Isoflavone aglycone-rich soymilk fermented by Lactobacillus delbrueckii subsp. delbrueckii, strain TUA-4408L (F4408) has stronger lipid metabolism-modulating effects than isoflavone aglycone-poor soymilk fermented by Lactobacillus delbrueckii subsp. delbrueckii, strain TUA-4404L (F4404). As such, fermentation products other than isoflavone aglycones may also exert lipid metabolism-modulating effects. Therefore, the present study aimed to compare the metabolites in soymilk (SM), F4404, and F4408 via a metabolomics approach. Various aglycones including isoflavones, flavones, flavonols, and flavanones increased in both F4404 and F4408 compared with SM. The increases in isoflavone and flavanone aglycones were greater in F4408 than in F4404. Some types of dipeptides and free amino acids, especially ornithine, increased in both fermented soymilks. The increase in free amino acids, especially ornithine, was higher in F4408 than in F4404. Thus, F4408 exhibited stronger glycosidase and protease activities than F4404. Functional components produced by lactic acid fermentation are known to improve lipid metabolism. Therefore, it is suggested that not only isoflavone aglycones but also other functional components exert lipid metabolism-modulating effects in fermented soymilks, especially soymilk fermented using TUA-4408L.
Sirtori, C.R., Lovati, M.R., Manzoni, C., Monetti, M., Pazzucconi, F. and Gatti, E. (1995) Soy and Cholesterol Reduction: Clinical Experience. Journal of Nutrition, 125, 598S-605S.
Meeker, D.R. and Kesten, H.D. (1940) Experimental Atherosclerosis and High Protein Diets. Experimental Biology and Medicine, 45, 543-545. https://doi.org/10.3181/00379727-45-11744P
Nagata, Y., Ishiwaki, N. and Sugano, M. (1982) Studies on the Mechanism of Antihypercholesterolemic Action of Soy Protein and Soy Protein-Type Amino Acid Mixtures in Relation to the Casein Counterparts in Rats. Journal of Nutrition, 112, 1614-1625. https://doi.org/10.1093/jn/112.8.1614
Yashiro, A., Oda, S. and Sugano, M. (1985) Hypocholesterolemic Effect of Soybean Protein in Rats and Mice after Peptic Digestion. Journal of Nutrition, 115, 1325-1336. https://doi.org/10.1093/jn/115.10.1325
Carroll, K.K. (1991) Review of Clinical Studies on Cholesterol-Lowering Response to Soy Protein. Journal of the American Dietetic Association, 91, 820-827.
Jenkins, D.J., Mirrahimi, A., Srichaikul, K., Berryman, C.E., Wang, L., Carleton, A., Abdulnour, S., Sievenpiper, J.L., Kendall, C.W. and Kris-Etherton, P.M. (2010) Soy Protein Reduces Serum Cholesterol by Both Intrinsic and Food Displacement Mechanisms. Journal of Nutrition, 140, 2302S-2311S. https://doi.org/10.3945/jn.110.124958
Orgaard, A. and Jensen, L. (2008) The Effects of Soy Isoflavones on Obesity. Experimental Biology and Medicine, 233, 1066-1080. https://doi.org/10.3181/0712-MR-347
Penza, M., Montani, C., Romani, A., Vignolini, P., Pampaloni, B., Tanini, A., Brandi, M.L., Alonso-Magdalena, P., Nadal, A., Ottobrini, L., Parolini, O., Bignotti, E., Calza, S., Maggi, A., Grigolato P.G. and Di Lorenzo, D. (2006) Genistein Affects Adipose Tissue Deposition in a Dose-Dependent and Gender-Specific Manner. Endocrinology, 147, 5740-5751. https://doi.org/10.1210/en.2006-0365
Ae Park, S., Choi, M.S., Cho, S.Y., Seo, J.S., Jung, U.J., Kim, M.J., Sung, M.K., Park, Y.B. and Lee, M.K. (2006) Genistein and Daidzein Modulate Hepatic Glucose and Lipid Regulating Enzyme Activities in C57BL/KsJ-db/db Mice. Life Sciences, 79, 1207-1213. https://doi.org/10.1016/j.lfs.2006.03.022
Takahashi, Y., Odbayar, T.O. and Ide, T.A. (2009) Comparative Analysis of Genistein and Daidzein in Affecting Lipid Metabolism in Rat Liver. Journal of Clinical Biochemistry and Nutrition, 44, 223-230.
