digestible). These include dietary in the colon (Lupton and Kurtz 1993). fibers, oligosaccharides, some starches and sugar alcohols, some Besides dietary fibers, resistant starch is also fermentable in of which are fermented in the colon (Cummings and Englyst the colon and decreases colonic mucosal proliferation (van 1987). The end products of the fermentation process are short Munster et al. 1994). Lactulose has a protective effect against chain fatty acids (principally acetate, propionate and butyrate) colon cancer (Samelson et al. 1985), perhaps in association and gases (carbon dioxide, methane and hydrogen). Butyrate with the lowering of the ph of colonic lumen (van Berge is the preferred fuel of colonic epithelial cells (Roedgier 1982), Henegouwen et al. 1987). slows the growth of cultured colon carcinoma cells and pro- Maltitol (a-d-glucopyranosyl-1,4-sorbitol) is a sugar alcomotes expression of differentiation markers (Gum et al. 1987, hol produced by the hydrogenation of maltose (Suzuki and Heruth et al. 1993, Kim et al. 1980). Tamura 1988). This sugar alcohol is hydrolyzed by small intes- Many investigators have examined the effect of dietary fi- tinal disaccharidases much more slowly than maltose (Yoshibers on carcinogen-induced colon cancer in rats and reported zawa et al. 1975). Therefore, when maltitol is ingested with a meal, the majority of dietary maltitol likely reaches the large intestine and then is fermented by microflora (Oku et al. 1 Presented at the American Gastroenterological Association annual meeting 1991). in San Francisco on May 19 22, [Tsukamura, M., Goto, H., Hase, S., Because maltitol has become a popular sugar substitute in Arisawa, T., Tachi, K., Okada, N., Hayakawa, T., Murakami, T., Nakai, N., Fujitsuka, N. & Shimomura, Y. (1996) Effects of maltitol on dimethylhydrazine induced Japan (Suzuki and Tamura 1988), it is important to determine colon cancer in rats. Gastroenterology 10: A606 (abs.).] whether dietary maltitol suppresses or promotes colon carcino- 2 The costs of publication of this article were defrayed in part by the payment genesis. In the present study, we examined effects of maltitol of page charges. This article must therefore be hereby marked advertisement in accordance with 18 USC section 1734 solely to indicate this fact. on the incidence of 1,2-dimethylhydrazine (DMH)-induced To whom reprint requests should be addressed. colon cancer in rats /98 $ American Society for Nutritional Sciences. Manuscript received 30 December Initial revision completed 3 February Revision accepted 1 December

2 DIETARY MALTITOL AND RAT COLON CANCER 537 TABLE 1 incidence data represent the combined results for adenomas and adenocarcinomas. Composition of experimental diets Experiment 2 Diet Animals and diets. Forty-three male F344 rats (4 wk old) were Ingredient 1% maltitol 5% maltitol used and were housed under the same conditions as described in experiment 1. After giving the CE2 nonpurified diet for 1 wk, rats g/100 g dry matter were divided randomly into two diet groups: control (fiber-free) diet group and 1% maltitol diet group. The rats were fed the appropriate Casein, milk diet for 9 wk and were allowed free access to tap water throughout Soybean oil the experiment. One week after giving the experimental diet, each DL-Methionine group of rats was subdivided into two groups: DMH-treated group Mineral mix (AIN-76) and placebo group. Rats were treated with DMH or placebo for 8 wk Vitamin mix (AIN-76) as described in experiment 1. Choline bitartrate Fecal samples, food intake and body weights. Rats were individu- Inositol ally caged, and average fecal wet weight/24 h was measured by collect- Cornstarch ing all feces, separate from urine, from cages during three serial 24- Maltitol h periods in the final week of the experiment. The feces were frozen Sucrose to make 100 g at 080 C and were used for measurement of fecal dry weight by 1 AIN the method of Lupton and Kurtz (1993). During the period of fecal collection, food intake of each rat also was measured. Body weight was measured weekly. MATERIALS AND METHODS Cecum contents. On the final day of the experiment, rats were killed as described in experiment 1, and cecum contents were col- This study was performed according to the guidelines for animal lected and stored at 080 C. experimentation set by Nagoya University. Analyses of