Aşılar ve Mikrobiyota

Yıl 2019, Cilt: 13 Sayı: 4, 310 - 323, 30.07.2019

Melda Çelik Sıddıka Songül Yalçın

https://doi.org/10.12956/tchd.509182

Öz

Aşılama enfeksiyon hastalıkları yükünü azaltan temiz
su erişiminden sonra ikinci en önemli yöntemdir. Aşı etkinliği bireyler
arasında farklılık göstermektedir. Mikrobiyotanın immün sistemin gelişmesinde
birçok role sahip olduğunun gösterilmesi aşı etkinliğinde de rol oynayabileceğini
düşündürmüştür. Bu derlemede, mikrobiyotanın aşı yanıtları üzerine etkileriyle
ilgili yayınları özetlemeyi hedefledik. Bazı çalışmalar, bağırsak
mikrobiyotasının farklı üyelerinin belli immün hücre bölümlerinin gelişimini
düzenleyerek sistemik bir etki yaptığını göstermiştir. Ayrıca yapılan
çalışmaların sonuçları gelişmekte olan ülkelerde aşıların etkinliğinin gelişmiş
ülkelere göre daha az olmasında mikrobiyotanın bozulmasının etkili
olabileceğini düşündürmektedir. Birçok çalışma probiyotiklerin uygulanmasının
ardından serum antikorlarının arttığını göstermekle birlikte, bu yanıtlar
plasebo kontrollerdeki yanıtlardan anlamlı olarak daha yüksek bulunmamıştır.
Bazı probiyotikler bir aşı için özgül etkiler göstermekle birlikte diğer
aşılarda etkisiz olmuştur. İnsanlarda yapılan çalışmalarda prebiyotik
kulanımının aşı etkinliğine etkisi gösterilememiştir. Mikrobiyotanın immün
sistemin gelişimindeki merkezi rolü nedeniyle, mikrobiyotanın aşı etkinliği
üzerinde etkili olması olağandır. Ancak şimdiye kadar az sayıda veri
bulunmaktadır. Burada özetlenen çalışmalar belli ölçüde aşı-mikrobiyota
ilişkisini göstermekle birlikte, bu konuyla ilgili daha fazla çalışmaya ihtiyaç
vardır. 

Anahtar Kelimeler

aşı, immün sistem, mikrobiyota, prebiyotik, probiyotik

Vaccines and Microbiota

Öz

Vaccination is the second
most important method after access to clean water that reduces the burden of
infectious diseases. Vaccine efficacy varies among individuals. The fact that
microbiota has many roles in the development of the immune system has suggested
that it may play a role in vaccine efficacy. In this review, we aimed to summarize
publications about the effects of microbiota on vaccine responses. Some studies
have shown that different members of the gut microbiota have a systemic effect
by regulating the development of certain immune cell segments. In addition, the
results of the studies suggest that microbiota deterioration may be effective on
the lower efficacy of vaccines in developing countries than developed
countries. Although many studies showed that serum antibodies increased after
the application of probiotics, these responses were not significantly higher
than the placebo controls. Some probiotics show specific effects for a vaccine
but have been ineffective for others. In human studies, the effect of prebiotic
use on vaccine efficacy has not been demonstrated. Due to the central role of
microbiota in the development of the immune system, it is common for the
microbiota to have an impact on the efficacy of the vaccine. However, there are
few data to date. Although the studies summarized here indicate a certain
degree of vaccine-microbiota relationship, further studies are needed.

