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Article

Psyllium Shifts the Fermentation Site of High-Amylose Cornstarch toward the Distal Colon and Increases Fecal Butyrate Concentration in Rats

Tatsuya Morita^1*, Seiichi Kasaoka^*, Koji Hase^* and Shuhachi Kiriyama

^* Azusawa Research Laboratories, Institute for Consumer Healthcare, Yamanouchi Pharmaceutical Co., Ltd. 1-8, Azusawa 1-Chome, Itabashi-ku, Tokyo 174-8511, Japan, and Laboratory of Nutritional Biochemistry, Otsuma Women's University, Sanbancho 12, Chiyoda-ku, Tokyo 102-8357, Japan

¹To whom correspondence should be addressed. Current address: Institute for Consumer Healthcare, Yamanouchi Pharmaceutical Co., Ltd. 17-1, Hasune 3-Chome, Itabashi-ku, Tokyo 174-8612, Japan. Telephone number: (03)-5916-5572. Fax number: (03)-5916-5618. E-mail: moritata{at}yamanouchi.co.jp

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
We examined the combination effects of psyllium (PS) and resistant starch on large bowel short-chain fatty acids (SCFA). Rats were fed one of the following four diets: low amylose (LAS) or high amylose cornstarch diets (HAS, 50 g/kg diet) with or without 15 g PS/kg diet (LAS/PS and HAS/PS diets). HAS and/or PS were substituted for the same amounts of LAS in diets. Cecal butyrate concentrations were significantly higher in rats fed the HAS and HAS/PS diets than in those fed the LAS and LAS/PS diets. However, butyrate and total SCFA concentrations in rats fed the HAS diet decreased along the length of the colon and fecal butyrate concentration was reduced to one-third of that in the cecum. In contrast, the HAS/PS diet maintained higher butyrate concentrations throughout the large bowel. Fecal butyrate concentration in the HAS/PS diet-fed group significantly exceeded the sum of the concentrations in rats fed the LAS/PS and HAS diets. PS supplementation to the HAS diet significantly increased fecal starch excretion by 10 fold compared with that of rats fed the HAS diet. There was a positive correlation between fecal butyrate concentration and fecal starch excretion (r = 0.709, P < 0.0001). In a further experiment, ileorectostomized rats were fed the HAS and HAS/PS diets. From the difference in fecal starch excretion between normal and ileorectostomized rats, starch degradation by large bowel microflora in rats fed the HAS and HAS/PS diets was deduced to be 96% and 63%, respectively. These findings support the hypothesis that PS may delay the fermentation rate of HAS in the cecum and shift the fermentation site of HAS toward the distal colon, leading to the higher butyrate concentration in the distal colon and feces.

KEY WORDS: • short-chain fatty acids • resistant starch • dietary fiber • cecal fermentation • rats

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The end products of microbial carbohydrate fermentation in the large bowel include short-chain fatty acids (SCFA)² , among which acetate, propionate and n-butyrate are quantitatively most important (Cummings 1981 ). SCFA have a range of effects that may be relevant to colonic health (Cummings 1981 , Pouillart 1998 ). Of these, n-butyrate is of particular interest because it exerts a concentration-dependent slowing of the rate of cancer cell proliferation and promotes expression of differentiation markers in vitro (Kim et al. 1980 , Whitehead et al. 1986 ), leading to reversion of cells from a neoplastic to a nonneoplastic phenotype (Willson 1989 ). Also, fecal n-butyrate concentrations of patients with colorectal cancer were reported to be lower than those of healthy controls (Weaver et al. 1988 ).

The presence of n-butyrate in the distal colon may be important in the prevention of colon cancer because the majority of tumors in both humans and experimentally induced rodent cancer models occur in the distal colon (Bufill 1990 , Holt et al. 1996 , Reddy et al. 1975 ). However, fermentation is normally more active in the cecum and proximal colon than in the distal colon (Cummings and Englyst 1987 , Mitchell et al. 1985 ), while SCFA are rapidly absorbed (Cummings 1981 ). For these reasons, highly fermentable dietary fibers such as pectin, guar gum and oat bran are fully fermented in the cecum and proximal colon and do not contribute n-butyrate to the distal colon (Lupton and Kurtz 1993 , McIntyre et al. 1991 ). This also might be the case for resistant starches (RS) such as high-amylose cornstarch (HAS) which has a fermentation rate that is relatively rapid (Topping et al. 1997 ). From the in vitro findings of Englyst et al. (1987) , starch might be intrinsically a butyrate-producer under an ideal substrate-condition, and in rat models, cecal fermentation of HAS resulted in relatively high amounts of cecal n-butyrate in the presence of appropriate amounts of resistant protein and/or peptide (Morita et al. 1998 , Morita et al. 1999 ). Therefore, it should be meaningful to establish a method by dietary manipulation to shift the fermentation site of HAS and to increase n-butyrate production in the distal colon and feces. Such delivery system of starch to the site where the incidence of colon cancer is higher might be of value to better understand the effects of n-butyrate on the large bowel physiology.

