PROSPECTS OF CREATING NEW THERAPEUTIC AND PROPHYLACTIC REMEDIES BASED ON SYMBIOTIC BACTERIAL STRAINS FOR CORRECTION OF IMMUNE REGULATION DISORDERS, MEDIATED BY INTESTINAL MICROBIOTA IN COVID-19

Abstract

Modern studies of the role of the intestinal microbiota in animals and humans show that microorganisms are an important determinant of host health, participating in the pathogenesis of various infectious and non-infectious diseases. Currently, the mechanisms of formation of the functional gut-lung axis in the new coronavirus COVID-19 infection are being actively investigated. The gastrointestinal tract may be the point of entry for infection, indicating the involvement of the intestinal microbiota in the infectious process. On the one hand, changes in the microbiota (dysbiosis) in SARS-CoV-2 patients is one of the factors contributing to the development of secondary bacterial infection, sepsis, systemic inflammation and multi-organ failure. On the other hand, impaired gut microbiota contributes to the development of severe course and mortality in patients due to bidirectional coupling of the gut microbiota through the immune system via cytokines. The studies have shown a link between the severity of COVID-19 in patients with the level of cytokines and the presence of particular types of “pro-inflammatory” and “anti-inflammatory” bacteria in the intestinal biotope. Immunological abnormalities in COVID-19 patients are also mediated by metabolome profile alteration associated with dysbiotic microbiota disturbances. The connection between the composition of the gut microbiota, cytokine levels and inflammatory markers suggests that the gut microbiome influences the progression of coronavirus infection, and the "symbiotic potential" of the normobiotic microbiota can be used to develop prevention and rehabilitation measures for patients. This can be facilitated by the development of research towards the problem of human-microbiota symbiosis. A number of key mechanisms for studying the integration of bifidobacteria and lactobacilli with the host, mediated by the system of immunity, hormones and neurotransmitters, open new perspectives for medicine, including obtaining new probiotic strains of different targeting for therapeutic and preventative correction of impaired functions of the organism. The study of microsymbiocenosis as one of the vectors of associative symbiosis has enabled the development of a method of intermicrobial “friend or foe identification”, where bifidobacteria are used as a diagnostic culture, since “friendly” strains are characterised by synergism (support), whereas encountering a "foreign cell" leads to antagonism. This fundamental mechanism may be used for choosing the “host-friendly” bacteria strains eligible for the creation of a probiotic composition.

1. Abdulrab S, Al-Maweri S, Halboub E. Ursodeoxycholic acid as a candidate therapeutic to alleviate and/or prevent COVID-19-associated cytokine storm. Med Hypotheses. 2020 Oct;143:109897. DOI: 10.1016/j.mehy.2020.109897

2. Ahlawat S, Asha, Sharma KK. Immunological co-ordination between gut and lungs in SARS-CoV-2 infection. Virus Res. 2020 Sep;286:198103. doi: 10.1016/j.virusres.2020.198103

3. Aktas B, Aslim B. Gut-lung axis and dysbiosis in COVID-19. Turk J Biol. 2020 Jun 21;44(3):265-272. doi: 10.3906/biy-2005-102.

4.

5. Aleman FDD, Valenzano DR (2019) Microbiome evolution during host aging. PLoS Pathog 15(7): e1007727. https://doi.org/10.1371/journal.ppat.1007727

6. Belkaid Y, Harrison OJ. Homeostatic immunity and the microbiota. Immunity (2017) 46(4):562–76. DOI: 10.1016/j.immuni.2017.04.008

7. Bingula R, Filaire M, Radosevic-Robin N, Bey M, Berthon JY, Bernalier-Donadille A, Vasson MP, Filaire E. Desired Turbulence? Gut-Lung Axis, Immunity, and Lung Cancer. J Oncol. 2017;2017:5035371. DOI: 10.1155/2017/5035371

8. Boursi B, Mamtani R, Haynes K, Yang YX. Recurrent antibiotic exposure may promote cancer formation--Another step in understanding the role of the human microbiota? Eur J Cancer. 2015 Nov;51(17):2655-64. DOI: 10.1016/j.ejca.2015.08.015

9. Bukharin O.V. Persistence of pathogenic bacteria. Moscow: Meditsina, 1999. 365 p.

10.

11. Bukharin O.V., Lobakova E.S., Nemtseva N.V., Cherkasov S.V. Associative symbiosis. Ekaterinburg; UD RAS 2007. 264 p.

12.

