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Fecal Microbiota Transplantation의 최근 동향

Recent Update in Fecal Microbiota Transplantation

  • 김혜진 (부산대학교 약학대학 약학과) ;
  • 강경민 (부산대학교 약학대학 약학과) ;
  • 김수진 (부산대학교 약학대학 약학과) ;
  • 임은옥 (부산대학교 약학대학 약학과)
  • Kim, Haejin (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kang, Kyungmin (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Kim, Sujin (Department of Pharmacy, College of Pharmacy, Pusan National University) ;
  • Im, Eunok (Department of Pharmacy, College of Pharmacy, Pusan National University)
  • 투고 : 2014.10.28
  • 심사 : 2014.11.19
  • 발행 : 2014.12.31

초록

장내 미생물은 사람의 장에 거주하는 미생물 집단으로 자신들의 효소를 이용해 사람에게 직접적인 에너지원이 되는 대사산물을 만들기도 하고 병원성 미생물의 침입에 대응하기도 하며 소화관의 구조와 기능유지 및 면역계의 발달에 영향을 미치는 등의 중요한 기능을 수행한다. 최근 다양한 분석기술을 통해 사람의 장에 있는 다종 및 다수의 미생물의 구성을 관찰하였고 그 결과 특정 질병을 지닌 사람의 장내 미생물 구성은 건강한 사람의 일반적인 구성과 다르다는 것을 확인하였다. 이러한 발견을 바탕으로 건강한 사람의 대변에 있는 장내 미생물을 질병을 지닌 수여자에게 이식하는 fecal microbiota transplantation (FMT) 시술이 각광을 받기 시작하였다. FMT는 장내 미생물의 구성변화로 인해 나타나는 여러 질병에 치료제로 적용할 수 있는데 특히 재발률이 높은 Clostridium difficile 감염에서 활발한 연구가 이루어지고 있다. 이 논문은 지금까지 밝혀진 장내 미생물과 관련된 질병들의 종류와 실제 질병에 FMT를 적용한 사례 등을 정리하고 장내 미생물을 이용하여 현재 연구개발 중인 치료제나 진단도구의 예를 기술함으로써 장내 미생물의 사람의 건강증진과 질병치료를 위한 차세대 생물학적 치료제로서의 가능성을 고찰하고자 한다.

Gut microbiota is a group of microorganisms that resides in the intestine and serves many important functions in human health. Using 16S ribosomal RNA sequencing analysis, a wide variety of bacteria in human gastrointestinal tract has been identified along with intriguing findings that there is a different bacterial composition among individuals. Fecal microbiota transplantation (FMT) is a procedure of stool transplantation from healthy donors to patients suffering from various diseases. Specifically, FMT is able to alter the composition of gut microbiota of recipients and therefore could be an effective treatment for the patients with gastrointestinal diseases including recurrent Clostridium difficile infection, inflammatory bowel disease, and irritable bowel syndrome. Here we review a list of human diseases related to gut microbiota disturbance and the case studies of FMT. We also summarize medicines and diagnostic tools that are under development. Therefore, gut microbiota can be a next generation's biotherapy for promotion of health and treatment of chronic diseases.

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참고문헌

  1. Abrahamsson, T.R., Jakobsson, H.E., Andersson, A.F., Bjorksten, B., Engstrand, L., and Jenmalm, M.C. 2012. Low diversity of the gut microbiota in infants with atopic eczema. J. Allergy Clin. Immunol. 129, 434-440. https://doi.org/10.1016/j.jaci.2011.10.025
  2. Aroniadis, O.C. and Brandt, L.J. 2013. Fecal microbiota transplantation: past, present and future. Curr. Opin. Gastroenterol. 29, 79-84. https://doi.org/10.1097/MOG.0b013e32835a4b3e
  3. Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., Yamasaki, S., Saito, T., Ohba, Y., and et al. 2011. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337-341. https://doi.org/10.1126/science.1198469
  4. Bajaj, J.S., Ridlon, J.M., Hylemon, P.B., Thacker, L.R., Heuman, D.M., Smith, S., Sikaroodi, M., and Gillevet, P.M. 2012. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am. J. Physiol. Gastrointest Liver Physiol. 302, G168-175. https://doi.org/10.1152/ajpgi.00190.2011
  5. Bakken, J.S. 2009. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 15, 285-289. https://doi.org/10.1016/j.anaerobe.2009.09.007
  6. Bakken, J.S., Borody, T., Brandt, L.J., Brill, J.V., Demarco, D.C., Franzos, M.A., Kelly, C., Khoruts, A., Louie, T., Martinelli, L.P., and et al. 2011. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin. Gastroenterol. Hepatol. 9, 1044-1049. https://doi.org/10.1016/j.cgh.2011.08.014
