Gut microbiota-associated bile acid deconjugation accelerates hepatic steatosis in ob/ob mice.

AIM: Nonalcoholic hepatic fat accumulation has been hypothesized to be associated with alterations in gut microbiota composition, although mechanistic explanations for this link are largely insufficient. The aim of this study was to elucidate the microbiota-driven mechanisms involved in the development of nonalcoholic hepatic steatosis. METHODS AND RESULTS: Ob/ob mice and their wild-type lean control mice were fed an AIN-93G diet for 12 weeks. Faecal microbiota composition, faecal bile acid (BA) profile and intestinal and hepatic markers of BA metabolism were analysed. Ob/ob mice had significantly less faecal taurine-conjugated BAs compared to their lean controls. The proportions of butyrate-producing bacteria were lower in ob/ob mice compared to those in lean mice. Intestinal expression of farnesoid X receptor (FXR) mRNA was significantly higher, whereas hepatic expression of cholesterol-7α-hydroxylase 1 (CYP7A1) and small heterodimer partner (SHP) were significantly lower in ob/ob mice compared to those in control mice. CONCLUSION: Microbiota-associated BAs deconjugation may induce nonalcoholic fatty liver disease (NAFLD) by activating intestinal FXR signalling and blocking hepatic FXR-SHP pathway, thereby accelerating fat synthesis. SIGNIFICANCE AND IMPACT OF THE STUDY: We provided evidences that changes in the gut microbiota and their metabolites can alter the profile of BAs, thereby providing a mechanism by which an altered microbiota profile contributes to the development of NAFLD.

A six-month supplementation of mulberry, korean red ginseng, and banaba decreases biomarkers of systemic low-grade inflammation in subjects with impaired glucose tolerance and type 2 diabetes.

We sought the long-term efficacy of traditionally used antidiabetic herbs in controlling blood glucose homeostasis and low-grade inflammation. Ninety-four subjects with either impaired glucose tolerance or mild T2D were randomized either to treatment arm or placebo arm and received 1 : 1 : 1 mixture of ginseng roots, mulberry leaf water extract, and banaba leaf water extract (6 g/d) for 24 weeks. Oral 75 g glucose tolerance test was performed to measure glucose and insulin responses. Blood biomarkers of low-grade inflammation were also determined. Results found no significant difference in glucose homeostasis control measure changes. However, plasma intracellular adhesion molecule-1 (ICAM-1) concentration was decreased showing a significant between-treatment changes (P = 0.037). The concentrations of vascular cell adhesion molecule-1 (VCAM-1) (P = 0.014) and ICAM-1 (P = 0.048) were decreased in the treatment group at week 24, and the oxidized low-density lipoprotein (ox-LDL) concentration was reduced at week 24 compared to the baseline value in the treatment group (P = 0.003). These results indicate a long-term supplementation of ginseng, mulberry leaf, and banaba leaf suppresses inflammatory responses in T2D.

Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice.

OBJECTIVE: Studies have indicated that obesity is associated with a higher risk of colorectal cancer. This study was performed to determine the effect of diet-induced obesity on the formation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumors and to identify adiposity-related mechanisms. METHODS: Male A/J mice were placed on either a high-fat diet (HFD; 45% of total calories from fat) or a normal diet (ND; 15% of calories from fat) for 12 weeks. To induce colon tumors, AOM was administered at a dose of 10 mg/kg body weight, followed by two cycles of DSS supply. RESULTS: Study results indicated that the HFD group had twofold higher numbers of colonic tumors, as compared with the ND group. The HFD group also had significantly increased body weight and epididymal fat weight, which were associated with increases of serum insulin, insulin-like growth factor-1, leptin, epididymal fat pad leptin mRNA and colonic leptin receptor (Ob-R) mRNA. Animals on HFD showed higher expressions of Ob-R, insulin receptor, phosphorylated Akt, phosphorylated extracellular signal-regulated kinases, Bcl-xL and Cyclin D1 proteins in the colon. CONCLUSION: The results suggest that HFD-induced obesity facilitates colon tumor formation, possibly by regulating downstream targets of circulating adiposity-related factors via receptor-mediated signaling of the phosphatidylinositol 3-kinase/Akt pathway.

