本研究を行うにあたり、終始ご指導とご鞭撻を賜りました、東北大学大学院 農学研究科 齋藤 忠夫 名誉教授、同 北澤 春樹 准教授、帯広畜産大学大学院 浦島 匡 教授、ならびに本論文の作成にあたり、ご懇篤なるご教示とご助言を 賜りました東北大学大学院農学研究科・栄養学教室 駒井 三千夫 教授、同・
応用微生物教室 阿部 敬悦 教授に深甚の謝意を表します。
また本研究を行う機会を与えていただきましたヤクルト本社中央研究所・所 長 石川 文保 博士、同 宮城 昭彦 元副主席研究員、同 牧野 孝 元参与、同・
審議役 長岡 正人 博士、ビフィズス菌の扱いに関するご指導をいただきまし た同・元参与 渡辺 幸一 博士、ヤクルト薬品工業株式会社 松本 圭介 相談役、
同・金井 晴彦 博士に感謝申し上げます。
終始、私と共に本研究に携わった、渡邉 陽子 主任研究員、石原 知代子 指 導研究員、また、水越 晴美 主任研究員、外谷 英嗣 指導研究員、森 陽子 指 導研究員他、ヤクルト本社中央研究所分析センターの皆様に心より感謝申し上 げます。
教壇に立ちながら博士課程に在籍することをご理解頂いた、新潟青陵大学短 期大学部 関 昭一 学長、五十嵐 由利子 副学長、荒井 威吉 博士に心より 感謝申し上げます。
博士課程を共に過ごし、適宜、励ましやご助言を頂きました合同酒精株式会 社 長畑 直樹氏に感謝申し上げます。
また博士論文の作成に当たり、詳細な校閲を行い、励ましを与えてくれた妻 木村 美実子に心より感謝いたします。
2018年8月
参 考 文 献
1. Gibson, G. R., Roberfroid, M. B.: Dietary Modulation of the Human Colonic Microbiota: Introducing the Concept of Prebiotics. J. Nutr., 125, 1401-1412 (1995)
2. Fuller, R.: Probiotics in man and animals. J. Appl. Bacteriol. 66, 365-378 (1989)
3. Yamashita, K., Kobata, A.: Oligosaccharides of human milk: V. Isolation and characterization of a new trisaccharide, 6’-galactosyllactose. Arch.
Biochem. Biophys. 161, 164-170 (1974)
4. 浦島匡, 斎藤忠夫 ミルクオリゴ糖の比較生化学. 化学と生物 31, 80-82 (1993)
5. Tanaka, R., Takayama, H., Morotomi, M., Kuroshima, T., Ueyama, S., Matsumoto, K., Kuroda, A., Mutai, M.: Effects of Administration of TOS and Bifidobacterium breve 4006 on the Human Fecal Flora.
Bifi;dobacteria Microflora. 2, 17-24 (1983)
6. 園池耕一郎, 馬田三男, 務台方彦 発酵乳製品中の Bifidobacterium 生菌 数の測定用選択培地の検討. 食品衛生学雑誌. 27, 238-244 (1986)
7. Ito, M., Deguchi, Y., Miyamori, A., Matsumoto, K., Kikuchi, H., Matsumoto, K., Kobayashi, Y., Yajima, T., Kan, T.: Effects of Administration of Galactooligosaccharides on the Human Faecal Microflora, Stool Weight and Abdominal Sensation. Microbial Ecology in Health and Disease. 3, 285-292 (1990)
8. Toba, T., Yokota, A., Adachi, S.: Oligosaccharide structures formed during the hydrolysis of lactose by Aspergillus oryzae β-galactosidase. Food
Chemistry. 16, 147-162 (1985)
9. Matsumoto, K., Kobayashi, Y., Tamura, N., Watanabe, T., Kan, T.:
Production of Galactooligosaccharides with β-Galactosidase. Denpun Kagaku. 36, 123-130 (1989)
10. Gosling, Aaron., Stevens, Geoff W., Barber, Andrew R., Kentish, Sandra E., Gras, Sally L.: Recent advances refining galactooligosaccharide production from lactose. Food Chemistry. 121, 307-318 (2010)
11. Torres, D. P. M., Gonçalves, Maria do Pilar F., Teixeira José A.,
Rodrigues. Lígia R.: Galacto-Oligosaccharides: Production, Properties, Applications, and Significance as Prebiotics. Comprehensive Reviews in Food Science and Food Safety. 9, 438–54 (2010)
12. Zarate, S., Lopetz-Leiva, M. H.: Oligosaccharide Formation During Enzymatic Lactose Hydrolysis: A Literature Review. J. Food Protection, 53, 262-268 (1990)
13. Messer, M. Trifonoff, E.: Structure of a marsupial-milk trisaccharide.
Carbohydrate Res., 83, 327-334 (1980)
14. Saito, T.: Chemical structure of three neutral trisaccharides isolated in free form from bovine colostrum. Carbohydrate Res. 165, 43-51 (1987)
15. Urasima, T., Sakamoto, T., Ariga, H.: Structure determination of three neutral oligosaccharides obtained from horse colostrum. Carbohydrate Res.
