DOI QR코드

DOI QR Code

장내 마이크로바이옴과 차세대 프로바이오틱스 연구 현황

Recent advances on next-generation probiotics linked to the gut microbiome

  • 최학종 (세계김치연구소 연구개발본부)
  • 투고 : 2019.08.25
  • 심사 : 2019.09.16
  • 발행 : 2019.09.30

초록

NGS 기술이 발전함에 따라 우리 몸의 생리와 면역조절에 있어서 장내미생물의 중요성이 알려지면서부터 장내미생물군집의 구조를 직접 조절할 수 있는 프로바이오틱스의 중요성 역시 재조명 받고 있다. 인류는 프로바이오틱스를 오랫동안 발효식품 등을 통하여 섭취하였는데, 프로바이오틱스는 식품의 보존성 및 영양성을 높일 뿐 아니라 인체의 건강에 이로운 역할을 한다. 특히 프로바이오틱스의 섭취는 생체 내에서 Treg의 기능을 활성화하여 장내 환경을 개선시켜 유익한 장내미생물의 생육을 도우며, 염증반응, 알러지질환, 자가면역질환 등을 완화시키는 효과가 있다. 특히 프로바이오틱스는 장내 유익균인 Bifidobacterium, Faecalibacterium, Akkermansia 및 Bacteroides 속 미생물의 빈도를 증가시키고, 이들은 단쇄지방산 및 신체에 이로운 대사체 등을 생산한다. 지금까지 프로바이오틱스는 대부분 건강기능식품으로 사용되어 왔으나, 최근 들어 장내 유익균에 대한 기능성이 알려지면서 기존 프로바이오틱스를 포함한 장내 미생물을 이용한 NGPs 개발이 활발히 진행되고 있다. 하지만 NGPs 개발에는 여전히 한계가 존재한다. 아직까지 장내 미생물의 분리, 동정은 일반 세균 배양에 비해 매우 까다롭고, 특별한 배양 기술이 필요하므로 현재까지 NGPs로 활용될 수 있는 장내 미생물은 매우 제한적이다. 또한 기존 프로바이오틱스와는 다르게 NGPs는 의약품처럼 전임상, 독성시험, 약물역학, 3단계의 임상시험을 거쳐야 한다. 하지만 기존 프로바이오틱스의 질병 개선 효과를 뛰어넘어 고형암, 대사질환 및 면역질환의 차세대 치료제로서의 활용 가능성이 매우 높기 때문에 앞으로 더 폭넓은 연구가 진행되어야 할 것이다.

Gut microbiome have recently provided evidence that the gut microbiota are capable of greatly influencing all aspects of physiology and immunology. Although a number of recent studies have shown that probiotics can modulate gut microbiota structure, the mechanism underlying this effect remains to be elucidated. In a disease state, the relative abundances of beneficial gut bacteria are generally reduced, which is restored by constant probiotic supplementation. Oral administration of probiotics improved the disease state by (1) inducing differentiation and function of regulatory T cells, (2) reducing inflammatory response, (3) modulating the gut environment, and (4) increasing the proportions of short-chain fatty acid- or beneficial metabolite-producing gut microbiota including the genera Bifidobacterium, Faecalibacterium, Akkermansia, etc. In this review, current knowledge on how probiotics can influence host's health by altering gut microbiota structure and on how probiotics and beneficial gut bacteria can be applied as next-generation probiotics will be discussed.