Anahtar Kelimeler

immune system, microbiota, prebiotic, probiotic

Kaynakça

• 1. Andre, F. E., Booy, R., Bock, H. L., Clemens, J., Datta, S. K., John, T. J., Lee, B. W., Lolekha, S., Peltola, H., Ruff, T. A., Santosham, M., Schmitt, H. J. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bull.World Health Organ. 2008; 86, 140–146.
• 2. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14691-6.
• 3. Jamieson, A. M. Influence of the microbiome on response to vaccination. Hum. Vaccin. Immunother. 2015; 11, 2329–2331.
• 4. Nguyen, Q. N., Himes, J. E., Martinez, D. R., Permar, S. R. The impact of the gut microbiota on humoral immunity to pathogens and vaccination in early infancy. PLoS Pathog. 2016; 12.
• 5. Bäckhed, F., Roswall, J., Peng, Y., Feng,Q., Jia, H., Kovatcheva-Datchary, P., Li, Y., Xia, Y., Xie, H., Zhong, H., Khan, M. T., Zhang, J., Li, J., Xiao, L., Al-Aama, J., Zhang, D., Lee, Y. S., Kotowska, D., Colding, C., Tremaroli, V., Yin, Y., Bergman, S., Xu, X., Madsen, L., Kristiansen, K., Dahlgren, J.,Wang, J. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 2015; 17, 852.
• 6. Madan, J. C., Hoen, A. G., Lundgren, S. N., Farzan, S. F., Cottingham,K. L., Morrison, H. G., Sogin, M. L., Li, H., Moore, J. H., Karagas, M. R. Association of cesarean delivery and formula supplementationwith the intestinal microbiome of 6-week-old infants. JAMA Pediatr.2016; 170, 212–219.
• 7. Fouhy, F., Ross, R. P., Fitzgerald, G. F., Stanton, C., Cotter, P. D. Composition of the early intestinalmicrobiota: knowledge, knowledge gaps and the use of high-throughput sequencing to address these gaps.Gut Microbes 2012; 3, 203–220.
• 8. Vangay, P., Ward, T., Gerber, J. S., Knights, D. Antibiotics, pediatricdysbiosis, and disease. Cell Host Microbe 2015; 17, 553–564.
• 9. Doan, T., Arzika, A. M., Ray, K. J., Cotter, S. Y., Kim, J., Maliki, R., Zhong,L., Zhou, Z., Porco, T. C., Vanderschelden, B., Keenan, J. D., Lietman,T. M.Gut microbial diversity in antibiotic-naive children after systemic antibiotic exposure: a randomized controlled trial. Clin. Infect. Dis. 2017;64, 1147–1153.
• 10. Azad, M. B.,Konya, T., Persaud, R. R.,Guttman,D. S.,Chari,R. S., Field, C. J., Sears, M. R., Mandhane, P. J., Turvey, S. E., Subbarao, P., Becker, A. B.,Scott, J. A., Kozyrskyj, A. L.; CHILD Study Investigators. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study. BJOG. ,2015;123, 983–993.
• 11. Bäckhed, F., Roswall, J., Peng, Y., Feng,Q., Jia, H., Kovatcheva-Datchary,P., Li, Y., Xia, Y., Xie, H., Zhong, H., Khan, M. T., Zhang, J., Li, J., Xiao, L.,Al-Aama, J., Zhang, D., Lee, Y. S., Kotowska, D., Colding, C., Tremaroli,V., Yin, Y., Bergman, S., Xu, X., Madsen, L., Kristiansen, K., Dahlgren, J.,Wang, J. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 2015; 17, 852.
• 12. Kuppala, V. S., Meinzen-Derr, J., Morrow, A. L., Schibler, K. R. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J. Pediatr.2011; 159, 720–725.
• 13. Honda, K., Littman, D. R. (2016) The microbiota in adaptive immune homeostasis and disease. Nature 2011; 535, 75–84.
• 14. Schirmer, M., Smeekens, S. P., Vlamakis, H., Jaeger, M., Oosting, M., Franzosa, E. A., ter Horst, R., Jansen, T., Jacobs, L., Bonder, M. J., Kurilshikov, A., Fu, J., Joosten, L. A., Zhernakova, A., Huttenhower, C., Wijmenga,C., Netea, M. G., Xavier, R. J. Linking the human gutmicrobiome to inflammatory cytokine production capacity. Cell 2016; 167,1897.