Goodman-Gruen, D. and Kritz-Silverstein, D. (2001) Usual Dietary Isoflavone Intake Is Associated with Cardiovascular Disease Risk Factors in Postmenopausal Women. The Journal of Nutrition, 131, 1202-1206. https://doi.org/10.1093/jn/131.4.1202
Zhuo, X.G., Melby, M.K. and Watanabe, S. (2004) Soy Isoflavone Intake Lowers Serum LDL Cholesterol: A Meta-Analysis of 8 Randomized Controlled Trials in Humans. The Journal of Nutrition, 134, 2395-2400. https://doi.org/10.1093/jn/134.9.2395
Zhan, S. and Ho, S.C. (2005) Meta-Analysis of the Effects of Soy Protein Containing Isoflavones on the Lipid Profile. The American Journal of Clinical Nutrition, 81, 397-408. https://doi.org/10.1093/ajcn.81.2.397
Taku, K., Umegaki, K., Sato, Y., Taki, Y., Endoh, K. and Watanabe, S. (2007) Soy Isoflavones Lower Serum Total and LDL Cholesterol in Humans: A Meta-Analysis of 11 Randomized Controlled Trials. The American Journal of Clinical Nutrition, 85, 1148-1156. https://doi.org/10.1093/ajcn/85.4.1148
Chun, J., Kim, G.M., Lee, K.W., Choi, I.D., Kwon, G.H., Park, J.Y., Jeong, S.J., Kim, J.S. and Kim, J.H. (2007) Conversion of Isoflavone Glucosides to Aglycones in Soymilk by Fermentation with Lactic Acid Bacteria. Journal of Food Science, 72, M39-M44. https://doi.org/10.1111/j.1750-3841.2007.00276.x
Izumi, T., Piskula, M.K., Osawa, S., Obata, A., Tobe, K., Saito, M., Kataoka, S., Kubota, Y. and Kikuchi, M. (2000) Soy Isoflavone Aglycones Are Absorbed Faster and in Higher Amounts than Their Glucosides in Humans. The Journal of Nutrition, 130, 1695-1699. https://doi.org/10.1093/jn/130.7.1695
Kobayashi, M., Harada, T., Takagi, N., Tsuzuki, K., Sugawara, M. and Fukuda, M. (2012) Effects of Lactic Acid-Fermented Soymilk on Lipid Metabolism-Related Gene Expression in Rat Liver. Bioscience, Biotechnology, and Biochemistry, 76, 19-24. https://doi.org/10.1271/bbb.100354
Kobayashi, M., Hirahata, R., Egusa, S. and Fukuda, M. (2012) Hypocholesterolemic Effects of Lactic Acid-Fermented Soymilk on Rats Fed a High Cholesterol Diet. Nutrients, 4, 1304-1316. https://doi.org/10.3390/nu4091304
Hirahata, R., Kobayashi, M., Egusa, S., Sakakibara, R. and Fukuda, M. (2012) Effects of Fermented Soymilk on Lipid Metabolism in Rats Fed a High Fat Diet. Nippon Shokuhin Kagaku Kogaku Kaishi, 59, 528-532. (In Japanese)
Hirahata, R., Kobayashi, M., Egusa, S., Sakakibara, R. and Fukuda, M. (2013) Lactic Fermented Soymilk Improves Hepatic Lipid Metabolism in Rats Fed a High Fat and High Cholesterol Diet. Nippon Shokuhin Kagaku Kogaku Kaishi, 60, 72-79. (In Japanese)
Kobayashi, M., Sakakibara, R., Egusa, S. and Fukuda, M. (2013) Effects of Isoflavone Aglycone Ratio in Lactic Acid-Fermented Soymilk on Hepatic Lipid Metabolism in Rats Fed a High Fat and High Cholesterol Diet. Nippon Shokuhin Kagaku Kogaku Kaishi, 60, 509-515. (In Japanese)
Kobayashi, M., Egusa, S. and Fukuda, M. (2014) Isoflavone and Protein Constituents of Lactic Acid-Fermented Soy Milk Combine to Prevent Dyslipidemia in Rats Fed a High Cholesterol Diet. Nutrients, 6, 5704-5723. https://doi.org/10.3390/nu6125704
Kobayashi, M., Egusa, S. and Fukuda, M. (2016) Isoflavone Aglycones and Oligopeptides in Lactic Acid-Fermented Soy Milk Differentially Regulate Lipid Metabolism-Related Gene Expression. Food and Nutrition Sciences, 7, 989-1009. https://doi.org/10.4236/fns.2016.711097
Seo, M.-J., Choi, H.-S., Jeon, H.-J., Woo, M.-S. and Lee, B.-Y. (2014) Baicalein Inhibits Lipid Accumulation by Regulating Early Adipogenesis and m-TOR Signaling. Food and Chemical Toxicology, 67, 57-64. https://doi.org/10.1016/j.fct.2014.02.009
Song, T.T., Hendrich, S. and Murphy, P.A. (1999) Estrogenic Activity of Glycitein, a Soy Isoflavone. Journal of Agricultural and Food Chemistry, 47, 1607-1610. https://doi.org/10.1021/jf981054j