키워드

참고문헌

  1. Ben Salah R, Trabelsi I, Hamden K, Chouayekh H, Bejar S. Lactobacillus plantarum TN8 exhibits protective effects on lipid, hepatic and renal profiles in obese rat. Anaerobe. 23: 55-61 (2013) https://doi.org/10.1016/j.anaerobe.2013.07.003
  2. Cheon S, Lee KW, Kim KE, Park JK, Park S, Kim CH, Kim D, Lee HJ, Cho D. Heat-killed Lactobacillus acidophilus La205 enhances NK cell cytotoxicity through increased granule exocytosis. Immunol. Lett. 136: 171-176 (2011) https://doi.org/10.1016/j.imlet.2011.01.007
  3. Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L; MICROObes Consortium, Dumas ME, Rizkalla SW, Dore J, Cani PD, Clement K. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 65: 426-436 (2016) https://doi.org/10.1136/gutjnl-2014-308778
  4. de Roock S, van Elk M, Hoekstra MO, Prakken BJ, Rijkers GT, de Kleer IM. Gut derived lactic acid bacteria induce strain specific $CD4^+$ T cell responses in human PBMC. Clin. Nutr. 30: 845-851 (2011) https://doi.org/10.1016/j.clnu.2011.05.005
  5. Deng H, Li Z, Tan Y, Guo Z, Liu Y, Wang Y, Yuan Y, Yang R, Bi Y, Bai Y, Zhi F. A novel strain of Bacteroides fragilis enhances phagocytosis and polarises M1 macrophages. Sci. Rep. 6: 29401 (2016) https://doi.org/10.1038/srep29401
  6. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. U. S. A. 110: 9066-9071 (2013) https://doi.org/10.1073/pnas.1219451110
  7. Farrar MD, Whitehead TR, Lan J, Dilger P, Thorpe R, Holland KT, Carding SR. Engineering of the gut commensal bacterium Bacteroides ovatus to produce and secrete biologically active murine interleukin-2 in response to xylan. J. Appl. Microbiol. 98: 1191-1197 (2005) https://doi.org/10.1111/j.1365-2672.2005.02565.x
  8. Frossard CP, Steidler L, Eigenmann PA. Oral administration of an IL-10-secreting Lactococcus lactis strain prevents food-induced IgE sensitization. J. Allergy Clin. Immunol. 119: 952-959 (2007) https://doi.org/10.1016/j.jaci.2006.12.615
  9. Fu L, Peng J, Zhao S, Zhang Y, Su X, Wang Y. Lactic acid bacteria-specific induction of $CD4^+Foxp3^+$ T cells ameliorates shrimp tropomyosin-induced allergic response in mice via suppression of mTOR signaling. Sci. Rep. 7: 1987 (2017) https://doi.org/10.1038/s41598-017-02260-8
  10. Gauffin Cano P, Santacruz A, Moya A, Sanz Y. Bacteroides uniformis CECT 7771 ameliorates metabolic and immunological dysfunction in mice with high-fat-diet induced obesity. PLoS One 7: e41079 (2012) https://doi.org/10.1371/journal.pone.0041079
  11. Gerard P, Lepercq P, Leclerc M, Gavini F, Raibaud P, Juste C. Bacteroides sp. strain D8, the first cholesterol-reducing bacterium isolated from human feces. Appl. Environ. Microbiol. 73: 5742-5749 (2007) https://doi.org/10.1128/AEM.02806-06
  12. Hamady ZZ, Scott N, Farrar MD, Lodge JP, Holland KT, Whitehead T, Carding SR. Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus. Gut 59: 461-469 (2010) https://doi.org/10.1136/gut.2008.176131
  13. Hamady ZZ, Scott N, Farrar MD, Wadhwa M, Dilger P, Whitehead TR, Thorpe R, Holland KT, Lodge JP, Carding SR. Treatment of colitis with a commensal gut bacterium engineered to secrete human TGF-${\beta}$1 under the control of dietary xylan 1. Inflamm. Bowel Dis. 17: 1925-1935 (2011) https://doi.org/10.1002/ibd.21565
  14. Hatcher GE, Lambrecht RS. Augmentation of macrophage phagocytic activity by cell-free extracts of selected lactic acid-producing bacteria. J. Dairy Sci. 76: 2485-2492 (1993) https://doi.org/10.3168/jds.S0022-0302(93)77583-9
