РОЛЬ КИШЕЧНОГО МИКРОБИОМА В РАЗВИТИИ ВИЧ/СПИД-ИНФЕКЦИИ

DOI: https://doi.org/10.29296/24999490-2019-05-02

Т.И. Хомякова(1), кандидат медицинских наук, Г.В. Козловская(1), А.Д. Магомедова(1), Н.Ф. Чертович(1), Ю.Е. Козловский(1), кандидат биологических наук, Ю.Г. Пархоменко(1, 2), доктор медицинских наук, профессор, Ю.Н. Хомяков(3), доктор биологических наук, кандидат медицинских наук 1-ФГБУН «НИИ морфологии человека», Российская Федерация, 117418, Москва, ул. Цюрупы, д. 3; 2-ГБУЗ «Инфекционная клиническая больница № 2» Департамента здравоохранения г. Москвы, Российская Федерация, 105275, Москва, 8-я ул. Соколиной горы, д. 15; 3-ФКУЗ «Противочумный центр» Роспотребнадзора, Российская Федерация, 127490, Москва, ул. Мусоргского, 4 E-mail: tatkhom@yandex.ru

Синдром приобретенного иммунодефицита (СПИД) – конечная стадия развития заболевания, вызванного вирусом иммунодефицита человека (ВИЧ). В отсутствие антиретровирусной терапии между заражением и смертью больного может пройти 10 лет, при этом на продолжительность и тяжесть течения заболевания влияет ряд факторов. В последние годы доказано, что важнейшим фактором, который оказывает воздействие на иммунную активацию, процессы воспаления и развитие сопутствующих заболеваний, является микробиом толстой кишки человека. Целью данного обзора было обобщение данных, полученных при изучении роли сдвигов микробиома в развитии воспаления, иммунной активации и осложнений ВИЧ-инфекции. Приводятся также данные собственных исследований, подтверждающих эндогенный путь летального инфицирования Klebsiella pneumoniaе больных СПИД путем транслокации из толстой кишки.
Ключевые слова: 
воспаление

Список литературы: 
  1. University College London. «HIV remission achieved in second patient». ScienceDaily. ScienceDaily, 5 March 2019. <www.sciencedaily.com/releases/2019/03/190305153644.htm>.
  2. Li Z., David W., Purcell, J.D., Sansom S.L., Hayes D., H. Hall I. Vital signs: HIV transmission along the continuum of care-United States, 2016// MMWR Morb Mortal Wkly Rep.2019;doi:10.15585/mmwr.mm6811e1
  3. UNAIDS. Global AIDS update 2016. 2016. http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update2016_en.pdf.]
  4. Grant M., Larijani M. Evasion of adaptive immunity by HIV through the action of host APOBEC3G/F enzymes.// AIDS Res Ther. 2017; 14 (1): 44. https://doi.org/10.1186/s12981-017-0173-8.
  5. Romani B., Allahbakhshi E. Underlying mechanisms of HIV-1 latency. Virus Genes. 2017; 53 (3): 329–39. https://doi.org/10.1007/s11262-017-1443-1. Epub 2017 Mar 3.
  6. Promer K., Karris M.Y. Current Treatment Options for HIV Elite Controllers: a Review. Curr. Treat Options Infect. Dis. 2018; 10 (2): 302–9. https://doi.org/10.1007/s40506-018-0158-8. Epub 2018 Apr 16.
  7. Бартлетт Дж., Галлант Дж., Фам П. Клинические аспекты ВИЧ-инфекции. 2009–2010. М.: Р. Валент, 2010; 490. ISBN 978-5-93439-298-8.
  8. [Bartlett Dzh., Gallant Dzh., Fam P. Klinicheskie aspekty VICH-infekcii. 2009–2010. M.: R. Valent, 2010; 490. ISBN 978-5-93439-298-8 (in Russian)]
  9. Шмагель К.В., Шмагель Н.Г., Черешнев В.А. Активация иммунитета при ВИЧ-инфекции. Медицинская иммунология. 2017; 19 (5): 489–504.