194, 280-287 (1989)
16. Urasima, T., Saito, T., Nishimura, J., Ariga, H.: New galactosyllactose containing -glycosidic linkage isolated from ovine (Booroola dorset) colostrum. Biochim. Biophis. Acta. 992, 375-378 (1989)
17. Urasima, T., Saito, T., Ohmisya, K., and Shimazaki, K.: Structural determination of three neutral oligosaccharides in bovine (Holstein-Friesian) colostrum, including the novel trisaccharide; GalNAcαl-3Galβ1-4Glc. Biochim. Biophis. Acta 1073, 225-229 (1991)
18. Urasima, T., W. A. Bubb, M. Messer, Tsuji, Y., Taneda. Y.: Studies of the neutral trisaccharides of goat (Capra hircus) colostrum and of the one- and two-dimensional 1H and 13C NMR spectra of 6’-N-acetylglucosaminyllactose. Carbohydrate Res. 262, 173-184 (1994)
19. Messer, M., 浦島匡: カンガルー、ワラビーやカモノハシの乳はヒトとどう
違うか. 化学と生物. 33, 816-824 (1995)
20. 木村一雅, 渡邉陽子, 松本圭介, 宮城昭彦: 市販牛乳に含まれる天然ガラク トオリゴ糖の分析. ヤクルト研究所報告集. 17, 1-7 (1997)
21. Martínez-Villaluenga, C., Alejandra Cardelle-Cobas, Nieves Corzo, Agustín Olano. : Study of galactooligosaccharide composition in
commercial fermented milks. Journal of Food Composition and Analysis.
21, 540-544. (2008)
22. Prakash, B. S., Suyama, K., Itoh, T., Adachi, S.: Structure elucidation of major galactooligosaccharides formed by growing cultures of Trichoderma harzianum. J. Agric Food Chem. 37, 334-337 (1989)
23. Hase, S., Ibuki, T., Ikenaka, T.: Reexamination of the pyridylamination used for fluorescence labeling of oligosaccharides and its application to glycoproteins. J. Biochem. 95, 197-203 (1984)
24. Kondo, A., Suzuki, J., Kuraya, N., Hayes, S., Kato, I., Ikenaka, T.:
Improved Method for Fluorescence Labeling of Sugar Chains with Sialic Acid Residues. Agric. Biol.Chem. 54, 2169-2170 (1990)
25. Suzuki, J., Kondo, A., Kato, I., Hase, S. Ikenaka, T.: Analysis by High-performance. Anion-exchange Chromatography of ComponentSugars as Their Fluorescent Pyridylamino Derivatives. Agric. Biol. Chem., 55, 283-284 (1991)
26. Takemoto, H., Hase, S., Ikenaka, T.: Microquantitative analysis of neutral and amino sugars as fluorescent pyridylamino derivatives by high-performance liquid chromatography. Anal. Biochem. 145, 245-250 (1985)
27. Allen, J. D., Thoma J. A.: Multimolecular Substrate Reactions Catalyzed by Carbohydrases. Aspergillus Oryzae -Amylase Degradation of
Maltooligosaccharides. Biochemistry. 17, 2338–2344 (1978)
28. Yanahira, S., Suguri, T., Yakabe, T., Ikeuchi, Y., Hanagata, G., Deya, E.:
Formation of oligosaccharides from lactitol by Aspergillus oryzae -D-galactosidase. Carbohydr. Res. 232, 151-159 (1992)
29. Ikura, M., Hikichi, K.: Two-dimensional 1H-N.M.R. studies of cello-oligosaccharides: The utility of multiple-relay chemical-shift-correlated spectroscopy. Carbohydrate Res. 163, 1-8 (1987)
30. 木村一雅, 石原知代子, 宮城昭彦: ピリジルアミノ化誘導体の処理法. 特許 第3231103号
31. Donald, A.S.R., Feeney, J.: Separation of human milk oligosaccharides by recycling chromatography. First isolation of lacto-N-neo-difucohexaose II and 3′-galactosyllactose from this source. Carobohydr. Res. 178, 79-91 (1988)
