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Nutrition and Cancer

Dietary Sodium Gluconate Protects Rats from Large Bowel Cancer by Stimulating Butyrate Production

Chiyoko Kameue^*, Takamitsu Tsukahara^*,, Kouji Yamada, Hironari Koyama^**,1, Yoshie Iwasaki, Keizo Nakayama^, and Kazunari Ushida^*,2

^* Laboratory of Animal Science, Kyoto Prefectural University, Shimogamo, Kyoto 606-8522, Japan; KYODOKEN Institute, Kyoto 612-8073, Japan; ^** Chemical Products Research Laboratories, Fujisawa Pharmaceutical Company, Ibaraki 300-2698, Japan; and Japan Cytology Research, Kyoto 612-8219, Japan

²To whom correspondence should be addressed. E-mail: k_ushida{at}kpu.ac.jp.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Butyrate has an antitumorigenic effect on colorectal cancer cell lines. Dietary sodium gluconate (GNA) promotes butyrate production in the large intestine. Accordingly, we examined the effect of dietary GNA on tumorigenesis in the large intestine in rats. Male Fisher-344 rats (n = 32) were divided into 4 groups: 2 diets (with or without 50 g GNA/kg basal diet) x 2 treatments (with or without carcinogen administration). Colonic tumors were induced by 3 intraperitoneal injections of azoxymethane (15 mg/kg body wt, 1 time/wk) and dietary deoxycholic acid (2 g/kg basal diet). The experiment was conducted for 33 wk except for a few rats. Ingestion of GNA increased cecal butyrate concentration at the end of experiment (P < 0.01). No tumor development occurred in the untreated groups. Ingestion of GNA decreased the incidence of tumors in rats administered the carcinogen (37.5 vs. 100%, P < 0.05). Ingestion of GNA also decreased the mean number of tumors per rat (0.5 ± 0.8 vs. 2.8 ± 1.5, P < 0.01). ß-Catenin accumulation and TdT-mediated dUTP nick end labeling (TUNEL) positive cells in tumors were histochemically examined. The results of this study suggested that the antitumorigenic effect of GNA may involve the stimulation of apoptosis through enhanced butyrate production in the large intestine.

KEY WORDS: • sodium gluconate • butyrate • colorectal cancer prevention • apoptosis • rat

Butyrate is an SCFA produced by bacterial fermentation in the large intestine (1). Butyrate is a relatively minor component compared to acetate and propionate in the lumen of the large intestine. However, butyrate is the major energy source for the epithelial cells of the large intestine (2,3), and it stimulates mucus release (4), epithelial cell proliferation (5,6), and mineral and water absorption from the lumen (7,8).

Butyrate also has an antitumorigenic effect in the large intestine. Clinical studies show that the fecal concentration of butyrate is significantly lower in patients with colonic adenoma or adenocarcinoma compared with that in healthy subjects (9,10), suggesting the preventive effect of butyrate against colorectal cancer. Several in vitro works suggest a role for butyrate in colorectal cancer prevention. Butyrate induces enterocytic differentiation in cancer cells (6). Butyrate inhibits the proliferation of colonic tumor cells by the induction of apoptosis of the genetically damaged cells (11). There is increasing evidence on the molecular level that butyrate prevents colorectal cancer by inducing cell cycle arrest and apoptosis. Nakano et al. (12) showed that butyrate specifically induces WAF1/Cip1 mRNA and protein in colonic cancer cells, resulting in G₁ arrest of the cell cycle progression. Along with these in vitro works, in vivo rat models suggest that butyrate has an antitumorigenic effect in the large intestine (13–15).

