Immunobiological efficacy of a new sodium polyprenyl phosphate based medicine for the treatment and prevention of experimenrtal metabolic syndrome

The aim of the research was to study the population composition of the splenic lymphoid cells, to assess the functional activity of lymphocytes as well as the state of the gastrointestinal tract microbiota in experimental modeling of metabolic syndrome (MS).

The studies were conducted using two experimental models of MS and hyperlipidemia (HL), based on prolonged drinking of animals with 20% aqueous fructose solution with added cholesterol and intraperitoneal administration of Poloxamer 407 to mice, respectively.

The results of the experiments indicate a change in the population composition of splenocytes (decrease in CD4⁺ and CD8⁺T cells, activation of CD4⁺CD25⁺FoxP3⁺Thed cells), accompanied by a decrease in T cell activity and increased proliferation of B lymphocytes, impaired production of IL-15 and IL-22, as well as lipid and carbohydrate metabolism (adiponectin, leptin, insulin), which serves as a prerequisite for the development of chronic inflammation, which is a pathogenetic sign of MS.

We found changes in the intestinal microbiota of mice characteristic of the manifestation of metabolic dysbiosis – an increase in the representation of Firmicutes bacteria (staphylococci, streptococci, enterococci) in the biomaterial, changes in the content of facultative (E. coli) and transient (Enterobacter) microflora.

In order to develop a new kind of medicine for therapy and prevention of HL and MS, we used a combination of sodium polyprenyl phosphate (PP) and beta-sitosterol (BSS), polyisoprenoid derivatives of plant origin.

More pronounced changes were found in the splenocyte population composition and activation parameters of Treg cells in HL modeling compared with the MS model. The introduction of PP and BSS has an immunocorrective effect during treatment.

The therapeutic effect of this drug, as well as the prevention of the MS symptoms, is accompanied by normalization of the microbiota state.

The data obtained indicate the prospects of using PP and BSS for the prevention and treatment of HL and MS in order to influence the leading links in the pathogenesis of metabolic disease.

1. Makarova M.N., Makarov V.G. Diet-induced models of metabolic disturbances. Report 2: experimental obesity. Laboratornyye zhivotnyye dlya nauchnykh issledovaniy = Laboratory Animals for Science, 2018, no. 1, pp. 79-91. (In Russ.)

2. Nikolaeva T.N., Cheknev S.B., Kozhevnikova T.N., Vostrova E.I., Sosnovskaya O.Yu., Sarycheva M.A., Kozlov V.V., Grigorieva E.A., Vostrov A.V., Sanin A.V., NarovlyanskyA.N., Pronin A.V. Microbiota state of the gastro-intestinal tract of laboratory animals with signs of metabolic dysbiosis during treatment with experimental medical drug. Eksperimentalnaya i klinicheskaya gastroenterologiya = Experimental and Clinical Gastroenterology, 2023, no. 217 (9), pp. 117-124. (In Russ.)

3. Bekkering S., Domiguez-Andres J., Joosten L.A., Riksen N.P., Netea M.G.Trained Immunity in Health and Dissease. Annu. Rev. Immunol., 2021, Vol. 39, no. 1, pp. 667-693.

4. Chavakis Т. Immunomebolism:Where Immunology and metabolism Meet. J. Innate Immun., 2022, Vol. 14, pp. 1-3.

5. Ferreira A.V., Domiguez-Andres J., Netea M.G. The Role of Cell Metabolism in Innate Immune Memory. J. Innate Immun., 2022, 14, pp. 42-50.

6. Johnston T.P. The P-407-induced murine model of dose-controlled hyperlipidemia and atherosclerosis: a review of findings to date. J. Cardiovasc. Pharmacol., 2004, Vol. 43, no. 4, pp. 595-606.

7. Karlsson E.A., Sheridan P.A., Beck M.A. Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells. J. Nutr., 2010, Vol. 140, pp. 1691-1697.

8. Lee Y.S., Olefsky J. Chronic tissue inflammation and metabolic disease. Genes Dev., 2021, Vol. 35, no. 5-6, pp. 307-328.

9. Magne F., Gotteland M., Gauthier L., Zazueta A., Pesoa S. The Firmicutes/Bacteroidetes ratio:a relevant marker of gut dysbiosis in obese patients. Nutrients, 2020, Vol. 12, no. 5, 1474. doi: 10.1530/JOE-20-0473.

10. Narovlyansky A.N., Pronin A.V., Sanin A.V., Veselovsky V.V., Danilov L.L., Sedov A.M., Ershov F.I. Isoprenoids: Polyprenols and Polyprenyl Phosphates as Physiologically Important Metabolic Regulators. Nova Science Publishers, Inc, NY, USA, 2018.

11. Nobs S.P., Zmora N., Elinav E. Nutrition regulates innate immunity in health and disease. Annu. Rev. Nutr., 2020, Vol. 40, pp. 189-219.

12. Pronin A.V., Danilov L.L., Narovlyansky A.N., Sanin A.V. Plant polyisoprenoids and control of cholesterol level. Arch. Immunol. Ther. Exp. (Warsz), 2014, Vol. 62, no. 1, pp. 31-39.

13. Regnier M., van Hul M.,Knauf C., Cani P.D.Gut microbiome, endocrine control of gut barrier function and metabolic diseases. J. Endocrinol., 2021, Vol. 248, pp. R67-R82

14. Santos-Marcos J.A., Perez-Jimenez F. Camargo A. The role of diet and intestinal microbiota in the development of metabolic syndrome. J. Nutr Biochem, 2019, Vol. 70, pp. 1-27.