32. Sumiyoshi, W., Urashima, T., Nakamura, T., Arai, I., Saito, T., Tsumura, N., Bing, W., Brand-Miller, J., Watanabe, Y., Kimura, K.: Determination
of each neutral oligosaccharide in the milk of Japanese women during the course of lactation. British Journal of nutrition. 89, 61-69, (2003)
33. 菅原牧裕ら: 公開特許公報. 特開平8-256730
34. 木村一雅ら: 1995年度日本農芸化学会大会講演要旨. １YP2 p.133
35. 渡邉陽子ら: 1995年度日本農芸化学会大会講演要旨. １YP3 p.133
36. Kimura, K., Matsumoto, K., Ishihara, C., Harada, K., Miyagi, A.:
Structure determination of galacto-oligosaccharides by pyridylamination and NMR spectroscopy. Carbohydr. Res. 270, 33-42 (1995)
37. 長南治, 柴原(曽根)春恵, 高橋理恵, 池田雅和, 菊地(早川)弘子, 石川文保, 木村一雅, 松本圭介: ガラクトオリゴ糖の難消化性の検討. 日本食品科学工 学会誌. 51, 23-33 (2004)
38. 木村一雅, 渡邉陽子, 松本圭介, 池田雅和, 宮城昭彦, 大江田和年, 溝渕尚 宏：３’ガラクトオリゴ糖含有組成物の製造法. 特許公報 特許第3871371号 (2006)
39. Kimura, K., Matsumoto, K., Ishihara, C., Harada, K., Miyagi, A.:
Analysis of regioselectivity of transgalactosylation for same -galactosidase by pyridylamination and NMR spectroscopy. XXIst International Carbohydrate Symposium. (2001)
40. Ito, M., Deguchi, Y., Miyamori, A., Matsumoto, K., Kikuchi, H., Matsumoto, K., Kobayashi, Y., Yajima, T., Kan, T.: Effect of Administration of Galactooligosaccha-rides on the Human Faecal Microflora, Stool Weight and Abdominal Sensation. Microb. Ecol. Health Dis. 3, 285-292 (1990)
41. Kaneko, K., Watanabe, Y., Kimura, K., Matsumoto, K., Mizobuchi, T., Onoue, M.: Development of hypoallergenic galacto-oligosaccharides on the basis of allergen analysis. Biosci Biotechnol Biochem. 78, 100-108 (2014)
42. Soh, J. Y., Huang, C. H., Chiang, W. C., Llanora, G. V., Lee A. J., Loh, W., Chin, Y. L., Tay, V. Y., Chan, Y. H., Dianne, D., Lee, B. W.: Anaphylaxis to galacto-oligosaccharides: An evaluation in an atopic population in Singapore. Allergy. 70, 1020-1023 (2015)
43. Ishikawa, E., Sakai, T., Ikemura, H., Matsumoto, K., Abe, H.:
Identification cloning and characterization of a Sporobolomyces singularis beta-galactosidase-like enzyme involved in galacto-oligosaccharide production. J Biosci Bioeng. 99, 331-339 (2005)
44. Hase, S., Hara, ., Matsushita, Y.: Tagging of sugars with a fluorescent compound, 2-aminopyridine. J. Biochem. 85, 217-220 (1979)
45. Hase, S., Ibuki, T., Ikenaka, T.: Reexamination of the Pyridylamination Used for Fluorescence Labeling of Oligosaccharides and Its Application to Glycoproteins. J. Biochem. 95, 197-203. (1984)
46. Hase, S., Ikenaka, T., Matsushima, Y.: Structure analyses of oligosaccharides by tagging of the reducing end sugars with a fluorescent compound. Biochem. Biophys. Res. Commun. 85, 257-263 (1978)
47. Hase, S., Ikenaka, T., Matsushima, Y.: Separation of oligomannose-type sugar chains having one to five mannose residues by high-performance liquid chromatography as their pyridylamino derivatives. Anal. Biochem.
185, 331-334 (1990)
48. Oku, H., Hase, S., Ikenaka, T.: Structure analyses of oligosaccharides by
tagging of the reducing end sugars with a fluorescent compound. Biochem.