  7. Belluck, P. 2014. A promising pill, not so hard to swallow. The new York Times, Vol. October 12, p. A21.
  8. Berggren, A.M., Nyman, E.M., Lundquist, I., and Bjorck, I.M. 1996. Influence of orally and rectally administered propionate on cholesterol and glucose metabolism in obese rats. Br. J. Nutr. 76, 287-294. https://doi.org/10.1079/BJN19960032
  9. Borody, T., Nowak, A., Torres, M., Campbell, J., Finlayson, S., and Leis, S. 2012. Bacteriotherapy in Chronic Fatigue Syndrome (CFS): a retrospective review. Am. J. Gastroenterol. 107, S591-S592.
  10. Borody, T.J. and Khoruts, A. 2011. Fecal microbiota transplantation and emerging applications. Nat. Rev. Gastroenterol. Hepatol. 9, 88-96. https://doi.org/10.1038/nrgastro.2011.244
  11. Brandt, L.J., Aroniadis, O.C., Mellow, M., Kanatzar, A., Kelly, C., Park, T., Stollman, N., Rohlke, F., and Surawicz, C. 2012. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am. J. Gastroenterol. 107, 1079-1087. https://doi.org/10.1038/ajg.2012.60
  12. Chang, J.Y., Antonopoulos, D.A., Kalra, A., Tonelli, A., Khalife, W.T., Schmidt, T.M., and Young, V.B. 2008. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J. Infect. Dis. 197, 435-438. https://doi.org/10.1086/525047
  13. Eckburg, P.B., Bik, E.M., Bernstein, C.N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S.R., Nelson, K.E., and Relman, D.A. 2005. Diversity of the human intestinal microbial flora. Science 308, 1635- 1638. https://doi.org/10.1126/science.1110591
  14. Eiseman, B., Silen, W., Bascom, G.S., and Kauvar, A.J. 1958. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 44, 854-859.
  15. Falk, P.G., Hooper, L.V., Midtvedt, T., and Gordon, J.I. 1998. Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology. Microbiol. Mol. Biol. Rev. 62, 1157-1170.
  16. Feltman, R. 2014. Good news: You can take your fecal transplants orally. The Washington Post.
  17. Frankel, W.L., Zhang, W., Singh, A., Klurfeld, D.M., Don, S., Sakata, T., Modlin, I., and Rombeau, J.L. 1994. Mediation of the trophic effects of short-chain fatty acids on the rat jejunum and colon. Gastroenterology 106, 375-380. https://doi.org/10.1016/0016-5085(94)90595-9
  18. Freeman, H.J. 2013. Long-term follow-up of patients with malignant pedunculated colon polyps after colonoscopic polypectomy. Can. J. Gastroenterol. 27, 20-24. https://doi.org/10.1155/2013/380389
  19. George, J.N. 2010. Management of immune thrombocytopenia--something old, something new. The New Engl. J. Med. 363, 1959-1961. https://doi.org/10.1056/NEJMe1009141
  20. Gibson, G.R. 2004. Fibre and effects on probiotics (the prebiotic concept). Clinical Nutrition Supplements 1, 25-31.
  21. Giongo, A., Gano, K.A., Crabb, D.B., Mukherjee, N., Novelo, L.L., Casella, G., Drew, J.C., Ilonen, J., Knip, M., Hyoty, H., and et al. 2011. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5, 82-91. https://doi.org/10.1038/ismej.2010.92
  22. Gough, E., Shaikh, H., and Manges, A.R. 2011. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin. Infect. Dis. 53, 994- 1002. https://doi.org/10.1093/cid/cir632
  23. Guarner, F. and Malagelada, J.R. 2003. Gut flora in health and disease. Lancet 361, 512-519. https://doi.org/10.1016/S0140-6736(03)12489-0
  24. Guo, B., Harstall, C., Louie, T., Veldhuyzen van Zanten, S., and Dieleman, L.A. 2012. Systematic review: faecal transplantation for the treatment of Clostridium difficile-associated disease. Aliment. Pharmacol. Ther. 35, 865-875. https://doi.org/10.1111/j.1365-2036.2012.05033.x
  25. Hamer, H.M., Jonkers, D., Venema, K., Vanhoutvin, S., Troost, F.J., and Brummer, R.J. 2008. Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104-119.