• 15. Quigley EM. Basic Definitions and Concepts: Organization of the Gut Microbiome. Gastroenterol Clin North Am. 2017 Mar;46(1):1-8. doi: 10.1016/j.gtc.2016.09.002. Epub 2017 Jan 3. Review.
• 16. Hansen CH, Nielsen DS, Kverka M, Zakostelska Z, Klimesova K, Hudcovic T, Tlaskalova-Hogenova H, Hansen AK. Patterns of early gut colonization shape future immune responses of the host. PLoS One. 2012;7(3):e34043.
• 17. Slack E, Hapfelmeier S, Stecher B, Velykoredko Y, Stoel M, Lawson MA, Geuking MB, Beutler B, Tedder TF, Hardt WD, Bercik P, Verdu EF, McCoy KD, Macpherson AJ. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science. 2009 Jul 31;325(5940):617-20.
• 18. Couturier-Maillard A, Secher T, Rehman A, Normand S, De Arcangelis A, Haesler R, Huot L, Grandjean T, Bressenot A, Delanoye-Crespin A, Gaillot O, Schreiber S, Lemoine Y, Ryffel B, Hot D, Nùñez G, Chen G, Rosenstiel P, Chamaillard M.NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest. 2013 Feb;123(2):700-11.
• 19. Macpherson AJ, Geuking MB, Slack E, Hapfelmeier S, McCoy KD. The habitat,double life, citizenship, and forgetfulness of IgA. Immunol Rev. 2012 Jan;245(1):132-46.
• 20. Zimmermann P, Curtis N. The influence of the intestinal microbiome on vaccine responses. Vaccine. 2018 Jul 16;36(30):4433-4439. doi:10.1016/j.vaccine.2018.04.066. Epub 2018 Jun 13. Review.
• 21. Eloe-Fadrosh EA, McArthur MA, Seekatz AM, Drabek EF, Rasko DA, Sztein MB, Fraser CM. Impact of oral typhoid vaccination on the human gut microbiota and correlations with s. Typhi-specific immunological responses. PLoS One. 2013 Apr 24;8(4):e62026.
• 22. Seekatz AM, Panda A, Rasko DA, Toapanta FR, Eloe-Fadrosh EA, Khan AQ, Liu Z, Shipley ST, Detolla LJ, Sztein MB, Fraser CM. Differential response of the cynomolgus macaque gut microbiota to Shigella infection. PLoS One. 2013 Jun 5;8(6):e64212.
• 23. Hallander HO, Paniagua M, Espinoza F, Askelöf P, Corrales E, Ringman M, Storsaeter J. Calibrated serological techniques demonstrate significant different serum response rates to an oral killed cholera vaccine between Swedish and Nicaraguan children. Vaccine. 2002 Nov 22;21(1-2):138-45.
• 24. Levine MM. Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine. BMC Biol. 2010 Oct 4;8:129. doi: 10.1186/1741-7007-8-129. Review.
• 25. Jiang V, Jiang B, Tate J, Parashar UD, Patel MM. Performance of rotavirus vaccines in developed and developing countries. Hum Vaccin. 2010 Jul;6(7):532-42.Review.
• 26. Lopman BA, Pitzer VE, Sarkar R, Gladstone B, Patel M, Glasser J, Gambhir M, Atchison C, Grenfell BT, Edmunds WJ, Kang G, Parashar UD. Understanding reduced rotavirus vaccine efficacy in low socio-economic settings. PLoS One.2012;7(8):e41720.
• 27. Grassly NC, Jafari H, Bahl S, Durrani S, Wenger J, Sutter RW, Aylward RB.Mucosal immunity after vaccination with monovalent and trivalent oral poliovirus vaccine in India. J Infect Dis. 2009 Sep 1;200(5):794-801.
• 28. Korpe PS, Petri WA Jr. Environmental enteropathy: critical implications of a poorly understood condition. Trends Mol Med. 2012 Jun;18(6):328-36.
• 29. Ghoshal UC, Ghoshal U, Ayyagari A, Ranjan P, Krishnani N, Misra A, Aggarwal R, Naik S, Naik SR. Tropical sprue is associated with contamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time. J Gastroenterol Hepatol. 2003 May;18(5):540-7.
• 30. Reikie BA, Adams RC, Ruck CE, Ho K, Leligdowicz A, Pillay S, Naidoo S, Fortuno ES 3rd, de Beer C, Preiser W, Cotton MF, Speert DP, Esser M, Kollmann TR. Ontogeny of Toll-like receptor mediated cytokine responses of South African infants throughout the first year of life. PLoS One. 2012;7(9):e44763. doi: 10.1371/journal.pone.0044763. Epub 2012 Sep 13.