13. Bukharin O.V., Perunova N.B., Ivanova E.V. Bifidoflora in human associative symbiosis. Ekaterinburg: UrD of the RAS, 2014. 212 p.

14. Bukharin O. V., Semenov A. V., Cherkasov S.V. Antagonistic activity of probiotic bacteria. Clinical Microbiology and Antimicrobial Chemotherapy. 2010; 12 (4): 347-352.

15. https://cmac-journal.ru/en/publication/2010/4/

16. Bukharin O.V., Stadnikov A.A., Perunova N.B. Oxytocin and microbiota role in regulation of pro- and eukaryote interactions in infection. Ekaterinburg: UrD of the RAS, 2018. 247 p.

17. Chervinets Yu.V., Cervinets V. M., Mironov A. Yu. Symbiotic relationships of lactobacilli and microorganisms of the gastrointestinal tract. Tver. Center. Tver state medical university Publ., 2016. 214 p

18. Cheung KS, Hung IFN, Chan PPY, Lung KC, Tso E, Liu R, Ng YY, Chu MY, Chung TWH, Tam AR, Yip CCY, Leung KH, Fung AY, Zhang RR, Lin Y, Cheng HM, Zhang AJX, To KKW, Chan KH, Yuen KY, Leung WK. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis. Gastroenterology. 2020 Jul;159(1):81-95.

19. DOI: 10.1053/j.gastro.2020.03.065

20. Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell (2012) 149(7):1578–93. DOI: 10.1016/j.cell.2012.04.037

21. Dhar D, Mohanty A. Gut microbiota and Covid-19- possible link and implications. Virus Res. 2020 Aug;285:198018. DOI: 10.1016/j.virusres.2020.198018

22. Dickson RP, Singer BH, Newstead MW, Falkowski NR, Erb-Downward JR, Standiford TJ, Huffnagle GB. Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome. Nat Microbiol. 2016 Jul 18;1(10):16113. DOI: 10.1038/nmicrobiol.2016.113

23. Fagundes CT, Amaral FA, Vieira AT, Soares AC, Pinho V, Nicoli JR, Vieira LQ, Teixeira MM, Souza DG. Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. J Immunol. 2012 Feb 1;188(3):1411-20. DOI: 10.4049/jimmunol.1101682

24. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021 Jan;19(1):55-71. DOI: 10.1038/s41579-020-0433-9

25. Feleszko W, Jaworska J, Rha RD, Steinhausen S, Avagyan A, Jaudszus A, Ahrens B, Groneberg DA, Wahn U, Hamelmann E. Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma. Clin Exp Allergy. 2007 Apr;37(4):498-505. DOI: 10.1111/j.1365-2222.2006.02629.x

26. Gaibani P, D'Amico F, Bartoletti M, Lombardo D, Rampelli S, Fornaro G, Coladonato S, Siniscalchi A, Re MC, Viale P, Brigidi P, Turroni S, Giannella M. The Gut Microbiota of Critically Ill Patients With COVID-19. Front Cell Infect Microbiol. 2021 Jun 29;11:670424. doi: 10.3389/fcimb.2021.670424.

27. Geva-Zatorsky N, Sefik E, Kua L, Pasman L, Tan TG, Ortiz-Lopez A, Yanortsang TB, Yang L, Jupp R, Mathis D, Benoist C, Kasper DL. Mining the Human Gut Microbiota for Immunomodulatory Organisms. Cell. 2017 Feb 23;168(5):928-943.e11. DOI: 10.1016/j.cell.2017.01.022

28. Gill HS, Rutherfurd KJ, Cross ML, Gopal PK. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr. 2001 Dec;74(6):833-9. DOI: 10.1093/ajcn/74.6.833

29. .

30. Gill HS, Rutherfurd KJ, Cross ML. Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes. J Clin Immunol. 2001 Jul;21(4):264-71. DOI: 10.1023/a:1010979225018

31. Giron LB, Dweep H, Yin X, Wang H, Damra M, Goldman AR, Gorman N, Palmer CS, Tang HY, Shaikh MW, Forsyth CB, Balk RA, Zilberstein NF, Liu Q, Kossenkov A, Keshavarzian A, Landay A, Abdel-Mohsen M. Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients. Front Immunol. 2021 Jun 9;12:686240. DOI: 10.3389/fimmu.2021.686240

32. Glushanova NA, Shenderov BA. [Relationships between the probiotic and host indigenous lactobacilli under the conditions of mixed cultivation in vitro]. Zh Mikrobiol Epidemiol Immunobiol. 2005 Mar-Apr;(2):56-61. Russian. PMID: 15881941.

