Yoshiya HATA* Minoru YAMAMOTO, and Kumiko NAKAJIMA

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1 J. Clin. Biochem. Nutr., 10, , 1991 Effects of Soybean Oligosaccharides on Human Digestive Organs: Estimation of Fifty Percent Effective Dose and Maximum Non-Effective Dose Based on Diarrhea Yoshiya HATA* Minoru YAMAMOTO, and Kumiko NAKAJIMA Department of Medicine and Gerontology, Kyorin University School of Medicine, Mitaka, Tokyo 181, Japan (Received November 23, 1990) Summary Soybean oligosaccharide extract (SOE) containing galactooligosaccharides like raffinose and stachyose has a sweet taste similar to that of sucrose. When ingested, these galactooligosaccharides are neither digested nor absorbed, but promote the growth of bifidobacteria in the human intestine. It therefore has the potential to be an alternative sweetener in dietary treatment for metabolic disorders. However, the indigestible oligosaccharides, in general, often cause diarrhea when taken beyond a specific amount. To determine the maximum non-effective dose (NEDmax) and the 50% effective dose (ED50) of SOE on diarrhea, we conducted a single blind comparative study on 106 adult healthy volunteers with an average age of 29± 12 years. They were randomly chosen to ingest either SOE in a concentration 1, 2, 4, 6, 8, or 10 times the standard dose of 0.16 g/kg body weight, or the equivalent proportions of sucrose as the control. The NEDmax was found to be 0.64 g/kg for males and 0.96 g/kg for females, while the ED50 was 0.88 g/kg for men and 2.41 g/kg for women. These values assure, for both genders, that man can ingest SOE at least four times the standard dosage per ingestion without intestinal disturbances. Key Words. soybean oligosaccharides, galactooligosaccharides, sugar substitute, diarrhea, bifidobacteria Soybean oligosaccharide extract (SOE) is a mixture of water-soluble oligosaccharides extracted from the soybean whey, a by-product of soy protein manufacturing [1, 2]. The saccharide composition of dried SOE is approximately 50% sucrose, 25% stachyose, 10% rafnose, and 15% monosaccharides including glucose and *To whom correspondence should be addressed. 135

2 136 Y. HATA, M. YAMAMOTO, and K. NAKAJIMA fructose. This colorless syrup has a sweet taste similar to that of sucrose, its sweetness being nearly 70% that of sucrose (dry weight basis); and it has no unpleasant aftertaste [1, 2]. In SUE, the galactooligosaccharides of raffinose and stachyose possess one or two galactose molecules attached to the glucosyl residue of sucrose. Raffinose thus has the structure of galactose (Gal)-glucose (G)-fructose (F), while stachyose has the Gal-Gal-G-F structure [1, 2], as shown in Fig. 1. When these galactooligosaccharides are administered to experimental animals or humans, they are neither digested nor absorbed [3, 4], suggesting the possibility that SUE can be used as an alternative sweetener for the treatment or prevention of such diseases as obesity, diabetes mellitus, or hyperlipidemias. Since subjects with these disorders are restricted to a low caloric diet and are prohibited from consuming sugary foods and beverages [5-7], they often hunger for sweets. It has been found that the galactooligosaccharides contained in SUE are utilized selectively in the intestinal lumen by bifidobacteria [1, 2, 8]. As recent advances in human physiological studies on intestinal microorganisms have shown that bifidobacteria play a central role in abolishing pathogens from the intestine [1, 2], the daily use of this product may thus be beneficial. However, oligosaccharides are known to cause abdominal discomfort and diarrhea when ingested beyond specific amounts [9], and the galactooligosaccharides contained within SUE are no exception. To determine the maximum non-effective dose (NEDmax) and 50% effective Stachyose Raffinose Sucrose Fig. 1. Chemical structures of soybean oligosaccharides. J. Clin. Biochem. Nutr.

