D.V. Komissarova1, D.N. Kashirina2, L.Kh. Pastushkova3, A.G. Goncharova4, N.A. Usanova5, O.I. Orlov6, I.M. Larina7, V.K. Ilyin8

1-8 State Scientific Center of the Russian Federation – Institute of Biomedical Problems of the Russian Academy of Sciences (Moscow, Russia)

1 d.komisarova@yandex.ru, 2 daryakudryavtseva@mail.ru, 3 lpastushkova@mail.ru, 4 goncharova.anna@gmail.com, 5 usanovasp@mail.ru, 6 info@imbp.ru, 7 irina.larina@gmail.com, 8 piton2004@bk.ru

The mammalian gut is a place where numerous external and internal signals constantly converge. Intestinal cells that influence the quantitative and qualitative composition of the microbiota are influenced by the blood proteome. Of particular interest is the study of the relationship between the level of proteins in human blood and the number of opportunistic microorganisms of the intestinal biotope in experiments simulating certain effects of space flight, for example, in “dry” immersion, since it is known that space mission factors negatively affect the microflora of the upper respiratory tract and intestines.

The purpose of this study was to identify the relationship between the levels of proteins in human blood, studied using proteomics methods based on mass spectrometry, with the number of opportunistic microorganisms in a 3-day “dry” immersion experiment.

6 female volunteers from 25 to 40 years old took part in the study. During the experiment, the participants did not take antibacterial drugs or other drugs that could affect the microflora. As a result of the studies, protein complexes were identified, the number of which correlated with the amount of opportunistic intestinal microbiota and which can be divided into 4 groups: proteins associated with the functions of the immune system, proteins associated with chaperonin, proteins affecting the attachment of bacterial cells or penetration of bacterial toxins into the cell, proteins that have a high regression coefficient when correlated with some microorganisms, but do not have an obvious functional connection with their number.

The data obtained confirm the hypothesis that there is a relationship between some blood proteins and intestinal microorganisms. The study of the relationship between the concentration of proteins in the blood and the number of bacteria in the intestines seems relevant both for maintaining the health of cosmonauts and for “terrestrial” medicine, since it allows not only to identify deep relationships in the “host-microbiota” system, but can also serve diagnostic purposes in within the framework of clinical trials.

Komissarova D.V., Kashirina D.N., Pastushkova L.Kh., Goncharova A.G., Usanova N.A., Orlov O.I., Larina I.M., Ilyin V.K. Opportunistic microflora of the human intestine and the host blood proteome – search for connection. Technologies of Living Systems. 2024.
V. 21. № 1. Р. 5-19. DOI: https://doi.org/10.18127/j20700997-202401-01 (In Russian)