Gluconic acid can be used as a prebiotic, which stimulates butyrate production in the large intestine (16). Escaping from digestion and absorption in the small intestine, 70% of dietary gluconic acid reaches the large intestine (17). Gluconic acid is fermented by a range of bacteria, namely Lactobacillus and Bifidobacterium (18). Lactate and acetate, which are produced from gluconic acid by these lactic acid bacteria, are converted to butyrate by acid-utilizing bacteria, such as Megasphaera elsdenii (16,19). In a preliminary examination, we found that butyrate production in the large intestine of pigs was stimulated by the ingestion of sodium gluconate (GNA)³ (16). Accordingly, in this study we investigated the antitumorigenic effect of GNA in rats in which azoxymethane (AOM) and deoxycholic acid (DCA) were used as the initiator and promoter, respectively, of colorectal carcinogenesis.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Animals and diet. The experimental protocol, such as the composition of the basal diet, the induction of carcinogenesis, and the rat strain studied, was principally the same as that described by Azuma et al. (20), except for the use of GNA. Male Fisher-344 rats (n = 32, age 9 wk) were purchased from Japan SLC. They were individually housed in wire-bottomed cages in a room kept at 25 ± 1°C, with a 12-h light and dark cycle. The rats were allowed free access to food and drinking water. During the 7-d acclimation period, they were fed a nonpurified diet (Nihon Nosan Kogyo) for the first 3 d, and the basal diet for the subsequent 4 d. After the acclimation period, the rats were divided into 4 groups (n = 8) to obtain the same mean body weight and were allowed free access to the respective diets: the control (C) diet, the GNA-supplemented (G) diet, the DCA-supplemented (D) diet, and the GNA- and DCA-supplemented (GD) diet (Table 1). The bitterness of sodium DCA was masked by coating it with cellulose acetate phthalate so as not to reduce palatability (20). Food intake was measured daily, and body weight was recorded weekly. Rats fed the D and GD diets were given weekly intraperitoneal injections of AOM solution (Nakarai Tesque) at a dose of 15 mg/kg body wt for the first 3 wk. The rats were killed for tumor assessment in wk 33 after the first AOM injection.

    Sampling procedure. In wk 33, the rats were anesthetized with urethane and killed by bloodletting. Several rats (1 in the D diet group and 2 in the GD diet group) were killed in wk 30 because they had severe diarrhea, melena, anemia, and/or body weight reduction. The cecum and colorectum were resected and weighed. The cecum was opened via the curve of the antimesenterial side, and the colorectum was opened longitudinally along the mesentery. While guarding against damage to the mucosal tissues, the cecal and colorectal contents were gently collected with a spatula and analyzed for organic acid concentration by ion-exclusion HPLC (21). The colorectal contents were not uniformly distributed in all rats at the time of sampling. Accordingly, the variables for the colorectal contents could not be statistically analyzed. The cecum and colorectum were gently flushed with saline to remove residual luminal contents and mounted on filter paper. The mucosa was examined carefully with the naked eye as well as with a stereoscopic microscope. Tumors, mostly polypoid, were counted, and the lengths of their major axes were measured with a ruler. All tumorous lesions found were excised, fixed in neutral buffered 10% (v/v) formalin solution (Wako Pure Chemical), and embedded in paraffin for further histological examination.

The stomach, jejuno-ileum, liver, spleen, kidney, adrenal gland, heart, lung, testis, pararenal fat, mesentery fat, and epididymal fat were also resected and weighed. They were fixed in neutral buffered 10% formalin solution after visual examination.

    Histological techniques. Cecal and colorectal sections were prepared from paraffin-embedded tissues. They were stained with hematoxylin and eosin (HE) and alcian green counterstained with hematoxylin, to classify the tumors histologically according to the general rules for clinical and pathological studies of cancer of the colon, rectum, and anus (22).

    Detection of ß-catenin. Immunohistochemical detection of ß-catenin was based on the streptavidin-biotin peroxidase complex method according to the manufacturer’s instructions, with some minor modifications (ImmunoCruz Staining System, ImmunoCruz). Malignant tumors were subjected to ß-catenin detection, except for signet ring–cell carcinoma. For comparison, the normal tissues of carcinogen-free groups were also examined.