  10. [Shmagel’ K.V., Shmagel’ N.G., Chereshnev V.A. Aktivaciya immuniteta pri VICH-infekcii. Medicinskaya immunologiya. 2017; 19 (5): 489–504 (in Russian)]
  11. Stecher B. The roles of inflammation, nutrient availability and the commensalmicrobiota in enteric pathogen infection. Microbiol Spectr. 2015; 3 (3). https://doi.org/10.1128/microbiolspec.MBP-0008-2014.
  12. Tincati C., Douek D.C. , Marchetti G. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection//AIDS Res Ther. 2016. 13: 19. https://doi.org/10.1186/s12981-016-0103-1
  13. 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: 1365–71. https://doi.org/10.1038/nm1511
  14. Brenchley J.M., Douek D.C. HIV infection and the gastrointestinal immune system. Mucosal. Immunol. 2008; 1: 23–30.
  15. Kamat A., Ancuta P., Blumberg R.S., Gabuzda D. Serological markers for inflammatory bowel disease in AIDS patients with evidence of microbial translocation. PloS ONE. 2010; 5 (11): e15533. https://doi.org/10.1371/journal.pone.0015533.
  16. Epple H.J., Schneider T., Troeger H., Kunkel D., Allers K., Moos V., Amasheh M., Loddenkemper C., Fromm M., Zeitz M., Schulzke J.D. Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients. Gut. 2009; 58: 220–7. https://doi.org/10.1136/gut.2008.150425. Epub 2008 Oct 20.
  17. Wang H., Kotler D.P. HIV enteropathy and aging: gastrointestinal immunity, mucosal epithelial barrier, and microbial translocation. Curr. Opin. HIV AIDS. 2014; 9 (4): 309–16. https://doi.org/10.1097/COH.0000000000000066.
  18. Sakai E., Higurashi T., Ohkubo H., Hosono K., Ueda A., Matsuhashi N., Nakajima A. Investigation of small bowel abnormalities in HIV-infected patients using capsule endoscopy. Gastroenterology Res Pract. 2017; 1932647. https://doi.org/10.1155/2017/1932647
  19. Nazli A., Chan O., Dobson-Belaire W.N., Ouellet M., Tremblay M.J., Gray-Owen S.D., Arsenault A.L., Kaushic C. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PloS Pathogens, 2010; 6: e1000852. https://doi.org/10.1371/journal.ppat.1000852
  20. Bode H., Lenzner L., Kraemer O.H., Kroesen A.J., Bendfeldt K., Schulzke J.D., Fromm M., Stoltenburg-Didinger G., Zeitz M., Ullrich R. The HIV protease inhibitors saquinavir, ritonavir, and nelfinavir induce apoptosis and decrease barrier function in human intestinal epithelial cells. Antivir Ther. 2005; 10 (5): 645–55.
  21. Pitrak D.L., Novak R.M., Estes R., Tschampa J., Abaya C.D., Martinson J., Bradley K., Tenorio A.R., Landay A.L. Short сommunication: Apoptosis pathways in HIV-1-infected patients before and after highly active antiretroviral therapy: relevance to immune recovery. AIDS Res Hum Retroviruses. 2015; 31 (2): 208–16. https://doi.org/10.1089/aid.2014.0038
  22. Somsouk M., Estes J.D., Deleage C., Dunham R.M., Albright R., Inadomi J.M., Martin J.N., Deeks S.G., McCune J.M., Hunt P.W. Gut epithelial barrier and systemic inflammation during chronic HIV infection. AIDS. 2015; 29 (1): 43–51. https://doi.org/10.1097/QAD.0000000000000511
  23. Abad-Fernández M., Vallejo A., Hernández-Novoa B., Diaz L., Gutiérrez C., Madrid N., Muñoz M.A., Moreno S. Correlation between different methods to measure microbial translocation and its association with immune activation in long-term suppressed HIV-1-infected individuals. J. Acquir Immune Defic Syndr. 2013; 64 (2): 149–53. https://doi.org/10.1097/QAI.0b013e31829a2f12.