1. Fang X., Miao R., Wei J., Wu H., Tian J. Advances in multi-omics study of biomarkers of glycolipid metabolism disorder. Comput. Struct. Biotechnol. J. 2022. V. 20. P. 5935–5951.
2. Ilin V.K., Volozhin A.I., Vikha G.V. Kolonizatsionnaya rezistentnost organizma v izmenennykh usloviyakh obitaniya. M.: Nauka. 2005. 280 s. (in Russian).
3. Plotnikova E.Yu., Krasnova M.V., Baranova E.N., Borshch M.V. Neproshennyye gosti: izbytochnyy bakterialnyy rost v tonkoy kishke. Chto delat? Consilium medicum. Gastroenterologiya. 2013. № 1. S. 36–42. (in Russian).
4. Wells J.M. Immunomodulatory mechanisms of lactobacilli. Microb. Cell. 2011. V. 10(1). P. 17.
5. Hiramatsu Y., Hosono A., Takahashi K. et al. Bifidobacterium components have immunomodulatory characteristics dependent on the method of preparation. Cytotechnology. 2007. V. 55. P.79–87.
6. Drakina S.A., Perevoshchikova N.K., Muratova R.N., Nurmekhamitova N.V. Probiotiki kak sredstvo profilaktiki ORVI u detey rannego vozrasta. MiD. 2019. T. 77. № 2. S. 40–46. (in Russian).
7. Zvyagintseva T.D., Chernobay A.I., Gridneva S.V. Kishechnyy mikrobiom i nealkogolnaya zhirovaya bolezn pecheni: patogeneticheskiye vzaimosvyazi i korrektsiya probiotikami. Gastroenterologiya. gepatologiya. koloproktologiya. 2016. T. 39. № 1. S. 44–45. (in Russian).
8. Pabst R., Russell M.W., Brandtzaeg P. Tissue distribution of lymphocytes and plasma cells and the role of the gut. Trends Immunol. 2008. V. 29. P. 206–208.
9. Guilliams M., Thierry G.R., Bonnardel J., Bajenoff M. Establishment and maintenance of the macrophage niche. Immunity. 2020. V. 52. P. 434–451.
10. Heinsbroek S.E., Gordon S. The role of macrophages in inflammatory bowel diseases. Expert Rev. Mol. Med. 2009. V. 11. P. 14.
11. Qian Cao, Randall Tyler Mertens, Sivanathan K.N., Cai X., Xiao P. Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine. J. Leukoc. Biol. 2022. V. 112(2). P. 313–331.
12. Turroni S., Magnani M., Lesnik P., Vidal H., Heer M. Gut Microbiome and Space Travelers' Health: State of the Art and Possible Pro/Prebiotic Strategies for Long-Term Space Missions. Frontiers in physiology. 2020. V. 11.
13. Ilin V.K., Komissarova D.V., Sadchikova E.R., Goldman I.L., Kolupayev A.K., Sadchikov P.E., Lukicheva N.A., Zhiganshina A.A., Usanova N.A., Morozova Yu.A. Vliyaniye priyema laktoferrina na kishechnuyu mikrofloru krys pri imitatsii mikrogravitatsii. Biomeditsinskaya radioelektronika. 2023. T. 26. № 1. S. 82–88. DOI: 10.18127/j15604136-202301-09 (in Russian).
14. Pastushkova L.Kh., Goncharov I.N., Kashirina D.N., Goncharova A.G., Larina I.M. Svyaz ryada dostoverno izmenyayushchikhsya belkov krovi s angiogenezom posle 21-sutochnoy sukhoy immersii. Tekhnologii zhivykh sistem. 2021. T. 18. № 1. S. 51–57. DOI: 10.18127/j20700997-202101-05 (in Russian).
15. Ilin V.K., Usanova N.A., Komissarova D.V., Shef K.A., Agureyev A.N. Kaspranskiy R.R., Kaspranskiy R.R., Morozova Yu.A., Sakharova A.V., Nosovskiy A.M. Sochetannoye ispolzovaniye napitkov brozheniya na osnove sakharomitset i probioticheskikh i autoprobioticheskikh preparatov dlya obespecheniya normalizatsii mikroflory cheloveka v izolyatsionnom eksperimente («SIRIUS-18/19»). Aviakosmicheskaya ekologiya i meditsina. 2020. T. 54. № 3. S. 49–53. (in Russian).
16. Pastushkova L.Kh., Goncharova A.G., Kashirina D.N., Larina I.M., Ilin E.A. Vliyaniye gipobaricheskoy gipoksii na proteom plazmy krovi zdorovogo cheloveka vo vremya zimovki na Antarkticheskoy stantsii «Vostok». Biomeditsinskaya radioelektronika. 2023. T. 26. № 4. S. 5–14.
    DOI: 10.18127/j15604136-202304-01 (in Russian).
17. Kashirinа D., Brzhozovskiy A., Sun W., Pastushkova L., Popova O., Rusanov V., Nikolaev E., Larina I., Kononikhin A. Proteomic characterization of dry blood spots of healthy women during simulation the microgravity effects using dry immersion. Front. Physiol. 2022. V. 12. P. 7.
18. Kulaichev A.P. Metody i sredstva kompleksnogo statisticheskogo analiza dannykh: Ucheb. posobiye. 5-e izd., pererab. i dop. M.: INFRA-M. 2017. 484 s. (in Russian).
19. Menon D., Innes A., Oakley A.J. GSTO1-1 plays a pro-inflammatory role in models of inflammation, colitis and obesity. Sci. Rep. 2017. V. 7. P. 15.
20. Everard A., Geurts L., Caesar R., et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat. Commun. 2015. V. 5. P. 12.
21. Vu B.G., Gourronc F.A., Bernlohr D.A., Schlievert P.M., Klingelhutz A.J. Staphylococcal superantigens stimulate immortalized human adipocytes to produce chemokines. PLOS ONE. 2013. V. 8(10).
22. Zhi Huang, Rose A., Hoffmann F., Hashimoto A., Bertino P., Denk T., Takano J., Iwata N., Saido T., Hoffmann P. Calpastatin prevents NF-κB–mediated hyperactivation of macrophages and attenuates colitis. J. Immunol. 2013. V. 191(7). P. 3778–3788.