  26. Hapfelmeier, S., Lawson, M.A., Slack, E., Kirundi, J.K., Stoel, M., Heikenwalder, M., Cahenzli, J., Velykoredko, Y., Balmer, M.L., Endt, K., and et al. 2010. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 328, 1705-1709. https://doi.org/10.1126/science.1188454
  27. Haverson, K., Rehakova, Z., Sinkora, J., Sver, L., and Bailey, M. 2007. Immune development in jejunal mucosa after colonization with selected commensal gut bacteria: a study in germ-free pigs. Vet. Immunol. Immunopathol. 119, 243-253. https://doi.org/10.1016/j.vetimm.2007.05.022
  28. Hill, D.A. and Artis, D. 2010. Intestinal bacteria and the regulation of immune cell homeostasis. Annu. Rev. Immunol. 28, 623-667. https://doi.org/10.1146/annurev-immunol-030409-101330
  29. Hooper, L.V. and Gordon, J.I. 2001. Commensal host-bacterial relationships in the gut. Science 292, 1115-1118. https://doi.org/10.1126/science.1058709
  30. Ismail, N.A., Ragab, S.H., ElBaky, A.A., Shoeib, A.R., Alhosary, Y., and Fekry, D. 2010. Frequency of Firmicutes and Bacteroidetes in gut microbiota of obese and normal weight Egyptian children and adults. Arch. Med. Sci. 7, 501-507.
  31. Ivanov, II, Atarashi, K., Manel, N., Brodie, E.L., Shima, T., Karaoz, U., Wei, D., Goldfarb, K.C., Santee, C.A., Lynch, S.V., and et al. 2009. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485-498. https://doi.org/10.1016/j.cell.2009.09.033
  32. Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Schumm, L.P., Sharma, Y., Anderson, C.A., and et al. 2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124. https://doi.org/10.1038/nature11582
  33. Kaplan, K. 2014. Study: Frozen poop pills may make fecal transplants simpler and safer los angeles times, Vol. Oct 11.
  34. Kelly, C.P. and LaMont, J.T. 2008. Clostridium difficile--more difficult than ever. New Engl. J. Med. 359, 1932-1940. https://doi.org/10.1056/NEJMra0707500
  35. Kelly, D., Delday, M.I., and Mulder, I. 2012. Microbes and microbial effector molecules in treatment of inflammatory disorders. Immunol. Rev. 245, 27-44. https://doi.org/10.1111/j.1600-065X.2011.01079.x
  36. Kriegel, M.A., Sefik, E., Hill, J.A., Wu, H.J., Benoist, C., and Mathis, D. 2011. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 108, 11548-11553. https://doi.org/10.1073/pnas.1108924108
  37. Kunde, S., Pham, A., Bonczyk, S., Crumb, T., Duba, M., Conrad, H. Jr., Cloney, D., and Kugathasan, S. 2013. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J. Pediatr. Gastroenterol. Nutr. 56, 597-601. https://doi.org/10.1097/MPG.0b013e318292fa0d
  38. Lawley, T.D., Clare, S., Walker, A.W., Stares, M.D., Connor, T.R., Raisen, C., Goulding, D., Rad, R., Schreiber, F., and Brandt, C. 2012. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoS Pathog. 8, e1002995. https://doi.org/10.1371/journal.ppat.1002995
  39. Lay, C., Rigottier-Gois, L., Holmstrom, K., Rajilic, M., Vaughan, E.E., de Vos, W.M., Collins, M.D., Thiel, R., Namsolleck, P., and Blaut, M. 2005. Colonic microbiota signatures across five northern European countries. Appl. Environ. Microbiol. 71, 4153-4155. https://doi.org/10.1128/AEM.71.7.4153-4155.2005
  40. Ley, R.E., Peterson, D.A., and Gordon, J.I. 2006a. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837-848. https://doi.org/10.1016/j.cell.2006.02.017
  41. Ley, R.E., Turnbaugh, P.J., Klein, S., and Gordon, J.I. 2006b. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022-1023. https://doi.org/10.1038/4441022a
  42. Lo Vecchio, A. and Cohen, M.B. 2014. Fecal microbiota transplantation for Clostridium difficile infection: benefits and barriers. Curr. Opin. Gastroenterol. 30, 47-53. https://doi.org/10.1097/MOG.0000000000000023
  43. Luckey, D., Marietta, E., Luthra, H.S., Patel, R., Murray, J.A., Mangalam, A. and Taneja, V. 2012. Commensal gut-derived bacteria as therapy for systemic autoimmune disease. Arthritis Rheumatism 64, Suppl 10:1636.