  15. Iemoli E, Trabattoni D, Parisotto S, Borgonovo L, Toscano M, Rizzardini G, Clerici M, Ricci E, Fusi A, De Vecchi E, Piconi S, Drago L. Probiotics reduce gut microbial translocation and improve adult atopic dermatitis. J. Clin. Gastroenterol. 46 Suppl: S33-S40 (2012) https://doi.org/10.1097/MCG.0b013e31826a8468
  16. Ji YS, Kim HN, Park HJ, Lee JE, Yeo SY, Yang JS, Park SY, Yoon HS, Cho GS, Franz CM, Bomba A, Shin HK, Holzapfel WH. Modulation of the murine microbiome with a concomitant antiobesity effect by Lactobacillus rhamnosus GG and Lactobacillus sakei NR28. Benef. Microbes. 3: 13-22 (2012) https://doi.org/10.3920/BM2011.0046
  17. Jounai K, Ikado K, Sugimura T, Ano Y, Braun J, Fujiwara D. Spherical lactic acid bacteria activate plasmacytoid dendritic cells immunomodulatory function via TLR9-dependent crosstalk with myeloid dendritic cells. PLoS One 7: e32588 (2012) https://doi.org/10.1371/journal.pone.0032588
  18. Kang JH, Yun SI, Park MH, Park JH, Jeong SY, Park HO. Antiobesity effect of Lactobacillus gasseri BNR17 in high-sucrose diet-induced obese mice. PLoS One. 8: e54617 (2013) https://doi.org/10.1371/journal.pone.0054617
  19. Karimi G, Sabran MR, Jamaluddin R, Parvaneh K, Mohtarrudin N, Ahmad Z, Khazaai H, Khodavandi A. The anti-obesity effects of Lactobacillus casei strain Shirota versus Orlistat on high fat dietinduced obese rats. Food. Nutr. Res. 59: 29273 (2015) https://doi.org/10.3402/fnr.v59.29273
  20. Kim HJ, Kim YJ, Kang MJ, Seo JH, Kim HY, Jeong SK, Lee SH, Kim JM, Hong SJ. A novel mouse model of atopic dermatitis with epicutaneous allergen sensitization and the effect of Lactobacillus rhamnosus. Exp. Dermatol. 21: 672-675 (2012) https://doi.org/10.1111/j.1600-0625.2012.01539.x
  21. Kim HJ, Kim YJ, Lee SH, Yu J, Jeong SK, Hong SJ. Effects of Lactobacillus rhamnosus on allergic march model by suppressing Th2, Th17, and TSLP responses via $CD4^+CD25^+Foxp3^+$ Tregs. Clin. Immunol. 153: 178-186 (2014) https://doi.org/10.1016/j.clim.2014.04.008
  22. Kim JH, Kim K, Kim W. Cream cheese-derived Lactococcus chungangensis CAU 28 modulates the gut microbiota and alleviates atopic dermatitis in BALB/c mice. Sci. Rep. 9: 446 (2019) https://doi.org/10.1038/s41598-018-36864-5
  23. Koizumi S, Wakita D, Sato T, Mitamura R, Izumo T, Shibata H, Kiso Y, Chamoto K, Togashi Y, Kitamura H, Nishimura T. Essential role of Toll-like receptors for dendritic cell and $NK1.1^+$ celldependent activation of type 1 immunity by Lactobacillus pentosus strain S-PT84. Immunol. Lett. 120: 14-19 (2008) https://doi.org/10.1016/j.imlet.2008.06.003
  24. Kwon HK, Lee CG, So JS, Chae CS, Hwang JS, Sahoo A, Nam JH, Rhee JH, Hwang KC, Im SH. Generation of regulatory dendritic cells and $CD4^+Foxp3^+$ T cells by probiotics administration suppresses immune disorders. Proc. Natl. Acad. Sci. U. S. A. 107: 2159-2164 (2010) https://doi.org/10.1073/pnas.0904055107
  25. Kwon MS, Lim SK, Jang JY, Lee J, Park HK, Kim N, Yun M, Shin MY, Jo HE, Oh YJ, Roh SW, Choi HJ. Lactobacillus sakei WIKIM30 ameliorates atopic dermatitis-like skin lesions by inducing regulatory T cells and altering gut microbiota structure in mice. Front. Immunol. 9: 1905 (2018) https://doi.org/10.3389/fimmu.2018.01905