Pakalapati, G., Li, L., Gretz, N., Koch, E. and Wink, M. (2009) Influence of Red Clover (Trifolium pratense) Isoflavones on Gene and Protein Expression Profiles in Liver of Ovariectomized Rats. Phytomedicine, 16, 845-855. https://doi.org/10.1016/j.phymed.2009.03.003
Mu, H., Bai, Y.H., Wang, S.T., Zhu, Z.M. and Zhang, Y.W. (2009) Research on Antioxidant Effects and Estrogenic Effect of Formononetin from Trifolium pratense (Red Clover). Phytomedicine, 16, 314-319. https://doi.org/10.1016/j.phymed.2008.07.005
Xu, N., Zhang, L., Dong, J., Zhang, X., Chen, Y.G., Bao, B. and Liu, J. (2014) Low-Dose Diet Supplement of a Natural Flavonoid, Luteolin, Ameliorates Diet-Induced Obesity and Insulin Resistance in Mice. Molecular Nutrition & Food Research, 58, 1258-1268. https://doi.org/10.1002/mnfr.201300830
Hanaki, M., Murakami, K., Akagi, K. and Irie, K. (2016) Structural Insights into Mechanisms for Inhibiting Amyloid β42 Aggregation by Non-Catechol-Type Flavonoids. Bioorganic & Medicinal Chemistry, 24, 304-313. https://doi.org/10.1016/j.bmc.2015.12.021
Zang, Y., Zhang, L., Igarashi, K. and Yu, C. (2015) The Anti-Obesity and Anti-Diabetic Effects of Kaempferol Glycosides from Unripe Soybean Leaves in High-Fat-Diet Mice. Food & Function, 6, 834-841. https://doi.org/10.1039/C4FO00844H
Yuan, L., Han, X., Li, W.F., Ren, D.Y and Yang, X.B. (2016) Isoorientin Prevents Hyperlipidemia and Liver Injury by Regulating Lipid Metabolism, Antioxidant Capability, and Inflammatory Cytokine Release in High-Fructose-Fed Mice. Journal of Agricultural and Food Chemistry, 64, 2682-2689. https://doi.org/10.1021/acs.jafc.6b00290
Kanashiro, A., Andrade, D.C., Kabeya, L.M., Turato, W.M., Faccioli, L.H., Uyemura, S.A. and Lucisano-Valim, Y.M. (2009) Modulatory Effects of Rutin on Biochemical and Hematological Parameters in Hypercholesterolemic Golden Syrian Hamsters. Anais da Academia Brasileira de Ciências, 81, 67-72. https://doi.org/10.1590/S0001-37652009000100009
Simeonova, R., Vitcheva, V., Kondeva-Burdina, M., Krasteva, I., Manov, V. and Mitcheva, M. (2013) Hepatoprotective and Antioxidant Effects of Saponarin, Isolated from Gypsophila trichotoma Wend. On Paracetamol-Induced Liver Damage in Rats. BioMed Research International, 2013, Article ID: 757126. https://doi.org/10.1155/2013/757126
Liang, Y.C., Tsai, S.H., Tsai, D.C., Lin-Shiau, S.Y. and Lin, J.K. (2001) Suppression of Inducible Cyclooxygenase and Nitric Oxide Synthase through Activation of Peroxisome Proliferator-Activated Receptor-γ by Flavonoids in Mouse Macrophages. FEBS Letters, 496, 12-18. https://doi.org/10.1016/S0014-5793(01)02393-6
Feng. X., Yu, W., Li, X., Zhou, F., Zhang, W., Shen, Q., Li, J., Zhang, C. and Shen, P. (2017) Apigenin, a Modulator of PPARγ, Attenuates HFD-Induced NAFLD by Regulating Hepatocyte Lipid Metabolism and Oxidative Stress via Nrf2 Activation. Biochemical Pharmacology, 136, 136-149. https://doi.org/10.1016/j.bcp.2017.04.014
Chanet, A., Milenkovic, D., Deval, C., Potier, M., Constans, J. and Mazur, A., Bennetau-Pelissero, C., Morand, C. and Bérard, A.M. (2012) Naringin, the Major Grapefruit Flavonoid, Specifically Affects Atherosclerosis Development in Diet-Induced Hypercholesterolemia in Mice. The Journal of Nutritional Biochemistry, 23, 469-477. https://doi.org/10.1016/j.jnutbio.2011.02.001
Jung, U.J., Kim, H.J., Lee, J.S., Lee, M.K., Kim, H.O., Park, E.J., Kim, H.K., Jeong, T.S. and Choi, M.S. (2003) Naringin Supplementation Lowers Plasma Lipids and Enhances Erythrocyte Antioxidant Enzyme Activities in Hypercholesterolemic Subjects. Clinical Nutrition, 22, 561-568. https://doi.org/10.1016/S0261-5614(03)00059-1
Shin, Y.W., Bok, SH., Jeong, T.S., Bae, K.H., Jeoung, N.H., Choi, M.S., Lee, S.H. and Park, Y.B. (1999) Hypocholesterolemic Effect of Naringin Associated with Hepatic Cholesterol Regulating Enzyme Changes in Rats. International Journal for Vitamin and Nutrition Research, 69, 341-347.