• 31. Humphrey JH. Child undernutrition, tropical enteropathy, toilets, and handwashing. Lancet. 2009 Sep 19;374(9694):1032-5. doi: 10.1016/S0140-6736(09)60950-8. Review.
• 32. Moon SS et al. Prevaccination rotavirus serum IgG and IgA are associated with lower immunogenicity of live, oral human rotavirus vaccine in South African infants. Clin Infect Dis 2016;62(2):157–65.
• 33. Chilengi R et al. Association of maternal immunity with rotavirus vaccine immunogenicity in Zambian infants. PLoS One 2016;11(3):e0150100.
• 34. Huda MN, Lewis Z, Kalanetra KM, Rashid M, Ahmad SM, Raqib R, Qadri F, Underwood MA, Mills DA, Stephensen CB. Stool microbiota and vaccine responses of infants. Pediatrics. 2014 Aug;134(2):e362-72. doi: 10.1542/peds.2013-3937. Epub2014 Jul 7.
• 35. Harris VC et al. The infant gut microbiome correlates significantly with rotavirus vaccine response in rural Ghana. J Infect Dis 2016.
• 36. Mullie C et al. Increased poliovirus-specific intestinal antibody response coincides with promotion of Bifidobacterium longum-infantis and Bifidobacterium breve in infants: a randomized, double-blind, placebocontrolled trial. Pediatr Res 2004;56(5):791–5.
• 37. Nemes E, Lefler E, Szegedi L, Kapitány A, Kovács JB, Balogh M, Szabados K, Tumpek J, Sipka S, Korponay-Szabó IR. Gluten intake interferes with the humoral immune response to recombinant hepatitis B vaccine in patients with celiac disease. Pediatrics. 2008 Jun;121(6):e1570-6.
• 38. Dorrestein, P. C.,Mazmanian, S. K., Knight, R. (2014) Finding the missing links among metabolites,microbes, and the host. Immunity 40, 824–832.
• 39. Rooks, M. G., Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 2016; 16, 341–352.
• 40. Kim, M., Qie, Y., Park, J., Kim, C. H. Gut microbial metabolites fuel host antibody responses. Cell Host Microbe 2016; 20, 202–214.
• 41. Kim, M., Kim, C. H. Regulation of humoral immunity by gut microbial products. Gut Microbes; 2017 [E-Pub ahead of print] 10.1080/19490976.2017.129931.
• 42. Oh JZ, Ravindran R, Chassaing B, Carvalho FA, Maddur MS, Bower M, Hakimpour P, Gill KP, Nakaya HI, Yarovinsky F, Sartor RB, Gewirtz AT, Pulendran B. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity. 2014 Sep 18;41(3):478-92.
• 43. Woo,P. C., Tsoi, H.W.,Wong, L.P., Leung, H.C.,Yuen,K.Y. Antibiotics modulate vaccine-induced humoral immune response. Clin.Diagn.Lab. Immunol.1999; 6, 832–837.
• 44. Lamousé-Smith, E. S., Tzeng, A., Starnbach, M. N. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ free mice. PLoS One 2011; 6, e27662.
• 45. Uchiyama, R., Chassaing, B., Zhang, B., Gewirtz, A. T. Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity. J. Infect. Dis. 2014;210, 171–182.
• 46. Biesbroek G, Bosch AA, Wang X, Keijser BJ, Veenhoven RH, Sanders EA, Bogaert D. The impact of breastfeeding on nasopharyngeal microbial communities in infants. Am J Respir Crit Care Med. 2014 Aug 1;190(3):298-308.
• 47. García-López R, Pérez-Brocal V, Diez-Domingo J, Moya A. Gut microbiota in children vaccinated with rotavirus vaccine. Pediatr Infect Dis J. 2012 Dec;31(12):1300-2.
• 48. Ang L, Arboleya S, Lihua G, Chuihui Y, Nan Q, Suarez M, Solís G, de los Reyes-Gavilán CG, Gueimonde M. The establishment of the infant intestinal microbiome is not affected by rotavirus vaccination. Sci Rep. 2014 Dec 10;4:7417.