    Assessment for apoptosis. Apoptotic cells in the sections were identified using a commercially available kit (Takara in situ Apoptosis Detection Kit, Takara Bio) based on the TdT-mediated dUTP nick end labeling (TUNEL) method as described by Gavrieli et al. (23). For each set of sections, histological sections of rat thymus provided by Takara were examined as the positive control. The apoptotic cells were estimated by counting the number of positively stained cells per total epithelial cells in a unit area of tumor section. The TUNEL-positive cells were counted in 10 randomly selected fields, if the size of the tumor section allowed, and the epithelial cells were counted in the same fields of the HE-stained adjacent section, using a light microscope at 200x magnification. The apoptotic index (AI) of a tumor was defined as the number of apoptotic cells in 100 epithelial cells of the tumor. All malignant tumors were subjected to TUNEL assay, except for 1 signet ring–cell carcinoma from a rat in the GD diet group and 1 mucinous carcinoma from a rat in the D diet group. For comparison, the normal tissues of untreated rats (C and G diet groups) were also subjected to TUNEL assay. The apoptotic index for normal tissue was defined as the number of apoptotic cells in 100 epithelial cells.

    Statistical analyses. Values are expressed as means ± SD (n = 8). Most variables were evaluated by two-way ANOVA. Differences in incidence of tumor formation were evaluated by Fisher’s exact probability test, and comparisons of the mean number of tumors per rat and the AI between the two carcinogen-treated groups were made using Welch’s t test. The difference between means was considered significant at P < 0.05 in all statistical analyses. All data were analyzed by Statcel (24), which is an add-in application of Microsoft Excel (version 2002, Microsoft).

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Food intake. Daily food intake did not differ among the four groups throughout the experiment (Table 2).

However, 1 rat in the D diet group developed melena in wk 21, and all other rats in this group developed melena after wk 28. One rat in this group was killed in wk 30 due to severe diarrhea and loss of body weight.

One rat in the GD diet group had diarrhea and loss of body weight from wk 22 onward. Another rat in this group also showed severe weight loss from wk 22 onward. Accordingly, these 2 rats were also killed in wk 30. They were anemic at the time of slaughter.

Carcinogen treatment decreased the body weight of rats (P < 0.05). Ingestion of GNA did not affect the body weight of rats except during wk 29 (Table 2).

    Weight of organs and tissues. Chemical carcinogens increased the relative weights of the stomach, jejuno-ileum, cecum, colon and liver (data not shown) and decreased those of the pararenal fat and epididymal fat (data not shown). Ingestion of GNA increased the relative weight of the spleen (1.80 ± 0.12, 1.87 ± 0.10, 2.41 ± 0.23, and 3.69 ± 1.74 g/kg body wt for rats in the C, G, D, and GD diet groups, respectively; P < 0.05).

    Organic acid concentrations. Ingestion of GNA increased cecal butyrate concentration (P < 0.01), irrespective of carcinogen-treatment (Table 3). Rats fed the G diet had the highest concentrations of cecal butyrate. The carcinogen treatment decreased cecal butyrate concentration (P < 0.01). Isovalerate concentrations were higher in the carcinogen-treated groups (D and GD diets) than in the untreated groups (C and G diets). Concentrations of the other organic acids did not differ among the groups (Table 3). Butyrate concentrations (mmol/kg) in the proximal colon were 10.8 ± 0.7 (n = 3), 16.2 ± 4.5 (n = 4), 7.1 ± 1.6 (n = 4), and 7.6 ± 1.2 (n = 3) for rats in the C, G, D, and GD diet groups, respectively. Butyrate concentrations (mmol/kg) in the distal colon and rectum were 5.1 ± 0.7 (n = 5), 7.3 ± 3.2 (n = 4), 3.3 ± 1.1 (n = 3), and 3.3 ± 1.2 (n = 5) for rats in the C, G, D, and GD diet groups, respectively.

    Detection of apoptotic cells. Tumors from rats in the D diet group had relatively low AIs, ranging from 0.05 to 0.13. Those from 2 rats in the GD diet group (rats 29 and 32) had relatively high AIs, but 1 small tumor from rat 26 in this group had a low AI (Table 4). A few TUNEL-positive cells were detected in the colorectal tissues of untreated rats (C and G diet groups). The mean AIs were 0.11 ± 0.13 (n = 8) and 0.07 ± 0.10 (n = 8), for rats fed the C and G diets, respectively.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The present data showed that the continuous ingestion of GNA by rats treated with AOM and DCA to induce carcinogenesis reduced the incidence of tumor development and the rate of cancer generation in the large intestine. The metabolism of AOM in the liver induces point mutation in many genes, particularly in the ß-catenin gene (25). ß-Catenin plays a critical role in the regulation of cellular proliferation and in colon carcinogenesis (26). Accumulation of ß-catenin is considered as a good biomarker for the preneoplastic lesions that become colon cancer (27). Because ß-catenin accumulated in the colorectal tumor cells of rats in both groups treated with chemical carcinogens, GNA might not affect the alteration of the Wnt signal pathway in carcinogenesis.