  26. Lee HY, Park JH, Seok SH, Baek MW, Kim DJ, Lee KE, Paek KS, Lee Y, Park JH. Human originated bacteria, Lactobacillus rhamnosus PL60, produce conjugated linoleic acid and show anti-obesity effects in diet-induced obese mice. Biochim. Biophys. Acta. 1761: 736-744 (2006) https://doi.org/10.1016/j.bbalip.2006.05.007
  27. Lee J, Jang JY, Kwon MS, Lim SK, Kim N, Lee J, Park HK, Yun M, Shin MY, Jo HE, Oh YJ, Ryu BH, Ko MY, Joo W, Choi HJ. Mixture of two Lactobacillus plantarum strains modulates the gut microbiota structure and regulatory T cell response in diet-induced obese mice. Mol. Nutr. Food Res. 62: e1800329 (2018) https://doi.org/10.1002/mnfr.201800329
  28. Lee JW, Shin JG, Kim EH, Kang HE, Yim IB, Kim JY, Joo HG, Woo HJ. Immunomodulatory and antitumor effects in vivo by the cytoplasmic fraction of Lactobacillus casei and Bifidobacterium longum. J. Vet. Sci. 5: 41-48 (2004) https://doi.org/10.4142/jvs.2004.5.1.41
  29. Lim SK, Kwon MS, Lee J, Oh YJ, Jang JY, Lee JH, Park HW, Nam YD, Seo MJ, Roh SW, Choi HJ. Weissella cibaria WIKIM28 ameliorates atopic dermatitis-like skin lesions by inducing tolerogenic dendritic cells and regulatory T cells in BALB/c mice. Sci. Rep. 7: 40040 (2017) https://doi.org/10.1038/srep40040
  30. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, Ritz T, Longerich T, Theriot CM, McCulloch JA, Roy S, Yuan W, Thovarai V, Sen SK, Ruchirawat M, Korangy F, Wang XW, Trinchieri G, Greten TF. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360: eaan5931 (2018) https://doi.org/10.1126/science.aan5931
  31. Masuda Y, Takahashi T, Yoshida K, Nishitani Y, Mizuno M, Mizoguchi H. TLR ligands of Lactobacillus sakei LK-117 isolated from seed mash for brewing sake are potent inducers of IL-12. J. Biosci. Bioeng. 112: 363-368 (2011) https://doi.org/10.1016/j.jbiosc.2011.06.007
  32. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122: 107-118 (2005) https://doi.org/10.1016/j.cell.2005.05.007
  33. Moon YJ, Baik SH, Cha YS. Lipid-lowering effects of Pediococcus acidilactici M76 isolated from Korean traditional makgeolli in high fat diet-induced obese mice. Nutrients 6: 1016-1028 (2014) https://doi.org/10.3390/nu6031016
  34. Mu Q, Zhang H, Liao X, Lin K, Liu H, Edwards MR, Ahmed SA, Yuan R, Li L, Cecere TE, Branson DB, Kirby JL, Goswami P, Leeth CM, Read KA, Oestreich KJ, Vieson MD, Reilly CM, Luo XM. Control of lupus nephritis by changes of gut microbiota. Microbiome 5: 73 (2017) https://doi.org/10.1186/s40168-017-0300-8
  35. O'Toole PW, Marchesi JR, Hill C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat. Microbiol. 2: 17057 (2017) https://doi.org/10.1038/nmicrobiol.2017.57
  36. Rossi O, van Berkel LA, Chain F, Tanweer Khan M, Taverne N, Sokol H, Duncan SH, Flint HJ, Harmsen HJ, Langella P, Samsom JN, Wells JM. Faecalibacterium prausnitzii A2-165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses. Sci. Rep. 6: 18507 (2016) https://doi.org/10.1038/srep18507
  37. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragon L, Jacquelot N, Qu B, Ferrere G, Clemenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359: 91-97 (2018) https://doi.org/10.1126/science.aan3706
  38. Shimbo I, Yamaguchi T, Odaka T, Nakajima K, Koide A, Koyama H, Saisho H. Effect of Clostridium butyricum on fecal flora in Helicobacter pylori eradication therapy. World J. Gastroenterol. 11: 7520-7524 (2005) https://doi.org/10.3748/wjg.v11.i47.7520
  39. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350: 1084-1089 (2015) https://doi.org/10.1126/science.aac4255