Hiramitsu, M., Shimada, Y., Kuroyanagi, J., Inoue, T., Katagiri, T., Zang, L., Nishimura, Y., Nishimura, N. and Tanaka, T. (2014) Eriocitrin Ameliorates Diet-Induced Hepatic Steatosis with Activation of Mitochondrial Biogenesis. Scientific Reports, 4, Article No. 3708. https://doi.org/10.1038/srep03708
Kim, Y.W., Kim, Y.M., Yang, Y.M., Kay, H.Y., Kim, W.D., Lee, J.W., Hwang, S.J. and Kim, S.G. (2011) Inhibition of LXRα-Dependent Steatosis and Oxidative Injury by Liquiritigenin, a Licorice Flavonoid, as Mediated with Nrf2 Activation. Antioxidants & Redox Signaling, 14, 733-745. https://doi.org/10.1089/ars.2010.3260
Na, A.Y., Yang, E.J., Jeon, J.M., Ki, S.H., Song, K.S. and Lee, S. (2018) Protective Effect of Isoliquiritigenin against Ethanol-Induced Hepatic Steatosis by Regulating the SIRT1-AMPK Pathway. Toxicological Research, 34, 23-29.
Kim, Y.M., Kim, T.H., Kim, Y.W., Yang, Y.M., Ryu, D.H., Hwang, S.J., Lee, J.R., Kim, S.C. and Kim, S.G. (2010) Inhibition of Liver X Receptor-α-Dependent Hepatic Steatosis by Isoliquiritigenin, a Licorice Antioxidant Flavonoid, as Mediated by JNK1 Inhibition. Free Radical Biology & Medicine, 49, 1722-1734. https://doi.org/10.1016/j.freeradbiomed.2010.09.001
Cunin, R., Glansdorff, N., Piérard, A. and Stalon, V. (1986) Biosynthesis and Metabolism of Arginine in Bacteria. Microbiological Reviews, 50, 314-352.
Chijimatsu, T., Yamada, A., Miyaki, H., Yoshinaga, T., Murata, N., Hata, M., Abe, K., Oda, H. and Mochizuki, S. (2008) Effect of Freshwater Clam (Corbicula fluminea) Extract on Liver Function in Rats. Nippon Shokuhin Kagaku Kogaku Kaishi, 55, 63-68. (In Japanese)
Sugino, T., Shirai, T., Kajimoto, Y. and Kajimoto, O. (2008) L-Ornithine Supplementation Attenuates Physical Fatigue in Healthy Volunteers by Modulating Lipid and Amino Acid Metabolism. Nutrition Research, 28, 738-743. https://doi.org/10.1016/j.nutres.2008.08.008
Shi, H.P., Fishel, R.S. and Efron, D.T. (2002) Effect of Supplemental Ornithine on Wound Healing. Journal of Surgical Research, 106, 299-302. https://doi.org/10.1006/jsre.2002.6471
Gupta, V.K., et al. (2013) Restoring Polyamines Protects from Age-Induced Memory Impairment in an Autophagy-Dependent Manner. Nature Neuroscience, 16, 1453-1460. https://doi.org/10.1038/nn.3512
Minois, N. (2014) Molecular Basis of the “Anti-Aging” Effect of Spermidine and Other Natural Polyamine—A Mini-Review. Gerontology, 60, 319-326. https://doi.org/10.1159/000356748
Kunkee, R.E. (1974) Malo-Lactic Fermentation and Winemaking. Advances in Chemistry, 137, 151-170.
Da Conceicao Neta,E.R., Johanningsmeier, S.D. and McFeeters, R.F. (2007) The Chemistry and Physiology of Sour Taste—A Review. Journal of Food Science, 72, R33-R38. https://doi.org/10.1111/j.1750-3841.2007.00282.x