Although GNA ingestion did not affect the incidence of duodenum and liver tumors, it markedly reduced tumorigenesis in the colon (Table 4). Because dietary GNA reaches the large intestine without being substantially digested or absorbed in the small intestine (17), and because GNA is fermented by bacteria in the large intestine (18), the effect of GNA in preventing cancer in the large intestine is due primarily to its metabolite. It has been suggested that dietary GNA stimulates the production of butyrate in the large intestine (16). Lactic acid bacteria metabolize GNA, and the resultant lactate is further metabolized by lactate-utilizing butyrate producers, such as M. elsdenii (16,19). In the present study, dietary GNA increased butyrate concentration in the cecum by 60% (Table 3). Butyrate affects the expression of p21/WAF, which can induce cell arrest (12). The expression of p21/WAF is controlled by p53, which mutates in the majority of cancer cells (28). Accordingly, butyrate can neutralize, at least in part, the tumorigenic effect of a p53 mutation. Butyrate also selectively induces apoptosis in colon cancer cells (29). The expression of bak and bcl-x in Caco-2 cells appears to be linearly affected by butyrate from 1 to 20 mmol/L (30). This suggests that the observed increase in luminal butyrate concentration (7.4 vs. 12.2 mmol/kg; Table 3) stimulated the induction of apoptosis in colorectal cancer cells in the present experiment. The rate of apoptosis in polypoid tumors was indeed greater in rats that ingested GNA than in those that did not, except for 1 tumor. The explanation for this exception is unclear.

Mechanisms other than luminal butyrate could be involved in the presently demonstrated antitumorigenic effect of GNA. The increased relative weight of the spleen suggests the possible involvement of the immune system. Sodium gluconate stimulates lactic acid bacteria such as Lactobacillus and Bifidobacterium (16,18). The antitumorigenic effect of these bacteria has been explained by their stimulation of the host immune system (31,32).

As discussed in our previous reports (16,33), the effect of the indigestible oligosaccharides, known previously as bifidogenic dietary supplements, is due to the stimulation of butyrate production in the large intestine. The present experiment may explain the role of dietary fiber (including the indigestible oligosaccharides) in the prevention of colorectal cancer. However, in the case of insoluble dietary fiber such as bran, the antitumorigenic effect is not due to the stimulation of butyrate production in the large intestine, but rather to physical properties such as fecal bulking ability (34). Therefore, this explanation, the "butyrate theory," is limited to soluble materials such as GNA, fructooligosaccharide (13), and maltitol (35) that stimulate butyrate production in the large intestine.

	ACKNOWLEDGMENTS

 
The authors thank Professor Ryuhei Kanamoto, Laboratory of Molecular Nutrition at Kyoto Prefectural University, for his assistance with the establishment of the experimental protocol, and also Akinobu Tamura, Japan Cytology Research, for his assistance with the histological work.

	FOOTNOTES

 
¹ Present address: Fujisawa Technical Service Co., Ltd., Osaka 532-0031, Japan.

³ Abbreviations used: AI, apoptotic index; AOM, azoxymethane; C diet, control diet; DCA, deoxycholic acid; D diet, deoxycholic acid–supplemented diet; GD diet, sodium gluconate– and deoxycholic acid–supplemented diet; G diet, sodium gluconate–supplemented diet; GNA, sodium gluconate; HE, hematoxylin and eosin; TUNEL, TdT-mediated dUTP nick end labeling.

Manuscript received 17 October 2003. Initial review completed 16 November 2003. Revision accepted 7 January 2004.

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