33. Groves HT, Cuthbertson L, James P, Moffatt MF, Cox MJ, Tregoning JS. Respiratory Disease following Viral Lung Infection Alters the Murine Gut Microbiota. Front Immunol. 2018 Feb 12;9:182. DOI: 10.3389/fimmu.2018.00182

34. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, Bikdeli B, Ahluwalia N, Ausiello JC, Wan EY, Freedberg DE, Kirtane AJ, Parikh SA, Maurer MS, Nordvig AS, Accili D, Bathon JM, Mohan S, Bauer KA, Leon MB, Krumholz HM, Uriel N, Mehra MR, Elkind MSV, Stone GW, Schwartz A, Ho DD, Bilezikian JP, Landry DW. Extrapulmonary manifestations of COVID-19. Nat Med. 2020 Jul;26(7):1017-1032 DOI: 10.1038/s41591-020-0968-3

35. Haase S, Haghikia A, Wilck N, Müller DN, Linker RA. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology. 2018 Jun;154(2):230-238. DOI: 10.1111/imm.12933

36. Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, Sigl V, Hanada T, Hanada R, Lipinski S, Wild B, Camargo SM, Singer D, Richter A, Kuba K, Fukamizu A, Schreiber S, Clevers H, Verrey F, Rosenstiel P, Penninger JM. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012 Jul 25;487(7408):477-81. DOI: 10.1038/nature11228

37. Hufnagl K, Pali-Schöll I, Roth-Walter F, Jensen-Jarolim E. Dysbiosis of the gut and lung microbiome has a role in asthma. Semin Immunopathol. 2020 Feb;42(1):75-93.

38. DOI: 10.1007/s00281-019-00775-y

39. Iacucci M, Cannatelli R, Labarile N, Mao R, Panaccione R, Danese S, Kochhar GS, Ghosh S, Shen B. Endoscopy in inflammatory bowel diseases during the COVID-19 pandemic and post-pandemic period. Lancet Gastroenterol Hepatol. 2020 Jun;5(6):598-606.

40. DOI: 10.1016/S2468-1253(20)30119-9

41. Il'in VK, Suvorov AN, Kiriukhina NV, Usanova NA, Starkova LV, Boiarintsev VV, Karaseva AB. [Autochthonous probiotics in prevention of infectious and inflammatory diseases of a human in the altered habitats]. Vestn Ross Akad Med Nauk. 2013;(2):56-62. Russian.

42. DOI: 10.15690/vramn.v68i2.550

43. Jia W, Xie G, Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018 Feb;15(2):111-128. DOI: 10.1038/nrgastro.2017.119

44. Kasabri V, Shawakri E, Akour A, Naffa R, Khawaja N, Al-Sarraf I, Bzour J. Cross-sectional correlates of increased IL-18 but reduced fetuin-A and oxytocin with adiposity and blood indices in metabolic syndrome patients with and without prediabetes. Ther Adv Endocrinol Metab. 2018 Aug 18;9(12):329-338. DOI: 10.1177/2042018818788802

45. .

46. Katz-Agranov N, Zandman-Goddard G. Autoimmunity and COVID-19 - The microbiotal connection. Autoimmun Rev. 2021 Aug;20(8):102865. DOI: 10.1016/j.autrev.2021.102865

47. .

48. Khan M, Mathew BJ, Gupta P, Garg G, Khadanga S, Vyas AK, Singh AK. Gut Dysbiosis and IL-21 Response in Patients with Severe COVID-19. Microorganisms. 2021 Jun 13;9(6):1292. DOI: 10.3390/microorganisms9061292

49. Koptyug A, Sukhovei Y, Kostolomova E, Unger I, Kozlov V. Novel Strategy in Searching for Natural Compounds with Anti-Aging and Rejuvenating Potential. Int J Mol Sci. 2023 Apr 28;24(9):8020. DOI: 10.3390/ijms24098020

50. Kostolomova E.G., Timokhina T.K., Perunova N.B., et al. In vitro evaluation of immunomodulatory activity of Bifidobacterium bifidum 791 in the cell model of innate and adaptive immunity // Russian Journal of Immunology. - 2022. - Vol. 25. - N. 2. - P. 213-218. doi: 10.46235/1028-7221-1133-IVE