  40. Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottiere HM, Dore J, Marteau P, Seksik P, Langella P. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. U. S. A. 105: 16731-16736 (2008) https://doi.org/10.1073/pnas.0804812105
  41. Tanida M, Shen J, Maeda K, Horii Y, Yamano T, Fukushima Y, Nagai K. High-fat diet-induced obesity is attenuated by probiotic strain Lactobacillus paracasei ST11 (NCC2461) in rats. Obes. Res. Clin. Pract. 2: I-II (2008) https://doi.org/10.1016/S1871-403X(08)00009-4
  42. Takata K, Kinoshita M, Okuno T, Moriya M, Kohda T, Honorat JA, Sugimoto T, Kumanogoh A, Kayama H, Takeda K, Sakoda S, Nakatsuji Y. The lactic acid bacterium Pediococcus acidilactici suppresses autoimmune encephalomyelitis by inducing IL-10-producing regulatory T cells. PLoS One 6: e27644 (2011) https://doi.org/10.1371/journal.pone.0027644
  43. Tsai YT, Cheng PC, Fan CK, Pan TM. Time-dependent persistence of enhanced immune response by a potential probiotic strain Lactobacillus paracasei subsp. paracasei NTU 101. Int. J. Food Microbiol. 128: 219-225 (2008) https://doi.org/10.1016/j.ijfoodmicro.2008.08.009
  44. Ulsemer P, Henderson G, Toutounian K, Loffler A, Schmidt J, Karsten U, Blaut M, Goletz S. Specific humoral immune response to the Thomsen-Friedenreich tumor antigen (CD176) in mice after vaccination with the commensal bacterium Bacteroides ovatus D-6. Cancer Immunol. Immunother. 62: 875-887 (2013) https://doi.org/10.1007/s00262-013-1394-x
  45. Ulsemer P, Toutounian K, Kressel G, Goletz C, Schmidt J, Karsten U, Hahn A, Goletz S. Impact of oral consumption of heat-treated Bacteroides xylanisolvens DSM 23964 on the level of natural TF${\alpha}$-specific antibodies in human adults. Benef. Microbes 7: 485-500 (2016) https://doi.org/10.3920/BM2015.0143
  46. Verma R, Lee C, Jeun EJ, Yi J, Kim KS, Ghosh A, Byun S, Lee CG, Kang HJ, Kim GC, Jun CD, Jan G, Suh CH, Jung JY, Sprent J, Rudra D, De Castro C, Molinaro A, Surh CD, Im SH. Cell surface polysaccharides of Bifidobacterium bifidum induce the generation of $Foxp3^+$ regulatory T cells. Sci. Immunol. 3: eaat6975 (2018) https://doi.org/10.1126/sciimmunol.aat6975
  47. Wang J, Tang H, Zhang C, Zhao Y, Derrien M, Rocher E, van-Hylckama Vlieg JE, Strissel K, Zhao L, Obin M, Shen J. Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. ISME J. 9:1-15 (2015) https://doi.org/10.1038/ismej.2014.99
  48. Wicken AJ, Knox KW. Immunogenicity of cell wall and plasma membrane components of some oral lactic acid bacteria. J. Dent. Res. 55: C34-C41 (1976)
  49. Won TJ, Kim B, Song DS, Lim YT, Oh ES, Lee DI, Park ES, Min H, Park SY, Hwang KW. Modulation of Th1/Th2 balance by Lactobacillus strains isolated from Kimchi via stimulation of macrophage cell line J774A.1 in vitro. J. Food Sci. 76: H55-H61 (2011) https://doi.org/10.1111/j.1750-3841.2010.02031.x
  50. Woo TD, Oka K, Takahashi M, Hojo F, Osaki T, Hanawa T, Kurata S, Yonezawa H, Kamiya S. Inhibition of the cytotoxic effect of Clostridium difficile in vitro by Clostridium butyricum MIYAIRI 588 strain. J. Med. Microbiol. 60: 1617-1625 (2011) https://doi.org/10.1099/jmm.0.033423-0
  51. Zhao X, Higashikawa F, Noda M, Kawamura Y, Matoba Y, Kumagai T, Sugiyama M. The obesity and fatty liver are reduced by plant-derived Pediococcus pentosaceus LP28 in high fat dietinduced obese mice. PLoS One 7: e30696 (2012) https://doi.org/10.1371/journal.pone.0030696