There is evidence that the substrate interaction between starch and dietary fiber fermentation may occur in the large bowel and that the colonic microflora preferentially use the more easily fermented carbohydrates in starch, indicating a dietary fiber-sparing effect by starch (Cummings et al. 1996 , Phillips et al. 1995 ). Just the opposite may hold true for the interaction of certain dietary fibers with higher fermentability and starch; that is, a starch-sparing effect by dietary fiber (Nyman et al. 1986 ). Psyllium (PS) may be a good candidate to spare and deliver starch to the distal colon. PS is slowly fermented and more than 50% of that consumed is devoid of bacterial degradation in the large bowel and is excreted into feces (Edwards et al. 1992 ). PS possesses a stronger gel-forming property and shows a higher water-holding capacity than do other dietary fibers (McBurney 1991 ). These characteristics of PS could protect starch from full fermentation in the upper colon by trapping starch granules in the gel.

In the present study, we attempted to increase n-butyrate concentration in the distal colon and feces in rats fed HAS in combination with PS as a starch carrier. We used a relatively small amount of HAS in diets (50 g HAS/kg diet), because 100 g or more HAS/kg diet resulted in a lower n-butyrate with higher succinate concentration in the cecum when rats were fed a purified diet with casein as the sole protein source (Kasaoka et al., unpublished observation), possibly due to an imbalance of carbohydrate and nitrogen as fermentation substrates in the cecum (Morita et al. 1998 , Morita et al. 1999 ). Also, the PS level in diet was set at 15 g/kg diet, based on a previous study (Edwards et al. 1992 ) in which these PS levels were enough to significantly increase fecal bulk.

	MATERIALS AND METHODS

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Materials.

Casein (125.5 mg nitrogen/g) was purchased from New Zealand Dairy Board (Wellington, New Zealand). Low-amylose cornstarch (LAS, cornstarch W) was purchased from Nihon Shokuhin Kako (Tokyo, Japan). High-amylose cornstarch (Hi-maize, 80% amylose) was from Starch Australasia (Lane Cove, New South Wales, Australia). PS was from Bizen Chemical Co. (Tokyo, Japan), and its total dietary fiber content was 90% as measured by the method of Prosky et al. (1988) . The water-holding capacity of PS was determined to be 22 mL/g (McConnel et al. 1974 ).

Care of animals.

Male Sprague-Dawley rats (purchased from Shizuoka Laboratory Animal Center, Hamamatsu, Japan) were housed in individual cages with wire screen-bottomed stainless steel in a room of controlled temperature (23 ± 2°C) and lighting (lights on from 0800–2000h). After adaptation to a control diet (Table 1 ) for 7 d, rats were divided into groups on the basis of body weight and allowed free access to experimental diets and water. Body weight and food intake were recorded in the every morning before replenishing the diet.

Studies in rats fed HAS or LAS diets with or without PS (experiment 1).

Thirty-two rats weighing 208–234 g were divided into four groups (n = 8) after acclimation and were allowed free access to one of the following diets: LAS, LAS + 1.5% PS (LAS/PS), 5% HAS (HAS) and 5% HAS + 1.5% PS (HAS/PS) diets. The composition of each diet is shown in Table 1 . Supplementations of 50 g HAS and/or 15 g PS/kg diet were performed at the expense of an equal amount of LAS. This experiment was terminated at 2 wk, because weekly fecal number, weight and volume in a previous study (Kasaoka et al., unpublished) showed that these variables became constant within 2 wk, indicating that adaptation to the diets had been completed in 2 wk. For the fecal starch assay, feces were collected for the last 3 d of the experimental period, and freeze-dried and stored at -20°C. For fecal pH and organic acid assays, fresh fecal sample was collected during 15:00–16:00 h on the day before the end of the experimental period and assayed immediately. At the end of the experimental period, rats were anesthetized with diethyl ether at 14:00–16:00 h, and the cecum and colon were removed and weighed. The cecal contents were transferred to a 50-mL glass tube with a screw-cap and stored at -20°C until analysis. The cecal wall was flushed clean with ice-cold 0.15 mol/L NaCl, gently blotted on filter paper and weighed. The colon was divided into two equal halves—the proximal and distal colon. The colonic contents and tissue were treated in the same manner as the cecum.