51. Jabczyk M, Nowak J, Hudzik B, Zubelewicz-Szkodzińska B. Microbiota and Its Impact on the Immune System in COVID-19-A Narrative Review. J Clin Med. 2021 Sep 30;10(19):4537. doi: 10.3390/jcm10194537

52. Li J, Richards EM, Handberg EM, Pepine CJ, Raizada MK. Butyrate Regulates COVID-19-Relevant Genes in Gut Epithelial Organoids From Normotensive Rats. Hypertension. 2021 Feb;77(2):e13-e16. DOI: 10.1161/HYPERTENSIONAHA.120.16647

53. Lin L, Jiang X, Zhang Z, Huang S, Zhang Z, Fang Z, Gu Z, Gao L, Shi H, Mai L, Liu Y, Lin X, Lai R, Yan Z, Li X, Shan H. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut. 2020 Jun;69(6):997-1001. DOI: 10.1136/gutjnl-2020-321013

54. Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science. 2018 Nov 30;362(6418):eaat9076. DOI: 10.1126/science.aat9076.

55. Mao X, Gu C, Ren M, Chen D, Yu B, He J, Yu J, Zheng P, Luo J, Luo Y, Wang J, Tian G, Yang Q. l-Isoleucine Administration Alleviates Rotavirus Infection and Immune Response in the Weaned Piglet Model. Front Immunol. 2018 Jul 16;9:1654. doi: 10.3389/fimmu.2018.01654

56. Markov A.A., Kostolomova E.G., Timokhina T.Kh., Solovyev G.S., Paromova Ya.I., Polyanskih E.D., Voronin K.A. Effect of Bifidobacterium bifidum supernatant on the morphological and functional characteristics of human fibroblasts in real time during an in vitro experiment. Medical Immunology (Russia). 2023;25(3):581-586. https://doi.org/10.15789/1563-0625-EOB-2720

57. Mizutani T, Ishizaka A, Koga M, Ikeuchi K, Saito M, Adachi E, Yamayoshi S, Iwatsuki-Horimoto K, Yasuhara A, Kiyono H, Matano T, Suzuki Y, Tsutsumi T, Kawaoka Y, Yotsuyanagi H. Correlation Analysis between Gut Microbiota Alterations and the Cytokine Response in Patients with Coronavirus Disease during Hospitalization. Microbiol Spectr. 2022 Apr 27;10(2):e0168921. DOI: 10.1128/spectrum.01689-21

58. Moens E, Veldhoen M. Epithelial barrier biology: good fences make good neighbours. Immunology. 2012 Jan;135(1):1-8. DOI: 10.1111/j.1365-2567.2011.03506.x

59. Nagata N, Takeuchi T, Masuoka H, Aoki R, Ishikane M, Iwamoto N, Sugiyama M, Suda W, Nakanishi Y, Terada-Hirashima J, Kimura M, Nishijima T, Inooka H, Miyoshi-Akiyama T, Kojima Y, Shimokawa C, Hisaeda H, Zhang F, Yeoh YK, Ng SC, Uemura N, Itoi T, Mizokami M, Kawai T, Sugiyama H, Ohmagari N, Ohno H. Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications. Gastroenterology. 2023 Feb;164(2):272-288. DOI: 10.1053/j.gastro.2022.09.024

60. Negi S, Das DK, Pahari S, Nadeem S, Agrewala JN. Potential Role of Gut Microbiota in Induction and Regulation of Innate Immune Memory. Front Immunol. 2019 Oct 25;10:2441. DOI: 10.3389/fimmu.2019.02441

61. Negi S, Pahari S, Bashir H, Agrewala JN. Gut Microbiota Regulates Mincle Mediated Activation of Lung Dendritic Cells to Protect Against Mycobacterium tuberculosis. Front Immunol. 2019 May 28;10:1142. DOI: 10.3389/fimmu.2019.01142

62. Nejadghaderi SA, Nazemalhosseini-Mojarad E, Asadzadeh Aghdaei H. Fecal microbiota transplantation for COVID-19; a potential emerging treatment strategy. Med Hypotheses. 2021 Feb;147:110476. DOI: 10.1016/j.mehy.2020.110476

63. Ostaff MJ, Stange EF, Wehkamp J. Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med. 2013 Oct;5(10):1465-83. doi: 10.1002/emmm.201201773.