Biophys. Res. Commun. 85, 257-63 (1978)
49. Oku, H., Hase, S., Ikenaka, T.: Separation of oligomannose-type sugar chains having one to five mannose residues by high-performance liquid chromatography as their pyridylamino derivatives. Anal Biochem. 185, 331-334 (1990)
50. Jian-Qiang FanLong, H. H., C. Lee Y., C.: Purification of 2-Aminopyridine Derivatives of Oligosaccharides and Related Compounds by Cation-Exchange ChromatographyAnalytical. Biochemistry. 232, 65-68 (1995)
51. 高橋禮子, 加藤晃一: GALAXY 糖鎖マップとは？.
http://www.glycoanalysis.info/galaxy2/systemman.jsp
52. Hase, S., Hara, S., Matsushita, Y.: Reexamination of the
Pyridylamination Used for Fluorescence Labeling of Oligosaccharides and Its Application to Glycoproteins. J. Biochem. 85, 217-220 (1979)
53. 外谷英嗣, 木村一雅, 石原知代子, 山根章宏, 渡邉陽子, 水越晴美: The 25th International Carbohydrate Symposium（ICS2010）
54. Lee, Y. K., Nomoto, K., Salminen, S., Gorbach, SL.: Handbook of probiotics and prebiotics. John Wiley & Sons, Inc., New York (1999)
55. Kaila, M., Isolauri, E., Virtanen, E., Lamne, S., Arvilommi, H.:
Enhancement of the Circulating Antibody Secreting Cell Response in Human Diarrhea by a Human Lactobacillus Strain. Pediatr. Res. 32, 141-144 (1992)
56. Hori, T., Kiyoshima, J., Shida, K., Yasui, H.: Immunomodulation of
Cellular Immunity and Protection against Influenza Virus by Lactobacillus casei Shirota. Milk Science. 50, 133-137 (2001)
57. Hidaka, H., Eida, T., Takizawa, T., Tokunaga, T., Tashiro, Y.: Effect of Fructooligosaccharides on Intestinal Flola in Human Health.
Bifidobacteria Microflora. 5, 37-50 (1986)
58. Gibson, G. R., Beatfy, E. R., Wang, X., Cummings, J. H.: Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology. 108, 975-982 (1995)
59. Yamada, T., Akiyaka, T., Hatano, H., Kimura, K.: In vitro Assessment of Oligosaccharides Assimilation by Intestinal Anaerobic Bacteria. Milk Science. 64, 87-98 (2015)
60. Akiyama, T., Kimura, K., Hatano, H.: Diverse galactooligosaccharides consumption by bifidobacteria: implications of -galactosidase-LacS operon. Biosci. Biotechnol. Biochem. 79, 664-72 (2015)
61. Asakuma, S., Urashima, T., Akahori, M., Obayashi, H., Nakamura, T., Kimura, K., Watanabe, Y., Arai, I., Sanai, Y.: Variation of minor neutral oligosaccharides levels in human colostrum. Eur. J. Clin. Nutr. 62, 488-494 (2008)
62. Schley, P. D., Field, C. J.: The Immune-enhancing Effects of Dietary Fibres and Prebiotics Brit. J. Nutr. 87, S221-S230 (2002)
63. Ward, R. E., Ninoneuvo, M., Mills, D. A., Lebrilla, C. B., German, J. B.: In vitro Fermentation of Brest Milk Oligosaccharides by Bifidobacterium infantis and Lactbacillus gasseri. Appl. Environ. Microbiol. 72, 4497-4499 (2006)
64. Ninoneuvo, M., Ward, R. E., LoCasico, R. G., German, J. B., Freeman, S.
L., Barboza, M., Mills,D. A., Lebrilla, C. B.: Methods for the quantitation of human milk oligosaccharides in bacterial fermentation by mass spectrometry. Anal. Biochem. 361, 15-23 (2007)
65. Asakuma, S., Hatakeyama, E., Urashima, T., Yoshida, E., Katayama, T., Yamamoto, K., Kumagai, H., Ashida, H., Hirose, J., Kitaoka, M.:
Physiology of Consumption of Human Milk Oligosaccharides by Infant Gut-associated Bifidobacteria. J. Biol. Chem. 286, 34853-34592 (2011)
66. Viborg, A. H., Katayama, T., Hachem, M. A., Anderson, M. C., Nishimoto, M., Clausen, M. H., Urashima, T., Svensson B., Kitaoka, M.: Distinct substrate specificities of three glycoside hydrolase family 42 -galactosidases from Bifidobacterium longum subsp. infantis ATCC 15697.
