乳酸菌与结肠癌
王淑梅
1 1，2，张兰威1 *，单毓娟 1哈尔滨工业大学食品科学与工程学院，黑龙江 哈尔滨 150090
2 哈尔滨学院工学院，黑龙江 哈尔滨 150080
外实验结果表明N-亚硝基吗啉(N -NitrosoMorpholine ，NMOR ) 减少了大鼠V79 细胞和人肠道黏膜细胞（实验选用人结肠癌Caco-2细胞模拟人肠道细胞）的活性
基金项目：国家“863计划”（2011AA100902）
*通讯作者。Tel: +86-451-86282901；E-mail ：[email protected]
作者简介：王淑梅(1979-) ，女，黑龙江省桦南人，讲师，在职博士研究生，从事食品科学与工程方面的研究。Tel: +86-451-86282901; E-mail：[email protected]
收稿日期：2014-09-28；修回日期：2015-01-04
[13]。而1,2-二甲基肼对实验动物则有很强的致癌作
用[11]。
1.2 饮食因素诱发的结肠癌
经常食用高脂肪、高蛋白和低纤维含量的食物诱发结肠癌的几率明显增高
的结肠癌发病率明显高于亚洲等不发达国家
的含量增加，可诱发结肠癌[15][14][11]。研究指出西方发达国家，这就表明饮食习惯确实是诱发结肠癌的关键因素。高脂肪[16]食物可促进肠道内一些厌氧细菌的生长，胆醇和胆盐经厌氧菌的分解则次级胆酸（如脱氧胆酸和石胆酸）。腌制食品过程产生的亚硝酸盐类化合物
[11]或烹饪、烧烤类食品产生的杂环
影响等[23, 28]。
2.1 提高机体的免疫力
免疫系统在机体肿瘤的发生与发展过程中起着至关重要的调控作用，近期的研究显示乳酸菌的抗结直肠癌功能与其对机体的免疫调控密切相关
化
[30][29]。研究显示乳酸菌可使巨噬细胞活性增加，小鼠的NK 细胞活[31]，促进人外周血单核细胞释放肿瘤坏死因子TNF-α、白介素IL-10[32]、IL-12[31-32]等，并且刺激树突
状细胞释放IL-12、调控IL-10的释放[29]。这就说明乳酸菌可通过提高机体免疫力来实现抗肿瘤功能。本实验室前期在对分离自天然发酵乳制品和婴儿粪便的乳酸菌研究显示，副干酪乳杆菌（Lactobacillus paracasei subsp. paracasei ，L. paracasei subsp. paracasei ）M5[31]、L. coryniformis subsp. torquens T3[31]、鼠李糖乳杆菌（Lactobacillus. rhamnosus，L. rhamnosus）SB5、SB31、J5、INI 的活菌体、细胞壁和菌体DNA 在体外可促进血液单核细胞（PBMCs ）的增殖，并促进IL-12 、IFN-γ和TNF-α的释放，从而实现了其促免疫功能
[33]。以上研究结果均说明乳酸菌对机体具有一定益生功效，尤其可提高机体的免疫力，但目前此部分研究
2.3.2 对肠道细菌酶致癌作用的阻断：乳酸菌和双歧杆菌不仅产生的肠道有害菌要比梭菌属和拟杆菌属少
[26]，而且还降低了可引发结肠癌的粪便酶的水平，并有降解亚硝基化合物的能力[24]。健康的成年人摄入L. rhamnosus LC705 与费氏丙酸杆菌（Propionibacterium freudenreichii ssp . shermanii）JS 的混合物就可降低肠道致病菌β-(葡萄) 糖甙酶的活性
活性
[44][26]。体外研究也显示，双歧杆菌SPM0212可明显抑制肠道细菌酶的。因此，保持或提高肠道内乳酸菌和双歧杆菌的数量对维持肠道微生态平衡，预防癌症的发生有一
定作用[25]。
(LS-174T ) 的增殖，还能抑制由1,2-二甲肼诱导的小鼠结肠癌
的凋亡[注]。我们课题组成员Wang 等研究也表明，副干酪乳杆菌M5肽聚糖也具有抗肿瘤功能，抑制HT-29增殖，并通过激活凋亡线粒体途径诱导HT-29细胞。
[注]：Wang SM, Shan YJ, Zhang LW. Whole peptidoglycan extracts from Lactobacillus paracasei subsp . paracasei exert anticancer activity in vitro. Journal of Food Protection, 2014, in submitted.