64. Poochi SP, Easwaran M, Balasubramanian B, Anbuselvam M, Meyyazhagan A, Park S, Bhotla HK, Anbuselvam J, Arumugam VA, Keshavarao S, Kanniyappan GV, Pappusamy M, Kaul T. Employing bioactive compounds derived from Ipomoea obscura (L.) to evaluate potential inhibitor for SARS-CoV-2 main protease and ACE2 protein. Food Front. 2020 Jun;1(2):168-179 DOI: 10.1002/fft2.29

65. Poutahidis T, Kearney SM, Levkovich T, Qi P, Varian BJ, Lakritz JR, Ibrahim YM, Chatzigiagkos A, Alm EJ, Erdman SE. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS One. 2013 Oct 30;8(10):e78898. DOI: 10.1371/journal.pone.0078898.

66. .

67. Prasad R, Patton MJ, Floyd JL, Fortmann S, DuPont M, Harbour A, Wright J, Lamendella R, Stevens BR, Oudit GY, Grant MB. Plasma Microbiome in COVID-19 Subjects: An Indicator of Gut Barrier Defects and Dysbiosis. Int J Mol Sci. 2022 Aug 15;23(16):9141. doi: 10.3390/ijms23169141

68. Proctor LM. The Human Microbiome Project in 2011 and beyond. Cell Host Microbe. 2011 Oct 20;10(4):287-91.

69. DOI: 10.1016/j.chom.2011.10.001

70. Qi F, Qian S, Zhang S, Zhang Z. Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun. 2020 May 21;526(1):135-140. DOI: 10.1016/j.bbrc.2020.03.044

71. Qian Q, Fan L, Liu W, Li J, Yue J, Wang M, Ke X, Yin Y, Chen Q, Jiang C. Direct Evidence of Active SARS-CoV-2 Replication in the Intestine. Clin Infect Dis. 2021 Aug 2;73(3):361-366. DOI: 10.1093/cid/ciaa925

72. Reinold J, Farahpour F, Fehring C, Dolff S, Konik M, Korth J, van Baal L, Hoffmann D, Buer J, Witzke O, Westendorf AM, Kehrmann J. A Pro-Inflammatory Gut Microbiome Characterizes SARS-CoV-2 Infected Patients and a Reduction in the Connectivity of an Anti-Inflammatory Bacterial Network Associates With Severe COVID-19. Front Cell Infect Microbiol. 2021 Nov 17;11:747816. DOI: 10.3389/fcimb.2021.747816

73. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009 May;9(5):313-23. DOI: 10.1038/nri2515

74. Saad MJ, Santos A, Prada PO. Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance. Physiology (Bethesda). 2016 Jul;31(4):283-93. DOI: 10.1152/physiol.00041.2015

75. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec 1;167(6):1469-1480.e12. DOI: 10.1016/j.cell.2016.11.018

76. Sarkesh A, Daei Sorkhabi A, Sheykhsaran E, Alinezhad F, Mohammadzadeh N, Hemmat N, Bannazadeh Baghi H. Extrapulmonary Clinical Manifestations in COVID-19 Patients. Am J Trop Med Hyg. 2020 Nov;103(5):1783-1796.

77. DOI: 10.4269/ajtmh.20-0986

78. Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, Geng Q, Auerbach A, Li F. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020 May;581(7807):221-224. DOI: 10.1038/s41586-020-2179-y

79. Song Y, Liu P, Shi XL, Chu YL, Zhang J, Xia J, Gao XZ, Qu T, Wang MY. SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19. Gut. 2020 Jun;69(6):1143-1144. DOI: 10.1136/gutjnl-2020-320891

80. Sun Z, Song ZG, Liu C, Tan S, Lin S, Zhu J, Dai FH, Gao J, She JL, Mei Z, Lou T, Zheng JJ, Liu Y, He J, Zheng Y, Ding C, Qian F, Zheng Y, Chen YM. Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients. BMC Med. 2022 Jan 20;20(1):24 DOI: 10.1186/s12916-021-02212-0

81. Tai N, Wong FS, Wen L. The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord. 2015 Mar;16(1):55-65. DOI: 10.1007/s11154-015-9309-0

82. Thibonnier M, Conarty DM, Preston JA, Plesnicher CL, Dweik RA, Erzurum SC. Human vascular endothelial cells express oxytocin receptors. Endocrinology. 1999 Mar;140(3):1301-9. DOI: 10.1210/endo.140.3.6546

83. Varian BJ, Poutahidis T, DiBenedictis BT, Levkovich T, Ibrahim Y, Didyk E, Shikhman L, Cheung HK, Hardas A, Ricciardi CE, Kolandaivelu K, Veenema AH, Alm EJ, Erdman SE. Microbial lysate upregulates host oxytocin. Brain Behav Immun. 2017 Mar;61:36-49. DOI: 10.1016/j.bbi.2016.11.002