  24. Estes J.D., Harris L.D., Klatt N.R., Tabb B., Pittaluga S., Paiardini M., Barclay G.R., Smedley J., Pung R., Oliveira K.M., Hirsch V.M., Silvestri G., Douek D.C., Miller C.J., Haase A.T., Lifson J., Brenchley J.M. Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PloS Pathog. 2010; 6: e1001052. https://doi.org/10.1371/journal.ppat.1001052.
  25. Marchetti G., Bellistri G.M., Borghi E., Tincati C., Ferramosca S., La Francesca M., Morace G., Gori A., Monforte A.D. Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS. 2008; 22 (15): 2035–8 https://doi.org/10.1097/QAD.0b013e3283112d29
  26. Vesterbacka J. The role of microbial translocation and gut microbiota in HIV-1 infection. Thesis The Division Of Infectious Diseases, Department Of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. September 2017. https://www.researchgate.net/publication/320166500
  27. Хасанова Г.Р., Биккинина О.И., Анохин В.А. Халиуллина C.В., Яковлев М.Ю. Кишечный эндотоксин как вероятный индуктор системного воспалительного ответа при ВИЧ-инфекции. Практическая медицина. 2012; 1 (56): 52–5.
  28. [Hasanova G.R., Bikkinina O.I., Anohin V.A. Haliullina C.V., YAkovlev M.YU. Intestinal endotoxin as a likely inducer of systemic inflammatory response in HIV infection. Prakticheskaya medicina. 2012; 1 (56): 52–5 (in Russian)]
  29. Kistler J.O., Arirachakaran P., Poovorawan Y., Dahlén G.,Wade W.G. The oral microbiome in human immunodeficiency virus (HIV)-positive individuals. J. Med. Microbiol. 2015; 64 (9): 1094–101.
  30. Berard A.R., Perner M., Mutch S., Farr Zuend C., McQueen P., Burgener A.D. Understanding mucosal and microbial functionality of the female reproductive tract by metaproteomics: Implications for HIV transmission. Amer J. Repr. Immunol. 2018; 80 (2): 12977 https://doi.org/10.1111/aji.12977
  31. Twigg H.L. 3rd, Weinstock G.M., Knox K.S. Lung microbiome in human immunodeficiency virus infection. Transl Res. 2017; 179: 97–107. https://doi.org/10.1016/j.trsl.2016.07.008. Epub 2016 Jul 18.
  32. Mamoudou S., Bellaud G., Ana C., Gilles P. Lung co-infection by Pneumocystis jirovecii and Pseudomonas aeruginosa in AIDS: report of two cases. Pan. Afr. Med. J. 2015; 21: 95. https://doi.org/10.11604/pamj.2015.21.95.5993. eCollection 2015.
  33. Salins N., Vallath N., Prince V.V. Pseudomonas Bronchopulmonary Infections in a Palliative Care Setting. Indian J. Palliat Care. 2012; 18 (1): 1–5 https://doi.org/10.4103/0973-1075.97341
  34. Barantsevich N.E., Orlova O.E., Shlyakhto E.V., Johnson E.M., Woodford N., Lass-Floerl C., Churkina I.V., Mitrokhin S.D., Shkoda A.S., Barantsevich E.P.Emergence of Candida auris in Russia. J. Hosp. Infect. 2019. pii: 0195-6701(19)30104-5. https://doi.org/10.1016/j.jhin.2019.02.021
  35. Sekyere J.O. Candida auris: A systematic review and meta-analysis of current updates on an emerging multidrug-resistant pathogen. Microbiologyopen. 2018; 7 (4): e00578. https://doi.org/10.1002/mbo3.578
  36. Vujkovic-Cvijin I., Dunham R.M., Iwai S., Maher M.C., Albright R.G., Broadhurst M.J., Hernandez R.D., Lederman M.M., Huang Y., Somsouk M., Deeks S.G., Hunt P.W., Lynch S.V., McCune J.M. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med. 2013; 5, 10, 5 (193): 193ra91. https://doi.org/10.1126/scitranslmed.3006438
  37. Mutlu E.A., Keshavarzian A., Losurdo J., Swanson G., Siewe B., Forsyth C., French A., Demarais P., Sun Y., Koenig L., Cox S., Engen P., Chakradeo P., Abbasi R., Gorenz A., Burns C., Landay A.A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog. 2014; 10 (2): e1003829. https://doi.org/10.1371/journal.ppat.1003829.