Digestibilities of HAS in ileorectostomized rats in the presence or absence of PS (Experiment 2).

After acclimation to the control diet, 12 rats weighing 225–250 g were subjected to an ileorectostomy in which the distal ileum is anastomozed to the rectum as described previously (Morita et al. 1998 ). After the operation, rats were fed the control diet for 10 d. Constant growth rates (5–7 g body weight gain/d) were achieved after 5 d. Following postoperative recovery, the rats weighing 250–275 g were divided into two groups (n = 6) on the basis of body weight. Rats were allowed free access to one of the following diets for 18 d: 5% HAS and 5% HAS + 1.5% PS diets [HAS and HAS/PS diet, respectively (Table 1) ]. In this experiment, sucrose was used as the sole carbohydrate source. Feces (ileal effluent) were collected for the last 3 d of the experimental period, and freeze-dried and stored at -20°C.

Digestibility of HAS was calculated by using the following equation.

Analytical procedures.

After homogenization of cecal or colonic contents, or feces, a portion of homogenate was diluted with an equal volume (cecal or colonic contents) or 10 vol (feces) of distilled water, and then the pH was measured with a compact pH meter (Model C-1; Horiba, Tokyo, Japan). Measurement of cecal and fecal organic acids was described previously (Morita et al. 1998 ). Fecal starch was determined using a Megazyme Total Starch Assay Kit (Megazyme Australia Pty. Ltd., Sydney, Australia) with a modification which involved pre-heating the samples in dimethylsulfoxide at 100°C for 30 min (Muir et al. 1995 ).

Statistical analyses.

Data were analyzed by one-way (Experiment 2) or two-way (Experiment 1) ANOVA, and significant differences among means were separated by Duncans multiple range test (Shibata 1974 ) or Scheffé's test (when sample number was different among the groups). When variances were not homogeneous by Bartlett test (Zar 1984 ), data were logarithmically transformed, and then transformed data were analyzed by ANOVA followed by multiple comparison. When variances were not homogenous even after logarithmical transformation, the results were presented as medians with range and then analyzed by Kruskal-Wallis ANOVA followed by Kolmogorov-Smirnov two-sample test (Zar 1984 ). When only two groups were compared, the results were analyzed by Student's t-test. Individual data of fecal starch and of fecal SCFA were analyzed by logarithmic regression using the Kaleida Grapf program (Synergy Software, Reading, PA) to test for their correlation. All statements of significant differences show the 5% level of probability.

	RESULTS

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Studies in rats fed HAS or LAS diets with or without PS (Experiment 1).

There were no significant differences in food intake and body weight gain among the groups (Table 2 ). The cecal tissue weights were highest in rats fed the HAS/PS diet, modest in those fed the LAS/PS and HAS diets, and lowest in the LAS diet fed rats, indicating that the cecal tissue weight was affected by both starch and PS. The cecal content weights were significantly greater in rats fed the LAS/PS, HAS and HAS/PS diets than in those fed the LAS diet. Both starch and PS affected the cecal contents, and there was a significant interaction between them. Cecal pH were significantly greater in rats fed the HAS and HAS/PS diets than in those fed LAS and LAS/PS diets, indicating that the cecal pH was affected only by starch.

Fecal dry weights were highest in rats fed the HAS/PS diet, modest in the LAS/PS diet group and lowest in rats fed the LAS and HAS diets. Both starch and PS affected fecal dry weight (Table 2) . Fecal starch excretions differed significantly among the groups. Both effects of starch and PS on fecal starch excretions were observed and there was a significant interaction. Fecal pH was highest in rats fed the LAS diet, modest in those fed the LAS/PS and HAS diets and lowest in the HAS/PS diet group. Both starch and fiber affected the fecal pH, and there was a significant interaction between the effects of starch and PS.