short-chain fatty acids. Short-chain fatty acids in cecal contents were measured by the gas-liquid chromatographic Experiment 1 method of McIntyre et al. (1993). Statistical analysis. Values are means { SD. To evaluate the Animals and diets. Eighty-nine male F344 rats (4 wk old) (CLEA differences among groups, data other than tumor incidence were ana- Japan, Tokyo) were used. The rats were housed three per cage in lyzed by two-way analysis of variance (diet 1 DMH treatment). If a suspended wire-bottomed cages in an animal room with constant significant difference was found, Scheff s test was employed (Ott temperature (23 C) and a 12-h light-dark cycle. Fresh air was supplied 1993). Values with P õ 0.05 were considered significant. Tumor constantly to the animal room, and a ventilation system for the room incidence or tumor numbers were analyzed by the chi-square test (P was designed to exchange all of the air in the room with fresh air õ 0.05). Statistical analyses were performed using Stat View 4.0 every 4.6 min. The rats consumed a nonpurified commercial diet (Abacus Concepts, Berkeley, CA). (CE2; CLEA Japan, Tokyo) for 1 wk and then were assigned randomly to three dietary groups: control (fiber-free) diet group, and 1 and 5% maltitol diet groups. The experimental diets were semipurified powder RESULTS diets and were prepared to our specifications by CLEA Japan. The composition of each experimental diet is shown in Table 1. Rats Experiment 1 were given free access to the appropriate experimental diet and tap Food intake and weights of body, cecum and colon. Food water for 27 wk. One week after giving the experimental diet, each intake measured during weeks 8, 17 and 26 in the experiment group of rats was subdivided into two groups: a DMH-treated group was not affected by supplementation of maltitol in the diet or and a placebo group. Rats in the DMH-treated group were injected DMH treatment (Table 2). Body weight on the final day of subcutaneously once each week with DMH (Aldrich Chemical, Milthe experiment was lower in DMH-treated rats than in those waukee, WI) dissolved in 0.2 mol/l sodium bicarbonate buffer (ph Ç8) with 1 mmol/l EDTA at a dosage of 20 mg/kg body weight for administered placebo. Weights of cecum and colon were not 14 wk (from week 2 through week 15). A fresh DMH solution was affected by the DMH treatment or the maltitol diet (Table 2). prepared immediately before use. Rats in the placebo group were ph of large intestinal contents. The ph of cecal contents injected with an equal volume of the buffer without DMH as de- in rats fed maltitol was significantly lower than in the control scribed above. (P õ 0.05), except that the ph decrease due to the 1 g/100 Measurements of body weight and food intake. Rat body weight g maltitol diet was not significant in the DMH treated rats was measured weekly, and food intake was measured during the exper- (Table 3). DMH treatment did not affect cecal ph, and the iment at weeks 8, 17 and 26. ph of colon contents was not affected by DMH treatment or Measurements of ph of cecum and colon contents. On the final the maltitol diet (Table 3). day of the experiment, rats were killed by cervical dislocation. A laparotomy was performed rapidly through a midline incision Tumor incidence. Tumors were not observed in the large exposing the large intestine. The ph of the intestinal contents was intestine of rats treated with placebo in any dietary group. Tumor measured using a glass electrode (needle combination ph probe) with incidence in rats treated with DMH was significantly lower in a digital ph meter (Toa HM-20E ph meter, Toa, Tokyo), which was those fed 1% maltitol diet group than in those fed the control inserted into a 5-mm incision of the bowel wall in the cecum and 5 diet (Table 3, P õ 0.05). The same trend was observed in the cm distal to the cecal-proximal colon junction. 5% maltitol diet group (P Å 0.072; Table 4). Tumor numbers Autopsy. The cecum and colon were removed, cut open, flushed and sizes (data not shown) in the tumor-bearing rats were not with ice cold saline and weighed. The presence or absence of tumors different among the three dietary groups (Table 4). was noted as was their relative position that is, either in cecum, Tumor incidence in the different sections of the large intestine proximal colon or distal colon. The tumor size was measured in three dimensions (at an angle of 90 ), and a tumor size index (mm 3 )asa (cecum, proximal colon and distal colon) is shown in Table 5. measure of mass was calculated for each rat by multiplying these Twenty percent of rats in the control group had a cecal tumor, dimensions. The majority of tumors were identified readily. When but no rats in either maltitol diet group had tumors. In the the identity of tumors was not clear, the tissue was examined histologically after staining with hematoxylin and eosin (Ward 1974). Tumor and the tumor incidence in this tissue was significantly lower proximal colon, 45% of rats in the control diet group had tumors, in