  38. Vesterbacka J., Rivera J., Noyan K., Parera M., Neogi U., Calle M., Paredes R., Sönnerborg A., Noguera-Julian M., Nowak P. Richer gut microbiota with distinct metabolic profile in HIV infected Elite Controllers Scientific Reports. 7: 6269. https://doi.org/10.1038/s41598-017-06675-1
  39. Ellis C.L., Ma Z.M., Mann S.K., Li C.S., Wu J., Knight T.H., Yotter T., Hayes T.L., Maniar A.H., Troia-Cancio P.V., Overman H.A., Torok N.J., Albanese A., Rutledge J.C., Miller C.J., Pollard R.B., Asmuth D.M. Molecular characterization of stool microbiota in HIV-infected subjects by pan bacterial and order-level 16s ribosomal DNA (rDNA) quantification and correlations with immune activation. J. Acq Imm Defic Syndromes. 2011; 57 (5): 363–70. 100. https://doi.org/10.1097/QAI.0b013e31821a603c
  40. Dillon S.M., Kibbie J., Lee E.J., Guo K., Santiago M.L., Austin G.L., Gianella S., Landay A.L., Donovan A.M., Frank D.N., McCARTER M.D., Wilson C.C. Low abundance of colonic butyrate-producing bacteria in HIV infection is associated with microbial translocation and immune activation. AIDS. 2017; 31 (4): 511–21. https://doi.org/10.1097/QAD.0000000000001366
  41. Nilsson J., Kinloch-de-Loes S., Granath A., Sönnerborg A., Goh L.E., Andersson J. Early immune activation in gut-associated and peripheral lymphoid tissue during acute HIV infection. AIDS. 2007; 21 (5): 565–74. https://doi.org/10.1097/QAD.0b013e3280117204
  42. Pinacchio C., Scheri G.C., Statzu M., Santinelli L., Ceccarelli G., Innocenti G.P., Vullo V., Antonelli G., Brenchley J.M., d’Ettorre G., Scagnolari C. Type I/II Interferon in HIV-1-Infected Patients: Expression in Gut Mucosa and in Peripheral Blood Mononuclear Cells and Its Modification upon Probiotic Supplementation. J. Immunol Res. 2018; 2018: 1738676. https://doi.org/10.1155/2018/1738676. eCollection 2018.
  43. Gori A., Tincati C., Rizzardini G., Torti C., Quirino T., Haarman M., Amor K.B., van Schaik J., Vriesema A.,Knol J., Marchetti G., Welling G., Clerici M. Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis. J. Clin Microb, Feb. 2008; 46 (2): 757–8 https://doi.org/10.1128/JCM.01729-07\\
  44. Neff C.P., Krueger O., Xiong K., Arif S., Nusbacher N., Schneider J.M., Cunningham A.W., Armstrong A., Li S., McCarter M.D., Campbell T.B., Lozupone C.A., Palmer B.E. Fecal Microbiota Composition Drives Immune Activation in HIV-infected Individuals. EBioMedicine. 2018; 30: 192–202. https://doi.org/10.1016/j.ebiom.2018.03.024. Epub 2018 Mar 26.
  45. Wan Saudi W.S., Sjöblom M. Short-chain fatty acids augment rat duodenal mucosal barrier function. Exp. Physiol. 2017; 102 (7): 791–803. https://doi.org/10.1113/EP086110
  46. Penny H.A., Hodge S.H., Hepworth M.R. Orchestration of intestinal homeostasis and tolerance by group 3 innate lymphoid cells. Semin Immunopathol. 2018; 40 (4): 357–70. https://doi.org/10.1007/s00281-018-0687-8. Epub 2018 May 8.