The principal SCFA concentrations including acetate, propionate and butyrate at the different sites of the lower gut are illustrated in Figure 1. Because colonic samples from the LAS and HAS diet-fed rats were pooled, the multiple comparison was only made in cecal and fecal SCFA concentrations. In the cecum, acetate concentrations were significantly higher in rats fed the LAS and HAS diets than in those fed the LAS/PS and HAS/PS diets. Supplementation of PS to the diets significantly reduced the acetate concentration. Propionate concentrations were significantly higher in rats fed the LAS, HAS and HAS/PS diets than in those fed the LAS/PS diet. Supplementation of PS to the diets also significantly reduced the propionate concentration. n-Butyrate concentrations were significantly higher in rats fed the HAS and HAS/PS diets than in those fed the LAS and LAS/PS diets, indicating that the n-butyrate concentration was affected only by starch. Total SCFA (acetate + propionate + n-butyrate) were significantly higher in rats fed the LAS and HAS diets than in those fed the LAS/PS, and the HAS/PS diet was intermediate. Both starch and PS affected the total SCFA concentration.

View larger version (32K): [in this window] [in a new window]   Figure 1. Short-chain fatty acid concentrations along the length of the large bowl and in feces of rats fed diets containing low amylose cornstarch (LAS) or high amylose cornstarch (HAS) diet with or without psyllium (PS) for 2 wk (Experiment 1). Each point for cecal and fecal samples represents means ± SEM, n = 8. Points with different letters are significantly different (P < 0.05) by Duncan's multiple range test. Samples of the proximal and distal digesta in rats fed the LAS and HAS diets were limited and pooled (n = 1). Sample numbers of the distal digesta in rats fed the LAS/PS and HAS/PS diets were seven and eight, respectively. *P < 0.05 vs. the LAS/PS diet when analyzed by Student's t-test. Fresh fecal samples were collected from 1500–1600 h on the day before the end of the experimental period.

From the cecum through the feces, SCFA concentration gradually decreased, but PS supplementation to the diets tended to slow the decline of SCFA concentrations. Because colonic digesta in the LAS diet- and HAS diet-fed groups were so small, samples in these two groups were pooled within the same group. Therefore, statistical analysis was by Student's t-test comparing the colonic SCFA concentrations of LAS/PS and HAS/PS diet-fed rats. The HAS/PS diet group had higher n-butyrate concentrations in the distal colon than those of the LAS/PS diet group.

The molar ratio of each SCFA in the cecum was affected by starch only (Table 3 ). The molar ratios of acetate were significantly higher in rats fed the LAS and LAS/PS diets, but those of n-butyrate were significantly higher in rats fed the HAS and HAS/PS diets. In feces, the molar ratios of n-butyrate were affected by starch only, but those of propionate were affected by both starch and PS.

View larger version (19K): [in this window] [in a new window]   Figure 2. Relationships between fecal n-butyrate or total short-chain fatty acids (SCFA) concentration and fecal starch excretion in rats fed diets containing low amylose cornstarch (LAS) or high amylose cornstarch (HAS) diet with or without psyllium (PS) for 2 wk (Experiment 1). Fecal samples for SCFA analysis were collected from 1500–1600 h on the day before the end of the experimental period. For fecal starch analysis, feces were collected for the last 3 d of the experimental period.

Rats fed the HAS diet had constant food intake (18–20 g/d) and body weight gain (4–6/d) throughout the experimental period. However, the food intake in rats fed the HAS/PS diet was considerably lower (10–14 g/d) for the first 9 d of the experimental period, and body weight loss was observed. After 10 d, food intake in the HAS/PS diet-fed group gradually increased and constant food intake (17–20 g/d) and body weight gain (1–2 g/d) were achieved from d 12. Therefore, we measured starch digestibility on the basis of food intakes during the last 3 d of the experimental period (d 16–18) (Table 4 ). There were no significant differences in food intake during the last 3 d between the diet groups, but fecal dry weights (i.e., excretion of ileal effluent) in rats fed the HAS/PS diet were significantly higher than in those fed the HAS diet. Starch digestibility was significantly greater in rats fed the HAS diet than in those fed the HAS/PS diet.