Effect of dietary soy intake on breast cancer risk according to menopause and hormone receptor status.

BACKGROUND: Although high soy consumption may be associated with lower breast cancer risk in Asian populations, findings from epidemiological studies have been inconsistent. OBJECTIVE: We investigated the effects of soy intake on breast cancer risk among Korean women according to their menopausal and hormone receptor status. METHODS: We conducted a case-control study with 358 incident breast cancer patients and 360 age-matched controls with no history of malignant neoplasm. Dietary consumption of soy products was examined using a 103-item food frequency questionnaire. RESULTS: The estimated mean intakes of total soy and isoflavones from this study population were 76.5 g per day and 15.0 mg per day, respectively. Using a multivariate logistic regression model, we found a significant inverse association between soy intake and breast cancer risk, with a dose-response relationship (odds ratios (OR) (95% confidence interval (CI)) for the highest vs the lowest intake quartile: 0.36 (0.20-0.64)). When the data were stratified by menopausal status, the protective effect was observed only among postmenopausal women (OR (95% CI) for the highest vs the lowest intake quartile: 0.08 (0.03-0.22)). The association between soy and breast cancer risk did not differ according to estrogen receptor (ER)/progesterone receptor (PR) status, but the estimated intake of soy isoflavones showed an inverse association only among postmenopausal women with ER+/PR+ tumors. CONCLUSIONS: Our findings suggest that high consumption of soy might be related to lower risk of breast cancer and that the effect of soy intake could vary depending on several factors.

Soybean saponins inhibit cell proliferation by suppressing PKC activation and induce differentiation of HT-29 human colon adenocarcinoma cells.

Soybeans are major dietary sources of saponins, which have been suggested as possible anticarcinogens. This study was performed to determine the effect of soybean saponins on cell proliferation, differentiation, and apoptosis in human colon cancer cells. HT-29 cells were incubated in various concentrations of saponins for 24, 48, and 72 hours. Cell growth and whole cell protein kinase C (PKC) activity were determined. Alkaline phosphatase activity and carcinoembryonic antigen level were measured as markers for cell differentiation. Apoptotic cells were quantified. Study results indicated that soybean saponin treatment decreased cell growth in a concentration-dependent manner, and pre-treatment of the cells with saponins significantly suppressed the 12-O-tetradecanoyl phorbol 13-acetate-stimulated PKC activity. Cells treated with 300 and 600 ppm of saponins significantly increased alkaline phosphatase activity by 146% and 242% of the control, respectively. Also, 4-10 times more carcinoembryonic antigen was produced in cells treated with saponins. However, at all the concentrations used, saponins did not induce apoptosis, although there were slight decreases in apoptotic activity in cells treated with 240 and 600 ppm of soybean saponins. These results suggest that crude soybean saponin extract effectively suppresses PKC activation and induces differentiation, which possibly mediate the growth inhibition of tumor cells. Further experiments, including preclinical efficacy studies, are required to fully evaluate soybean saponins for their chemopreventive properties.

Mammalian lignans inhibit the growth of estrogen-independent human colon tumor cells.

PURPOSE: The mammalian lignans enterolactone (EL) and enterodiol (ED) derived from precursors in foods, particularly flaxseed, have been shown to reduce the mammary tumor growth due to their antiestrogenic properties. Our objective was to investigate whether lignans have growth inhibitory effects against colon tumor cells and whether these effects are mediated through their antiestrogenic activity. METHODS: Four human colon tumor cell lines (LS174T, Caco-2, HCT-15, T-84) were incubated with various levels of EL, ED or 17 beta-estradiol for 8 to 10 days. Cell proliferation was measured by the BrdU method. RESULTS: At 100 microM concentration, both lignans significantly reduced the proliferation of all cell lines. EL was more than twice as effective as ED at this concentration. The growth was not affected by the presence of 17 beta-estradiol implying that these cells are not estrogen-sensitive. CONCLUSION: Lignans are growth inhibitors of colon tumor cells and they may act through mechanism(s) other than antiestrogenic activity.