  47. Guo X., Fu Y.X. The tragic fate of group 3 innate lymphoid cells during HIV-1 infection. J. Clin. Invest. 2015; 125 (10): 3992. https://doi.org/10.1172/JCI84529.
  48. Корогодская Е. Г., Умбетова К.Т., Белая О.Ф., Мазус А.И., Юдина Ю.В., Белая Ю.А., Сметанина С.В., Алленов М. Н., Пак С.Г. Разнообразие ЛПС\0 – антигенов возбудителей кишечных инфекций у больных ВИЧ-инфекцией на стадии вторичных заболеваний. Эпидемиология и инфекционные болезни. 2015; 20 (1): 4–7.
  49. [Korogodskaya E.G., Umbetova K.T., Belaja O.F., Mazus A.I., Judina Ju.V., Belaja Ju.A., Smetanina S.V., Allenov M. N., Pak S.G. Diversity of LPS/0-antigens of causative agents of intestinal infections in patients with HIV infection at the stage of secondary diseases. Epidemiologiya i Infectsionnye Bolezni. 2015; 20 (1): 4–7. (in Russian)]
  50. Bandera A., De Benedetto I., Bozzi G., Gori A. Altered gut microbiome composition in HIV infection: causes, effects and potential intervention. Curr. Opin. HIV AIDS. 2018; 13 (1): 73–80. https://doi.org/10.1097/COH.0000000000000429.
  51. Dicks L.M., Fraser T., ten Doeschate K., van Reenen C.A. Lactic acid bacteria population in children diagnosed with human immunodeficiency virus. J. Paediatr. Child Health. 2009; 45: 567–72.
  52. Wang J., Ji H., Wang S., Liu H., Zhang W., Zhang D., Wang Y. Probiotic Lactobacillus plantarum promotes intestinal barrier function by strengthening the epithelium and modulating gut microbiota. Front Microbiol. 2018; 9: 1953. https://doi.org/10.3389/fmicb.2018.01953. eCollection 2018
  53. Bengmark S., Jeppsson B. Gastrointestinal surface protection and mucosa reconditioning. JPEN J. Parenter Enteral. Nutr. 1995; 19 (5): 410–5. Review.
  54. Cunningham-Rundles S., Ahrné S., Johann-Liang R., Abuav R., Dunn-Navarra A.M., Grassey C., Bengmark S., Cervia J.S. Effect of probiotic bacteria on microbial host defense, growth, and immune function in human immunodeficiency virus type-1 infection. Nutrients. 2011; 3 (12): 1042–70. https://doi.org/10.3390/nu3121042. Epub 2011 Dec 19.
  55. Kazemi A., Djafarian K., Speakman J.R., Sabour P., Soltani S., Shab-Bidar S. Effect of Probiotic Supplementation on CD4 Cell Count in HIV-Infected Patients: A Systematic Review and Meta-analysis. J. Diet Suppl. 2018; 15 (5): 776–88. https://doi.org/10.1080/19390211.2017.1380103. Epub 2017 Nov 29.
  56. Rijkers G.T., Bengmark S., Enck P., Haller D., Herz U., Kalliomaki M., Kudo S., Lenoir-Wijnkoop I., Mercenier A., Myllyluoma E. et al. Guidance for substantiating the evidence for beneficial effects of probiotics: Current status and recommendations for future research. J. Nutr. 2010; 140: 671–6. https://doi.org/10.3945/jn.109.113779.
  57. D’Angelo Ch., Reale M., . Costantini E. Microbiota and Probiotics in Health and HIV Infection. Nutrients. 2017; 9 (6): 615 https://doi.org/10.3390/nu9060615
  58. Cheng S., Ma X., Geng S., Jiang X., Li Y., Hu L., Li J., Wang Y., Han X. Fecal Microbiota Transplantation Beneficially Regulates Intestinal Mucosal Autophagy and Alleviates Gut Barrier Injury. mSystems. 2018; 3 (5). pii: e00137-18. https://doi.org/10.1128/mSystems.00137-18. eCollection 2018 Sep-Oct