3 538 TSUKAMURA ET AL. TABLE 2 Effects of 1 and 5% maltitol diets and dimethylhydrazine (DMH) treatment on food intake and body, cecum and colon weights in rats1 Group n Food intake2 Body Cecum Colon g/d g g g Placebo { { 18a 0.53 { { 0.13 DMH { { 26b 0.62 { { 0.37 Placebo { { 23a 0.53 { { 0.16 DMH { { 24b 0.51 { { % Maltitol Placebo { { 38ab 0.56 { { 0.16 DMH { { 23b 0.65 { { 0.45 ANOVA (P-value) Diet NS NS NS NS DMH NS õ0.001 NS NS Diet 1 DMH NS NS NS NS 1 Values are means { SD. Values in a column with different superscript letters are significantly different (P õ 0.05). NS, not significant; P ANOVA, analysis of variance. 2 Food intake was measured during weeks 8, 17 and 26 in experiment 1, and an average value (g/d) for the 3 wk for each rat was used in calculation of mean { SD in each group. the 5% maltitol diet group (P õ 0.05) and tended to be lower maltitol was observed even with 1 g/100 g maltitol, so the 1 in the 1% maltitol diet group (P Å 0.091). On the other hand, g/100 g maltitol diet was used in experiment 2. the tumor incidence in the distal colon was 30% for rats in the Food intake, body weight and fecal dry weight. Food intake control diet group and was not different among the three dietary was not significantly affected by the maltitol diet or DMH groups, indicating that dietary maltitol did not affect tumor inci- treatment, but in the control groups, it tended to be less in dence in the distal colon. Tumor numbers and sizes (data not rats treated with DMH than in those treated with placebo (P shown) in the tumor-bearing rats for both proximal and distal Å 0.071; Table 6). Body weight in the control groups was colon were not different among the three dietary groups. significantly less in rats treated with DMH than in those treated with placebo, but in the maltitol diet groups, there was no difference between placebo- and DMH-treated rats (Table Experiment 2 6). There were no significant differences in the food intakes or body weights due to diet (Table 6) as observed in experiment 1. It was found in experiment 1 that supplementation of malti- Fecal dry weight of rats did not different among the groups tol in the diet had a suppressive effect on DMH-induced tumor (Table 6). incidence in the cecum and proximal colon. This effect of Short-chain fatty acids in cecum contents. The major short-chain fatty acids in cecum contents were acetate, propionate and butyrate. Concentrations of acetate and propionate TABLE 3 were not different among the groups (Table 7). Butyrate concentration in the contents of rats fed 1 g/100 g maltitol was Effects of 1 and 5% maltitol diets and dimethylhydrazine twice that of controls (P õ 0.05). (DMH) treatment on the ph of cecum and colon DISCUSSION contents in rats1 The present study examined the effect of dietary maltitol on Group n Cecum ph Colon ph colon cancer induced by DMH treatment in rats. Experiment 1 Placebo { 0.18a 7.30 { 0.21 TABLE 4 DMH { 0.25a 7.20 { 0.21 Effect of the maltitol diet on tumor incidence in the whole large intestine (cecum and colon) in rats treated with Placebo { 0.16b 7.21 { 0.21 DMH { 0.11a 7.42 { 0.17 diemthylhydrazine (DMH)1 5% Maltitol Placebo { 0.08b 7.35 { 0.12 Tumor Tumors per DMH { 0.19b 7.23 { 0.17 Group n incidence tumor-bearing rat2 ANOVA (P-value) Diet õ0.001 NS / DMH 20 15/20a (75) 1.60 { 0.83 DMH NS NS / DMH 20 8/20b (40) 1.13 { 0.35 Diet 1 DMH NS NS 5% Maltitol / DMH 21 10/21a (47.6) 1.20 { Values are means { SD. Values in a column with different superscript letters are significantly different (P õ 0.05). NS, not significant; P Values in a column with different superscript letters are significantly different (P õ 0.05). Values in parentheses are percentages. 2 Values are means { SD.