  44. Macpherson, A.J. and Harris, N.L. 2004. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4, 478-485. https://doi.org/10.1038/nri1373
  45. Marchesi, J.R. 2010. Prokaryotic and eukaryotic diversity of the human gut. Adv. Appl. Microbiol. 72, 43-62. https://doi.org/10.1016/S0065-2164(10)72002-5
  46. Mariat, D., Firmesse, O., Levenez, F., Guimaraes, V., Sokol, H., Dore, J., Corthier, G., and Furet, J. 2009. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 9, 123. https://doi.org/10.1186/1471-2180-9-123
  47. Mazmanian, S.K., Liu, C.H., Tzianabos, A.O., and Kasper, D.L. 2005. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107-118. https://doi.org/10.1016/j.cell.2005.05.007
  48. McIntosh, J. 2014. FDA struggles to regulate fecal transplants. CBS News/AP/ June 26, 2014, 5:35 PM.
  49. Megerlin, F., Fouassier, E., Lopert, R., and Bourlioux, P. 2014. Faecal microbiota transplantation: A sui generis biological drug, not a tissue. Ann. Pharm. Fr. 72, 217-220. https://doi.org/10.1016/j.pharma.2014.04.008
  50. Ng, K.M., Ferreyra, J.A., Higginbottom, S.K., Lynch, J.B., Kashyap, P.C., Gopinath, S., Naidu, N., Choudhury, B., Weimer, B.C., Monack, D.M., and et al. 2013. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96-99. https://doi.org/10.1038/nature12503
  51. Nistal, E., Caminero, A., Herran, A.R., Arias, L., Vivas, S., de Morales, J.M., Calleja, S., de Miera, L.E., Arroyo, P., and Casqueiro, J. 2012. Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. Inflamm. Bowel Dis. 18, 649-656. https://doi.org/10.1002/ibd.21830
  52. Palmer, C., Bik, E.M., DiGiulio, D.B., Relman, D.A., and Brown, P.O. 2007. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177. https://doi.org/10.1371/journal.pbio.0050177
  53. Prakash, S., Rodes, L., Coussa-Charley, M., and Tomaro-Duchesneau, C. 2011. Gut microbiota: next frontier in understanding human health and development of biotherapeutics. Biologics 5, 71-86.
  54. Rajilic-Stojanovic, M., Biagi, E., Heilig, H.G., Kajander, K., Kekkonen, R.A., Tims, S., and de Vos, W.M. 2011. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 141, 1792-1801. https://doi.org/10.1053/j.gastro.2011.07.043
  55. Reardon, S. 2014. Microbiome therapy gains market traction. Nature 509, 269-270. https://doi.org/10.1038/509269a
  56. Research, C.f.B.E.a. 2013. Guidance for industry: Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies. Food and Drug Administration, 1-4.
  57. Roberfroid, M.B., Bornet, F., Bouley, C., and Cummings, J.H. 1995. Colonic microflora: nutrition and health. Summary and conclusions of an International Life Sciences Institute (ILSI) [Europe] workshop held in Barcelona, Spain. Nutr. Rev. 53, 127-130.
  58. Round, J.L. and Mazmanian, S.K. 2009. The gut microbiota shapes intestinal immune responses during health and disease. Nat. Rev. Immunol. 9, 313-323. https://doi.org/10.1038/nri2515
  59. Saulnier, D.M., Riehle, K., Mistretta, T.A., Diaz, M.A., Mandal, D., Raza, S., Weidler, E.M., Qin, X., Coarfa, C., Milosavljevic, A., and et al. 2011. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology 141, 1782 -1791. https://doi.org/10.1053/j.gastro.2011.06.072
  60. Singh, R., Nieuwdorp, M., Berge, I., Bemelman, F., and Geerlings, S. 2014. The potential beneficial role of faecal microbiota transplantation in diseases other than Clostridium difficile infection. Clin. Microbiol. Infect. doi: 10.1111/1469-0691.12799.