• 49. Chen SY, Tsai CN, Lee YS, Lin CY, Huang KY, Chao HC, Lai MW, Chiu CH. Intestinal microbiome in children with severe and complicated acute viral gastroenteritis. Sci Rep. 2017 Apr 11;7:46130.
• 50. Biavati B et al. Species of the Bifidobacterium in the feces of infants. Microbiologica 1984;7(4):341–5.
• 51. Harmsen HJ et al. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J Pediatr Gastroenterol Nutr 2000;30(1):61–7.
• 52. Pabst HF, Spady DW. Effect of breast-feeding on antibody response to conjugate vaccine. Lancet 1990;336(8710):269–70.
• 53. Hahn-Zoric M et al. Antibody responses to parenteral and oral vaccines are impaired by conventional and low protein formulas as compared to breastfeeding. Acta Paediatr Scand 1990;79(12):1137–42.
• 54. Guaraldi F, Salvatori G. Effect of breast and formula feeding on gut microbiota shaping in newborns. Front Cell Infect Microbiol. 2012 Oct 16;2:94.
• 55. Jost T, Lacroix C, Braegger CP, Chassard C. New insights in gut microbiota establishment in healthy breast fed neonates. PLoS One. 2012;7(8):e44595.
• 56. Glass RI, Ing DJ, Stoll BJ, Ing RT. Immune response to rotavirus vaccines among breast-fed and nonbreast-fed children. Adv Exp Med Biol 1991;310:249–54.
• 57. Rennels MB. Influence of breast-feeding and oral poliovirus vaccine on the immunogenicity and efficacy of rotavirus vaccines. J Infect Dis. 1996 Sep;174 Suppl 1:S107-11. Review.
• 58. Vesikari T, Prymula R, Schuster V, Tejedor JC, Cohen R, Bouckenooghe A et al. Efficacy and immunogenicity of live-attenuated human rotavirus vaccine in breast-fed and formula-fed European infants. Pediatr Infect Dis J 2012;31:509–13.
• 59. Brüssow H, Benitez O, Uribe F, Sidoti J, Rosa K, Cravioto A. Rotavirus-inhibitory activity in serial milk samples from Mexican women and rotavirus infections in their children during their first year of life. J Clin Microbiol 1993;31:593–7.
• 60. Rennels MB, Wasserman SS, Glass RI, Keane VA; US Rotavirus Vaccine Efficacy Group. Comparison of immunogenicity and efficacy of rhesus rotavirus reassortant vaccines in breastfed and nonbreastfed children. Pediatrics 1995;96:1132–6. PMID:7491235
• 61. Moon SS, Tate JE, Ray P, Dennehy PH, Archary D, Coutsoudis A et al. Differential profiles and inhibitory effect on rotavirus vaccines of nonantibody components in breast milk from mothers in developing and developed countries. Pediatr Infect Dis J 2013;32:863–70.
• 62. Groome MJ, Moon SS, Velasquez D, Jones S, Koen A, van Niekerk N, Jiang B, Parashar UD, Madhi SA. Effect of breastfeeding on immunogenicity of oral live-attenuated human rotavirus vaccine: a randomized trial in HIV-uninfected infants in Soweto, South Africa. Bull World Health Organ. 2014 Apr.
• 63. John TJ, Devarajan LV, Luther L, Vijayarathnam P. Effect of breast-feeding on seroresponse of infants to oral poliovirus vaccination. Pediatrics. 1976 Jan;57(1):47-53.
• 64. Davidson LE, Fiorino AM, Snydman DR, Hibberd PL. Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial. Eur J Clin Nutr. 2011 Apr;65(4):501-7.
• 65. Paineau D, Carcano D, Leyer G, Darquy S, Alyanakian MA, Simoneau G, Bergmann JF, Brassart D, Bornet F, Ouwehand AC. Effects of seven potential probiotic strains on specific immune responses in healthy adults: a double-blind, randomized, controlled trial. FEMS Immunol Med Microbiol. 2008 Jun;53(1):107-13.