脂磷壁酸也具有免疫功能，可刺激单核细胞产生IL-1、肿瘤坏死因子(TNF-α) 和IL-6。L. acidophilus 就通过其细胞壁脂磷壁酸发挥免疫调节作用的。乳酸菌脂磷壁酸通过Toll-2刺激树突状细胞释放免疫细胞因子，而当细胞壁脂磷壁酸被去除后L. acidophilus (NCK2025) 的免疫调节机能丧失，不能有效地刺激树突状细胞释放免疫因子IL-12和TNF-α，也不能调控IL-10的释放[29]。此外，乳酸菌的细胞壁肽聚糖和脂
[48, 52]磷壁酸是NO 合成酶的诱导剂, 能刺激小鼠巨噬细胞和其他免疫细胞产生NO
信息传递、疾病防御等方面起重要作用。
。NO 在机体物质代谢、chemoprevention for colorectal cancer. World Journal of Gastroenterol, 2008, 14(42): 6453-6457.
[2] Guo CF, Li JY. Hypocholesterolaemic action of Lactobacillus casei F0822 in rats fed a cholesterol-enriched
diet. International Dairy Journal, 2013, 32:144-149.
[3] Hoarau C, Lagaraine C, Martin L, Roussel FV, Lebranchu Y. Supernatant of Bifidobacterium breve induces
dendritic cell maturation, activation, and survival through a Toll-like receptor 2 pathway. Journal of Allergy
and Clinical iImmunology, 2006, 117(3): 696-702.
[4] Xue CH, Zhang LW, Li HB, Wang SM, Li Q, Luo X, Liu WL, Du M, Yi HX, Han X. Functionality of the
S-layer proteins from lactobacillus in the competitive against enteropathogens infection. European Food Research and Technology, 2013, 236: 249-255.
[5] Minelli EB, Benini A, Marzotto M, Sbarbati A, Ruzzenente O, Ferrario R. Assessment of novel probiotic
Lactobacillus casei strains for the production of functional dairy foods. International Dairy Journal, 2004,
[15] Cara L, Crowley W, Katerina D. Nicotine increases oxidative stress, activates NF-kB and GRP78,
induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chemico-Biological Interactions, 2003, 145: 53-66.
[16] Gunter GC, Kuhnle A, Giles W, Reda T, Mani A, Moore K, Lunn JC, Bingham SA. Diet-induced
endogenous formation of nitroso compounds in the GI tract, Free Radical Biology & Medicine , 2007,
43:1040-1047.
[17]
[18] Lucas MBW, Ulrich B. Bile salts and cholestasis. Digestive and Liver Disease, 2010, 42: 409-418. Mahmoud N. Administration of an unconjugated bile acid increases duodenal tumors in a murine model
of familial adenomatous polyposis. Carcinogenesis , 1999, 20: 299-303.
[19] Debruyne PR, Bruyneel EA, Li X, Zimber A, Gespach C, Mareel MM. The role of bile acids in
carcinogenesis. Mutation Research, 2001, 480-481: 359-369.
cytotoxicity delayed murine carcinogenesis by a probiotic microor granism. Carcinogenesis , 2001, 22(4): 599-605.
[31] Tuo YF, Zhang LW, Han X, Du M, Yi HX, Zhang WQ, Jiao YH. In vitro assessment of
immunomodulating activity of the two lactobacillus strains isolated from traditional fermented milk. World Journal of Microbiology & Biotechnology, 2011, 27:505-511.
[32] Christina H, Bengt A, Agnes EW. Gram-positive bacteria are potent inducers of monocytic
interleukin-12 (IL-12) while gram-negative bacteria preferentially stimulate IL-10 production. Infection and Immunnity , 2000, 3581-3586.