Effect of soybean saponins and gypsophila saponin on morphology of colon carcinoma cells in culture.

The effect of saponins on colonic epithelial carcinoma cell (HCT-15) morphology was studied. Cells in culture were incubated with different concentrations of soybean saponins (SS) or gypsophila saponin (GS) for 24 hr. Scanning electron microscopy revealed a very rough and granular cell surface in cells treated with the lowest concentration of GS (40 ppm). Minor morphological changes were observed in the cell surface of soybean saponin-treated cells at a concentration of 1200 ppm. Examination by transmission electron microscopy indicated a dose-dependent effect of saponins on intracellular morphology of colonic epithelial carcinoma cells. Cells treated with 600 ppm or more of soybean saponins developed numerous cytoplasmic vesicles, had decreased density of cytoplasmic material and demonstrated deformations in plasma and nuclear membranes. Gypsophila saponin at a concentration of 40 ppm produced few changes in intracellular and membrane structure, whereas 80 ppm saponin induced the formation of vesicles. However, at both concentrations, changes in the density of cytoplasmic material was less extensive than in soybean saponin-treated cells. The highest concentration of gypsophila saponin used (160 ppm) completely destroyed the plasma membrane. These results indicate that soybean saponins and gypsophila saponin interact with cell membranes and induce significant dose-dependent cell morphological changes; however, they appear to act through different mechanisms.

Saponins as anticarcinogens.

Saponins, which are present in plants, have been suggested as possible anticarcinogens. They possess surface-active characteristics that are due to the amphiphilic nature of their chemical structure. The proposed mechanisms of anticarcinogenic properties of saponins include direct cytotoxicity, immune-modulatory effects, bile acid binding and normalization of carcinogen-induced cell proliferation. However, the anticarcinogenic effects of saponins from commonly consumed plant foods have not been studied. Soybeans are one of the most important sources of dietary saponins. They are the main protein supplier in many vegetarian diets. Our results showed that soybean saponins at the concentration of 150-600 ppm had a dose-dependent growth inhibitory effect on human carcinoma cells (HCT-15). Viability was also significantly reduced. Soybean saponins did not increase cell membrane permeability in a dose-dependent fashion, whereas gypsophilla saponin, a nondietary saponin, increased permeability with increasing concentrations. Electron microscopy indicated that soybean and gysophilla saponins alter cell morphology and interact with the cell membrane in different ways.

Effect of soybean saponins and gypsophilla saponin on growth and viability of colon carcinoma cells in culture.

The effects of soybean saponins (SS) and gypsophilla saponin (GS) on the growth and viability of colon tumor (HCT-15) cells in culture were investigated. Cells were incubated in various concentrations of saponins for 1 hour (short term) or 48 hours (long term). Cell growth and viability were monitored at 24 and 48 hours. SS and GS inhibited cell growth and reduced cell viability in a dose-dependent manner in long-term treatment. The viability of cells was also reduced by short-term treatment with GS. The saponins differed in their effects on cell surface morphology: GS induced a rough and granular cell surface, whereas SS-treated cells displayed only minor morphological alterations. Changes in membrane permeability were assessed by measuring leakage of the cytoplasmic enzyme lactate dehydrogenase from cells. GS showed a concentration-dependent increase in lactate dehydrogenase leakage, whereas SS did not exhibit this effect. These results suggest that SS and GS have a significant growth-inhibitory effect on colon tumor cells in culture. However, it would appear that they are acting through different mechanisms.