FROM TRADITIONAL FERMENTED BEVERAGE TO EVIDENCE-BASED IMMUNOMODULATOR: PHARMACOLOGICAL CHARACTERIZATION OF BACTERIAL-YEAST MILK NUCLEOTIDES IN SECONDARY IMMUNODEFICIENCY MANAGEMENT (LITERATURE REVIEW AND ORIGINAL RESEARCH)

Nucleotides—the structural units of nucleic acids—function not merely as metabolites but as fully-fledged pharmacologically active substances with well-characterized receptor and molecular mechanisms of action. The fermented milk bacterial-yeast beverage with high nucleic acid content combines the pharmacological activity of nucleotides with probiotic and prebiotic effects, positioning it as a unique natural immunomodulator fundamentally distinct from synthetic immunotropic agents. Objective: To systematically synthesize scientific evidence regarding the pharmacological status of dietary nucleotides—including mechanisms of action, classification, pharmacodynamics, and position within the immunotropic agent framework—and to consolidate clinical data on the efficacy of the bacterial-yeast beverage in secondary immunodeficiency states and related pathological conditions. Methods: Narrative literature review (PubMed/MEDLINE, Scopus, WoS, 2000–2025) combined with the author's own clinical and laboratory investigations (1993–2016). Results: Nucleotides from the bacterial-yeast beverage exert pharmacological activity through: (1) TLR9 agonism (CpG-DNA → MyD88 → NF-κB → Type I IFN, IL-12); (2) salvage pathway utilization—supporting lymphocyte and enterocyte proliferation; (3) purinergic signaling (adenosine → A₂A receptors → cAMP → immunoregulation); and (4) Nod-like receptor (NLR) activation. Clinically: post-vaccination immunity enhancement by 15–22%, CD4⁺/CD8⁺ ratio and phagocytic index correction, and sIgA normalization. Unlike pharmaceutical immunotropic agents, the beverage's nucleotides act synphysiologically—through the same receptor systems activated during natural immune responses. Conclusion: The fermented milk bacterial-yeast beverage represents a pharmacologically substantiated, multi-target natural immunomodulator. Its advantages over synthetic immunotropic agents include: pleiotropic pharmacodynamics, physiological route of administration, absence of receptor saturation, probiotic and microbiome-normalizing effects, and population-level accessibility. Its inclusion in clinical nutrition standards for secondary immunodeficiency states is warranted.

• Bonilla F.A., Barlan I., Chapel H. et al. International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract, 2016; 4(1): 38–59.
• Chinen J., Shearer W.T. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol, 2010; 125(2): S195–S203.
• Aziz T., Sarwar A., Perveen S. et al. A comprehensive review on kefir: composition, microbial diversities, meta-analysis and biological significances on human health. Food Prod. Process. Nutr., 2025; 7: 15. https://doi.org/10.1186/s43014-025-00351-y
• Grimble R.F., Westwood O.M. Nucleotides as immunomodulators in clinical nutrition. Curr Opin Clin Nutr Metab Care, 2001; 4(1): 57–64.
• Sánchez-Pozo A., Gil A. Nucleotides as semiessential nutritional components. Br J Nutr., 2002; 87(Suppl 1): S135–S137.
• Young J.D., Yao S.Y., Baldwin J.M. et al. The human concentrative and equilibrative nucleoside transporter families. Xenobiotica, 2008; 38(7–8): 995–1021.
• Wierzbicka A., Brzóska M.M. Dietary supplements containing nucleic acids, nucleotides and nucleosides. Food Res Int. 2026 [in press].
• Kulkarni A.D., Rudolph F.B., Van Buren C.T. The role of dietary sources of nucleotides in immune function. J Nutr., 1994; 124(8 Suppl): 1442S–1446S.
• Van Buren C.T., Kulkarni A.D., Fanslow W.C., Rudolph F.B. Dietary nucleotides, a requirement for helper/inducer T lymphocytes. Transplantation, 1985; 40(6): 694–697.
• Jyonouchi H., Zhang-Shanbhag L., Tomita Y., Minocha R. Nucleotide-free diet impairs T-helper cell functions in antibody production. J Nutr., 1994; 124(4): 475–484.
• Kulkarni A.D., Rudolph F.B., Van Buren C.T. Influence of nucleotides on natural killer cell activity in mice. Transplant Proc., 1992; 24(6): 2987–2988.
• Corthésy B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front Immunol, 2013; 4: 185.