  61. Smith, M.B., Kelly, C., and Alm, E.J. 2014. Policy: How to regulate faecal transplants. Nature 506, 290-291. https://doi.org/10.1038/506290a
  62. Sokol, H., Pigneur, B., Watterlot, L., Lakhdari, O., Bermudez-Humaran, L.G., Gratadoux, J.J., Blugeon, S., Bridonneau, C., Furet, J.P., Corthier, G., and et al. 2008. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl. Acad. Sci. USA 105, 16731-16736. https://doi.org/10.1073/pnas.0804812105
  63. Sprinz, H., Kundel, D.W., Dammin, G.J., Horowitz, R.E., Schneider, H., and Formal, S.B. 1961. The response of the germfree guinea pig to oral bacterial challenge with Escherichia coli and Shigella flexneri. Am. J. Pathol. 39, 681-695.
  64. Stappenbeck, T.S., Hooper, L.V., and Gordon, J.I. 2002. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl. Acad. Sci. USA 99, 15451-15455. https://doi.org/10.1073/pnas.202604299
  65. Sullivan, A., Edlund, C., and Nord, C.E. 2001. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect. Dis. 1, 101-114. https://doi.org/10.1016/S1473-3099(01)00066-4
  66. Surawicz, C.M. and Alexander, J. 2011. Treatment of refractory and recurrent Clostridium difficile infection. Nat. Rev. Gastroenterol. Hepatol. 8, 330-339. https://doi.org/10.1038/nrgastro.2011.59
  67. Taymount. 2010. Probiotics can help behaviour, ADD and Asthma. Taymount FMT Clinic Wednesday, 18 August 1.
  68. Thomas, F., Hehemann, J.H., Rebuffet, E., Czjzek, M., and Michel, G. 2011. Environmental and gut bacteroidetes: the food connection. Front. Microbiol. 30, 93.
  69. Turnbaugh, P.J., Backhed, F., Fulton, L., and Gordon, J.I. 2008. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213-223. https://doi.org/10.1016/j.chom.2008.02.015
  70. van Nood, E., Speelman, P., Kuijper, E.J., and Keller, J.J. 2009. Struggling with recurrent Clostridium difficile infections: is donor faeces the solution? Euro Surveill. 14, pii=19316.
  71. van Nood, E., Speelman, P., Nieuwdorp, M., and Keller, J. 2014. Fecal microbiota transplantation: facts and controversies. Curr. Opin. Gastroenterol. 30, 34-39. https://doi.org/10.1097/MOG.0000000000000024
  72. Vrieze, A., de Groot, P.F., Kootte, R.S., Knaapen, M., van Nood, E., and Nieuwdorp, M. 2013. Fecal transplant: a safe and sustainable clinical therapy for restoring intestinal microbial balance in human disease? Best Pract. Res. Clin. Gastroenterol. 27, 127-137. https://doi.org/10.1016/j.bpg.2013.03.003
  73. Vrieze, A., Van Nood, E., Holleman, F., Salojarvi, J., Kootte, R.S., Bartelsman, J.F., Dallinga-Thie, G.M., Ackermans, M.T., Serlie, M.J., Oozeer, R., and et al. 2012. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913-916. https://doi.org/10.1053/j.gastro.2012.06.031
  74. Walsh, N. 2014. Frozen or Powdered: Fecal Transplant Works in C. Diff. Med Page Today.
  75. Wong, J.M., de Souza, R., Kendall, C.W., Emam, A., and Jenkins, D.J. 2006. Colonic health: fermentation and short chain fatty acids. J. Clin. Gastroenterol. 40, 235-243. https://doi.org/10.1097/00004836-200603000-00015
  76. You, D.M., Franzos, M.A., and Holman, R.P. 2008. Successful treatment of fulminant Clostridium difficile infection with fecal bacteriotherapy. Ann. Intern. Med. 148, 632-633. https://doi.org/10.7326/0003-4819-148-8-200804150-00024
  77. Zoetendal, E.G., Vaughan, E.E., and de Vos, W.M. 2006. A microbial world within us. Mol. Microbiol. 59, 1639-1650. https://doi.org/10.1111/j.1365-2958.2006.05056.x

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