4 DIETARY MALTITOL AND RAT COLON CANCER 539 TABLE 5 Effect of the maltitol diet on tumor incidence in cecum, proximal colon and distal colon in rats treated with diemthylhydrazine (DMH)1 Cecum Proximal colon Distal colon Tumor Tumors per Tumor Tumors per Tumor Tumors per Group n incidence tumor-bearing rat2 incidence tumor-bearing rat2 incidence tumor-bearing rat2 / DMH 20 4/20a (20) 1.00 { /20a (45) 1.22 { /20 (30) 1.50 { 0.55 / DMH 20 0/20b (0) 0 4/20a (20) 1.00 { /20 (25) 1.00 { % Maltitol / DMH 21 0/21b (0) 0 3/21b (14.3) 1.33 { /21 (33) 1.14 { Values in a column with different superscript letters are significantly different (P õ 0.05). Values in parentheses are percentages. 2 Values are means { SD. in this study showed that 1 g/100 g (P õ 0.05) and 5 g/100 g In the present study, acetate, propionate and butyrate were (P Å 0.072) supplementation of maltitol in the experimental found in the cecum contents, and only the butyrate concentradiet decreased tumor incidence in the whole large intestine. tion was increased by supplementation of 1 g/100 g maltitol When the tumor incidence was analyzed on different sections in the diet, suggesting that butyrate may play an important of the large intestine, a significant effect was observed in the role in the protective effect of dietary maltitol against DMHinduced cecum for the 1% maltitol diet group and in both the cecum carcinogenesis in rat cecum and proximal colon. Mccecum and the proximal colon for the 5% maltitol diet group but not Intyre et al. (1991) have reported that the ph of colonic in the distal colon. The maltitol supplementation decreased contents gradually rises during the transport from cecum to the ph of the cecal contents but not the ph of the content in sigmoid colon, probably due to the absorption of short-chain the colon, indicating that the maltitol ingested was fermented fatty acids. They also reported that oat bran and guar gum are exclusively in the cecum as reported previously (Oku et al. highly fermented in the proximal colon but do not influence 1991). These results suggest that the fermentation of maltitol the distal luminal environment because short-chain fatty acids is responsible for the protective effect against colon cancer. are absorbed rapidly (McIntyre et al. 1991). Maltitol may have It has been reported that indigestible components of food the same effect as these fibers; therefore, the maltitol did not produce different amounts and compositions of short-chain affect the distal colon. McIntyre et al. (1991) proposed that the fatty acids when they are fermented (Lupton and Kurtz 1993, best way to maintain relatively high butyrate concentrations as McIntyre et al. 1993). Therefore we measured the fatty acids well as low ph in the distal colon, the major site for colon in the cecal contents. Among the fatty acids, butyrate is especially cancer (Schottenfeld and Haas 1978), may be by feeding a interesting because it has been reported to be an im- fiber with medium fermentability, such as wheat bran. portant energy source for normal colonocytes (Roediger 1982), The degree of fermentation is dependent upon the physical to slow the growth of cultured colon carcinoma cells and to nature of the fiber (Cummings 1981), the surface area exposed promote expression of differentiation markers (Gum et al. to bacteria (Hsu and Penner 1989) and duration of the expo- 1987, Heruth et al. 1993, Kim et al. 1980). Furthermore, the sure (Stephen et al. 1987). Highly fermentable fibers such as fecal butyrate concentration of patients with colorectal cancer guar gum and pectin enhance tissue hypertrophy and carcino- is lower than those of healthy controls (Weaver et al. 1988). genesis (Jacob and Lupton 1986). It has been reported that fermentation of dietary guar gum and pectin increased the TABLE 6 Effect of the 1% maltitol diet and dimethylhydrazine (DMH) TABLE 7 treatment on body weight, food intake and fecal dry weights Effects of the maltitol diet and dimethylhydrazine (DMH) in rats1 Food Body Fecal dry Group n intake2 weight weight treatment on short-chain fatty acid concentrations in cecum contents1 Gruop n Acetate Propionate Butyrate g/d g g/d mmol/g wet weight Placebo { { 12a 0.22 { 0.04 DMH { { 18b 0.23 { 0.05 Placebo { { { 0.65b DMH { { { 0.73b Placebo { { 23a 0.27 { 0.06 DMH { { 14ab 0.29 { 0.06 Placebo { { { 1.37a ANOVA (P-value) DMH { { { 1.56a Diet NS NS NS ANOVA (P-value) DMH NS õ0.001 NS Diet NS NS õ0.001 Diet 1 DMH NS NS NS DMH NS NS NS Diet 1 DMH NS NS NS 1 Values are means { SD. Values in a column with different superscript letters are significantly different (P õ 0.05). NS, not significant; 1 Values are means { SD. Values in a column with different superscript P letters are significantly different (P õ 0.05). NS, not significant; 2 Food intake was measured during week 11 in experiment 2. P 0.05.