• 66. Rizzardini G, Eskesen D, Calder PC, Capetti A, Jespersen L, Clerici M. Evaluation of the immune benefits of two probiotic strains Bifidobacterium animalis ssp. lactis, BB-12® and Lactobacillus paracasei ssp. paracasei, L. casei 431® in an influenza vaccination model: a randomised, double-blind, placebo-controlled study. Br J Nutr. 2012 Mar;107(6):876-84.
• 67. Kukkonen K, Nieminen T, Poussa T, Savilahti E, Kuitunen M. Effect of probiotics on vaccine antibody responses in infancy--a randomized placebo-controlled double-blind trial. Pediatr Allergy Immunol. 2006 Sep;17(6):416-21.
• 68. Matsuda F, Chowdhury MI, Saha A, Asahara T, Nomoto K, Tarique AA, Ahmed T, Nishibuchi M, Cravioto A, Qadri F. Evaluation of a probiotics, Bifidobacterium breve BBG-01, for enhancement of immunogenicity of an oral inactivated cholera vaccine and safety: a randomized, double-blind, placebo-controlled trial in Bangladeshi children under 5 years of age. Vaccine. 2011 Feb 24;29(10):1855-8.
• 69. West NP, Cripps AW. Are vaccination models suitable to determine whether probiotics have beneficial health effects in the general population? Hum Vaccin Immunother. 2013 Mar;9(3):621-4. Epub 2013 Jan 4. Review.
• 70. Youngster I, Kozer E, Lazarovitch Z, Broide E, Goldman M. Probiotics and the immunological response to infant vaccinations: a prospective, placebo controlled pilot study. Arch Dis Child. 2011 Apr;96(4):345-9.
• 71. Chattha KS, Vlasova AN, Kandasamy S, Rajashekara G, Saif LJ. Divergent immunomodulating effects of probiotics on T cell responses to oral attenuated human rotavirus vaccine and virulent human rotavirus infection in a neonatal gnotobiotic piglet disease model. J Immunol. 2013 Sep 1;191(5):2446-56.
• 72. Chattha KS, Vlasova AN, Kandasamy S, Esseili MA, Siegismund C, Rajashekara G, Saif LJ. Probiotics and colostrum/milk differentially affect neonatal humoral immune responses to oral rotavirus vaccine. Vaccine. 2013 Apr 8;31(15):1916-23.
• 73. Zimmermann P, Curtis N. The influence of probiotics on vaccine responses – A systematic review. Vaccine. 2018 Jan 4;36(2):207-213.
• 74. Benyacoub J, Rochat F, Saudan KY, Rochat I, Antille N, Cherbut C, von der Weid T, Schiffrin EJ, Blum S. Feeding a diet containing a fructooligosaccharide mix can enhance Salmonella vaccine efficacy in mice. J Nutr. 2008 Jan;138(1):123-9.
• 75. Vos AP, Knol J, Stahl B, M'rabet L, Garssen J. Specific prebiotic oligosaccharides modulate the early phase of a murine vaccination response. IntImmunopharmacol. 2010 May;10(5):619-25.
• 76. Stam J, van Stuijvenberg M, Garssen J, Knipping K, Sauer PJ. A mixture of three prebiotics does not affect vaccine specific antibody responses in healthy term infants in the first year of life. Vaccine. 2011 Oct 13;29(44):7766-72.
• 77. Duggan C, Penny ME, Hibberd P, Gil A, Huapaya A, Cooper A, Coletta F, Emenhiser C, Kleinman RE. Oligofructose-supplemented infant cereal: 2 randomized, blinded, community-based trials in Peruvian infants. Am J Clin Nutr. 2003 Apr;77(4):937-42.
• 78. van den Berg JP, Westerbeek EA, van der Klis FR, Berbers GA, Lafeber HN, van Elburg RM. Neutral and acidic oligosaccharides supplementation does not increase the vaccine antibody response in preterm infants in a randomized clinical trial. PLoS One. 2013 Aug 8;8(8):e70904.
• 79. Enani S, Przemska-Kosicka A, Childs CE, Maidens C, Dong H, Conterno L, Tuohy K, Todd S, Gosney M, Yaqoob P. Impact of ageing and a synbiotic on the immune response to seasonal influenza vaccination; a randomised controlled trial. Clin Nutr. 2017 Jan 28.