• Brunser O., Espinoza J., Araya M. et al. Effect of dietary nucleotide supplementation on diarrhoeal disease in infants. Acta Paediatr, 1994; 83(2):         188–191.
• Hemmi H., Takeuchi O., Kawai T. et al. A Toll-like receptor recognizes bacterial DNA. Nature, 2000; 408(6813): 740–745.
• Liu X., Yang J., Li C. et al. Nucleotide supplementation improves intestinal barrier function after chemotherapy. JPEN J Parenter Enteral Nutr., 2020; 44(7): 1248–1259.
• Hanagata N. CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies. Int J Nanomedicine, 2012; 7: 2217–2230.
• Cronstein B.N. Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol, 1994; 76(1):    5–13.
• Bhattacharya A., Bhattacharya S., Bhattacharya S. P2X7 receptor in immunity and inflammation. Cell Mol Immunol, 2021; 18(3): 553–566.
• Ishikawa H., Barber G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature, 2008; 455(7213): 674–678.
• Cantó C., Menzies K.J., Auwerx J. NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab., 2015; 22(1): 31–53.
• Spickett G.P. Secondary immunodeficiency. Medicine, 2016; 44(7): 430–434.
• Bauer S., Kirschning C.J., Häcker H. et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci USA., 2001; 98(16): 9237–9242.
• Dong H., Rowland I., Yaqoob P. Comparative effects of six probiotic strains on immune function in vitro. Br. J. Nutr., 2012; 108(3): 459–470. https://doi.org/10.1017/S0007114511005824
• Weimann A., Braga M., Carli F. et al. ESPEN guideline: Clinical nutrition in surgery. Clin Nutr., 2017; 36(3): 623–650.
• Bourrie B.C.T., Willing B.P., Cotter P.D. The microbiota and health promoting characteristics of the fermented beverage kefir. Front Microbiol, 2016; 7: 647.
• Rosa D.D., Dias M.M.S., Grześkowiak Ł.M. et al. Milk kefir: nutritional, microbiological and health benefits. Nutr Res Rev., 2017; 30(1): 82–96.
• Turnbaugh P.J., Ley R.E., Hamady M. et al. The human microbiome project. Nature, 2007; 449(7164): 804–810.
• Shreiner A.B., Kao J.Y., Young V.B. The gut microbiome in health and disease. Curr Opin Gastroenterol, 2015; 31(1): 69–75.
• Hamsho K. et al. Kefir: a potential gut microbiota modulator: a systematic review of human interventional studies. Microbiology Open, 2026; 15: e70297. https://doi.org/10.1002/mbo3.70297
• Furusawa Y., Obata Y., Fukuda S. et al. Commensal microbe-derived butyrate induces differentiation of colonic regulatory T cells. Nature, 2013; 504(7480): 446–450.
• Haiser H.J., Turnbaugh P.J. Is it time for a metagenomic basis of therapeutics? Science, 2012; 336(6086): 1253–1255.
• Koroleva N.S. Technology of kefir and kumiss. Bull Int Dairy Fed., 1988; 227: 96–100.
• Ahmed Z., Wang Y., Ahmad A. et al. Kefir and health: a contemporary perspective. Crit Rev Food Sci Nutr., 2013; 53(5): 422–434.
• Gil A. Modulation of the immune response mediated by dietary nucleotides. Eur J Clin Nutr., 2002; 56(Suppl 3): S1–S4.
• Hrytsko R.Y. Physiological substantiation of the effect of a dietary biostimulator in secondary immunodeficiencies: Author's abstract of PhD thesis. Lviv, 1997; 21 p.
• Hrytsko R.Y. A new approach to enhancing anti-diphtheria protection of the population. Experimental and Clinical Physiology and Biochemistry, 1997; 2(1): 260–264.
• Hrytsko R.Y. Immunomodulatory fermented milk bacterial-yeast beverage for clinical use in family medicine practice. Family Medicine, 2016; 1(63): 52–57.
• Ostadrahimi A., Taghizadeh A., Mobasseri M. et al. Effect of probiotic fermented milk (kefir) on glycemic control and lipid profile in type 2 diabetic patients. Iran J Public Health, 2015; 44(2): 228–237.
• Donohoe D.R. et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab., 2011; 13(5):         517–526. https://doi.org/10.1016/j.cmet.2011.02.018
• Biagi E., Franceschi C., Rampelli S. et al. Gut microbiota and extreme longevity. Curr Biol., 2016; 26(11): 1480–1485.