5 540 TSUKAMURA ET AL. concentrations of short-chain fatty acids, especially acetate Bauer, H. G., Asp, N. G., Öste, R., Dahlqvist, A. & Fredlund, P. E. (1979) Effect of dietary fiber on the induction of colorectal tumors and fecal b-glucuronidase and propionate, in the contents of the large intestine. These activity in the rat. Cancer Res. 39: fatty acids were reported to be a primary factor in lowering the Cummings, J. H. (1981) Dietary fiber. Br. Med. Bull. 37: ph in the cecum contents, being associated with promotion of Cummings, J. H. & Englyst, H. N. (1987) Fermentation in the human large in- testine and the available substrates. Am. J. Clin. Nutr. 45: cell proliferation (Jacob and Lupton 1986, Lupton and Kurtz Gum, J. R., Kam, W. K., Byrd, J. C., Hicks, J. W., Sleisenger, M. H. & Kim, Y. S. 1993). Because butyrate production by fermentation was in- (1987) Effects of sodium butyrate on human colonic adenocarcinoma cells. duced by guar gum, but not pectin, cecum hypertrophy does J. Biol. Chem. 262: not appear to be related to the increase in butyrate (Lupton Heruth, D. P., Zirnstein, G. W., Bradley, J. F. & Rothberg, P. G. (1993) Sodium butyrate causes an increase in the block to transcriptional elongation in the and Kurtz 1993, McIntyre et al. 1993). Because acetate and c-myc gene in SW837 rectal carcinoma cells. J. Biol. Chem. 268: propionate are the major short-chain fatty acids produced by fermentation, these fatty acids were reported to be important Hsu, J. C. & Penner, M. H. (1989) Influence of cellulose structure on its digest- ibility in rat. J. Nutr. 119: in lowering the ph in the cecum contents; these effects of Jacob, L. R. & Lupton, J. R. (1986) Relationship between colonic luminal ph, fatty acids are associated with promotion of cell proliferation cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine treated (Jacob and Lupton 1986, Lupton and Kurtz 1993). It has been rats fed high fiber diet. Cancer Res. 46: Kim, Y. S., Tsao, D., Siddiqui, B., Whitehead, J. S., Arnstein, P., Bennet, J. & reported that an increase in cell proliferation in the presence Hicks, J. (1980) Effects of sodium butyrate and dimethylsulfoxide on bioof a carcinogen may enhance colon tumorigenesis (Newmark chemical properties of human colon cancer cells. Cancer 45: and Lupton 1990). It is possible that fermentation vigorous Lupton, J. R. & Kurtz, P. P. (1993) Relationship of colonic luminal short-chain fatty acids and ph to in vivo cell proliferation in rats. J. Nutr. 123: enough to produce hypertrophy may increase the risk of colon McIntyre, A., Gibson, P. R. & Young, G. P. (1993) Butyrate production from cancer. On the other hand, hypertrophy of the cecum was not dietary fiber and protection against large bowel cancer in a rat model. Gut observed in this study using 1 and 5 g/100 g maltitol diets. 34: McIntyre, A., Young, G. P., Taranto, T., Gibson, P. R. & Ward, P. B. (1991) Differ- This may be due to the relatively small amounts of maltitol ent fibers have different regional effects on luminal contents of rat colon. supplemented in the diet, because 10 g/100 g maltitol supple- Gastroenterology 101: mentation has been reported to cause hypertrophy of the celonic luminal ph: implications for colon cancer. Nutr. Cancer 14: Newmark, H. L. & Lupton, J. R. (1990) Determinants and consequences of co- cum (Oku et al. 1983). It remains to be clarified whether the Oku, T., Akiba, M., Lee, M. H., Moon, S. J. & Hosoya, N. (1991) Metabolic fate amount of maltitol supplementation that causes hypertrophy of ingested [ 14 C]-maltitol in man. J. Nutr. Sci. Vitaminol. 