[33] Tuo YF, Zhang WQ, Zhang LW, Ai LZ, Zhang YC, Han X, Yi HX. Study of probiotic potential of four
wild Lactobacillus rhamnosus strains. Anaerobe , 2013, 21: 22-27.
[34] Fu GF, Li X, Hou YY, Fan YR, Liu WH, Xu GX. Bifidobacterium longum as an oral delivery system of
Caderni G. Antitumorigenic activity of the prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis on azoxymethane induced colon carcinogenesis in rats. Carcinogenesis , 2002, 23(11): 1953-1960.
[44] Yuna K, Dokyung L, Donghyun K, Cho JY, Yang J, Chung M, Kim K, Ha N. Inhibition of proliferation
in colon cancer cell Lines and harmful enzyme activity of colon Bacteria by Bifidobacterium adolescentis
SPM0212. Archives of Pharmacal Research, 2008, 31(4): 468-473.
[45] Hayatsu H, Hayatsu T. Suppressing effect of Lactobacillus casei administration on the urinary
mutagenicity arising from ingestion of fried ground beef in the human. Cancer Letter, 1993, 73: 173-179.
[46] Franceschi F, Marini M, Piscaglia A, Soulier N, Puglisi A, Ricci R, Giupponi B, Marco GD, Roccarina
D, Gigante G, Barbaro F, Mancini F, Silveri NG, Gasbarrini G, Gasbarrini A. Effect of bacillus clausii administration in the rectal mucosa of mice treated with intrarectal instillation of the carcinogen
K1. Carbohydrate Research, 1990, 204: 227-232.
Lactobacilli and colon carcinoma — A review
Shumei Wang 1, 2, Lanwei Zhang 1*, Yujuan Shan1
1 School of Food Science and Engineering, Harbin Institute of Technology, Harbin 150090, Heilongjiang Province, China
Supported by the National Programs for High Technology Research and Development of China
(2011AA100902)
* Corresponding author. Tel: + 86-451-86282901; E-mail: [email protected]
Received: 28 September 2014/ Revice: 4 January 2015
乳酸菌与结肠癌
王淑梅
1 1，2，张兰威1 *，单毓娟 1哈尔滨工业大学食品科学与工程学院，黑龙江 哈尔滨 150090
2 哈尔滨学院工学院，黑龙江 哈尔滨 150080
外实验结果表明N-亚硝基吗啉(N -NitrosoMorpholine ，NMOR ) 减少了大鼠V79 细胞和人肠道黏膜细胞（实验选用人结肠癌Caco-2细胞模拟人肠道细胞）的活性
基金项目：国家“863计划”（2011AA100902）
*通讯作者。Tel: +86-451-86282901；E-mail ：[email protected]
作者简介：王淑梅(1979-) ，女，黑龙江省桦南人，讲师，在职博士研究生，从事食品科学与工程方面的研究。Tel: +86-451-86282901; E-mail：[email protected]
收稿日期：2014-09-28；修回日期：2015-01-04
[13]。而1,2-二甲基肼对实验动物则有很强的致癌作
用[11]。
1.2 饮食因素诱发的结肠癌
经常食用高脂肪、高蛋白和低纤维含量的食物诱发结肠癌的几率明显增高
的结肠癌发病率明显高于亚洲等不发达国家
的含量增加，可诱发结肠癌[15][14][11]。研究指出西方发达国家，这就表明饮食习惯确实是诱发结肠癌的关键因素。高脂肪[16]食物可促进肠道内一些厌氧细菌的生长，胆醇和胆盐经厌氧菌的分解则次级胆酸（如脱氧胆酸和石胆酸）。腌制食品过程产生的亚硝酸盐类化合物