3 SOYBEAN OLIGOSACCHARIDES AND DIARRHEA 137 dose (ED50) thresholds for the SOE galactooligosaccharides ingested by humans, we have conducted a single blind, comparative study on healthy volunteers ingesting varied amounts of SOE solubilized in water or solubilized sucrose as the control. MATERIALS, SUBJECTS, AND METHODS The SOE material used in this study was syrup containing 75% dry matter. The saccharide composition, on a dry weight basis, was 50.5% sucrose, 24.5% stachyose, 9.2% raffinose, 6.9% glucose, 6.1% fructose, and 2.8% other saccharides (Table 1). The control syrup was made by eliminating the portions of stachyose, raffinose, and other minor saccharides contained in SOE, resulting in a final proportion of 79.5% sucrose, 10.9% glucose, and 9.6% fructose (Table 1). One hundred and six healthy adult volunteers (34 males and 72 females) having given informed consent, participated in this study. Excluded were those who had gastric or intestinal disorders, habitual constipation, or were using laxatives. Their age distribution is shown in Table 2, the average age being years (males, 24± 8; and females, 32± 13); and average body weight was 55±9 kg (males, 64+7 kg; and females, 50+6 kg). Table 1. Saccharide composition of diet supplement. adry weight basis. Table 2. Subjects' age and body weight distribution. avalues are mean+sd. Vol. 10, No. 2, 1991

4 Table 3. Amount of diet supplement ingested by each group. aconcentration fold (g/kg-body weight, dry weight for supplement values ; bdry weight. M, Male; F, female.

5 SOYBEAN OLIGOSACCHARIDES AND DIARRHEA 139 The volunteers were randomly selected either to ingest the SOE at single intake doses of 0.16, 0.32, 0.64, 0.96, 1.28, and 1.60 g/kg (g dry matter per kg body weight), respectively, or to take the control supplement on single intake doses that had the equal amounts of mono- and di-saccharides that were respectively contained within the doses administered to the SOE groups. The number of subjects, average age, body weight, and ingested amount in each group are given in Table 3. Each subject was asked to ingest an assigned sample, dissolved in 180 ml of water contained in a sterilized laminated aluminum pouch, within 2 h after breakfast, and stay home for the day. Otherwise, they were allowed to eat and drink as usual. Each participant described any abdominal symptoms, according to a set format, observed during the first 24 h after ingestion, including defecation time after ingestion and fecal conditions before and after intake. The fecal conditions were described as stony, ordinary, loosely formed, muddy, or watery. Statistical analyses employed were Student's t-test, f-test, and Mann- Whitney test; and statistical significance was calculated at the level of 5% with two-tail tests. RESULTS All the participants reported the results of abdominal symptoms according to the set format, from which we determined the effects of SOE on abdominal conditions, defecation time, fecal conditions, and other, if any, unpleasant symp- Table 4. Effects of diet supplement on abdominal symptoms. aconcentration fold (g/kg-body weight, dry weight for supplement values). M, Male; F, female. Vol. 10, No. 2, 1991

6 140 Y. HATA, M. YAMAMOTO, and K. NAKAJIMA Table 5. Average defecation time after ingestion of diet supplement. aunit, h (mean+se); bconcentration fold (g/kg-body weight, dry weight basis). For those who had no defecation within 24 h after ingestion, the defecation time was recorded as 24 h (C 1). Table 6. Fecal conditions before and after ingestion of diet supplement. B, Before ingestion; A, after ingestion. aconcentration fold (g/kg-body weight, dry weight for supplement values). M, Male; F, female. J. Clan. Biochem. Nutr.

7 SOYBEAN OLIGOSACCHARIDES AND DIARRHEA 141 tom(s), and deduced the ED50 and the NEDmax. In Table 4, the effects of SOE on abdominal symptoms are listed for each test group. The incidence of diarrhea, abdominal pain, gurgling sounds, flatulence, and flatus discharge was higher in the SOE groups than in the control groups, especially at the high dosages. However, the incidence of none of the abdominal symptoms was statistically significant between the two groups. The average defecation time for each group is shown in Table 5. For those who had no stool evacuation within 24 h after ingestion of the test material, the defecation time was recorded as 24 h. The defecation time was shorter in the SOE groups of 0.96 and 1.28 g/kg compared with the 0.16 g/kg group, while in the highest dose group of 1.60 g/kg group, there were some subjects who had no defecation within 24 h. Therefore, the defecation time did not appear to correlate with the amount of SOE ingested. The fecal conditions assessed are summarized in Table 6. The stools tended to be softer in the SOE group, when the dosage was at the 0.96 g/kg level or higher (Fig. 2). They were significantly different (p <0.05) when compared between the two groups of the highest dosage of 1.60 g/kg. No other adverse symptoms were observed after ingestion of SOE except for 0.16g/ kg 0.96g/kg 0.32g/kg 1.28g/kg 0.64g/kg 1.60g/kg Fig. 2. The incidence of fecal conditions after ingestion for each group. A, stony; B, ordinary; C, loosely formed; D, muddy; E, watery. 0, Control; soybean oligosaccharides. Vol. 10, No. 2, 1991