• 80. Licciardi PV, Tang ML. Vaccine adjuvant properties of probiotic bacteria. Discov Med. 2011 Dec;12(67):525-33. Review.
• 81. Pabst,O.,Hornef, M. Gutmicrobiota: a natural adjuvant for vaccination. Immunity 2014; 41, 349–351.
• 82. Kasturi, S. P., Skountzou, I., Albrecht, R. A., Koutsonanos, D., Hua, T., Nakaya, H. I., Ravindran, R., Stewart, S., Alam, M., Kwissa, M., Villinger, F., Murthy, N., Steel, J., Jacob, J., Hogan, R. J., García-Sastre, A., Compans,R., Pulendran, B.Programming themagnitude and persistence of antibody responses with innate immunity. Nature 2011; 470, 543–547.
• 83. Kim, D., Kim, Y. G., Seo, S. U., Kim, D. J., Kamada, N., Prescott, D.,Philpott, D. J., Rosenstiel, P., Inohara, N., Núñez, G. (2016) Nod2- mediated recognition of the microbiota is critical formucosal adjuvantactivity of cholera toxin. Nat. Med. 22, 524–530.
• 84. Chow, J. C., Young, D. W., Golenbock, D. T., Christ, W. J., Gusovsky, F.Toll-like receptor-4 mediates lipopolysaccharide-induced signaltransduction. J. Biol. Chem. 1999; 274, 10689–10692.
• 85. Vatanen, T., Kostic, A. D., d’Hennezel, E., Siljander, H., Franzosa, E. A., Yassour, M., Kolde, R., Vlamakis, H., Arthur, T. D., Hämäläinen, A. M.,Peet, A., Tillmann, V., Uibo, R., Mokurov, S., Dorshakova, N., Ilonen, J.,Virtanen, S. M., Szabo, S. J., Porter, J. A., Lähdesmäki, H., Huttenhower,C., Gevers, D., Cullen, T. W., Knip, M., DIABIMMUNE Study Group,Xavier, R. J. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 2016; 165, 842–853.
• 86. Pulendran, B., Kumar, P., Cutler, C.W., Mohamadzadeh, M., Van Dyke,T., Banchereau, J. Lipopolysaccharides from distinct pathogens induce different classes of immune responses in vivo. J. Immunol. 2001; 167,5067–5076.
• 87. Zeng,M.Y., Inohara,N., Nuñez, G. Mechanisms of inflammationdriven bacterial dysbiosis in the gut. Mucosal Immunol. 2017; 10, 18–26.
• 88. Fei, N., Zhao, L. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. ISME J. 2013; 7, 880–884.
• 89. Tulstrup, M. V., Christensen, E. G., Carvalho, V., Linninge, C., Ahrné, S.,Højberg, O., Licht, T. R., Bahl, M. I. Antibiotic treatment affectsintestinal permeability and gut microbial composition in Wistar rats dependent on antibiotic class. PLoS One 2015; 10, e0144854.
• 90. Brenchley, J. M.,Douek,D. C.Microbial translocation across the GI tract. Annu. Rev. Immunol. 2012; 30, 149–173.
• 91. Brenchley, J. M., Price, D. A., Schacker, T. W., Asher, T. E., Silvestri, G.,Rao, S., Kazzaz, Z., Bornstein, E., Lambotte, O., Altmann, D., Blazar, B.R., Rodriguez, B., Teixeira-Johnson, L., Landay, A., Martin, J. N., Hecht, F. M., Picker, L. J., Lederman, M. M., Deeks, S. G., Douek, D. C.Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 2006; 12, 1365–1371.
• 92. Cooke, K. R.,Olkiewicz, K., Erickson, N., Ferrara, J. L. The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. J. Endotoxin Res. 2002; 8, 441–448.
• 93. Caradonna, L., Amati, L., Magrone, T., Pellegrino, N. M., Jirillo, E., Caccavo, D. Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance.J. Endotoxin Res. 2000; 6, 205–214.
• 94. Zeng, M. Y., Cisalpino, D., Varadarajan, S., Hellman, J., Warren, H. S.,Cascalho, M., Inohara, N., Núñez, G. Gut microbiota-induced immunoglobulin G controls systemic infection by symbiotic bacteria and pathogens. Immunity 2016; 44, 647–658.
• 95. Kim YG. Microbiota Influences Vaccine and Mucosal Adjuvant Efficacy. Immune Netw. 2017 Feb;17(1):20-24. doi: 10.4110/in.2017.17.1.20. Epub 2017 Feb 23.Review.