[11]或烹饪、烧烤类食品产生的杂环
影响等[23, 28]。
2.1 提高机体的免疫力
免疫系统在机体肿瘤的发生与发展过程中起着至关重要的调控作用，近期的研究显示乳酸菌的抗结直肠癌功能与其对机体的免疫调控密切相关
化
[30][29]。研究显示乳酸菌可使巨噬细胞活性增加，小鼠的NK 细胞活[31]，促进人外周血单核细胞释放肿瘤坏死因子TNF-α、白介素IL-10[32]、IL-12[31-32]等，并且刺激树突
状细胞释放IL-12、调控IL-10的释放[29]。这就说明乳酸菌可通过提高机体免疫力来实现抗肿瘤功能。本实验室前期在对分离自天然发酵乳制品和婴儿粪便的乳酸菌研究显示，副干酪乳杆菌（Lactobacillus paracasei subsp. paracasei ，L. paracasei subsp. paracasei ）M5[31]、L. coryniformis subsp. torquens T3[31]、鼠李糖乳杆菌（Lactobacillus. rhamnosus，L. rhamnosus）SB5、SB31、J5、INI 的活菌体、细胞壁和菌体DNA 在体外可促进血液单核细胞（PBMCs ）的增殖，并促进IL-12 、IFN-γ和TNF-α的释放，从而实现了其促免疫功能
[33]。以上研究结果均说明乳酸菌对机体具有一定益生功效，尤其可提高机体的免疫力，但目前此部分研究
2.3.2 对肠道细菌酶致癌作用的阻断：乳酸菌和双歧杆菌不仅产生的肠道有害菌要比梭菌属和拟杆菌属少
[26]，而且还降低了可引发结肠癌的粪便酶的水平，并有降解亚硝基化合物的能力[24]。健康的成年人摄入L. rhamnosus LC705 与费氏丙酸杆菌（Propionibacterium freudenreichii ssp . shermanii）JS 的混合物就可降低肠道致病菌β-(葡萄) 糖甙酶的活性
活性
[44][26]。体外研究也显示，双歧杆菌SPM0212可明显抑制肠道细菌酶的。因此，保持或提高肠道内乳酸菌和双歧杆菌的数量对维持肠道微生态平衡，预防癌症的发生有一
定作用[25]。
(LS-174T ) 的增殖，还能抑制由1,2-二甲肼诱导的小鼠结肠癌
的凋亡[注]。我们课题组成员Wang 等研究也表明，副干酪乳杆菌M5肽聚糖也具有抗肿瘤功能，抑制HT-29增殖，并通过激活凋亡线粒体途径诱导HT-29细胞。
[注]：Wang SM, Shan YJ, Zhang LW. Whole peptidoglycan extracts from Lactobacillus paracasei subsp . paracasei exert anticancer activity in vitro. Journal of Food Protection, 2014, in submitted.
脂磷壁酸也具有免疫功能，可刺激单核细胞产生IL-1、肿瘤坏死因子(TNF-α) 和IL-6。L. acidophilus 就通过其细胞壁脂磷壁酸发挥免疫调节作用的。乳酸菌脂磷壁酸通过Toll-2刺激树突状细胞释放免疫细胞因子，而当细胞壁脂磷壁酸被去除后L. acidophilus (NCK2025) 的免疫调节机能丧失，不能有效地刺激树突状细胞释放免疫因子IL-12和TNF-α，也不能调控IL-10的释放[29]。此外，乳酸菌的细胞壁肽聚糖和脂
[48, 52]磷壁酸是NO 合成酶的诱导剂, 能刺激小鼠巨噬细胞和其他免疫细胞产生NO
信息传递、疾病防御等方面起重要作用。
。NO 在机体物质代谢、chemoprevention for colorectal cancer. World Journal of Gastroenterol, 2008, 14(42): 6453-6457.
[2] Guo CF, Li JY. Hypocholesterolaemic action of Lactobacillus casei F0822 in rats fed a cholesterol-enriched
diet. International Dairy Journal, 2013, 32:144-149.
[3] Hoarau C, Lagaraine C, Martin L, Roussel FV, Lebranchu Y. Supernatant of Bifidobacterium breve induces
dendritic cell maturation, activation, and survival through a Toll-like receptor 2 pathway. Journal of Allergy
and Clinical iImmunology, 2006, 117(3): 696-702.
[4] Xue CH, Zhang LW, Li HB, Wang SM, Li Q, Luo X, Liu WL, Du M, Yi HX, Han X. Functionality of the
S-layer proteins from lactobacillus in the competitive against enteropathogens infection. European Food Research and Technology, 2013, 236: 249-255.