8 142 Y. HATA, M. YAMAMOTO, and K. NAKAJIMA Fig. 3. Dose effect curve between incidence of diarrhea and amount of SOE ingested (dry weight). o, Male;, female. the above abdominal symptoms, all of which were temporary and did not require any treatment. The incidence of watery diarrhea is expressed as a function of SOE dosage in Fig. 3. Not a single case of diarrhea was seen in the SOE groups at the dosage of 0.16 to 0.64 g/kg for males, and up to 0.96 g/kg for females, indicating that the NEDmax for SOE is 0.64 g/kg for males and 0.96 g/kg for females. The ED50 was estimated by examining the intersection of the cumulative frequency curve with the cut-off at 50% incidence. The ED50 was thus found to be 0.88 g/kg for males and 2.41 g/kg (extrapolated) for females (Fig. 3). DISCUSSION In this study, the dosage of SOE was arranged in multiples of 0.16 g/kg, since it is the necessary dose to establish effective growth promotion of human intestinal bifidobacteria [1, 2, 5]. At this dosage, SOE can also be used as a common sweetner for daily use. The NEDmax of SOE (dry weight) for diarrhea was found to be 0.64 g/kg for males and 0.96 g/kg for females, indicating that the ingestion of SOE does not cause diarrhea, unless it is taken at four or more times the common usage of 0.16 g/kg for men, and six or more times for women. The ED50 was determined as 0.88 g/kg for men and 2.41 g/kg (extrapolated) for women; six and over ten times the normal dosage, respectively. The NEDmax and ED50 taken together, for both genders, indicate that humans can ingest SOE at least up to four times the standard dosage without abdominal disturbances. Therefore, a subject with the body weight of 60 kg, for example, may take as much as 40 g of SOE per ingestion without any gastrointestinal troubles. J. Clin. Biochem. Nutr.

9 SOYBEAN OLIGOSACCHARIDES AND DIARRHEA 143 Table 7. NEDmax and ED50 values for soybean oligosaccharides and other sugar substitutes. Values in g/kg-body weight. The cause for abdominal disturbances, including diarrhea, are not fully understood, but they may arise either from the increased osmotic pressure due to a temporal accumulation of indigestible oligosaccharides with high molecular weight [10], or from chemical stimulation of the intestinal wall by organic acids [11] or polyamines [12] produced by bacterial degradation of oligosaccharides. The gender differences in the NEDmax and ED50values also remain to be explained. It is unknown why these differences occur, but women in general appear to have a common tendency for constipation, which may be the result of dietary restriction for cosmetic reasons or anatomical oppression of the colon by the uterus [13]. When comparison is made of the NEDmax and ED50 values among unmetabolized monosaccharides such as sorbose [14], the sugar alcohols sorbitol and maltitol [15, 16], and the undigestible oligosaccharide fructooligosaccharide [17], then the ED50 values are all within a narrow range of 0.7 to 1.0 g/kg, except for the low value of sorbitol for men (0.4 g/kg). The ED50 of SOE (0.88 g/kg for men) lies in the middle of this range, while that for women (2.41 g/kg) is exceptionally high (Table 7). However, when the NEDmax values are compared, the SOE values are 1.5 to 2 times higher than those of the other saccharides. This indicates that the asymptomatic range is large enough for common use of SOE. Soybean oligosaccharides are contained in many traditionally used Japanese foods, such as baked soybean flour (kinako), soybean milk (tohnyu), boiled beans (nimame), and azuki bean jam (azuki an) [1, 2], though they are not present in fermented products like soy sauce (shoyu), soybean paste (miso), and fermented soybeans (natto) [1, 2]. Soybean oligosaccharides have had a long history of safe consumption, and in addition to their safety, these oligosaccharides have been found to selectively promote the growth of intestinal bifidobacteria which are known to be beneficial to the maintenance of good health [1, 2, 5]. Thus, SOE is a practical sugar substitute that can be used in diets for the control of various metabolic risk factors. REFERENCES 1. Masai, T. (1987): Physical action and food application of soybean oligosaccharides. Food Vol. 10, No. 2, 1991