23. Rydengård V., Shannon O., Lundqvist K., Kacprzyk L., Chalupka A. Histidine-rich glycoprotein protects from systemic candida infection. PLOS Pathogens. 2008. V. 4(8).
24. Shannon O., Rydengård V., Schmidtchen A., Mörgelin M., Per Alm M., Sørensen O., Björck L. Histidine-rich glycoprotein promotes bacterial entrapment in clots and decreases mortality in a mouse model of sepsis. Blood. 2010. V. 116 (13). P. 2365–2372.
25. Ruetz T., Cornick S., Guttman J.A. The spectrin cytoskeleton is crucial for adherent and invasive bacterial pathogenesis. PLOS ONE. 2011. V 6(5). P. e19940.
26. Mackness M., Mackness B. Human paraoxonase-1 (PON1): Gene structure and expression, promiscuous activities and multiple physiological roles. Gene. 2015. V. 567(1). P. 12–21.
27. Clough B., Fisch D., Mize T., Encheva V., Snijders A., Frickel E-M. p97/VCP targets Toxoplasma gondii vacuoles for parasite restriction in interferon-stimulated human cells. BioRxiv. 2023. P. 45566. DOI: https://doi.org/10.1101/2023.06.20.545566
28. Grdiša M., Vitale L. Types and localization of aminopeptidases in different human blood cells. Int. J. Biochem. 1991. V. 23(3). P. 339–345.
29. Thauland T.J., Khan H.A., Butte M.J. The actin-capping protein alpha-adducin is required for T-cell costimulation. Front. Immunol. 2019. V. 10. P. 2706.
30. Hendriks A., Mnich M.E., Clemente B., Cruz A.R., Tavarini S., Bagnoli F., Soldaini E. Staphylococcus aureus-specific tissue-resident memory CD4+ T cells are abundant in healthy human skin. Front. Immunol. 2021. V. 12. P. 642711.
31. Ben-Neriah Y. Regulatory functions of ubiquitination in the immune system. Nat. Immunol. 2002. V. 3. P. 20–26.
32. Fon Huang K., Chung Dai H., Herndon David N. Insulin-like Growth factor 1 (igf-1) reduces gut atrophy and bacterial translocation after severe burn injury. Archives of Surgery. 1993. V. 128(1). P. 47–53.
33. Schroeder B. Fight them or feed them: how the intestinal mucus layer manages the gut microbiota. Gastroenterology Report. 2019. V. 7(1). P. 3–12.
34. Omar K.H. Domi B., Darmani H. Syzygium aromaticum extracts debilitate Candida albicans by radically inhibiting its morphological plasticity and biofilm formation. Journal of Herbs, Spices & Medicinal Plants. 2023. V. 29(4). P. 392–404.
35. Jensen E., Young J., Mathes S, List E., Carroll R., Kuhn J., Onusko M., Kopchick J., Murphy E, Berryman D. Crosstalk between the growth hormone/insulin-like growth factor-1 axis and the gut microbiome: A new frontier for microbial endocrinology. Growth Hormone & IGF Research. 2020. V. 53–54. P. 101333.
36. Chen J., Toyomasu Y., Hayashi Y. Altered gut microbiota in female mice with persistent low body weights following removal of post-weaning chronic dietary restriction. Genome Med. 2016. V. 8(1). P. 103.
37. Zheng Yu., Song Y., Han Q., Liu W., Xu J., Yu Z., Zhang R, Li N. Intestinal epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis. American Journal of Physiology-Endocrinology and Metabolism. 2018. V. 315(4). P. 638–649.
38. Kubinak J., Stephens W., Soto R. MHC variation sculpts individualized microbial communities that control susceptibility to enteric infection. Nat. Commun. 2015. V. 6. P. 8642.
39. Marín E., Parra-Giraldo C.M., Hernández-Haro C., Hernáez M.L., Nombela C., Monteoliva L., Gil C. Candida albicans Shaving to Profile Human Serum Proteins on Hyphal Surface. Front. Microbiol. 2015. V. 6. P. 1343.
40. Bosi A., Banfi D., Bistoletti M., Moretto P., Moro E., Crema F., Maggi F., Karousou E., Viola M., Passi A. Hyaluronan: A Neuroimmune Modulator in the Microbiota-Gut Axis. Cells. 2022. V. 11(1). P. 126.
41. Hoter A., Naim H.Y. The Functions and therapeutic potential of heat shock proteins in inflammatory bowel disease – an update. Int. J. Mol. Sci. 2019. V. 20(21). P. 5331.
42. Deng X., Gao F., Flagg T., Anderson J., May W.S. Bcl2's flexible loop domain regulates p53 binding and survival. Mol. Cell Biol. 2006. V. 26(12). P. 4421–4434.
43. Ito N., Kii I., Shimizu N. Direct reprogramming of fibroblasts into skeletal muscle progenitor cells by transcription factors enriched in undifferentiated subpopulation of satellite cells. Sci. Rep. 2018. V. 7(1). P. 8097.
44. Kambayashi T., Laufer T.M. Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell?. Nat. Rev. Immunol. 2014. V. 14(11). P. 719–730.
45. Li S.C., Lan K.-C., Hung H.-N., Huang W.-T., Lai Y.-J., Cheng H.-H., Tsai C.-C., Huang K.-L., You H.-L., Hsu T.-Y. HSPA4 is a biomarker of placenta accreta and enhances the angiogenesis ability of vessel endothelial cells. Int. J. Mol. Sci. 2022. V. 23. P. 5682.