84. Vatanen T, Kostic AD, d'Hennezel E, Siljander H, Franzosa EA, Yassour M, Kolde R, Vlamakis H, Arthur TD, Hämäläinen AM, Peet A, Tillmann V, Uibo R, Mokurov S, Dorshakova N, Ilonen J, Virtanen SM, Szabo SJ, Porter JA, Lähdesmäki H, Huttenhower C, Gevers D, Cullen TW, Knip M; DIABIMMUNE Study Group; Xavier RJ. Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans. Cell. 2016 May 5;165(4):842-53. DOI: 10.1016/j.cell.2016.04.007

85. Viana SD, Nunes S, Reis F. ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities - Role of gut microbiota dysbiosis. Ageing Res Rev. 2020 Sep;62:101123. doi: 10.1016/j.arr.2020.101123

86. Wang B, Zhang L, Wang Y, Dai T, Qin Z, Zhou F, Zhang L. Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022 Apr 29;7(1):143. DOI: 10.1038/s41392-022-00986-0

87. West CE, Dzidic M, Prescott SL, Jenmalm MC. Bugging allergy; role of pre-, pro- and synbiotics in allergy prevention. Allergol Int. 2017 Oct;66(4):529-538. DOI: 10.1016/j.alit.2017.08.001

88. Wu C, Xu Q, Cao Z, Pan D, Zhu Y, Wang S, Liu D, Song Z, Jiang W, Ruan Y, Huang Y, Qin N, Lu H, Qin H. The volatile and heterogeneous gut microbiota shifts of COVID-19 patients over the course of a probiotics-assisted therapy. Clin Transl Med. 2021 Dec;11(12):e643. DOI: 10.1002/ctm2.643

89. Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, Yin H, Xiao Q, Tang Y, Qu X, Kuang L, Fang X, Mishra N, Lu J, Shan H, Jiang G, Huang X. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020 May;5(5):434-435. DOI: 10.1016/S2468-1253(20)30083-2

90. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020 May;158(6):1831-1833.e3. DOI: 10.1053/j.gastro.2020.02.055

91.

92. Yao Y, Cai X, Fei W, Ye Y, Zhao M, Zheng C. The role of short-chain fatty acids in immunity, inflammation and metabolism. Crit Rev Food Sci Nutr. 2022;62(1):1-12. DOI: 10.1080/10408398.2020.1854675

93. Yeoh YK, Zuo T, Lui GC, Zhang F, Liu Q, Li AY, Chung AC, Cheung CP, Tso EY, Fung KS, Chan V, Ling L, Joynt G, Hui DS, Chow KM, Ng SSS, Li TC, Ng RW, Yip TC, Wong GL, Chan FK, Wong CK, Chan PK, Ng SC. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. 2021 Apr;70(4):698-706. DOI: 10.1136/gutjnl-2020-323020

94.

95. Zhang F, Wan Y, Zuo T, Yeoh YK, Liu Q, Zhang L, Zhan H, Lu W, Xu W, Lui GCY, Li AYL, Cheung CP, Wong CK, Chan PKS, Chan FKL, Ng SC. Prolonged Impairment of Short-Chain Fatty Acid and L-Isoleucine Biosynthesis in Gut Microbiome in Patients With COVID-19. Gastroenterology. 2022 Feb;162(2):548-561.e4. DOI: 10.1053/j.gastro.2021.10.013

96. Zhao Y, Liu Y, Li S, Peng Z, Liu X, Chen J, Zheng X. Role of lung and gut microbiota on lung cancer pathogenesis. J Cancer Res Clin Oncol. 2021 Aug;147(8):2177-2186. doi: 10.1007/s00432-021-03644-0.

97. Zhou Y, Shi X, Fu W, Xiang F, He X, Yang B, Wang X, Ma WL. Gut Microbiota Dysbiosis Correlates with Abnormal Immune Response in Moderate COVID-19 Patients with Fever. J Inflamm Res. 2021 Jun 17;14:2619-2631. doi: 10.2147/JIR.S311518.

98. Zhou B, Pang X, Wu J, Liu T, Wang B, Cao H. Gut microbiota in COVID-19: new insights from inside. Gut Microbes. 2023 Jan-Dec;15(1):2201157. doi: 10.1080/19490976.2023.2201157.