	DISCUSSION

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In contrast, supplementation of PS to the diet containing HAS (HAS/PS diet) maintained higher n-butyrate concentrations in the distal colon and feces than those in rats fed the diet containing HAS (HAS diet) or PS (LAS/PS diet) alone (Fig. 1) . Moreover, fecal n-butyrate concentrations in rats fed the HAS/PS diet exceeded the sum of those in rats fed the LAS/PS and HAS diets. Although two-way ANOVA analysis indicated that both starch and PS affected the fecal n-butyrate concentration, the contribution of PS alone to n-butyrate production itself is unlikely to be important because cecal and fecal n-butyrate concentrations in rats fed the LAS/PS diet were considerably lower than those in rats fed the HAS diet (Fig. 1) . It is more likely that PS supplementation shifted the fermentation site of HAS toward the distal colon. Edwards et al. (1992) reported in rats that PS was slowly fermented throughout the colon and more than 50% of that consumed avoided bacterial degradation in the large bowel, and was excreted into feces. This slowly fermentable property of PS, presumably due to the chemical structure and its strong gel-forming potency, might depress the rate of fermentation of HAS in the cecum when they are present together. In fact, fecal starch excretion was significantly increased by PS supplementation to the LAS or HAS diets (Table 2) . When PS was supplemented to the HAS diet, the fecal starch excretion in rats fed the HAS/PS diet was 10-fold greater than in those fed the HAS diet. From the difference in fecal starch excretion between normal (Experiment 1) and ileorectostomized rats (Experiment 2), starch degradation by large bowel microflora in rats fed the HAS/PS diet was calculated to be 63%. Also, regression analysis showed that there were strong positive correlations between fecal n-butyrate (r = 0.709, P < 0.0001) and total SCFA (r = 0.620, P = 0.0002) concentrations, and fecal starch excretion (Fig. 2) . These findings support the hypothesis that PS may delay the fermentation rate of HAS in the cecum and shift the fermentation site of HAS toward the distal colon, leading to higher n-butyrate concentrations in the digesta of distal colon and feces.

The higher fecal n-butyrate concentrations in rats fed the HAS/PS diet may be due to a decreased rate of absorption of SCFA from the lumen. The PS used in the present study had a potent water-holding capacity (22 mL/g) and therefore, might reduce the water absorption and inhibit diffusion of n-butyrate. In the present study, the water-holding capacities of the pooled samples of cecal contents measured by the centrifugation method (McConnel et al. 1974 ) were 3.09 (LAS), 4.73 (LAS/PS), 2.84 (HAS) and 5.48 mL/g (HAS/PS), respectively. Those of the pooled samples of feces were 2.78 (LAS), 4.00 (LAS/PS), 2.06 (HAS) and 4.91 mL/g (HAS/PS), respectively. Therefore, PS still maintains its water-holding capacity, even after passing through the large bowel. On the other hand, Edwards et al. (1992) reported in rats that feeding 0.5 to 5% PS in diets for 4 wk did not affect fecal water-holding capacity. However, the water-holding capacity was measured by a different method employing dialysis. We do not know which method for measuring water-holding capacity best reflects the physiological condition of n-butyrate absorption from the lumen. However, the n-butyrate concentrations in rats fed the LAS/PS diet declined along the length of the colon, and the accumulation of n-butyrate in the lumen was not observed (Fig. 1) . This might simply mean that the remaining water-holding capacity in the distal colon did not have a profound effect on n-butyrate absorption. In addition, the pH values of distal colonic contents were lowest in rats fed the HAS/PS diet, and such a colonic environment would hasten SCFA absorption from the lumen (Sellin and Soignie 1990 ). Therefore, it seems unlikely that PS per se would cause the reduction of SCFA absorption from the lumen of the colon.

Cummings et al. (1996) and Phillips et al. (1995) indicated in human studies that an interaction between dietary starch and fiber occurred in large bowel fermentation and that starch was fermented in preference to fiber, suggesting that starch might exert a sparing effect on certain dietary fibers. Also, the present study clearly showed the interactive effects of RS and PS on large bowel SCFA and suggests that it is possible to maintain relatively high butyrate concentration in the distal large bowel by dietary manipulation. The amounts of RS and PS used in the present study were conservative (5 g HAS and 1.5 g PS/100 g in rat diet may correspond to a human intake of ~25 g HAS and 7.5 g PS intake/d), within the range recommended for adults to consume in a healthy diet. These findings might have an important implication for large bowel physiology since Cassidy et al. (1994) showed that there were strong inverse associations between the incidence of colorectal cancer and starch intake or the sum of dietary fiber and RS intake, while dietary fiber alone did not show any significant relationships. Given that fermentation in the colon is the mechanism for achieving colorectal cancer protection, via the specific contribution of n-butyrate to reduction of proliferation and induction of differentiation of the mucosal cells (Cummings 1981 ), it is probable that dietary manipulations which slow the fermentation rate of starch and dietary fiber would be of benefit in cancer protection in the distal colon and rectum.

	FOOTNOTES

 
² Abbreviations used: HAS, high-amylose cornstarch; LAS, low-amylose cornstarch; PS, psyllium; RS, resistant starch; SCFA, short-chain fatty acids.

Manuscript received April 29, 1999. Initial review completed June 11, 1999. Revision accepted August 6, 1999.

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