10 144 Y. HATA, M. YAMAMOTO, and K. NAKAJIMA Ind., 30, (in Japanese). 2. Masai, T. (1988): Soybean oligosaccharides-characteristics and application. Food Sci., 11, (in Japanese). 3. Ohmura, K., Maruta, K., Kato, Y., and Hayakawa, K. (1990): Changes of soybean oligosaccharides in the digestive tract, in Caloric Evaluation of Carbohydrates, Research Foundation for Sugar Metabolism, ed. by Hosoya, N., Tokyo, pp Ruttloff, H., Taufel, A., Krause, W., Haenel, H., and Taufel, K. (1967): Die intestinalenzymatische Spaltung von Galactooligosacchariden im Darm von Tier and Menschen mit besondever Beruchsichtigung von Lactobacillus bifidus. Nahrung, 11, Stern, J. (1983): Diet and exercise, in Obesity, ed. by Greenwood, M.R.C., Churchill Livingstone, New York, pp Vinik, A., and Wing, R.R. (1990): Nutritional management of the person with diabetes, in Diabetes mellitus-theory and Practice (4th ed.), ed. by Rifkin, H. and Porte, D., Jr., Elsevier, Amsterdam, pp Marinetti, G.V. (1990): Dietary management of elevated blood lipids, in Disorders of Lipid Metabolism, Plenum Press, New York, pp Hayakawa, K., Mizutani, J., Wada, K., Masai, T., Yoshihara, I., and Mitsuoka, T. (1990): Effects of soybean oligosaccharides on human faecal flora. Micro Eco. Health Dis., 3: Kameoka, S., Nogata, S., Yoshioka, A., and Hamano, K. (1986): Clinical experience with neosugar on chronic constipation. Clin. Nutr., 68, (in Japanese). 10. Mutoh, Y. (1988): Digestion and Absorption, Daiichi-Shuppan, Tokyo, pp (in Japanese). 11. Shimoyama, T., Ohno, T., Hori, N., Kawaura, A., Shiomi, M., Furiya, T., Hirakawa, H., and Yamazaki, K. (1985): Relation of Neosugar P and chronic constipation. Proc. Res. Neosugar, 2, (in Japanese). 12. Sakurai, E., Fukuse, H., Ueda, K., Murata, R., Hikichi, N., and Niwa, K. (1980): Changes in tissue serotonin, histamine and polyamines during diarrhea induced by various laxatives. Folia Pharmacol. Jpn., 76, (in Japanese). 13. Douthwaite, A.H. (1969): French's Index of Differential Diagnosis (9th ed.), John Wright & Sons, Bristol, pp Hata, Y., and Nakajima, K. (1990): Oral ingestion of sorbose and symptoms of digestive organs-maximum non-effective dose and 50% effective dose on diarrhea. Jpn. J. Clin. Nutr., 11, (in Japanese). 15. Koizumi, N. (1983): Studies on transitory laxative effects of sorbitol and maltitol. I. Estimation of 50% effective dose and maximum non-effective dose. Chemoshere, 12, Koizumi, N. (1983): Studies on the transitory laxative effects of sorbitol and maltitol. II. Differences in laxative effects among various foods containing sweetening agents. Chemoshere, 12, Hata, Y., and Nakajima, K. (1985): Ingestion of fructooligosaccharides and gastrointestinal symptoms-observation of 50% effective dose and maximum non-effective dose on diarrhea. Geriat. Med., 23, (in Japanese). J. Clin. Biochem. Nutr.

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