[5] Minelli EB, Benini A, Marzotto M, Sbarbati A, Ruzzenente O, Ferrario R. Assessment of novel probiotic
Lactobacillus casei strains for the production of functional dairy foods. International Dairy Journal, 2004,
[15] Cara L, Crowley W, Katerina D. Nicotine increases oxidative stress, activates NF-kB and GRP78,
induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chemico-Biological Interactions, 2003, 145: 53-66.
[16] Gunter GC, Kuhnle A, Giles W, Reda T, Mani A, Moore K, Lunn JC, Bingham SA. Diet-induced
endogenous formation of nitroso compounds in the GI tract, Free Radical Biology & Medicine , 2007,
43:1040-1047.
[17]
[18] Lucas MBW, Ulrich B. Bile salts and cholestasis. Digestive and Liver Disease, 2010, 42: 409-418. Mahmoud N. Administration of an unconjugated bile acid increases duodenal tumors in a murine model
of familial adenomatous polyposis. Carcinogenesis , 1999, 20: 299-303.
[19] Debruyne PR, Bruyneel EA, Li X, Zimber A, Gespach C, Mareel MM. The role of bile acids in
carcinogenesis. Mutation Research, 2001, 480-481: 359-369.
cytotoxicity delayed murine carcinogenesis by a probiotic microor granism. Carcinogenesis , 2001, 22(4): 599-605.
[31] Tuo YF, Zhang LW, Han X, Du M, Yi HX, Zhang WQ, Jiao YH. In vitro assessment of
immunomodulating activity of the two lactobacillus strains isolated from traditional fermented milk. World Journal of Microbiology & Biotechnology, 2011, 27:505-511.
[32] Christina H, Bengt A, Agnes EW. Gram-positive bacteria are potent inducers of monocytic
interleukin-12 (IL-12) while gram-negative bacteria preferentially stimulate IL-10 production. Infection and Immunnity , 2000, 3581-3586.
[33] Tuo YF, Zhang WQ, Zhang LW, Ai LZ, Zhang YC, Han X, Yi HX. Study of probiotic potential of four
wild Lactobacillus rhamnosus strains. Anaerobe , 2013, 21: 22-27.
[34] Fu GF, Li X, Hou YY, Fan YR, Liu WH, Xu GX. Bifidobacterium longum as an oral delivery system of
Caderni G. Antitumorigenic activity of the prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis on azoxymethane induced colon carcinogenesis in rats. Carcinogenesis , 2002, 23(11): 1953-1960.
[44] Yuna K, Dokyung L, Donghyun K, Cho JY, Yang J, Chung M, Kim K, Ha N. Inhibition of proliferation
in colon cancer cell Lines and harmful enzyme activity of colon Bacteria by Bifidobacterium adolescentis
SPM0212. Archives of Pharmacal Research, 2008, 31(4): 468-473.
[45] Hayatsu H, Hayatsu T. Suppressing effect of Lactobacillus casei administration on the urinary
mutagenicity arising from ingestion of fried ground beef in the human. Cancer Letter, 1993, 73: 173-179.
[46] Franceschi F, Marini M, Piscaglia A, Soulier N, Puglisi A, Ricci R, Giupponi B, Marco GD, Roccarina
D, Gigante G, Barbaro F, Mancini F, Silveri NG, Gasbarrini G, Gasbarrini A. Effect of bacillus clausii administration in the rectal mucosa of mice treated with intrarectal instillation of the carcinogen
K1. Carbohydrate Research, 1990, 204: 227-232.
Lactobacilli and colon carcinoma — A review
Shumei Wang 1, 2, Lanwei Zhang 1*, Yujuan Shan1
1 School of Food Science and Engineering, Harbin Institute of Technology, Harbin 150090, Heilongjiang Province, China
Supported by the National Programs for High Technology Research and Development of China
(2011AA100902)
* Corresponding author. Tel: + 86-451-86282901; E-mail: [email protected]
Received: 28 September 2014/ Revice: 4 January 2015