Glycobiobogy. 24, 208-216, (2014)
67. Rossi, M., Corradini, C., Amaretti, A., Nicolini, M., Pompei, A., Zanoni, S., Matteuzzi, D.: Fermentation of Fructooligosaccharides and Inulin by Bifidobacteria: a Comparative Study of Pure and Fecal Cultures. Appl.
Environ. Microbiol. 71, 6150-6158 (2005)
68. Watson, D., O’Connell Motherway, M., Schoterman, M. H. C., Joost van Neerven, R. J., Nauta, A., van Sinderen, D.: Selective carbohydrate utilization by lactobacilli and bifidobacteria. J. Appl. Microbiol. 114, 1132-1146 (2012)
69. Murasaki, S., Muroyama, K., Yamamoto, Y., Kusaka, H., Liu, T., Yoshikai, Y.: Immunopotentiating Activity of Nigerooligosaccharides for the T Helper 1-Like Immune Response in Mice. Biosci. Biotechnol. Biochem. 63, 373-378 (1999)
70. Matsuki, T., Watanabe, K., Fujimoto, J., Kado, Y., Takada, T., Matsumoto, K., Tanaka, R.: Quantitative PCR with 16S rRNA-Gene-Targeted Species-Specific Primers for Analysis of Human Intestinal Bifidobacteria. Appl.
Environ. Microbiol. 70, 167-173 (2004)
71. Matsuki, T., Watanabe, K., Fujimoto, J., Takada, T., Tanaka, R.: Use of 16S rRNA Gene-Targeted Group-Specific Primers for Real-Time PCR Analysis of Predominant Bacteria in Human Feces. Appl. Environ.
Microbiol. 70, 7220-7228 (2004)
72. Yasuno, S., Murata, T., Kokubo, K., Yamaguchi, T., Kamei, M.: Two-mode Analysis by High-performance Liquid Chromatographyof ρ-Aminobenzoic Ethyl Ester-derivatized Monosaccharides. Biosci. Biotechnol. Biochem. 61, 1944-1946 (1997)
73. 奥村龍, 竹田潔: 腸管上皮細胞と腸内細菌との相互作用. 領域融合レビュー.
5, e007 (2016)
74. 光岡知足: 腸内フローラの研究と機能性食品. 腸内細菌学雑誌, 15, 57-89 (2002)
75. 清水(肖)金忠:ヒトに棲息するビフィズス菌の特徴とヨーグルトに応用する 技術の開発. ミルクサイエンス. 66, 45-51 (2017)
76. Makino, H., Kushiro, A., Ishikawa, E., Kubota, H., Gawad, A., Sakai, T., Oishi, K., Martin, R., Ben-Amor, K., Knol, J., Tanaka R.: Mother-to-Infant Transmission of Intestinal Bifidobacterial Strains Has an Impact on the Early Development of Vaginally Delivered Infant's Microbiota. PLOS ONE. 8, e78331 (2013)
77. Urashima, T., Sato, S., Hirabayashi, J., Kobata, A.: Galectin and human
milk oligosaccharides: Database on human milk oligosaccharide structures as a tool for the study of the sugar specificity of galectins.
Trends Glycosci. Glycotech. 30, SE51-SE65 (2017)
78. 片山高嶺: ビフィズス菌とヒトミルクオリゴ糖. 応用糖質科学. 4, 287-294 (2014)
79. 北岡本光: ビフィズス菌由来ヒトミルクオリゴ糖分解酵素のカタログ化.
ミルクサイエンス. 66, 235-240 (2017)
80. Matsuki, T., Yahagi, K., Mori, H., Matsumoto, H., Hara, T., Tajima, S., Ogawa, E., Kodama, H., Yamamoto, K., Yamada, T., Matsumoto, S., Kurokawa, K.: A key genetic factor for fucosyllactose utilization affects infant gut microbiota development. Nat. Commun., 7, 11939 (2016)
81. 松本星隆, 松木隆広: 乳児腸内フローラの形成に影響するビフィズス菌鍵 因子の解明. ミルクサイエンス. 66, (2017) 255-260
82. 藤田清貴: ビフィズス菌が持つ糖タンパク質糖鎖の分解システム. 化学と 生物. 55, 242-248 (2017)
83. Vandenplas, Y., Greef, E. D., Veereman, G.: Prebiotics in infant formula.
Gut Microbes. 5, 681-687 (2014)
84. Sotoya, H., Shigehisa, A., Hara, T., Matsumoto, H., Hatano, H., Matsuki, T.: Identification of genes involved in galacto-oligosaccharide utilization in Bifidobacterium breve strain YIT 4014T. Microbiology. 163, 1420-1428 (2017)