37: of the cecum would have a protective effect against colon Oku, T., Konishi, F., Kanda, A. & Hosoya, N. (1983) Biochemical and morpho- cancer. logical changes of gastrointestinal tract by nondigestible carbohydrate. In: Dietary Fiber Its Food Scientific and Nutritional Approach (Inami, S., ed.), In conclusion, the present study demonstrated that dietary pp Shinohara Publisher, Tokyo. maltitol has a protective effect against carcinogenesis in the Ott, R. L. (1993) Multiple comparisons. In: An Introduction to Statistical cecum and the proximal colon induced by DMH treatment in Method and Data Analysis (Lozyniak, K. & Krikorian, S., eds.), 4th ed., pp , Duxbury Press, Belmont, CA. rats, and butyrate produced by bacterial fermentation of malti- Roediger, W.E.W. (1982) Utilization of nutrients by isolated epithelial cells of tol in the cecum may be involved in the protective effect. the rat colon. Gastroenterology 83: Many sugar alcohols are used industrially as sugar substitutes. Samelson, S. L., Nelson, R. L. & Nyhus, L. M. (1985) Protective role of fecal ph in experimental colon carcinogenesis. J. R. Soc. Med. 78: However, it has not been reported whether sugar alcohols Schottenfeld, D. & Haas, J. F. (1978) Epidemiology of colon cancer. In: Gastroaffect colon carcinogenesis. This is the first report to show the intestinal Tract Cancer (Lipin, M. & Good, R. A., eds.), pp Plenum, protective effect of maltitol against colon cancer. Other sugar New York. Stephen, A. M., Wiggins, H. S. & Cummings, J. H. (1987) Effect of changing alcohols may have the same effect on colon cancer, but this transit time on colonic microbial metabolism in man. Gut 28: remains to be examined. Butyrate production by bacterial fer- Suzuki, M. & Tamura, T. (1988) Sweeteners: low-energetic and low- insulinogenic. In: Diet and Obesity (Bray, G. A., Leblanc, J., Inoue, S. & Suzuki, M., mentation in the cecum might be a useful index for the proteceds.), pp Japan Sci. Soc. Press Tokyo/S., Karger Basel. tive effect of sugar alcohols against colon cancer, and therefore Tulung, B., Remesy, C. & Demigne, C. (1987) Specific effects of gur gum or it may be important to find sugar alcohols which increase the gum arabic on adaptation of cecal digestion to high fiber diets in the rat. J. butyrate concentration throughout the large intestine. Nutr. 117: ACKNOWLEDGMENTS van Berge Henegouwen, G. P., van der Werf, S.D.J. & Ruben, A. T. (1987) Effect of long term lactulose ingestion on secondary bile salt metabolism in man: potential protective effect of lactulose in colonic carcinogenesis. Gut 28: van Munster, I. P., Tangerman, A. & Nagengast, F. M. (1994) Effect of resistant We would like to express our gratitude to Michael V. Bodman, starch on colonic fermentation, bile acid metabolism, and mucosal proliferalanguage consultant of our department, for giving us suggestions on tion. Dig. Dis. Sci. 39: language. Yoshizawa, S., Moriuchi, S. & Hosoya, N. (1975) The effects of maltitol on rat intestinal disaccharidases. J. Nutr. Sci. Vitaminol. 21: Ward, J. M. (1974) Morphogenesis of chemically induced neoplasms of the LITERATURE CITED colon and small intestine in rats. Lab. Invest. 30: Weaver, G. A., Krause, J. A., Miller, T. L. & Wolin, M. J. (1988) Short chain fatty American Institute of Nutrition (1977) Report of the American Institute of Nutri- acid distributions of enema samples from a sigmoidoscopy population: an tion ad hoc committee on standards for nutritional studies. J. Nutr. 107: 1340 association of high acetate and low butyrate ratios with adenomatous polyps and colon cancer. Gut 29: